HK1157768A

HK1157768A - Substituted 7-sulfanylmethyl, 7-sulfinylmethyl and 7-sulfonylmethyl indoles and use thereof

Info

Publication number: HK1157768A
Application number: HK11112162.4A
Authority: HK
Inventors: Peter Kolkhof; Astrid BRÜNS; Kai Thede; Karl-Heinz Schlemmer; Alexander Hillisch; Dieter Lang; Michael Gerisch; Andreas GÖLLER; Rolf Grosser; Carsten Schmeck; Elisabeth Woltering; Olaf Prien; Holger Paulsen; Armin Kern
Original assignee: Bayer Schering Pharma Aktiengesellschaft
Priority date: 2008-06-25
Filing date: 2009-06-16
Publication date: 2012-07-06

Description

Substituted 7-sulfanylmethyl-, 7-sulfinylmethyl-and 7-sulfonylmethylindoles and their use

The present application relates to novel 7-sulfanylmethyl-, 7-sulfinylmethyl-and 7-sulfonylmethylindole derivatives, to processes for their preparation, to their use alone or in combination for the treatment and/or prophylaxis of diseases, and to their use for the preparation of medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular disorders.

By promoting sodium retention and potassium secretion in the epithelial cells of the distal nephron, aldosterone plays a critical role in maintaining fluid and electrolyte homeostasis, thus helping to keep the extracellular volume constant and thereby regulate blood pressure. In addition, aldosterone has shown direct effects on the structure and function of the heart and vascular system, but its underlying mechanism has not been fully elucidated [ r.e. booth, j.p. johnson, j.d. stockand, adv.physiol.educ. 26(1)，8-20(2002)]。

Aldosterone is a steroid hormone formed in the adrenal cortex. Its production is indirectly regulated, which depends very much on the renal blood supply. Any reduction in the blood supply to the kidneys causes the enzyme renin to be released into the circulating blood in the kidneys. This in turn activates the formation of angiotensin II, which on the one hand has a constrictive effect on arterial blood vessels, but on the other hand also stimulates the formation of aldosterone in the adrenal cortex. The kidney thus acts as a blood pressure sensor in the circulating blood and thus as an indirect volume sensor and counteracts the severe loss of volume via the renin-angiotensin-aldosterone system, on the one hand by increasing the blood pressure (angiotensin II effect) and on the other hand by re-balancing the filling state of the vascular system (by increasing sodium and water reabsorption in the kidney (aldosterone effect)).

This control system may be damaged in various ways. Thus, chronic reduction of the blood supply to the kidneys (for example due to heart failure and the resulting blockage of the blood in the venous system) leads to a chronic, excessively high release of aldosterone. This is in turn followed by an expansion of the blood volume and thereby increases the heart weakening by over-providing volume to the heart. The result may be an obstruction of blood in the lungs with shortness of breath and edema in the extremities as well as abdominal and pleural effusions; the renal blood supply drops further. In addition, excessively elevated aldosterone action results in a decrease in potassium concentration in the blood and in the extracellular fluid. In heart muscles that were otherwise damaged, if the deviation is below a critical minimum level, a cardiac arrhythmia with a fatal outcome may be induced. This is likely one of the major causes of sudden cardiac death that frequently occurs in heart failure patients.

In addition, aldosterone is also thought to determine the many myocardial remodeling processes typically observed in heart failure. Thus, hyperaldosteronism is a decisive element in the pathogenesis and prognosis of heart failure, which may be initially induced by various types of injury, such as myocardial infarction, myocardial inflammation or hypertension. This assumption is supported by the fact that: in extensive clinical studies with aldosterone antagonists in groups of patients with chronic heart failure and post-acute myocardial infarction, the overall mortality rate was significantly reduced [ b.pitt, f.zannad, w.j.remme et al, n.engl.j.med ].341709- "717 (1999); pitt, w.remme, f.zanard et al, n.engl.j.med.348，1309-1321(2003)]. This can be achieved in particular by reducing the incidence of sudden cardiac death.

According to recent studies, a significant fraction of patients with essential hypertension have also been found to have the so-called eukalemic variant of essential aldosteronism [ incidence of up to 11% among all hypertension: seiler and M.Reincke, Der Aldosteron-Renin-Quantitent beiHypertonie，Herz 28，686-691(2003)]. The best diagnostic method for kalemia-normal aldosteronism is the corresponding plasma concentration of the aldosterone/renin ratio, so that the relative increase in aldosterone relative to the renin plasma concentration can also be diagnosed and ultimately treated. Therefore, for the diagnosis of essential hypertension, the diagnosis of aldosteronism is the starting point for a causal and prophylactically meaningful therapy.

Much less common than the type of hyperaldosteronism detailed above are pathological states: where the damage is either found in cells of the adrenal gland itself producing hormones or its number or mass is increased by proliferation or proliferation. Adenomas or diffuse hyperplasia of the adrenal cortex are the most common causes of primary hyperaldosteronism known as Conn syndrome, the leading symptoms of which are hypertension and low kalemic alkalosis. In addition to surgical removal of diseased tissue, medical therapy with aldosterone antagonists is also preferred herein [ H.A. Kuhn and J.Schirmeister (ed.), Innere Medizin, fourth edition, Springer Verlag, Berlin, 1982 ].

Another pathological condition typically associated with elevated plasma aldosterone concentrations is late-stage cirrhosis. The cause of aldosterone elevation in this situation is primarily restricted aldosterone breakdown due to impaired liver function. Volume overload, edema and hypokalemia are typical consequences which can be successfully alleviated in clinical practice by aldosterone antagonists.

The action of aldosterone is mediated through the mineralocorticoid receptor, which is located intracellularly in the target cell. Receptors closely related to the mineralocorticoid receptor are the glucocorticoid receptor, glucocorticoids (e.g. glucocorticoid Cortisone, cortisol or corticosterone) through which the activity is mediated. Mineralocorticoid receptors bind endogenous glucocorticoids [ Funder jw. hypertension ] in addition to aldosterone.47，634-635(2006)]. This interaction of the mineralocorticoid receptor with glucocorticoids appears to play an important, but generally unexplained role in the pathophysiology of cardiac disorders as such. In addition, an interaction between the mineralocorticoid receptor and the glucocorticoid receptor has been proposed, for example in the form of heterodimer formation, which may be involved in the development of cardiovascular disorders [ Liu W, Wang J, Sauter NK, Pearl D.Proc Natl Acad Sci U S A.92，12480-12484(1995)]。

Aldosterone antagonists available to date have a basic steroid structure similar to aldosterone itself. The utility of such steroid antagonists is limited by interactions with receptors for other steroid hormones, particularly testosterone and progestin, which in some cases lead to considerable side effects such as gynecomastia and sexual impotence, and to discontinuation of therapy [ m.a. zaman, s.oparil, d.a. calhoun, Nature rev.drug Disc.1，621-636(2002)]。

The identification of potent nonsteroidal mineralocorticoid receptor antagonists, which show improved selectivity in particular with respect to androgen (testosterone) and progestogen receptors, offers the possibility of achieving significant therapeutic advantages [ cf. m.j. meyers and x.hu, Expert opin 17(1)，17-23(2007)]。

It is therefore an object of the present invention to provide novel compounds which act as potent mineralocorticoid receptor antagonists, which are selective with respect to androgen (testosterone) and progestogen receptors, and which exhibit an improved side effect profile compared to the compounds known in the prior art, and which can thus be used for the treatment of disorders, in particular cardiovascular disorders.

Indol-3-yl (phenyl) acetic acid derivatives are disclosed in WO 97/43260 as endothelin receptor antagonists and α -amino (indol-3-yl) acetic acid derivatives having an antidiabetic effect are disclosed in WO 90/05721. WO 2004/067529, WO 2005/092854 and m.g. bell, j.med.chem.2007, 50(26), 6443-6445 describe various indole derivatives substituted at the 3-position as modulators of steroid hormone receptors. WO 2007/062994 and WO 2005/118539 claim 3- (3-amino-1-arylpropyl) indoles for the treatment of melancholic and anxiolytic states. WO2007/040166 claims fused pyrrole derivatives as glucocorticoid receptor modulators with anti-inflammatory and anti-diabetic effects. WO2007/070892 and WO2008/019357 describe substituted indoles for the treatment of anxiety, pain, inflammatory disorders and cognitive disorders. WO2008/157740 describes various substituted indoles, particularly for the treatment of pain and inflammatory disorders. 3- (indol-3-yl) -3-phenylpropanenitrile derivatives are described inter alia in US2752358, US2765320 and US 2778819. The preparation of 2-unsubstituted indoles is disclosed in WO98/06725 and US5,808,064. The preparation of 2- (indol-3-yl) -2-phenylethanol derivatives is reported inter alia in M.L. Kantam et al Tetrahedron Lett.2006, 47(35), 6213-.

The invention relates to compounds of general formula (I)

Wherein

A is-S-, -S (═ O) -or-S (═ O)₂-，

R¹Is (C)₁-C₄) -an alkyl group or a cyclopropyl group,

R²is hydrogen, fluorine or chlorine,

R³is hydrogen, fluorine, chlorine or methyl,

R⁴is hydrogen or fluorine, and is selected from the group consisting of,

R⁵is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

d is-CH₂-、-O-、-CH₂-CH₂-or-CH₂-O-，

R⁶Is (C)₁-C₄) -alkyl or (C)₃-C₆) -a cycloalkyl group,

wherein (C)₁-C₄) -alkyl can be substituted with 1 to 3 substituents independently from each other selected from fluoro, trifluoromethyl, hydroxy and cyano,

and

wherein (C)₃-C₆) Cycloalkyl can be substituted with 1 to 3 substituents independently of one another selected from fluorine, hydroxyl and cyano,

R⁷is hydrogen, halogen, (C)₁-C₄) -alkyl, trifluoromethyl or (C)₁-C₄) -an alkoxy group,

R⁸is hydrogen, halogen, methyl or trifluoromethyl,

R⁹is phenyl, naphthyl or 5-to 10-membered heteroaryl,

wherein phenyl, naphthyl and 5-to 10-membered heteroaryl can be selected from halogen, cyano, (C) independently of one another by 1 to 3₁-C₄) -alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, (C)₁-C₄) -alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy and trifluoromethylthio,

or

Wherein two substituents bound to adjacent carbon atoms of the phenyl ringTogether form a group of the formula: -O-CH ₂-O-、-O-CHF-O-、-O-CF₂-O-、-O-CH₂-CH₂-O-or-O-CF₂-CF₂-O-，

R¹⁰Is (C)₁-C₆) Alkyl radicals, (C)₃-C₇) -a cycloalkyl group or a phenyl group,

wherein (C)₁-C₆) -alkyl can be substituted with 1 to 3 substituents independently chosen from: fluorine, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy and cyano,

and

wherein (C)₃-C₇) -cycloalkyl can be substituted with 1 to 3 substituents independently chosen from: fluorine, a hydroxyl group and a cyano group,

and

wherein phenyl can be substituted with 1 to 3 substituents independently selected from: halogen, cyano, (C)₁-C₄) -alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, (C)₁-C₄) -alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy and trifluoromethylthio,

R¹¹is hydrogen, methyl, ethyl, trifluoromethyl or cyclopropyl,

and salts, solvates and solvates of salts thereof.

The compounds of the present invention are compounds of the general formula (I) and salts, solvates and solvates of salts thereof, the compounds of the formulae mentioned below, and the solvates of salts, solvates and salts thereof, encompassed by the formula (I), and the compounds encompassed by the formula (I) and mentioned below as working examples, and the solvates of salts, solvates and salts thereof, provided that the compounds encompassed by the formula (I) and mentioned below are not already solvates of salts, solvates and salts.

The compounds of the invention may, depending on their structure, exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore relates to the enantiomers or diastereomers and the respective mixtures thereof. The stereomerically pure components can be separated from the mixture of enantiomers and/or diastereomers in a known manner.

If a compound of the invention can occur in tautomeric forms, the invention encompasses all tautomeric forms.

Preferred salts for the purposes of the present invention are the physiologically acceptable salts of the compounds of the invention. Salts which are not suitable per se for pharmaceutical use but which can be used, for example, for isolating or purifying the compounds of the invention are also encompassed.

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

Physiologically acceptable salts of the compounds of the invention include salts of customary bases, such as, by way of 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 from 1 to 16 carbon atoms, such as, by way of example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, 1, 2-ethylenediamine and N-methylpiperidine.

Solvates for the purposes of the present invention are those forms of the compounds of the invention which form complexes in the solid or liquid state by coordination with solvent molecules. Hydrates are a particular form of solvate in which coordination with water is carried out. Hydrates are preferably solvates within the scope of the present invention.

The invention further encompasses prodrugs of the compounds of the invention. The term "prodrug" encompasses compounds that may themselves be biologically active or inactive, but which convert to the compounds of the invention (e.g., by metabolism or hydrolysis) during their residence time in the body.

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

alkyl in the context of the present invention denotes straight-chain or branched alkyl having 1 to 6 or 1 to 4 carbon atoms. Straight or branched chain alkyl groups having 1 to 4 carbon atoms are preferred. For example and preferably mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl and n-hexyl.

Cycloalkyl in the context of the present invention denotes a saturated monocyclic carbocyclic ring having 3 to 7 or 3 to 6 ring carbon atoms. For example and preferably mentioned are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Alkoxy in the context of the present invention denotes a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. For example and preferably mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.

Heteroaryl in the context of the present invention denotes a monocyclic or optionally (gegegebenenfarls) bicyclic aromatic heterocycle (heteroaromatic compound) having a total of 5 to 10 ring atoms, which comprises up to three identical or different ring heteroatoms from the series N, O and/or S and is bound via a ring carbon atom or optionally via a ring nitrogen atom. Mention is made by way of example of: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl,Azolyl radical, isoAzolyl, isothiazolyl, triazolyl,Oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzimidazolylOxazolyl, benzothiazolyl, benzotriazolyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinazolinyl, quinoxalinyl, 2, 3-naphthyridinyl, imidazo [1, 2-a [ ]]Pyridyl and pyrazolo [3, 4-b]A pyridyl group.

Halogen includes fluorine, chlorine, bromine and iodine within the scope of the invention. Fluorine, chlorine and bromine are preferred, with fluorine and chlorine being particularly preferred.

In the respect of R⁵、R⁹、R¹⁰And R¹¹Possible radical chemical formulae are those in which the end of the line segment with the symbol #, # # or # # # does not represent a carbon atom or CH₂Radicals, but forms a bond to the radical indicated in each case and R⁵、R⁹、R¹⁰And R¹¹The bond of the atom to which each is bonded.

If a group in a compound of the invention is substituted, the group may be substituted one or more times, unless otherwise specified. In the context of the present invention, all radicals occurring more than once have mutually independent meanings. Substitution by one or two identical or different substituents is preferred. Substitution by one substituent is very particularly preferred.

Preferred within the scope of the present invention are compounds of the formula (I), in which

A is-S-, -S (═ O) -or-S (═ O)₂-，

R¹Is (C)₁-C₄) -an alkyl group or a cyclopropyl group,

R²is hydrogen, fluorine or chlorine,

R³is hydrogen, fluorine, chlorine or methyl,

R⁴is hydrogen or fluorine, and is selected from the group consisting of,

R⁵is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

d is-CH₂-、-O-、-CH₂-CH₂-or-CH₂-O-，

R⁶Is (C)₁-C₄) -alkyl or (C)₃-C₆) -a cycloalkyl group,

wherein (C)₁-C₄) -alkyl can be substituted with 1 to 3 substituents independently chosen from: fluorine, trifluoromethyl, hydroxy and cyano,

and

wherein (C)₃-C₆) -cycloalkyl can be substituted with 1 to 3 substituents independently chosen from: fluorine, a hydroxyl group and a cyano group,

R⁸is hydrogen, halogen, methyl or trifluoromethyl,

R⁹is phenyl, naphthyl or 5-to 10-membered heteroaryl,

wherein phenyl, naphthyl and 5-to 10-membered heteroaryl can be substituted with 1 to 3 substituents independently from each other selected from the group consisting of: halogen, cyano, (C)₁-C₄) -alkyl, trifluoromethyl, (C)₁-C₄) -alkoxy, trifluoromethylAn oxy group and a trifluoromethylthio group,

or

Wherein two substituents bonded to adjacent carbon atoms of the phenyl ring together form a group of the formula: -O-CH₂-O-、-O-CHF-O-、-O-CF₂-O-、-O-CH₂-CH₂-O-or-O-CF₂-CF₂-O-，

wherein (C)₁-C₆) -alkyl can be substituted with 1 to 3 substituents independently chosen from: fluorine, trifluoromethyl, hydroxy and cyano,

and

wherein phenyl can be substituted with 1 to 3 substituents independently selected from: halogen, cyano, (C)₁-C₄) -alkyl, trifluoromethyl, (C)₁-C₄) -alkoxy, trifluoromethoxy and trifluoromethylthio,

R¹¹is hydrogen, methyl, ethyl or trifluoromethyl,

and salts, solvates and solvates of salts thereof.

Also preferred in the scope of the present invention are compounds of formula (I), wherein

A is-S (═ O) -or-S (═ O)₂-，

R¹Is a methyl group or an ethyl group,

R²is hydrogen or fluorine, and is selected from the group consisting of,

R³is hydrogen or fluorine, and is selected from the group consisting of,

R⁴is a hydrogen atom, and is,

R⁵is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

R⁹is phenyl, naphthyl or benzothienyl,

wherein phenyl, naphthyl and benzothienyl can be substituted by 1 to 3 substituents which are selected independently of one another from the group consisting of: fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl and methoxy,

or

Wherein two substituents bonded to adjacent carbon atoms of the phenyl ring together form a group of the formula: -O-CH₂-O-or-O-CF₂-O-，

R¹⁰Is 1-cyanoeth-2-yl, 1-cyano-1-methylethyl-2-yl, 1-cyano-2-methylethyl-2-yl, 1-cyano-1, 2-dimethylethyl-2-yl, 1-cyano-2, 2-dimethylethyl-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1-cyano-2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano-2, 3-dimethylprop-3-yl, 1-hydroxyeth-2-yl, 1-cyanoethyl-2-yl, 1-cyanomethyl-2-methylethyl-2-yl, 1-hydroxy-1-methylethyl-2-yl, 1-hydroxy-2-methylethyl-2-yl, 1-hydroxy-1, 2-dimethylethyl-2-yl, 1-hydroxy-2, 2-dimethylethyl-2-yl, 1-hydroxypropan-3-yl, 1-hydroxy-1-methylpropan-3-yl, 1-hydroxy-2-methylpropan-3-yl, 1-hydroxy-3-methylpropan-3-yl, 1-hydroxy-2, 3-dimethylpropan-3-yl, cyclopropyl, 1-cyanocyclopropan-2-yl, 1-hydroxycyclopropan-2-yl or phenyl,

Wherein 1-cyanoeth-2-yl, 1-cyano-1-methylethyl-2-yl, 1-cyano-2-methylethyl-2-yl, 1-cyano-1, 2-dimethylethyl-2-yl, 1-cyano-2, 2-dimethylethyl-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1-cyano-2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano-2, 3-dimethylprop-3-yl, 1-hydroxyeth-2-yl, 1-cyanoethyl-2-yl, 1-cyanomethyl-2-methylethyl-2-yl, 1-hydroxy-1-methylethyl-2-yl, 1-hydroxy-2-methylethyl-2-yl, 1-hydroxy-1, 2-dimethylethyl-2-yl, 1-hydroxy-2, 2-dimethylethyl-2-yl, 1-hydroxypropan-3-yl, 1-hydroxy-1-methylpropan-3-yl, 1-hydroxy-2-methylpropan-3-yl, 1-hydroxy-3-methylpropan-3-yl, 1-hydroxy-2, 3-dimethylpropan-3-yl, cyclopropyl, 1-cyanocyclopropan-2-yl and 1-hydroxycyclopropan-2-yl can be substituted with 1 or 2 fluoro substituents,

and

wherein phenyl can be substituted by 1 or 2 substituents which are selected independently of one another from the group consisting of fluorine, chlorine, cyano and methyl,

R¹¹is a hydrogen atom, and is,

and salts, solvates and solvates of salts thereof.

A is-S (═ O) -or-S (═ O)₂-，

R¹Is a methyl group or an ethyl group,

R²is hydrogen or fluorine, and is selected from the group consisting of,

R³is hydrogen or fluorine, and is selected from the group consisting of,

R⁴is a hydrogen atom, and is,

R⁵is a radical of the formula

Wherein

# is the point of attachment to the indole,

And

R⁹is phenyl, naphthyl or benzothienyl,

wherein phenyl, naphthyl and benzothienyl can be substituted by 1 to 3 substituents which are selected independently of one another from the group consisting of: fluorine, chlorine, cyano, methyl, ethyl and trifluoromethyl,

And

R¹¹is a hydrogen atom, and is,

and salts, solvates and solvates of salts thereof.

A is-S (═ O) -or-S (═ O)₂-，

R¹Is a methyl group or an ethyl group,

R²is hydrogen or fluorine, and is selected from the group consisting of,

R³is hydrogen or fluorine, and is selected from the group consisting of,

R⁴is a hydrogen atom, and is,

R⁵is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

d is-CH₂-or-CH₂-O，

R⁶Is (C)₁-C₄) -alkyl or (C)₃-C₆) -a cycloalkyl group,

wherein (C)₁-C₄) -alkyl and (C)₃-C₆) Cycloalkyl can be substituted by 1 or 2 fluoro substituents,

and

wherein (C)₁-C₄) -alkyl can be substituted by a substituent selected from hydroxyl and cyano,

and

wherein (C)₃-C₆) -cycloalkanesWhich can be substituted by substituents selected from hydroxy and cyano,

R⁷is hydrogen, fluorine, chlorine, methyl or trifluoromethyl,

R⁸is hydrogen, fluorine, chlorine, methyl or trifluoromethyl,

R⁹is phenyl, naphthyl or benzothienyl,

or

Wherein two substituents bonded to adjacent carbon atoms of the phenyl ring together form a group of the formula: -O-CH ₂-O-or-O-CF₂-O-，

R¹⁰Is 1-cyanoeth-2-yl, 1-cyano-1-methylethyl-2-yl, 1-cyano-2-methylethyl-2-yl, 1-cyano-1, 2-dimethylethyl-2-yl, 1-cyano-2, 2-dimethylethyl-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1-cyano-2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano-2, 3-dimethylprop-3-yl, 1-hydroxyeth-2-yl, 1-cyanoethyl-2-yl, 1-cyanomethyl-2-methylethyl-2-yl, 1-hydroxy-1-methylethyl-2-yl, 1-hydroxy-2-methylethyl-2-yl, 1-hydroxy-1, 2-dimethylethyl-2-yl, 1-hydroxy-2, 2-dimethylethyl-2-yl, 1-hydroxypropan-3-yl, 1-hydroxy-1-methylpropan-3-yl, 1-hydroxy-2-methylpropan-3-yl, 1-hydroxy-3-methylpropan-3-yl, 1-hydroxy-2, 3-dimethylpropan-3-yl, (C) hydroxy-1-methylethyl-2-yl, 1-hydroxy-2-methylethyl-2-yl, 1-hydroxy-3-methylpropan-3-yl, etc₃-C₇) -a cycloalkyl group or a phenyl group,

wherein 1-cyanoeth-2-yl, 1-cyano-1-methylethyl-2-yl, 1-cyano-2-methylethyl-2-yl, 1-cyano-1, 2-dimethylethyl-2-yl, 1-cyano-2, 2-dimethylethyl-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1-cyano-2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano-2, 3-dimethylprop-3-yl, 1-hydroxyeth-2-yl, 1-cyanoethyl-2-yl, 1-cyanomethyl-2-methylethyl-2-yl, 1-hydroxy-1-methylethyl-2-yl, 1-hydroxy-2-methylethyl-2-yl, 1-hydroxy-1, 2-dimethylethyl -2-yl, 1-hydroxy-2, 2-dimethylethyl-2-yl, 1-hydroxypropan-3-yl, 1-hydroxy-1-methylpropan-3-yl, 1-hydroxy-2-methylpropan-3-yl, 1-hydroxy-3-methylpropan-3-yl, 1-hydroxy-2, 3-dimethylpropan-3-yl and (C)₃-C₇) Cycloalkyl can be substituted by 1 or 2 fluoro substituents,

and

wherein (C)₃-C₇) -cycloalkyl can be substituted by a substituent selected from hydroxy and cyano,

and

R¹¹is a methyl group or an ethyl group,

and salts, solvates and solvates of salts thereof.

A is-S (═ O) -or-S (═ O)₂-，

R¹Is a methyl group or an ethyl group,

R²is hydrogen or fluorine, and is selected from the group consisting of,

R³is hydrogen or fluorine, and is selected from the group consisting of,

R⁴is a hydrogen atom, and is,

R⁵is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

d is-CH₂-or-CH₂-O，

R⁶Is (C)₁-C₄) -alkyl or (C)₃-C₆) -a cycloalkyl group,

and

wherein (C)₃-C₆) -cycloalkyl can be substituted by a substituent selected from hydroxy and cyano,

R⁷is hydrogen, fluorine, chlorine, methyl or trifluoromethyl,

R⁸Is hydrogen, fluorine, chlorine, methyl or trifluoromethyl,

R⁹is phenyl, naphthyl or benzothienyl,

R¹⁰is 1-cyanoeth-2-yl, 1-cyano-1-methylethyl-2-yl, 1-cyano-2-methylethyl-2-yl, 1-cyano-1, 2-dimethylethyl-2-yl, 1-cyano-2, 2-dimethylethyl-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1-cyano-2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano-2, 3-dimethylprop-3-yl, 1-hydroxyeth-2-yl, 1-cyanoethyl-2-yl, 1-cyanomethyl-2-methylethyl-2-yl, 1-hydroxy-1-methylethyl-2-yl, 1-hydroxy-2-methylethyl-2-yl, 1-hydroxy-1, 2-dimethylethyl-2-yl, 1-hydroxy-2, 2-dimethylethyl-2-yl, 1-hydroxypropan-3-yl, 1-hydroxy-1-methylpropan-3-yl, 1-hydroxy-2-methylpropan-3-yl, 1-hydroxy-3-methylpropan-3-yl, 1-hydroxy-2, 3-dimethylpropan-3-yl, (C)₃-C₇) -cycloalkyl or phenyl，

Wherein 1-cyanoeth-2-yl, 1-cyano-1-methylethyl-2-yl, 1-cyano-2-methylethyl-2-yl, 1-cyano-1, 2-dimethylethyl-2-yl, 1-cyano-2, 2-dimethylethyl-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1-cyano-2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano-2, 3-dimethylprop-3-yl, 1-hydroxyeth-2-yl, 1-cyanoethyl-2-yl, 1-cyanomethyl-2-methylethyl-2-yl, 1-hydroxy-1-methylethyl-2-yl, 1-hydroxy-2-methylethyl-2-yl, 1-hydroxy-1, 2-dimethylethyl-2-yl, 1-hydroxy-2, 2-dimethylethyl-2-yl, 1-hydroxypropan-3-yl, 1-hydroxy-1-methylpropan-3-yl, 1-hydroxy-2-methylpropan-3-yl, 1-hydroxy-3-methylpropan-3-yl, 1-hydroxy-2, 3-dimethylpropan-3-yl and (C) ₃-C₇) Cycloalkyl can be substituted by 1 or 2 fluoro substituents,

and

R¹¹is a methyl group or an ethyl group,

and salts, solvates and solvates of salts thereof.

Particular preference is given within the scope of the present invention to compounds of the formula (I) in which

A is-S (═ O)₂-，

R¹Is a methyl group, and the compound is,

R²is hydrogen or fluorine, and is selected from the group consisting of,

R³is hydrogen or fluorine, and is selected from the group consisting of,

R⁴is a hydrogen atom, and is,

R⁵is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

R⁹is a radical of the formula

Wherein

Is connected to-CR¹⁰R¹¹The point (c) of (a) is,

R¹²are fluorine, chlorine, methyl and trifluoromethyl,

R¹³is hydrogen, fluorine or chlorine,

R¹⁴is hydrogen, fluorine or chlorine,

R¹⁵is hydrogen, fluorine or chlorine,

provided that the group R¹³、R¹⁴And R¹⁵At least one of which is hydrogen,

R¹⁰is a cyclopropyl group, and the compound is a cyclopropyl group,

wherein the cyclopropyl group can be substituted with 1 or 2 fluoro substituents,

and

wherein the cyclopropyl group can be substituted with a cyano substituent,

R¹¹is a methyl group, and the compound is,

and salts, solvates and solvates of salts thereof.

Particular preference is also given within the scope of the present invention to compounds of the formula (I) in which

A is-S (═ O)₂-，

R¹Is a methyl group or an ethyl group,

R²is hydrogen or fluorine, and is selected from the group consisting of,

R³is hydrogen or fluorine, and is selected from the group consisting of,

R⁴Is a hydrogen atom, and is,

R⁵is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

R⁹is a phenyl group or a benzothienyl group,

wherein phenyl and benzothienyl can be substituted by 1 or 2 substituents which are selected independently of one another from the group consisting of: fluorine, chlorine, methyl and trifluoromethyl,

R¹⁰is a cyclopropyl group, and the compound is a cyclopropyl group,

and

wherein the cyclopropyl group can be substituted with a cyano substituent,

R¹¹is a methyl group, and the compound is,

and salts, solvates and solvates of salts thereof.

A is-S (═ O)₂-，

R¹Is a methyl group or an ethyl group,

R²is hydrogen or fluorine, and is selected from the group consisting of,

R³is hydrogen or fluorine, and is selected from the group consisting of,

R⁴is a hydrogen atom, and is,

R⁵is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

d is-CH₂-，

R⁶Is a methyl group, an ethyl group or a cyclopropyl group,

R⁷is hydrogen, fluorine, chlorine or methyl,

R⁸is hydrogen, fluorine or chlorine,

and salts, solvates and solvates of salts thereof.

A is-S (═ O)₂-，

R¹Is a methyl group, and the compound is,

R²is hydrogen or fluorine, and is selected from the group consisting of,

R³is hydrogen or fluorine, and is selected from the group consisting of,

R⁴is a hydrogen atom, and is,

R⁵is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

R⁹is a radical of the formula

Wherein

Is connected to-CR¹⁰R¹¹The point (c) of (a) is,

R¹²are fluorine, chlorine, methyl and trifluoromethyl,

R¹³Is hydrogen, fluorine or chlorine,

R¹⁴is hydrogen, fluorine or chlorine,

R¹⁵is hydrogen, fluorine or chlorine,

R¹⁰is 1-cyanoeth-2-yl, 1-cyano-2-methylethyl-2-yl or 1-cyanoprop-3-yl,

R¹¹is a methyl group or an ethyl group,

and salts, solvates and solvates of salts thereof.

A is-S (═ O)₂-，

R¹Is a methyl group, and the compound is,

R²is hydrogen or fluorine, and is selected from the group consisting of,

R³is hydrogen or fluorine, and is selected from the group consisting of,

R⁴is a hydrogen atom, and is,

R⁵is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

R⁹is a radical of the formula

Wherein

Is connected to-CR¹⁰R¹¹The point (c) of (a) is,

and

R¹²are fluorine, chlorine, methyl and trifluoromethyl,

R¹³is hydrogen, fluorine or chlorine,

R¹⁴is hydrogen, fluorine or chlorine,

R¹⁵is hydrogen, fluorine or chlorine,

R¹⁰is a radical of the formula

Wherein

Is linked to-CR⁹R¹¹The point (c) of (a) is,

and

R¹⁶is a fluorine or chlorine compound, and is,

R¹¹is a hydrogen atom, and is,

and salts, solvates and solvates of salts thereof.

A is-S (═ O)₂-，

R¹Is a methyl group or an ethyl group,

R²is hydrogen or fluorine, and is selected from the group consisting of,

R³is hydrogen or fluorine, and is selected from the group consisting of,

R⁴is a hydrogen atom, and is,

R⁵is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

R⁹is a phenyl group or a benzothienyl group,

R¹⁰is a phenyl group, and the phenyl group,

wherein the phenyl group can be substituted with a substituent selected from the group consisting of fluorine and chlorine,

R¹¹is a hydrogen atom, and is,

and salts, solvates and solvates of salts thereof.

A is-S (═ O)₂-，

R¹Is a methyl group, and the compound is,

R²is hydrogen or fluorine, and is selected from the group consisting of,

R³is hydrogen or fluorine, and is selected from the group consisting of,

R⁴is a hydrogen atom, and is,

R⁵is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

R⁹is a phenyl group or a benzothienyl group,

R¹⁰is 1-cyanoeth-2-yl, 1-cyano-2-methylethyl-2-yl or 1-cyanoprop-3-yl,

R¹¹is a hydrogen atom, and is,

and salts, solvates and solvates of salts thereof.

A is-S (═ O)₂-，

R¹Is a methyl group, and the compound is,

R²is hydrogen or fluorine, and is selected from the group consisting of,

R³is hydrogen or fluorine, and is selected from the group consisting of,

R⁴is a hydrogen atom, and is,

R⁵is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

R⁹is a radical of the formula

Wherein

Is connected to-CR¹⁰R¹¹The point (c) of (a) is,

R¹²are fluorine, chlorine, methyl and trifluoromethyl,

R¹³Is hydrogen, fluorine or chlorine,

R¹⁴is hydrogen, fluorine or chlorine,

R¹⁵is hydrogen, fluorine or chlorine,

R¹⁰is a cyclopropyl group, and the compound is a cyclopropyl group,

wherein the cyclopropyl group can be substituted with a cyano substituent,

or

R¹¹is a hydrogen atom, and is,

and salts, solvates and solvates of salts thereof.

A is-S (═ O)₂-，

R¹Is a methyl group, and the compound is,

R²is hydrogen or fluorine, and is selected from the group consisting of,

R³is hydrogen or fluorine, and is selected from the group consisting of,

R⁴is a hydrogen atom, and is,

R⁵is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

R⁹is a radical of the formula

Wherein

Is connected to-CR¹⁰R¹¹The point (c) of (a) is,

R¹²is fluorine, chlorine, methyl and trisA fluorine-containing methyl group,

R¹³is hydrogen, fluorine or chlorine,

R¹⁴is hydrogen, fluorine or chlorine,

R¹⁵is hydrogen, fluorine or chlorine,

R¹⁰is a radical of the formula

Wherein

The # # is linked to-CR⁹R¹¹The point (c) of (a) is,

R¹¹is a hydrogen atom, and is,

and salts, solvates and solvates of salts thereof.

A is-S (═ O)₂-，

R¹Is a methyl group, and the compound is,

R²is hydrogen or fluorine, and is selected from the group consisting of,

R³is hydrogen or fluorine, and is selected from the group consisting of,

R⁴is a hydrogen atom, and is,

R⁵is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

R⁹is a radical of the formula

Wherein

Is connected to-CR¹⁰R¹¹The point (c) of (a) is,

R¹²are fluorine, chlorine, methyl and trifluoromethyl,

R¹³is hydrogen, fluorine or chlorine,

R¹⁴is hydrogen, fluorine or chlorine,

R¹⁵is hydrogen, fluorine or chlorine,

R¹⁰is a radical of the formula

Wherein

The # # is linked to-CR⁹R¹¹The point (c) of (a) is,

R¹¹is a hydrogen atom, and is,

and salts, solvates and solvates of salts thereof.

Also preferred within the scope of the present invention are compounds of formula (I) wherein a is-S-, -S (═ O) -or-S (═ O)₂-。

Also preferred within the scope of the present invention are compounds of formula (I) wherein a is-S (═ O) -.

Also preferred within the scope of the present invention are compounds of formula (I) wherein a is-S (═ O)₂-。

R⁵Is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

R⁹is phenyl, naphthyl or 5-to 10-membered heteroaryl,

wherein phenyl, naphthyl and 5-to 10-membered heteroaryl can be substituted with 1 to 3 substituents independently from each other selected from the group consisting of: halogen, cyano (C)₁-C₄) -alkyl, trifluoromethyl, (C)₁-C₄) -alkoxy, trifluoromethoxy and trifluoromethylthio,

R¹⁰is 1-cyanoeth-2-yl, 1-cyano-2-methylethyl-2-yl or 1-cyanoprop-3-yl,

R¹¹is hydrogen.

R⁵Is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

R⁹is phenyl, naphthyl or benzothienyl,

And

R¹¹is hydrogen.

R⁵Is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

R⁹is phenyl, naphthyl or benzothienyl,

and

R¹¹is methyl.

Also preferred in the scope of the present invention are compounds of formula (I) wherein R¹¹Is hydrogen.

Also preferred in the scope of the present invention are compounds of formula (I) wherein R¹¹Is methyl.

Also preferred in the scope of the present invention are compounds of formula (I) wherein R¹¹Is methyl, ethyl or cyclopropyl.

Also preferred in the scope of the present invention are compounds of formula (I) wherein R¹⁰Is cyclopropyl.

R¹⁰Is cyclopropyl,

Wherein the cyclopropyl group can be substituted with a cyano substituent,

or

Wherein the cyclopropyl group can be substituted with 1 or 2 fluoro substituents.

R¹⁰Is a radical of the formula

Wherein

The # # is linked to-CR⁹R¹¹Point (2) of (c).

R¹⁰Is phenyl,

R¹⁰Is a radical of the formula

Wherein

Is linked to-CR⁹R¹¹The point (c) of (a) is,

R¹⁶is fluorine or chlorine.

R⁹Is a radical of the formula

Wherein

Is connected to-CR¹⁰R¹¹The point (c) of (a) is,

R¹²are fluorine, chlorine, methyl and trifluoromethyl,

R¹³is hydrogen, fluorine or chlorine,

R¹⁴is hydrogen, fluorine or chlorine,

R¹⁵is hydrogen, fluorine or chlorine,

provided that the group R¹³、R¹⁴And R¹⁵Is hydrogen.

R⁹Is phenyl, naphthyl or benzothienyl,

wherein phenyl, naphthyl and benzothienyl can be substituted by 1 to 3 substituents which are selected independently of one another from the group consisting of: fluoro, chloro, cyano, methyl, ethyl and trifluoromethyl.

R⁹Is a phenyl group or a benzothienyl group,

wherein phenyl and benzothienyl can be substituted by 1 or 2 substituents which are selected independently of one another from the group consisting of: fluorine, chlorine, methyl and trifluoromethyl.

The radical definitions given individually in the respective combinations or preferred combinations of radicals are optionally also replaced by radical definitions of other combinations, independently of the radical combination given in each case.

Combinations of two or more of the above preferred ranges are very particularly preferred.

The invention also relates to a method for producing the compounds of the invention of formula (I), characterised in that

[A] Indole derivatives of formula (I-1)

Wherein R is¹、R²、R³、R⁴And R⁵In each case having the meaning as indicated above,

with a suitable oxidizing agent, preferably m-chloroperbenzoic acid, in an inert solvent to give the compound of formula (I-2)

or

[B] Indole derivatives of formula (I-1)

with a suitable oxidizing agent, preferably m-chloroperbenzoic acid, in an inert solvent to give a compound of the formula (I-3)

Wherein R is ¹、R²、R³、R⁴And R⁵In each case having the meaning as indicated above,

or

[C] Indole derivatives of formula (II)

Wherein R is¹、R²、R³And R⁴In each case having the meaning as described above,

oxidation to the compound of formula (II-2) with a suitable oxidizing agent, preferably m-chloroperbenzoic acid, in an inert solvent

the latter is then reacted with a compound of the formula (XI) in an inert solvent in the presence of a suitable acid and/or Lewis acid

Wherein R is⁵Has the meaning of the above-mentioned formula,

to obtain a compound of formula (I-2),

or

[D] Indole derivatives of formula (II)

oxidation to the compound of formula (II-3) with a suitable oxidizing agent, preferably m-chloroperbenzoic acid, in an inert solvent

Wherein R is⁵Has the meaning of the above-mentioned formula,

to obtain a compound of formula (I-3),

and the optionally obtained compound of formula (I-2) or (I-3) is separated into its enantiomers and/or diastereomers by methods known to those skilled in the art and/or converted into its solvates, salts and/or solvates of the salts with a suitable (I) solvent and/or (ii) base or acid.

The compounds of formulae (I-1), (I-2) and (I-3) together form the group of compounds of the present invention of formula (I).

Suitable solvents for the reactions (I-1) → (I-2) or (I-3) and (II) → (II-2) or (II-3) are all organic solvents which are inert under the reaction conditions. These include ketones such as acetone and methyl ethyl ketone, acyclic and cyclic ethers such as diethyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, tetrahydrofuran and dioxane, alcohols such as methanol, ethanol, isopropanol and tert-butanol, esters such as ethyl acetate or butyl acetate, hydrocarbons such as benzene, toluene, xylene, hexane and cyclohexane, chlorinated hydrocarbons such as dichloromethane, chloroform and chlorobenzene, or other solvents such as Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), acetonitrile or pyridine. Mixtures of the above solvents may likewise be used. Preferably, dichloromethane is used.

Suitable oxidizing agents for the reactions (I-1) → (I-2) or (I-3) and (II) → (II-2) or (II-3) are organic oxidizing agents such as tert-butyl peroxide, m-chloroperbenzoic acid, and inorganic oxidizing agents such as hydrogen peroxide, OXONE (CAS-RN 37222-66-5) or tetrabutylammonium perruthenate together with N-methylmorpholine oxide (TPAP/NMO). Preference is given to using m-chloroperbenzoic acid.

For reactions (I-1) → (I-2) and (II) → (II-2), the oxidizing agent may be used in an amount of 1 to 1.2 moles, preferably 1 to 1.05 moles, based on 1 mole of the compound of formula (I-1) or (II).

For reactions (I-1) → (I-3) and (II) → (II-3), the oxidizing agent may be used in an amount of 2 to 4 moles, preferably 2 to 2.2 moles, based on 1 mole of the compound of formula (I-1) or (II).

The reaction (I-1) → (I-2) or (I-3) and (II) → (II-2) or (II-3) usually take place at a temperature in the range of-78 ℃ to +50 ℃, preferably at a temperature in the range of-20 ℃ to +50 ℃, in particular at a temperature in the range of 0 ℃ to +30 ℃. The reaction can be carried out at normal pressure, at elevated or reduced pressure (for example in the range from 0.5 to 5 bar). It is usually carried out at normal pressure.

Suitable solvents for process steps (II-2) + (XI) → (I-2) and (II-3) + (XI) → (I-3) are all organic solvents which are inert under the reaction conditions. These include acyclic and cyclic ethers such as diethyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, tetrahydrofuran and dioxane, primary alcohols such as methanol, ethanol, N-propanol and N-butanol, hydrocarbons such as benzene, toluene, xylene, hexane and cyclohexane, chlorinated hydrocarbons such as dichloromethane, chloroform, 1, 2-dichloroethane and chlorobenzene, or dipolar aprotic solvents such as Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and acetonitrile. Mixtures of the above solvents may likewise be used. Preference is given to using methylene chloride, 1, 2-dichloroethane and toluene.

Suitable acids for process steps (II-2) + (XI) → (I-2) and (II-3) + (XI) → (I-3) are acetic acid, trifluoroacetic acid, sulfuric acid, p-toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid or hydrochloric acid. Trifluoroacetic acid is preferably used. The amount of acid that can be used in the reaction is 0.9 to 2.0 moles, preferably 1 to 1.2 moles, based on 1 mole of the compound of formula (II).

Suitable Lewis acids for process steps (II-2) + (XI) → (I-2) and (II-3) + (XI) → (I-3) are boron trifluoride-diethyl ether complex, cerium (IV) ammonium nitrate (CAN), tin (II) chloride, lithium perchlorate, zinc (II) chloride, indium (III) chloride or indium (III) bromide. Indium (III) chloride is preferably used. The lewis acid may be used in the reaction in an amount of 0.2 to 2.0 moles, preferably 0.7 to 1.2 moles, based on 1 mole of the compound of formula (II).

The reactions (II-2) + (XI) → (I-2) and (II-3) + (XI) → (I-3) can, if desired, also be carried out using mixtures of acids and Lewis acids, in which case trifluoroacetic acid and indium (III) chloride are preferred. The acid and Lewis acid may be used in a ratio of from 1: 99 to 99: 1, preferably from 2: 1 to 4: 3.

The reaction is carried out at a temperature of use of the acid generally in the range from-40 ℃ to +40 ℃, preferably from 0 ℃ to +30 ℃, and at a temperature of use of the Lewis acid generally in the range from +20 ℃ to +150 ℃, preferably from +40 ℃ to +100 ℃.

The process is illustrated by the following scheme:

scheme 1

[ a): 1 equivalent of m-chloroperbenzoic acid, 0 ℃ → RT, CH₂Cl₂(ii) a b) The method comprises the following steps 2.2 equivalents of m-chloroperbenzoic acid, 0 ℃→ RT, CH₂Cl₂]。

Scheme 12

[ a): 2 equivalents of m-chloroperbenzoic acid, CH₂Cl₂0 ℃→ RT; b) the method comprises the following steps Trifluoroacetic acid, CH₂Cl₂，RT]。

Scheme 13

[ a): 1 equivalent of m-chloroperbenzoic acid, CH₂Cl₂0 ℃→ RT; b) the method comprises the following steps Trifluoroacetic acid, CH₂Cl₂，RT]。

Alternatively, the reactions (II-2) → (I-2) and (II-3) → (I-3) can be carried out using the acetate (XI-A)

Wherein R is⁵Has the meaning of the above-mentioned formula,

(see scheme 14).

Scheme 14

[a)：In(III)Cl₃，ClCH₂CH₂Cl, reflux]。

The compounds of the invention of the formula (I-1), wherein

R⁵Is a radical of the formula

Wherein # and R⁹Each having the above-mentioned meanings, are disclosed,

can be prepared by: firstly, indole derivatives of formula (II)

Wherein R is¹、R²、R³And R⁴Has the meaning of the above-mentioned formula,

with a compound of formula (III) in an inert solvent, optionally in the presence of an acid and/or a base

Wherein R is⁹Has the meaning of the above-mentioned formula,

with malonic esters of the formula (IV)

Wherein

T¹And T²Are the same or different and are (C)₁-C₄) Alkyl or both together form > C (CH)₃)₂The bridge is provided with a plurality of bridges,

to give a compound of the formula (V)

Wherein R is¹、R²、R³、R⁴、R⁹，T¹And T²Each having the above-mentioned meanings, are disclosed,

then cleaving the diester by decarboxylation to obtain the compound of formula (VI)

Wherein R is¹、R²、R³、R⁴And R⁹Each having the above-mentioned meanings, are disclosed,

and

T³is hydrogen or (C)₁-C₄) -an alkyl group,

the compound of formula (VI) is then converted to the compound of the invention of formula (I-1A) with a suitable reducing agent such as lithium aluminum hydride in an inert solvent

Wherein R is¹、R²、R³、R⁴And R⁹Each having the above-mentioned meanings.

The compounds of the invention of the formula (I-1), wherein

R⁵Is a radical of the formula

Wherein # and R⁹Each having the above-mentioned meanings, are disclosed,

can be prepared by the following steps: starting from the compound of formula (I-1A) the reaction is carried out by standard methods to give the compound of formula (VII)

and

x is a suitable leaving group, for example halogen, methanesulfonate, toluenesulfonate or trifluoromethylsulfonate,

followed by substitution with an alkali metal cyanide to give the compound of the invention of the formula (I-1B)

Process steps (II) + (III) + (IV) → (V) can be carried out in one stage as a 3-component reaction, or in two stages: the aldehyde of formula (III) is first condensed with a malonate of formula (IV) by standard methods to give a compound of formula (VIII)

Wherein R is⁹，T¹And T²Each toolHas the meaning of the above-mentioned formula,

the compound of formula (VIII) is then reacted with the indole of formula (II) in a separate reaction step.

When the reactions (II) + (III) + (IV) → (V) are carried out in one stage, the malonate component (IV) preferably used is Meldrum-acid (cyclo-isopropylidene malonate). Wherein a product of formula (Va) is produced

followed by solvolysis with methanol or ethanol in the presence of pyridine and copper powder to the ester [ T ] of formula (VI)³Methyl or ethyl][ reference Y.Oikawa et al Tetrahedron Lett., 1759-]。

This one-stage process variant (II) + (III) + (IV) → (V) and-when the reaction is carried out in two stages-condensing (III) + (IV) → (VIII) preferably in the presence of an acid/base catalyst such as, for example, D, L-proline or piperidine acetateIs carried out in the case of (1). The reaction (VIII) + (II) → (V) can advantageously take place, if desired, with the aid of amine bases, such as triethylamine, or lewis acids, such as copper (II) trifluoromethanesulfonate or ytterbium.

Suitable solvents for process steps (II) + (III) + (IV) → (V) and (VIII) + (II) → (V) are all organic solvents which are inert under the reaction conditions. These include acyclic and cyclic ethers such as diethyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, tetrahydrofuran and dioxane, hydrocarbons such as benzene, toluene, xylene, hexane and cyclohexane, chlorinated hydrocarbons such as dichloromethane, chloroform and chlorobenzene or dipolar aprotic solvents such as Dimethylmethylamine (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and acetonitrile. Mixtures of the above solvents may likewise be used. Acetonitrile is preferably used.

The reaction generally takes place at a temperature in the range from 0 ℃ to +120 ℃, preferably 0 ℃ to +60 ℃. The reaction may be carried out at atmospheric pressure, at elevated or reduced pressure (for example in the range from 0.5 to 5 bar). They are usually carried out at normal pressure.

Suitable reducing agents in process step (VI) → (I-1A) are in particular lithium aluminum hydride or lithium borohydride. In the presence of a carboxylic acid (VI) [ T ]³＝H]In the case of (2), diborane or borane complexes may alternatively be used. The reaction is preferably carried out in an ether as an inert solvent, such as diethyl ether or tetrahydrofuran, at a temperature in the range from 0 ℃ to +80 ℃.

Inert solvents which are particularly suitable for process step (VII) → (I-1B) are ethers such as diethyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, tetrahydrofuran and dioxane, or dipolar aprotic solvents such as Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and acetonitrile. Mixtures of these solvents may likewise be used. Dimethylformamide is preferably used. The reaction generally takes place at a temperature ranging from +20 ℃ to +150 ℃, preferably from +40 ℃ to +100 ℃.

The compounds of the formulae (III) and (IV) are commercially available, known from the literature or can be prepared analogously to methods known from the literature.

The above process is illustrated by the following synthetic scheme:

scheme 2

[ a): cat.d, L-proline, acetonitrile, RT; b) the method comprises the following steps Refluxing cat, copper powder and EtOH/pyridine; c) the method comprises the following steps LiAlH₄，Et₂O，0℃→RT；d)：MsCl，Et₃N，DMAP，CH₂Cl₂，RT；e)：KCN，DMF，80℃]。

The indoles of formula (II) can be prepared by: reacting a 6-nitrobenzyl bromide derivative of formula (IX)

Wherein R is²、R³And R⁴Each having the above-mentioned meanings, are disclosed,

reaction with alkali metal alkylmercaptides (X) in an inert solvent

Wherein R is¹Has the meaning of the above-mentioned formula,

and

Ak⁺is a mixture of alkali metal ions, preferably sodium,

to give a compound of the formula (XI)

Wherein R is¹、R²、R³And R⁴Each having the above-mentioned meanings, are disclosed,

the compound of formula (XI) is then converted to the indole of formula (II) in a Bartoli reaction with vinylmagnesium bromide

Wherein R is¹、R²、R³And R⁴Each having the above-mentioned meanings.

Suitable solvents for process step (IX) + (X) → (XI) are all organic solvents which are inert under the reaction conditions. These include acyclic and cyclic ethers such as diethyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, tetrahydrofuran and dioxane, hydrocarbons such as benzene, toluene, xylene, hexane and cyclohexane, chlorinated hydrocarbons such as dichloromethane, chloroform and chlorobenzene, or dipolar aprotic solvents such as Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and acetonitrile. Mixtures of the above solvents may likewise be used. Preference is given to using tetrahydrofuran or DMF.

The reaction is generally carried out at a temperature ranging from-20 ℃ to +100 ℃, preferably from 0 ℃ to +60 ℃. The reaction may be carried out at atmospheric pressure, at elevated or reduced pressure (for example in the range from 0.5 to 5 bar). They are usually carried out at normal pressure.

Solvents suitable for Grignard reaction (XI) → (II) are all organic solvents which are inert under the reaction conditions. These include acyclic and cyclic ethers such as diethyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, tetrahydrofuran and dioxane, hydrocarbons such as benzene, toluene, xylene, hexane and cyclohexane, chlorinated hydrocarbons such as dichloromethane, chloroform and chlorobenzene, or dipolar aprotic solvents such as Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and acetonitrile. Mixtures of the above solvents may likewise be used. Tetrahydrofuran is preferably used.

The reaction is generally carried out at a temperature ranging from-100 ℃ to +50 ℃, preferably from-78 ℃ to +25 ℃. The reaction may be carried out at atmospheric pressure, at elevated or reduced pressure (for example in the range from 0.5 to 5 bar). They are usually carried out at normal pressure.

The compounds of the formula (IX) are commercially available, known from the literature or can be prepared analogously to methods known from the literature.

The above process is illustrated by the following synthetic scheme:

scheme 3

[ a): NaSMe, THF, RT; b) the method comprises the following steps Vinyl magnesium bromide, -78 ℃.

Alternatively, indoles of formula (II) wherein R²、R³And R⁴Is H, can each be prepared starting from 7-methylindole, as exemplified in the following synthetic schemes:

scheme 4

[ a): NaH, THF, 0 ℃→ RT; di-tert-butyl dicarbonate, RT; b) the method comprises the following steps N-bromosuccinimide, CCl₄H.v. refluxing; c) the method comprises the following steps NaSMe, DMF, RT; d) the method comprises the following steps NaOMe, MeOH, RT]。

Further compounds according to the invention of the formula (I-1), in which

R⁵Is a radical of the formula

Wherein # and R⁹Each having the above-mentioned meanings, are disclosed,

can be prepared by: the hydrolysis of the compound of formula (I-1B) is a compound of formula (XII)

Wherein R is¹、R²、R³、R⁴And R⁹Each having the above meaning, and

T⁴is hydrogen or (C)₁-C₄) -an alkyl group,

followed by reaction with a suitable reducing agent, such as lithium aluminum hydride, in an inert solvent to give the compounds of the invention of the formula (I-1C)

Further compounds according to the invention of the formula (I-1), in which

R⁵Is a radical of the formula

Wherein # and R⁹Each having the above-mentioned meanings, are disclosed,

can be prepared by: the compound of formula (I-1C) is again converted via the compound of formula (XIII) by standard methods,

and

and subsequent substitution with an alkali metal cyanide to give the compound of the invention of the formula (I-1D)

The hydrolysis of the nitrile (I-1B) to the carboxylic acid (XII) is preferably carried out with an aqueous solution of an alkali metal or alkaline earth metal hydroxide, such as lithium, sodium, potassium, calcium or barium hydroxide. Suitable cosolvents are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, tetrahydrofuran, dioxane or 1, 2-dimethoxyethane, further solvents such as acetone, Dimethylformamide (DMF) or dimethyl sulfoxide (DMSO), or mixtures of these solvents. The hydrolysis is generally carried out at a temperature ranging from +50 ℃ to +150 ℃, preferably from +60 ℃ to +100 ℃.

For the synthesis sequence (I-1C) → (XII) → (I-1D) is carried out under the reaction conditions mentioned for the sequence (I-1A) → (VII) → (I-1B).

The preparation of the compounds of the invention can be illustrated by the following synthetic schemes:

scheme 5

[ a): aqueous KOH, EtOH, 80 ℃; b) the method comprises the following steps LiAlH ₄，THF，60℃；c)：MsCl，Et₃N，DMAP，CH₂Cl₂，RT；d)：KCN，DMF，80℃]。

The above-described process (II) → (I-1A) → (I-1B) → (I-1C) → (I-1D) can also alternatively be carried out starting from the compound of the formula (II-2) or (II-3) to prepare analogous compounds of the formulae (I-2A), (I-3A), (I-2B), (I-3B) and the like, as shown in the following synthetic schemes:

scheme 15

[ a): 2 equivalents of m-CPBA, CH₂Cl₂0 ℃→ RT; b) the method comprises the following steps cat.d, L-proline, acetonitrile, RT; c) the method comprises the following steps Refluxing cat, copper powder and EtOH/pyridine; d) the method comprises the following steps LiAlH₄，Et₂O，0℃→RT；e)：MsCl，Et₃N，DMAP，CH₂Cl₂，RT；f)：KCN，DMF，80℃]。

Further compounds according to the invention of the formula (I-1), in which

R⁵Is a radical of the formula

Wherein # and R⁹Each having the above meaning, and

R¹⁰is (C)₄-C₆) -an alkyl group,

wherein (C)₄-C₆) -alkyl is substituted by a substituent selected from the group consisting of hydroxy and cyano,

and

R¹¹is a hydrogen atom, and is,

can be carried out starting from the compound of the formula (I-1D) by repeating the process steps (I-1B) → (XII) → (I-1C) → (XIII) → (I-1D).

The compounds of the invention of the formula (I), wherein

R⁵Is a radical of the formula

Wherein # and R⁹Each having the above-mentioned meanings, are disclosed,

and

R¹⁰is 1-cyano-1-methylethyl-2-yl, 1-cyano-2-methylethyl-2-yl, 1-cyano-1, 2-dimethylethyl-2-yl, 1-cyano-2, 2-dimethylethyl-2-yl, 1-cyano-1-methylpropyl-3-yl, 1-cyano-2-methylpropyl-3-yl, 1-cyano-3-methylpropyl-3-yl, 1-cyano-2, 3-dimethylpropyl-3-yl, 1-hydroxy-1-methylethyl-2-yl, 1-hydroxy-2-methylethyl-2-yl, 1-hydroxy-1, 2-dimethylethyl-2-yl, 1-hydroxy-2, 2-dimethylethyl-2-yl, 1-hydroxy-1-methylpropyl-3-yl, 1-hydroxy-2-methylpropyl-3-yl, 1-hydroxy-3-methylpropyl-3-yl or 1-hydroxy-2, 3-dimethylpropyl-3-yl,

R¹¹Is a hydrogen atom, and is,

can be prepared by methods known to the skilled person starting from the compounds of the above formulae (VI) and (XII) for the alpha-methylation or alpha-dimethylation of carbonyl compounds [ see, for example, scheme 6 ].

Scheme 6

[ a): di-tert-butyl dicarbonate, DMAP, THF, 50 ℃; b) the method comprises the following steps LDA, THF, -78 ℃; then MeI, -78 ℃→ RT; c) the method comprises the following steps TFA, CH₂Cl₂，RT；d)：LiAlH₄，THF，60℃；e)：MsCl，NEt₃，DMAP，CH₂Cl₂RT; f) the method comprises the following steps KCN, DMSO, 80 ℃; g) the method comprises the following steps 2 equivalents of m-chloroperbenzoic acid, CH₂Cl₂，0℃→RT]。

The compounds of the invention of the formula (I), wherein

R⁵Is a radical of the formula

Wherein # and R⁹Each having the above-mentioned meanings, are disclosed,

and

R¹⁰is 1-cyanoeth-2-yl, 1-cyano-1-methylethyl-2-yl, 1-cyano-2-methylethyl-2-yl, 1-cyano-1, 2-dimethylethyl-2-yl, 1-cyano-2, 2-dimethylethyl-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylpropyl-3-yl, 1-cyano-2-methylpropyl-3-yl, 1-cyano-3-methylpropyl-3-yl, 1-cyano-2, 3-dimethylprop-3-yl, 1-hydroxyeth-2-yl, 1-hydroxy-1-methylethyl-2-yl, 1-hydroxy-2-methylethyl-2-yl, 1-hydroxy-1, 2-dimethylethyl-2-yl, 1-hydroxy-2, 2-dimethylethyl-2-yl, 1-hydroxypropan-3-yl, 1-hydroxy-1-methylpropan-3-yl, 1-hydroxy-2-methylpropan-3-yl, 1-hydroxy-3-methylpropan-3-yl or 1-hydroxy-2, 3-dimethylpropan-3-yl,

Wherein 1-cyanoeth-2-yl, 1-cyano-1-methylethyl-2-yl, 1-cyano-2-methylethyl-2-yl, 1-cyano-1, 2-dimethylethyl-2-yl, 1-cyano-2, 2-dimethylethyl-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylpropyl-3-yl, 1-cyano-2-methylpropyl-3-yl, 1-cyano-3-methylpropyl-3-yl, 1-cyano-2, 3-dimethylprop-3-yl, 1-hydroxyeth-2-yl, 1-hydroxy-1-methylethyl-2-yl, 1-hydroxy-2-methylethyl-2-yl, 1-hydroxy-1, 2-dimethylethyl-2-yl, 1-hydroxy-2, 2-dimethylethyl-2-yl, 1-hydroxypropan-3-yl, 1-hydroxy-1-methylpropan-3-yl, 1-hydroxy-2-methylpropan-3-yl, 1-hydroxy-3-methylpropan-3-yl and 1-hydroxy-2, 3-dimethylpropan-3-yl groups being substituted with 1 or 2 fluoro substituents,

R¹¹is a hydrogen atom, and is,

can be prepared by methods known for the fluorination of carbonyl compounds starting from compounds of the above-mentioned formula (VI), (XII), (I-1B) or (I-1D) [ references, for example, Z.xu et al, J.Fluorine chem.1992, 58(1), 71-79; W.H.Bunnel, J.org.chem.1990, 55, 768-770 ].

The compounds of the invention of the formula (I-1), wherein

R⁵Is a radical of the formula

Where #, D, R⁶、R⁷、R⁸And R⁹Each having the above-mentioned meanings, are disclosed,

and

R¹⁰is (C)₁-C₆) -alkyl, (C)₃-C₇) -a cycloalkyl group or a phenyl group,

Wherein (C)₃-C₇) -cycloalkyl can be substituted with 1 or 2 substituents independently chosen from: fluorine, a hydroxyl group and a cyano group,

and

wherein phenyl can be substituted with 1 to 3 substituents independently selected from: halogen, cyano (C)₁-C₄) -alkyl, trifluoromethyl, (C)₁-C₄) -alkoxy, trifluoromethoxy and trifluoromethylthio,

R¹¹is hydrogen, methyl, ethyl or trifluoromethyl,

can be prepared by reacting an indole of formula (II) with a compound of formula (XI) in an inert solvent in the presence of a suitable acid or Lewis acid

Wherein R is⁵Have the above-mentioned meanings.

Process steps (II) + (XI) → (I-1) are carried out under the conditions mentioned for reaction steps (II-2) + (XI) → (I-2) and (II-3) + (XI) → (I-3).

The above methods are exemplified, for example, by synthesis schemes 7 and 8:

scheme 7

[ a): indium (III) chloride, toluene, 80 ℃ C.)

Scheme 8

[ a): trifluoroacetic acid, CH₂Cl₂，RT]

Or, a compound of formula (I), wherein

R⁵Is a radical of the formula

Where #, R⁹And R¹¹Each having the above-mentioned meanings, are disclosed,

it can also be prepared by: reacting a compound of formula (XIV)

Wherein R is⁹And R¹¹Each having the above-mentioned meanings, are disclosed,

by methods known to those skilled in the art with compounds of formula (XV)

Wherein

T⁴Is (C)₁-C₄) -an alkyl group or a benzyl group,

reaction to give a compound of formula (XVI)

Wherein R is⁹、R¹¹And T⁴Each having the above-mentioned meanings, are disclosed,

then reacting the compound of formula (XVI) with the compound of formula (II), (II-2) or (II-3) in the presence of a Lewis acid or acid in an inert solvent to obtain the compound of formula (XVII), (XVII-2) or (XVII-3)

Wherein R is¹、R²、R³、R⁴、R⁹、R¹¹And T⁴Each having the above-mentioned meanings, are disclosed,

then reducing the compound of formula (XVII), (XVII-2) or (XVII-3) to the compound of formula (I-1A), (I-2A) or (I-3A) with a suitable reducing agent in an inert solvent,

or reducing the compound of formula (XVI) to the compound of formula (XVIII) with a suitable reducing agent in an inert solvent

then reacting the compound of the formula (XVIII) with the compound of the formula (II), (II-2) or (II-3) under the above-mentioned conditions to obtain the compound of the formula (I-1A), (I-2A) or (I-3A).

Suitable inert solvents for process steps (XVII) → (I-1A), (XVII-2) → (I-2A), (XVII-3) → (I-3A) and (XVI) → (XVIII) are in this case alcohols such as methanol, ethanol, n-propanol or isopropanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diglycol dimethyl ether, or halogenated hydrocarbons such as dichloromethane, chloroform, tetrachloromethane or 1, 2-dichloroethane, or other solvents such as dimethylformamide. Mixtures of the above solvents may likewise be used. Tetrahydrofuran is preferably used.

Suitable reducing agents for process steps (XVII) → (I-1A), (XVII-2) → (I-2A), (XVII-3) → (I-3A) and (XVI) → (XVIII) are boron hydrides, such as sodium borohydride, sodium triacetoxyborohydride, lithium borohydride or sodium cyanoborohydride, aluminum hydrides, such as lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride or diisobutyl aluminum hydride or boron-tetrahydrofuran complexes.

The reaction (IV-C) → (V-C) is usually carried out at a temperature in the range of from 0 ℃ to +60 ℃, preferably from 0 ℃ to +40 ℃.

The compounds of the formulae (XI), (XI-A), (XIV) and (XV) are commercially available, known from the literature or can be prepared analogously to methods known from the literature, as illustrated, for example, by the following synthetic schemes:

scheme 9

[a)：THF/Et₂O，0℃→RT]。

Scheme 10

[a)：THF/Et₂O，0℃→RT]。

Scheme 11

[ a): n-butyllithium (1.6N in hexanes), THF, -78 deg.C; then p-chlorobenzaldehyde, -78 ℃ → RT ].

Scheme 16

[ a): LiHMDS, THF, -78 ℃; then ethyl acetate, -78 ℃; b) the method comprises the following steps Diisobutylaluminum hydride (1N in CH)₂Cl₂Middle), THF, RT; c) the method comprises the following steps Indium (III) chloride, toluene, 80 ℃ C]。

Scheme 17

[ a): vinylmagnesium bromide in THF, Et₂O, RT-refluxing; b) the method comprises the following steps MnO₂，CH₂Cl₂Refluxing followed by H₂SO₄，K₂Cr₂O₇15-20 ℃; c) the method comprises the following steps 2, 2-difluoro-2- (fluorosulfonyl) acetic acid trimethylsilyl ester, NaF, 110 ℃; d) the method comprises the following steps NaBH ₄EtOH, ethyl acetate, 40 ℃; e) the method comprises the following steps (CH)₃CO)₂O, pyridine, RT]。

Scheme 18

[ a): benzyltriethylammonium chloride, K₂CO₃DMF, RT; b) the method comprises the following steps Aqueous sodium hydroxide, MeOH, RT; hydrochloric acid; SOCl₂(ii) a N, O-dimethylhydroxylamine hydrochloride, Et₃N，CH₂Cl₂RT; c) the method comprises the following steps Chlorophenylmagnesium bromide in Et₂In O, THF, RT-refluxing; d) the method comprises the following steps NaBH₄EtOH, ethyl acetate, 40 deg.C]。

Further compounds of the invention can also be converted, if desired, by starting from the compounds of the formula (I) obtained by the process described above, into the functional groups of the individual substituents, in particular with respect to A, R⁷、R⁸、R⁹、R¹⁰And R¹¹Those mentioned, to prepare. These transformations are carried out by conventional methods known to those skilled in the art and include, for example, reactions such as nucleophilic, electrophilic or transition metal-catalyzed substitution reactions, oxidations, reductions, hydrogenations, alkylations, acylations, aminations, esterifications, ester cleavage, etherifications, ether cleavage, formation of carboxamides and sulfonamides, and introduction and removal of temporary protecting groups.

The compounds of the present invention are potent mineralocorticoid receptor antagonists which are selective with respect to androgen (testosterone) and progestin receptors and which are characterized by an unpredictable range of valuable pharmacological effects, as well as by a favorable CYP inhibitory profile compared to the compounds disclosed in the prior art. They are therefore suitable as medicaments for the treatment and/or prophylaxis of diseases in humans and animals.

The compounds of the invention are suitable for the prevention and/or treatment of various disorders and disease-related conditions, in particular disorders which are characterized by an elevated plasma aldosterone concentration or a change in plasma aldosterone concentration relative to plasma renin concentration, or disorders associated with such changes. Examples which may be mentioned are: spontaneous primary hyperaldosteronism, hyperaldosteronism in case of adrenal hyperplasia, adrenal adenoma and/or adrenal carcinoma, hyperaldosteronism in case of liver cirrhosis, hyperaldosteronism in case of heart failure, and (relative) hyperaldosteronism in case of primary hypertension.

Due to its mechanism of action, the compounds of the invention are also suitable for use in the prevention of sudden cardiac death in patients at increased risk of sudden cardiac death. These are in particular patients suffering from, for example, one of the following conditions: primary and secondary hypertension, hypertensive heart disease with or without congestive heart failure, hypertension with resistance to therapy, acute and chronic heart failure, coronary heart disease, stable and unstable angina, myocardial ischemia, myocardial infarction, dilated cardiomyopathy, congenital primary cardiomyopathy, such as Brugada syndrome, cardiomyopathy induced by chagas' disease, shock, arteriosclerosis, atrial and ventricular disorders of heart rhythm, transient and ischemic attacks, stroke, inflammatory cardiovascular disorders, peripheral and cardiovascular disorders, peripheral blood flow disorders, arterial occlusive diseases such as intermittent claudication, asymptomatic left ventricular dysfunction, myocarditis, hypertrophic changes of the heart, pulmonary hypertension, coronary and peripheral arterial spasm, thrombosis, thromboembolic disorders, and vasculitis.

The compounds of the invention may additionally be used for the prevention and/or treatment of edema formation, for example pulmonary edema, nephrogenic edema or heart failure-related edema, and restenosis, for example after thrombolytic therapy, Percutaneous Transluminal Angioplasty (PTA) and coronary angioplasty (PTCA), heart transplantation and bypass surgery.

The compounds of the invention can additionally be used for the prophylaxis and/or treatment of erectile dysfunction.

The compounds of the invention are further suitable for use as potassium sparing diuretics and for electrolyte disorders such as hypercalcemia, hypernatremia or hypokalemia, including genetically related forms such as Gitelman or Barrter's syndrome.

The compounds of the invention are likewise suitable for the treatment of renal disorders such as acute and chronic renal failure, hypertensive renal disease, glomerulosclerosis nephritis (chronic and interstitial), nephrosclerosis, chronic renal failure and renal disorders of the bladder, for the prevention of renal injury which may be caused, for example, by immunosuppressive agents such as cyclosporin a during organ transplantation, and for kidney cancer.

The compounds of the invention can additionally be used for the prophylaxis and/or treatment of diabetes and the sequelae thereof, such as neuropathy, nephropathy and cardiomyopathy.

The compounds of the invention can additionally be used for the prophylaxis and/or treatment of eye disorders, in particular based on angiogenic and neovascularization forms, such as neoretinopathy, diabetic retinopathy, and macular degeneration and glaucoma due to aging.

The compounds of the invention may further be used for the prevention and/or treatment of microalbuminuria (e.g. caused by diabetes or hypertension) and proteinuria.

The compounds of the invention are also suitable for the prevention and/or treatment of conditions associated with an increased plasma glucocorticoid concentration or with a local increase in the glucocorticoid concentration in tissues, such as the heart. Examples which may be mentioned are: adrenal dysfunction leading to glucocorticoid overproduction (cushing's syndrome), adrenocortical tumors with glucocorticoid overproduction consequences, and pituitary tumors that spontaneously produce ACTH (adrenocorticotropic hormone) and thus lead to adrenal hyperplasia with cushing's disease consequences.

The compounds of the invention can additionally be used for the prophylaxis and/or treatment of obesity, metabolic syndrome and obstructive sleep apnea.

The compounds of the invention can further be used for the prophylaxis and/or treatment of inflammatory disorders which are caused, for example, by viruses, spirochetes, fungi, bacteria or mycobacteria, and inflammatory disorders of unknown etiology, such as polyarthritis, lupus erythematosus, periarteritis or polyarteritis, dermatomyositis, scleroderma and sarcoidosis.

The compounds of the invention may further be useful in the treatment of central nervous disorders such as depression, anxiety states and chronic pain, in particular migraine, and in neurodegenerative disorders such as alzheimer's disease and parkinson's syndrome.

The compounds of the invention are also suitable for the prevention and/or treatment of vascular damage, for example after procedures such as Percutaneous Transluminal Coronary Angioplasty (PTCA), stent grafting, coronary transluminal angioplasty, reocclusion or restenosis (after bypass surgery), and for endothelial dysfunction, for raynaud's disease, for Buerger's disease (Buerger syndrome) and for tinnitus syndrome.

The compounds of the invention are also suitable for the prophylaxis and/or treatment of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea.

The invention further relates to the use of the compounds according to the invention for the treatment and/or prophylaxis of disorders, in particular of the disorders mentioned above.

The invention further relates to the use of the compounds according to the invention for the preparation of a medicament for the treatment and/or prophylaxis of disorders, in particular of the disorders mentioned above.

The invention further relates to methods for the treatment and/or prophylaxis of disorders, in particular of the above-mentioned disorders, by using an effective amount of at least one compound according to the invention.

The invention further relates to compounds of the invention for use in a method for the treatment and/or prevention of aldosteronism, hypertension, acute and chronic heart failure, myocardial infarction sequence signs, cirrhosis, renal failure and stroke.

The compounds of the invention may be used alone or in combination with other active ingredients, if desired. The invention further relates to medicaments comprising at least one compound according to the invention and one or more further active ingredients, in particular for the treatment and/or prophylaxis of the abovementioned conditions. Suitable active ingredients for the combination are for example and preferably:

a blood pressure lowering active ingredient, such as and preferably selected from calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers and rho kinase inhibitors;

diuretics, especially loop diuretics, and thiazide and thiazine-like diuretics;

an agent having an antithrombotic effect, for example and preferably selected from platelet aggregation inhibitors, anticoagulants or fibrinolytic substances;

active ingredients which alter lipid metabolism, such as, and preferably selected from, thyroid receptor agonists, cholesterol synthesis inhibitors such as, and preferably, HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid resorption inhibitors and lipoprotein (a) antagonists;

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

compounds with positive inotropy (positiv-inotrop) action, such as cardiac glycosides (digoxin), β -adrenergic and dopaminergic agonists such as isoproterenol, epinephrine, norepinephrine, dopamine and dobutamine;

compounds which inhibit the breakdown of cyclic guanosine monophosphate (cGMP) and/or cyclic adenosine monophosphate (cAMP), for example Phosphodiesterase (PDE)1, 2, 3, 4 and/or 5 inhibitors, in particular PDE 5 inhibitors such as sildenafil, vardenafil and tadalafil, and PDE 3 inhibitors such as amrinone and milrinone;

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

calcium sensitizers such as and preferably levosimendan;

NO-and heme-activators which are independent of guanylate cyclase, such as in particular Cinaciguat and the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO01/19780, WO 02/070462 and WO 02/070510;

NO-independent but heme-dependent agonists of guanylate cyclase such as, inter alia, Riociguat and the compounds described in WO00/06568, WO00/06569, WO02/42301 and WO 03/095451;

modulators of adenosine receptors, particularly adenosine A1 antagonists such as KW-3902, SLV-320 or BG-9928 (Adentri);

vasopressin receptor antagonists, such as conivaptan (Vaprisol), tolvaptan, sataptan (Satavaptan), lixivaptan, relcovaptan, RWJ-339489 or RWJ-351647.

Inhibitors of Human Neutrophil Elastase (HNE), such as cevelsitol or DX-890 (relan);

compounds which inhibit the signal transduction cascade, such as tyrosine kinase inhibitors, in particular Sorafenib (Sorafenib), imatinib, Gefitinib (Gefitinib) and Erlotinib (Erlotinib); and/or

A compound which affects cardiac energy metabolism, such as, and preferably, etomoxider, dichloroacetate, ranolazine or trimetazidine.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a diuretic such as, and preferably, for example, Verbenamic acid, bumetanide, torsemide, bendroflumethiazide, clorsulone, hydrochlorothiazide, hydroflumethiazide, methylchlorothiazide, polythiazide, trichlorthiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichloramidone, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.

The blood pressure lowering agent preferably refers to a compound selected from the group consisting of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, rho-kinase inhibitors, and diuretics.

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

In a preferred embodiment of the invention, the compounds of the 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 of the invention are administered in combination with an endothelin antagonist such as, and preferably, bosentan, darussan, Ambrisentan (Ambrisentan) or stastastanin (Sitaxsentan).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a renin inhibitor such as, and preferably, aliskiren, SPP-600, SPP-635, SPP-676, SPP-800 or SPP-1148.

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

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a beta-receptor blocker, such as and preferably propranolol, atenolol, timolol, pindolol, oxprenolol, penbutolol, blanolol, metipranolol, mepindolol, caraalol (carazalol), sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, eparnolol or bucindolol.

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

The agent having an antithrombotic action (antithrombotic agent) preferably means a compound selected from the group consisting of a platelet aggregation inhibitor, an anticoagulant or a fibrinolytic substance.

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

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thrombin inhibitor, such as and preferably ximelagatran, melagatran, bivalirudin or cricet.

In a preferred embodiment of the invention, the compound of the invention is administered in combination with a GPIIb/IIIa antagonist, such as, and preferably, tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a factor Xa inhibitor, such as, and preferably, rivaroxaban (BAY59-7939), DU-176b, Apixaban (Apixaban), omixaban (Otamixaban), Feidexaban (Fidexaban), rizoxaban (razaxaban), fondaparinux sodium, edanaparin sodium, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MCM-1021, DX 9065a, DPC906, JTV 803, SSR-126512 or SSR-128428.

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

The agent which alters lipid metabolism preferably means a compound selected from the group consisting of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbents, bile acid resorption inhibitors, lipase inhibitors and lipoprotein (a) antagonists.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a CETP inhibitor, such as and preferably Dalcettrapib (Dalcettrapib), BAY 60-5521, Anacetrapid or CETP vaccine (CETi-1).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thyroid receptor agonist such as, and preferably, D-thyroxine, 3, 5, 3' -triiodothyronine (T3), CGS 23425 or acitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an HMG-CoA reductase inhibitor selected from the statin class such as and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

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

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an ACAT inhibitor such as, and preferably, avasimibe, melinamide, Patetimibe (Pactimibe), ezetimibe (Eflucomibe) or SMP-797.

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

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR-gamma-agonist, such as and preferably pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR-delta-agonist, such as and preferably GW-501516 or BAY 68-5042.

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

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a lipase inhibitor, such as, and preferably orlistat.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a polymeric bile acid adsorbent such as, and preferably, cholestyramine, colestipol, Colesolvam, colestim or Colestimid.

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

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a lipoprotein (a) antagonist such as, and preferably, Gemcabene calcium (CI-1027) or niacin.

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

The compounds of the invention may have systemic and/or local effects. For this purpose, they can be administered by a suitable route, for example by the buccal, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or otic route or as an implant or stent.

The compounds of the invention may be administered in a form suitable for such administration.

Suitable for oral administration are administration forms which function according to the prior art and deliver the compounds of the invention rapidly and/or in a modified manner and which comprise the compounds of the invention in crystalline and/or amorphous and/or dissolved form, for example tablets (uncoated or coated tablets, for example with a coating which is resistant to gastric juice or is insoluble or dissolves with delayed and controlled release of the compounds of the invention), tablets which disintegrate rapidly in the mouth, or films/tablets, films/lyophilisates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can occur bypassing an absorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or involving absorption (e.g., intramuscular, subcutaneous, intradermal, transdermal, or intraperitoneal). Administration forms suitable for parenteral administration are, in particular, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

Suitable for other administration routes are, for example, pharmaceutical forms for inhalation dosage forms (in particular powder inhalers, nebulizers), nasal drops, nasal solutions, nasal sprays; tablets for lingual, sublingual or buccal administration, films/tablets or capsules, suppositories, preparations for the ear and eye, vaginal capsules, aqueous suspensions (lotions, ironing agents), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), milks, pastes, foams, dusting powders, implants or stents.

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

The compounds of the invention can be converted into the prescribed administration forms. This can be carried out in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable auxiliaries. These include, inter alia, carriers (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), 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), colorants (e.g. inorganic pigments, e.g. iron oxides) and taste and/or odor correctors.

It has generally been shown that for parenteral administration an advantageous amount of administration is about 0.001 to 1 mg/kg body weight, preferably about 0.01 to 0.5 mg/kg body weight, to achieve effective results. For oral administration, the dose is about 0.01 to 100 mg/kg of body weight, preferably about 0.01 to 20 mg/kg of body weight, and very particularly preferably about 0.1 to 10 mg/kg of body weight.

Nevertheless, the amounts may vary from the stated amounts as the case may be, particularly with respect to body weight, route of administration, individual response to the active ingredient, type of formulation and time or interval over which administration is carried out. Thus, in some cases it may be sufficient to be less than the above-mentioned minimum amount, while in other cases the mentioned upper limit must be exceeded. In the case of relatively large amounts to be administered, it is advisable to divide these amounts into a plurality of individual doses during the day.

The following working examples illustrate the invention. The present invention is not limited to these examples.

Unless otherwise indicated, the percentage data in the following tests and examples are percentages by weight; parts are parts by weight. The solvent ratio, dilution ratio and concentration data for the liquid/liquid solution are in each case based on volume.

A. Examples of the embodiments

Abbreviations and acronyms:

ac acetyl group

Bn benzyl group

Bu butyl

cat, catalysis

CI chemical ionization (in MS)

DAST diethylaminosulfur trifluoride

dd doublet (in NMR)

doublet of ddd doublets (in NMR)

DMAP 4-N, N-dimethylaminopyridine

DMF dimethyl formamide

DMSO dimethyl sulfoxide

Of th theoretical value (in the case of yield)

EI Electron impact ionization (in MS)

eq. equivalent

ESI electrospray ionization (in MS)

Et Ethyl group

EtOAc ethyl acetate

h hours

HPLC high pressure, high performance liquid chromatography

Concentration of konz

LC-MS coupling liquid chromatography-mass spectrum

Me methyl group

min for

Ms methylsulfonyl (methylsulfonyl)

MS Mass Spectrometry

NMR nuclear magnetic resonance spectroscopy

Ph phenyl

RT Room temperature

R_tRetention time (in HPLC)

SFC superfluid chromatography

THF tetrahydrofuran

UV ultraviolet spectroscopy

Aqueous, aqueous solutions

LC-MS and HPLC methods:

method 1 (HPLC):

the instrument comprises the following steps: HP 1100 with DAD detection; column: kromasil 100RP-18, 60 mm x2.1 mm, 3.5 microns; eluent A: 5 ml HClO₄(70%)/liter water, eluent B: acetonitrile; gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 9 min 90% B → 9.2 min 2% B → 10 min 2% B; flow rate: 0.75 ml/min; column temperature: 30 ℃; UV detection: 210 nm.

Method 2 (HPLC):

the instrument comprises the following steps: HP 1100 with DAD detection; column: kromasil 100RP-18, 60 mm x2.1 mm, 3.5 microns; eluent A: 5 ml HClO₄(70%)/liter water, eluent B: acetonitrile; gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 6.5 min 90% B → 6.7 min 2% B → 7.5 min 2% B; flow rate: 0.75 ml/min; column temperature: 30 ℃; UV detection: 210 nm.

Method 3 (LC-MS):

MS instrument type: micromass ZQ; HPLC instrument type: waters Alliance 2795; column: phenomenex Synergi 2. mu. MAX-RP 100A Mercury 20 mm x4 mm; eluent A: 1 liter of water +0.5 ml of 50% formic acid, eluent B: 1 l acetonitrile +0.5 ml 50% formic acid; gradient: 0.0 min 90% a → 0.1 min 90% a → 3.0 min 5% a → 4.0 min 5% a → 4.01 min 90% a; flow rate: 2 ml/min; furnace: 50 ℃; UV detection: 210 nm.

Method 4 (LC-MS):

the instrument comprises the following steps: micromass Quattro Premier with Waters UPLC Acquity; column: thermo Hypersil GOLD 1.9 μ 50 mm x1 mm; eluent A: 1 liter of water +0.5 ml of 50% formic acid, eluent B: 1 l acetonitrile +0.5 ml 50% formic acid; gradient: 0.0 min 90% a → 0.1 min 90% a → 1.5 min 10% a → 2.2 min 10% a; flow rate: 0.33 ml/min; furnace: 50 ℃; UV detection: 210 nm.

Method 5 (LC-MS):

MS instrument type: micromass ZQ; HPLC instrument type: HP 1100 series; UVDAD; column: phenomenex Gemini 3 mu 30 mm x3.00 mm; eluent A: 1 liter of water +0.5 ml of 50% formic acid, eluent B: 1 l acetonitrile +0.5 ml 50% formic acid; gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; flow rate: 0.0 min 1 ml/min → 2.5 min/3.0 min/4.5 min 2 ml/min; furnace: 50 ℃; UV detection: 210 nm.

Method 6 (LC-MS):

MS instrument type: water (Micromass) Quattro Micro; HPLC instrument type: agilent1100 series; column: thermo Hypersil GOLD 3 μ 20 mm x4 mm; eluent A: 1 liter of water +0.5 ml of 50% formic acid, eluent B: 1 l acetonitrile +0.5 ml 50% formic acid; gradient: 0.0 min 100% a → 3.0 min 10% a → 4.0 min 10% a → 4.01 min 100% a (flow rate 2.5 ml) → 5.0 min 100% a; flow rate: 2 ml/min; furnace: 50 ℃; UV detection: 210 nm.

Method 7 (GC-MS):

the instrument comprises the following steps: micromass GCT, GC 6890; column: restek RTX-35, 15 meters x200 microns x0.33 microns; constant helium flow rate: 0.88 ml/min; furnace: 70 ℃; an inlet: 250 ℃; gradient: 70 ℃, 30 ℃/min → 310 ℃ (held for 3 min).

Method 8 (LC-MS):

MS instrument type: waters ZQ; HPLC instrument type: agilent 1100 series; UV DAD; column: thermo Hypersil GOLD 3 μ 20 mm x4 mm; eluent A: 1 liter of water +0.5 ml of 50% formic acid, eluent B: 1 l acetonitrile +0.5 ml 50% formic acid; gradient: 0.0 min 100% A → 3.0 min 10% A → 4.0 min 10% A → 4.1 min 100% flow rate: 2.5 ml/min, furnace: 55 ℃; flow rate: 2 ml/ml; UV detection: 210 nm.

Method 9 (LC-MS):

the instrument comprises the following steps: waters ACQUITY SQD UPLC System; column: waters acquityurlc HSS T31.8 μ 50 × 1 mm; eluent A: 1 liter of water +0.25 ml of 99% formic acid, eluent B: 1 l acetonitrile +0.25 ml 99% formic acid; gradient: 0.0 min 90% a → 1.2 min 5% a → 2.0 min 5% a furnace: 50 ℃; flow rate: 0.40 ml/min; UV detection: 210- "400 nm".

Starting compounds and intermediates:

example 1A

2- (bromomethyl) -4-fluoro-1-nitrobenzene

574 g (3.70 mol) of 5-fluoro-2-nitrotoluene and 659 g (3.70 mol) of N-bromosuccinimide were introduced into 3.7L of chloroform, 30.0 g (183 mmol) of 2, 2' -azobis-2-methylpropanenitrile was added, and the mixture was heated by irradiation with a UV lamp under reflux conditions for 18 hours. After cooling, suction filtration, the filtrate was concentrated, the residue was taken up in diethyl ether and filtered by suction, and the filtrate was concentrated. The residue was dissolved in dichloromethane and petroleum ether and purified by flash chromatography (mobile phase: petroleum ether/ethyl acetate gradient) to yield 92.0 g (10% of theory) of the title compound.

¹H-NMR(400MHz，CDCl₃)：δ＝4.83(s，2H)，7.14-7.21(m，1H)，7.32(dd，1H)，8.14(dd，1H)。

Example 2A

1-fluoro-2- [ (methylsulfanyl) methyl ] -3-nitrobenzene

16.36 g (69.9 mmol) of 2-fluoro-6-nitrobenzyl bromide are introduced into 410 ml of THF, 5.88 g (83.9 mmol) of sodium methanethiolate are added in portions, and the mixture is stirred at room temperature for 24 hours. The solid was filtered off and the filtrate was freed of solvent in a rotary evaporator. The residue is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 10/1) to yield 11.43 g (81% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.02(d，3H)，3.40(d，2H)，7.56-7.72(m，2H)，7.89(d，1H)。

GC-MS (method 7): r_t5.14 minutes; ms (eipos): m/z is 201[ M ═ M ]⁺。

Example 3A

1- [ (ethylsulfanyl) methyl ] -2-nitrobenzene

10.0 g (46.3 mmol) of 2-nitrobenzyl bromide are introduced into 100 ml of DMF at 0 ℃, 3.89 g (46.3 mmol) of sodium ethanethiol are added in portions, and the mixture is stirred at room temperature for 4 hours. It is diluted with water and extracted with ethyl acetate, the organic phase is dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 9/1) to yield 7.40 g (81% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.12(t，3H)，2.39(q，2H)，4.05(s，2H)，7.50-7.56(m，1H)，7.57-7.61(m，1H)，7.68(dt，1H)，7.99(dd，1H)。

Example 4A

4-fluoro-2- [ (methylsulfanyl) methyl ] -1-nitrobenzene

10.0 g (42.7 mmol) of the compound from example 1A are introduced into 100 ml of tetrahydrofuran at room temperature, 3.29 g (47.0 mmol) of sodium methanethiol are added and the mixture is stirred at room temperature for 4 hours. It is filtered through celite and washed with tetrahydrofuran, and the filtrate is concentrated to give 9.00 g (100% of theory) of the title compound, which is reacted without further purification.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.97(s，3H)，4.02(s，2H)，7.40(ddd，1H)，7.51(dd，1H)，8.15(dd，1H)。

Example 5A

1-Boc-7-methyl-1H-indole

22.8 g (174 mmol) of 7-methyl-1H-indole are introduced under argon at 0 ℃ into 800 ml of anhydrous tetrahydrofuran, a suspension of 7.30 g (183 mmol) of sodium hydride in mineral oil at 60% concentration is added, and the mixture is stirred at room temperature for 15 minutes. 39.8 g (183 mmol) of di-tert-butyl dicarbonate are added and the mixture is stirred at room temperature for 1 hour. Water was then added and concentrated. The residue was taken up in water and extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate gradient) to yield 27.0 g (67% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.53(s，3H)，1.60(s，9H)，6.66(d，1H)，7.09(d，1H)，7.15(t，1H)，7.44(d，1H)，7.63(d，1H)。

Example 6A

7- (bromomethyl) -1-tert-butoxycarbonyl-1H-indole

200 mg (865. mu. mol) of the compound from example 5A were introduced into 10 ml of tetrachloromethane, 169 mg (951. mu. mol) of N-bromosuccinimide were added, and the mixture was heated under reflux conditions while being irradiated with a fluorescent lamp for 4 hours. The concentrated residue is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate gradient) to yield 168 mg (63% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.64(s，9H)，5.28(s，2H)，6.76(d，1H)，7.23(t，1H)，7.40(d，1H)，7.66(d，1H)，7.73(d，1H)。

Example 7A

1-tert-Butoxycarbonyl-7- [ (methylsulfanyl) methyl ] -1H-indole

160 mg (516. mu. mmol) of the compound from example 6A and 36.2 mg (516. mu. mol) of sodium methanethiolate are stirred in 5 ml of dimethylformamide at room temperature for three days. Water was then added and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate gradient) to yield 64 mg (45% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.61(s，9H)，1.68(s，3H)，4.21(s，2H)，6.70(d，1H)，7.15-7.18(m，2H)，7.53-7.58(m，1H)，7.66(d，1H)。

MS(EIpos)：m/z＝277[M]⁺。

Example 8A

7- [ (methylsulfanyl) methyl ] -1H-indole

1.16 g (4.18 mmol) of the compound from example 7A are introduced into 23 ml of methanol, 26 ml (113 mmol) of a 25% strength sodium methoxide methanol solution are added and the mixture is stirred at room temperature overnight. Ice-water was then added and the mixture was extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate gradient) to yield 549 mg (74% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.95(s，3H)，3.96(s，2H)，6.44(dd，1H)，6.91-6.98(m，2H)，7.34(t，1H)，7.44(d，1H)，11.1(s，1H)。

LC-MS (method 4):R_t1.13 minutes; ms (esipos): m/z 178[ M + H ]]⁺。

Example 9A

6-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indole

A solution of 11.42 g (56.7 mmol) of the compound from example 2A in 127 ml of tetrahydrofuran was slowly added dropwise under argon at-78 ℃ to a 0.7N solution of 284 ml (283.7 mmol) of vinyl magnesium bromide in tetrahydrofuran, which was then stirred at-78 ℃ for 2 hours. The reaction mixture was added to ice-cold saturated aqueous ammonium chloride solution, some ethyl acetate was added, the phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, then dried over sodium sulfate, filtered and the solvent was removed in vacuo. Purification of the residue by flash chromatography (mobile phase: cyclohexane/toluene/dichloromethane 10/10/1) afforded 6.31 g (57% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.99(s，3H)，3.99(s，2H)，6.43-6.46(m，1H)，6.85(dd，1H)，7.34-7.37(m，1H)，7.43(dd，1H)，11.26(s，1H)。

HPLC (method 2): r_t2.03 minutes; ms (esipos): 194[ M-H ] M/z]^-。

Example 10A

7- [ (ethylsulfanyl) methyl ] -1H-indole

A solution of 7.40 g (37.5 mmol) of the compound from example 3A in 195 ml of tetrahydrofuran is added dropwise at-78 ℃ under argon to a solution of 134 ml (93.8 mmol) of vinyl magnesium bromide in tetrahydrofuran 0.7N and the mixture is stirred at-78 ℃ for 2 hours. The reaction mixture was then slowly added to ice-cold saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 9/1) to yield 4.98 g (69% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.16(t，3H)，2.40(q，2H)，4.00(s，2H)，6.44(dd，1H)，6.93(t，1H)，6.97(d，1H)，7.33(t，1H)，7.44(d，1H)，11.1(s，1H)。

LC-MS (method 3): r_t2.03 minutes; ms (esipos): 192[ M + H ] M/z]⁺。

Example 11A

5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indole

180 ml (180 mmol) of a 1N solution of vinylmagnesium bromide in tetrahydrofuran are added dropwise under argon at-40 ℃ to a solution of 9.00 g (44.7 mmol) of the compound from example 4A in 100 ml of tetrahydrofuran and the mixture is stirred at-40 ℃ for 3 hours. The reaction mixture was then added to saturated aqueous ammonium chloride solution and extracted with tert-butyl methyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is purified by flash chromatography (mobile phase: petroleum ether/ethyl acetate 9/1) to yield 5.00 g (57% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.96(s，3H)，3.96(s，2H)，6.43(dd，1H)，6.86(dd，1H)，7.20(dd，1H)，7.41(t，1H)，11.2(s，1H)。

LC-MS (method 6): r_t2.18 minutes; ms (esipos): 196[ M + H ] M/z]⁺。

Example 12A

2, 2-dimethyl-5- ({7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } [4- (trifluoromethyl) phenyl ] methyl) -1, 3-dioxane-4, 6-dione

268 mg (1.54 mmol) of 4- (trifluoromethyl) benzaldehyde, 222 mg (1.54 mmol) of Meldrum's acid and 8.4 mg (0.07 mmol) of D, L-proline are added to a solution of 260 mg (1.47 mmol) of the compound from example 8A in 12 ml of acetonitrile. The reaction mixture was stirred at room temperature overnight. It is concentrated and the crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 504 mg (72% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.61(s，3H)，1.85(s，3H)，1.97(s，3H)，3.90-4.01(m，2H)，5.38(d，1H)，5.47(d，1H)，6.87(t，1H)，6.97(d，1H)，7.13(d，1H)，7.19(d，1H)，7.51-7.56(m，2H)，7.59-7.64(m，2H)，11.1(s，1H)。

LC-MS (method 5): r_t2.91 min; ms (esipos): m/z 478[ M + H ═]⁺。

Example 13A

5- [ (4-chlorophenyl) {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } methyl ] -2, 2-dimethyl-1, 3-dioxane-4, 6-dione

350 mg (2.49 mmol) of 4-chlorobenzaldehyde, 359 mg (2.49 mmol) of Meldrum's acid and 13.6 mg (0.12 mmol) of D, L-proline are added to a solution of 420 mg (2.40 mmol) of the compound from example 8A in 20 ml of acetonitrile. The reaction mixture was stirred at room temperature overnight. It is concentrated and the crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 650 mg (62% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.59(s，3H)，1.84(s，3H)，1.96(s，3H)，3.93-3.97(m，2H)，5.29(d，1H)，5.38(d，1H)，6.86(t，1H)，6.96(d，1H)，7.10(d，1H)，7.19(d，1H)，7.27-7.35(m，4H)，11.1(s，1H)。

LC-MS (method 4): r_t1.42 minutes; ms (esineg): 443[ M-H ] M/z]^-。

Example 14A

5- [ (4-chlorophenyl) {7- [ (ethylsulfanyl) methyl ] -1H-indol-3-yl } methyl ] -2, 2-dimethyl-1, 3-dioxane-4, 6-dione

1.00 g (7.14 mmol) of 4-chlorobenzaldehyde, 1.03 g (7.14 mmol) of Meldrum's acid and 39.1 mg (0.34 mmol) of D, L-proline are added to a solution of 1.30 g (6.80 mmol) of the compound from example 10A in 57 ml of acetonitrile. The reaction mixture was stirred at room temperature overnight. It is concentrated and the crude product is stirred in diethyl ether and filtered, and the precipitate is dried under high vacuum to yield 1.38 g (44% of theory) of the title compound.

LC-MS (method 5): r_t2.90 minutes; ms (esipos): 458[ M + H ] M/z]⁺。

Example 15A

5- [ (4-chloro-2-fluorophenyl) {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } methyl ] -2, 2-dimethyl-1, 3-dioxane-4, 6-dione

1.48 g (9.31 mmol) of 4-chloro-2-fluorobenzaldehyde, 1.34 g (9.31 mmol) of Meldrum's acid and 48.7 mg (0.42 mmol) of D, L-proline are added to a solution of 1.50 g (8.46 mmol) of the compound from example 8A in 70 ml of acetonitrile. The reaction mixture was stirred at room temperature overnight. It is concentrated, the residue taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. 3.60 g of the title compound are obtained, which is converted without further purification.

LC-MS (method 3): r_t2.43 minutes; ms (esineg): 460[ M-H ] M/z]^-。

Example 16A

5- [ (4-chloro-2-fluorophenyl) { 5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } methyl ] -2, 2-dimethyl-1, 3-dioxane-4, 6-dione

0.70 g (4.41 mmol) of 4-chloro-2-fluorobenzaldehyde, 0.64 g (4.41 mmol) of Meldrum's acid and 24 mg (0.21 mmol) of D, L-proline are added to a solution of 1.00 g of the compound of example 11A (4.20 mmol) with a purity of 82% in 35 ml of acetonitrile. The reaction mixture was stirred at room temperature overnight. It was concentrated and the residue taken up in ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. 2.20 g of the title compound are obtained in 71% purity (78% of theory), which is converted without further purification.

LC-MS (method 5): r_t2.94 minutes; ms (esipos): m/z 480[ M + H ]]⁺。

Example 17A

5- [ (2, 4-dichlorophenyl) {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } methyl ] -2, 2-dimethyl-1, 3-dioxane-4, 6-dione

1.63 g (9.31 mmol) of 2, 4-dichlorobenzaldehyde, 1.34 g (9.31 mmol) of Meldrum's acid and 48.7 mg (0.42 mmol) of D, L-proline are added to a solution of 1.50 g (8.46 mmol) of the compound from example 8A in 70 ml of acetonitrile. The reaction mixture was stirred at room temperature overnight. It is concentrated, the residue taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. 3.99 g (98% of theory) of the title compound are obtained, which is converted without further purification.

LC-MS (method 3): r_t2.54 minutes; ms (esipos): m/z 478[ M + H ═]⁺。

Example 18A

5- [ (2, 4-dichlorophenyl) { 5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } methyl ] -2, 2-dimethyl-1, 3-dioxane-4, 6-dione

0.81 g (4.60 mmol) of 2, 4-dichlorobenzaldehyde, 0.66 g (4.60 mmol) of Meldrum's acid and 25 mg (0.22 mmol) of D, L-proline are added to a solution of 0.95 g (4.38 mmol) of the compound from example 11A in 36 ml of acetonitrile. The reaction mixture was stirred at room temperature overnight. It was concentrated to give 3.10 g (97% of theory) of the title compound in 68% purity, which was reacted without further purification.

LC-MS (method 6): r_t2.75 minutes; ms (esipos): m/z is 496[ M + H ═ M]⁺。

Example 19A

5- [ (4-chlorophenyl) { 5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl) methyl ] -2, 2-dimethyl-1, 3-dioxane-4, 6-dione

0.62 g (4.41 mmol) of 4-chlorobenzaldehyde, 0.64 g (4.41 mmol) of Meldrum's acid and 24 mg (0.21 mmol) of D, L-proline are added to a solution of 1.00 g (4.20 mmol) of the compound from example 11A in 34 ml of acetonitrile. The reaction mixture was stirred at room temperature overnight. Concentration thereof yielded 2.21 g (73% of theory) of the title compound in 64% purity, which was reacted without further purification.

LC-MS (method 5): r_t2.87 min; ms (esipos): 462[ M + H ] M/z]⁺。

Practice ofExample 20A

2, 2-dimethyl-5- [ {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } (naphthalen-2-yl) methyl ] -1, 3-dioxane-4, 6-dione

694 mg (4.44 mmol) of naphthalene-2-carbaldehyde, 640 mg (4.44 mmol) of Meldrum's acid and 24 mg (0.21 mmol) of D, L-proline are added to a solution of 750 mg (4.23 mmol) of the compound from example 8A in 35 ml of acetonitrile. The reaction mixture was stirred at room temperature overnight. A further 35 ml of acetonitrile was then added and the mixture was stirred at room temperature for two days. It is concentrated, the residue is stirred in water, and the precipitate is filtered off with suction and dried in vacuo at 50 ℃ for 1 hour. The crude product is stirred in acetonitrile and the precipitate is filtered off with suction and dried under high vacuum to yield 882 mg (45% of theory) of the title compound, which is reacted without further purification.

LC-MS (method 5): r_t2.80 minutes; ms (esipos): 460[ M + H ] M/z]⁺。

Example 21A

5- [ (4-chlorophenyl) { 6-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } methyl ] -2, 2-dimethyl-1, 3-dioxane-4, 6-dione

1.44 g (10.24 mmol) of 4-chlorobenzaldehyde, 1.48 g (10.24 mmol) of Meldrum's acid and 0.06 g (0.51 mmol) of D, L-proline are added to a solution of 2.00 g (10.24 mmol) of the compound from example 9A in 15 ml of acetonitrile. The reaction mixture was stirred at room temperature overnight. The precipitated solid is filtered off with suction, washed with acetonitrile and dried under high vacuum. 3.32 g (67% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.59(s，3H)，1.84(s，3H)，2.01(s，3H)，3.98(s，2H)，5.28-5.38(m，2H)，6.78(dd，1H)，7.07(dd，1H)，7.19-7.34(m，5H)，11.24(s，1H)。

HPLC (method 1): r_t4.91 min; ms (esineg): 460[ M-H ] M/z]^-。

Example 22A

2, 2-dimethyl-5- ({ 6-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } [4- (trifluoromethyl) phenyl ] methyl) -1, 3-dioxane-4, 6-dione

The title compound was prepared starting from 2.00 g (10.24 mmol) of the compound from example 9A and 1.78 g (10.24 mmol) of 4- (trifluoromethyl) benzaldehyde in analogy to the synthesis of the compound from example 21A. 3.83 g (75% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.61(s，3H)，1.85(s，3H)，2.01(s，3H)，3.98(s，2H)，5.37-5.47(m，2H)，6.79(dd，1H)，7.12(dd，1H)，7.21(d，1H)，7.53(d，2H)，7.62(d，2H)，11.28(s，1H)。

HPLC (method 1): r_t4.96 minutes; ms (esineg): m/z 494[ M-H ═]^-。

Example 23A

5- [ (1-benzothien-5-yl) {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } methyl ] -2, 2-dimethyl-1, 3-dioxane-4, 6-dione

1.02 g (5.66 mmol) of 1-benzothiophene-5-carbaldehyde, 0.82 g (5.66 mmol) of Meldrum's acid and 0.03 g (0.28 mmol) of D, L-proline are added to a solution of 1.00 g (5.66 mmol) of the compound from example 8A in 8 ml of acetonitrile. The reaction mixture was stirred at RT overnight and then the solvent was removed in vacuo. Purification of the residue by preparative HPLC (mobile phase: acetonitrile/water gradient) gives 1.73 g (71% purity, 47% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.55(s，3H)，1.83(s，3H)，1.97(s，3H)，3.96(dd，2H)，5.31(d，1H)，5.53-5.56(m，1H)，6.82(dd，1H)，6.94(dd，1H)，7.09(d，1H)，7.27(s，1H)，7.37(d，2H)，7.69(d，1H)，7.77(s，1H)，7.85(d，1H)，11.08(s，1H)。

HPLC (method 1): r_t4.84 minutes; ms (esineg): m/z 464[ M-H ]]^-。

Example 24A

5- [ (2-bromo-1, 3-thiazol-5-yl) {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } methyl ] -2, 2-dimethyl-1, 3-dioxane-4, 6-dione

1.02 g (7.08 mmol) of Meldrum's acid, 0.04 g (0.34 mmol) of D, L-proline and 1.36 g (7.08 mmol) of 2-bromo-5-formylthiazole are successively added to a solution of 1.30 g (6.75 mmol) of the compound from example 8A in 50 ml of acetonitrile. The reaction mixture was stirred at RT overnight and then the solvent was removed in vacuo. Purification of the residue by flash chromatography on silica gel (mobile phase: dichloromethane/methanol 95/5) gives 3.58 g (81% purity, 87% of theory) of the title compound.

LC-MS (method 5): r_t3.01 minutes; ms (esipos): 495[ M + H ] M/z]⁺。

Example 25A

3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } -3- [4- (trifluoromethyl) phenyl ] propionic acid ethyl ester

0.7 mg (0.01 mmol) of copper powder was added to 504 mg (1.06 mmol) of the compound from example 12A in 8 ml of pyridine and 2 ml of ethanol. The reaction mixture was heated under reflux conditions for 1 hour. It is concentrated and the crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 241 mg (54% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.04(t，3H)，1.93(s，3H)，3.13(dd，1H)，3.21(dd，1H)，3.90(s，2H)，3.96(q，2H)，4.73(t，1H)，6.85(t，1H)，6.92(d，1H)，7.29(d，1H)，7.39(d，1H)，7.57-7.63(m，4H)，11.0(s，1H)。

LC-MS (method 5): r_t2.93 minutes; ms (esipos): 422[ M + H ] M/z]⁺。

Example 26A

3- { 3-ethoxy-3-oxo-1- [4- (trifluoromethyl) phenyl ] propyl } -7- [ (methylsulfanyl) methyl ] -1H-indole-1-carboxylic acid tert-butyl ester

3.20 g (7.59 mmol) of the compound from example 25A, 1.99 g (9.11 mmol) of di-tert-butyl dicarbonate and 0.09 g (0.76 mmol) of 4-N, N-dimethylaminopyridine are dissolved in 30 ml of tetrahydrofuran and stirred at 50 ℃ for 2 hours. The reaction solution was mixed with water, the phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with saturated aqueous sodium bicarbonate and dried over sodium sulfate, the solid was filtered off and the solvent was removed in vacuo. 3.91 g (96% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.06(t，3H)，1.63(s，9H)，1.67(s，3H)，3.14-3.31(m，2H)，3.92-4.06(m，2H)，4.17(dd，2H)，4.73(t，1H)，7.05-7.16(m，2H)，7.39(d，1H)，7.61-7.68(m，4H)，7.75(s，1H)。

LC-MS (method 5): r_t3.23 minutes; ms (esipos): 522[ M + H ] M/z]⁺。

Example 27A

3- { 3-ethoxy-2-methyl-3-oxo-1- [4- (trifluoromethyl) phenyl ] propyl } -7- [ (methylsulfanyl) methyl ] -1H-indole-1-carboxylic acid tert-butyl ester

1.60 g (3.07 mmol) of the compound from example 26A are dissolved in tetrahydrofuran at-78 ℃ and 3.2 ml (6.44 mmol) of a 2N solution of lithium diisopropylamide in tetrahydrofuran/N-heptane are slowly added dropwise. After 5 minutes, 0.40 ml (6.44 mmol) of methyl iodide is added and the mixture is stirred at-78 ℃ for 2 hours and then warmed to room temperature over the course of a further 2 hours. The reaction solution was mixed with water, the phases were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, the solid was filtered off and the solvent was removed in vacuo. The crude product is purified by preparative HPLC (mobile phase: acetonitrile-water gradient) to yield 1.20 g (73% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.82-1.08(m，4H)，1.10-1.22(m，2H)，1.60-1.70(m，12H)，3.40-4.04(m，3H)，4.12-4.20(m，2H)，7.05-7.17(m，2H)，7.48-7.79(m，6H)。

LC-MS (method 5): r_t＝3.26min。

Example 28A

2-methyl-3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } -3- [4- (trifluoromethyl) phenyl ] propionic acid ethyl ester

2.52 g (4.71 mmol) of the compound from example 27A are dissolved in 70 ml of dichloromethane and 14.5 ml (188.56 mmol) of trifluoroacetic acid are added. After stirring at room temperature for 3 hours, the reaction solution was mixed with water, the phases were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium bicarbonate and dried over sodium sulfate, the solid was filtered off and the solvent was removed in vacuo. Purification of the crude product by flash chromatography on silica gel (mobile phase: dichloromethane/methanol 95/5) and preparative HPLC (mobile phase: acetonitrile-water gradient) gives 1.01 g (48% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.82-1.20(m，6H)，1.90-1.95(m，3H)，3.39-3.58(m，1H)，3.77-3.95(m，4H)，4.35-4.47(m，1H)，6.82-6.95(m，2H)，7.37-7.70(m，6H)，10.95-11.10(m，1H)。

LC-MS (method 6): r_t2.74 minutes; ms (esipos): m/z 436[ M + H ]]⁺。

Example 29A

3- (4-chlorophenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propanoic acid ethyl ester

18 mg (0.28 mmol) of copper powder are added to 12.2 g (27.5 mmol) of the compound from example 13A in 200 ml of pyridine and 55 ml of ethanol. The reaction mixture was heated under reflux conditions for 4 hours. It is concentrated and the residue is taken up in dichloromethane, washed with water, 1N hydrochloric acid and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient). 6.68 g (56% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.05(t，3H)，1.93(s，3H)，3.05(dd，1H)，3.16(dd，1H)，3.90(s，2H)，3.92-3.99(m，2H)，4.63(t，1H)，6.84(t，1H)，6.92(d，1H)，7.24-7.31(m，3H)，7.33-7.40(m，3H)，11.0(s，1H)。

LC-MS (method 4): r_t1.50 minutes; ms (esipos): m/z 388[ M + H ]]⁺。

Example 30A

3- [1- (4-chlorophenyl) -3-ethoxy-3-oxopropyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole-1-carboxylic acid tert-butyl ester

3.13 g (8.07 mmol) of the compound from example 29A, 2.11 g (9.68 mmol) of di-tert-butyl dicarbonate and 0.10 g (0.81 mmol) of 4-N, N-dimethylaminopyridine are dissolved in 30 ml of tetrahydrofuran and stirred at 50 ℃ for 2 hours. The reaction solution was mixed with water, the phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and dried over sodium sulfate, the solid was filtered off and the solvent was removed in vacuo. The crude product is purified by preparative HPLC (mobile phase: acetonitrile-water gradient) to yield 4.10 g (91% purity, 95% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.07(t，3H)，1.62(s，9H)，1.67(s，3H)，3.10(dd，1H)，3.20(dd，1H)，3.92-4.06(m，2H)，4.17(dd，2H)，4.62(t，1H)，7.05-7.15(m，2H)，7.29-7.46(m，5H)，7.70(s，1H)。

LC-MS (method 5): r_t3.23 minutes; ms (esipos): m/z 488[ M + H ]]⁺。

Example 31A

3- [1- (4-chlorophenyl) -3-ethoxy-2-methyl-3-oxopropyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole-1-carboxylic acid tert-butyl ester

The title compound was prepared starting from 1.62 g (91% purity, 3.01 mmol) of the compound from example 30A in analogy to the synthesis of the compound from example 27A. 0.89 g (59% of theory) of the title compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.89-1.19(m，6H)，1.59-1.69(m，12H)，3.33-3.62(m，1H)，3.81-4.37(m，5H)，7.06-7.16(m，2H)，7.27-7.35(m，2H)，7.43-7.60(m，2H)，7.71-7.90(m，1H)。

LC-MS (method 5): r_t＝3.31min。

Example 32A

3- (4-chlorophenyl) -2-methyl-3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propionic acid ethyl ester

0.85 g (1.69 mmol) of the compound from example 31A are dissolved in 10 ml of dichloromethane and 2.61 ml (33.86 mmol) of trifluoroacetic acid are added. After stirring at room temperature for 2 hours, the reaction solution was concentrated and the residue was purified twice by preparative HPLC (after mobile phase: acetonitrile-water gradient). 0.42 g (61% of theory) of the title compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.87-1.18(m，6H)，1.90-1.95(m，3H)，3.31-3.51(m，1H)，3.80-3.95(m，4H)，4.25-4.36(m，1H)，6.82-6.95(m，2H)，7.27-7.52(m，6H)，10.90-11.05(m，1H)。

LC-MS (method 6): r_t2.77/2.82 min; ms (esineg): m/z 400[ M-H ]]^-。

Example 33A

3- (4-chlorophenyl) -3- {7- [ (ethylsulfanyl) methyl ] -1H-indol-3-yl } propanoic acid ethyl ester

2 mg (0.03 mmol) of copper powder are added to 1.38 g (3.00 mmol) of the compound from example 14A in 15 ml of pyridine and 5 ml of ethanol. The reaction mixture was heated under reflux conditions for 1 hour. It is concentrated and the residue is taken up in ethyl acetate, washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered through silica gel and concentrated. 1.13 g of the target compound are obtained with a purity of 84% (78% of theory).

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.05(t，3H)，1.15(t，3H)，2.38(q，2H)，3.05(dd，1H)，3.16(dd，1H)，3.90-4.00(m，4H)，4.62(t，1H)，6.84(t，1H)，6.93(d，1H)，7.24-7.31(m，3H)，7.33-7.40(m，3H)，11.0(s，1H)。

LC-MS (method 3): r_t2.63 minutes; ms (esipos): m/z is 402[ M + H [ ]]⁺。

Example 34A

3- (4-chloro-2-fluorophenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propanoic acid ethyl ester

5.0 mg (0.08 mmol) of copper powder are added to 3.60 g (7.79 mmol) of the compound from example 15A in 56 ml of pyridine and 14 ml of ethanol. The reaction mixture was heated under reflux conditions for 1 hour. It is concentrated and the residue is taken up in ethyl acetate, washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered through silica gel and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 2.23 g (70% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.05(t，3H)，1.93(s，3H)，3.09-3.24(m，2H)，3.90(s，2H)，3.92-4.01(m，2H)，4.89(t，1H)，6.88(t，1H)，6.94(d，1H)，7.17(dd，1H)，7.26(d，1H)，7.32-7.38(m，2H)，7.41(t，1H)，11.0(s，1H)。

LC-MS (method 4): r_t1.52 min; ms (esipos): 406[ M + H ] M/z ]⁺。

Enantiomers were purified by preparative HPLC on a chiral phase [ column with chiral selector poly (N-methacryloyl-L-leucine dicyclopropylmethylamide), 10 μm, 250 mm x30 mm; eluent: isohexane/ethyl acetate 82: 18; flow rate: 45 ml/min; temperature: RT; UV detection: 260 nm ] separation. The separated enantiomer was again purified by preparative HPLC on the achiral phase (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid):

enantiomer 34A-1:

R_t4.37 min [ column with chiral selector poly (N-methacryloyl-L-leucine dicyclopropylmethylamide), 5 μm, 250 mm x4 mm; eluent: isohexane/ethyl acetate 4: 1; flow rate: 1.5 ml/min; temperature: RT; UV detection: 260 nm]；

Enantiomer 34A-2:

R_t5.62 min [ column with chiral selector poly (N-methacryloyl-L-leucine dicyclopropylmethylamide), 5 μm, 250 mm x4 mm; eluent: isohexane/ethyl acetate 4: 1; flow rate: 1.5 ml/min; temperature: RT; UV detection: 260 nm]。

Example 35A

3- [1- (4-chloro-2-fluorophenyl) -3-ethoxy-3-oxopropyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole-1-carboxylic acid tert-butyl ester

5.00 g (12.3 mmol) of the compound from example 34A are introduced under argon at 0 ℃ into 50 ml of anhydrous tetrahydrofuran, 0.52 g (12.9 mmol) of a 60% suspension of sodium hydride in mineral oil is added and the mixture is stirred at room temperature for 15 minutes. 2.82 g (12.9 mmol) of di-tert-butyl dicarbonate are added and the mixture is stirred at room temperature overnight. Water was then added, the mixture was extracted with dichloromethane, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography (mobile phase: toluene/ethyl acetate gradient) to yield 6.1 g (98% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.07(t，3H)，1.62(s，9H)，1.67(s，3H)，3.15-3.28(m，2H)，3.92-4.06(m，2H)，4.17(q，2H)，4.85(t，1H)，7.10-7.22(m，3H)，7.33(dd，1H)，7.40(dd，1H)，7.46(t，1H)，7.69(s，1H)。

LC-MS (method 5): r_t3.26 minutes; ms (esipos): m/z 506[ M + H ═]⁺。

Example 36A

3- [1- (4-chloro-2-fluorophenyl) -3-ethoxy-2-methyl-3-oxopropyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole-1-carboxylic acid tert-butyl ester

3.55 ml (7.10 mmol) of a 2N solution of lithium diisopropylamide in tetrahydrofuran are introduced at-78 ℃ into 40 ml of anhydrous tetrahydrofuran, a solution of 3.00 g (5.93 mmol) of the compound from example 35A in 20 ml of tetrahydrofuran is added and the mixture is stirred for 1 hour. 1.01 g (7.11 mmol) of methyl iodide was added at-78 ℃ and the reaction mixture was warmed to room temperature. It is then diluted with dichloromethane, the phases are separated, and the organic phase is washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 2.45 g (80% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.93(t，1.5H)，0.97-1.04(m，3H)，1.18(d，1.5H)，1.63(s，9H)，1.67(s，1.5H)，1.67(s，1.5H)，3.41-3.51(m，0.5H)，3.63-3.73(m，0.5H)，3.88(q，1H)，3.92-4.06(m，1H)，4.11-4.21(m，2H)，4.56(d，0.5H)，4.60(d，0.5H)，7.10-7.24(m，3H)，7.30-7.36(m，1H)，7.42-7.47(m，0.5H)，7.50-7.57(m，1H)，7.63(t，0.5H)，7.73(s，0.5H)，7.87(s，0.5H)。

LC-MS (method 4): r_t1.80 and 1.82 minutes; ms (esipos): 520[ M + H ] M/z]⁺。

Example 37A

3- (4-chloro-2-fluorophenyl) -3- { 5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propanoic acid ethyl ester

1.9 mg (0.03 mmol) of copper powder were added to 2.20 g of the 71% pure compound from example 16A (3.26 mmol) in 25 ml of pyridine and 6.7 ml of ethanol. The reaction mixture was heated under reflux conditions for 1 hour. It is concentrated and the residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient) to yield 1.22 g (88% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.05(t，3H)，1.94(s，3H)，3.10-3.24(m，2H)，3.90(s，2H)，3.93-4.00(m，2H)，4.83(t，1H)，6.84(dd，1H)，6.99(dd，1H)，7.19(dd，1H)，7.36(dd，1H)，7.40-7.48(m，2H)，11.1(s，1H)。

LC-MS (method 5): r_t2.92 minutes; ms (esipos): 424[ M + H ] M/z]⁺。

Example 38A

3- (2, 4-dichlorophenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propionic acid ethyl ester

5.3 mg (0.08 mmol) of copper powder are added to 3.99 g (8.34 mmol) of the compound from example 17A in 59 ml of pyridine and 15 ml of ethanol. The reaction mixture was heated under reflux conditions for 1 hour. It is concentrated and the residue is taken up in ethyl acetate, washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered through silica gel and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 2.34 g (67% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.06(t，3H)，1.94(s，3H)，3.06(dd，1H)，3.17(dd，1H)，3.91(s，2H)，3.97(q，2H)，5.09(t，1H)，6.87(t，1H)，6.94(d，1H)，7.25(d，1H)，7.29-7.34(m，2H)，7.40(d，1H)，7.58(d，1H)，11.0(s，1H)。

LC-MS (method 4): r_t1.59 minutes; ms (esipos): 422[ M + H ] M/z]⁺。

Example 39A

3- (2, 4-dichlorophenyl) -3- { 5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propionic acid ethyl ester

2.8 mg (0.05 mmol) of copper powder are added to 3.10 g of the 68% pure compound from example 18A (4.23 mmol) in 34 ml of pyridine and 8 ml of ethanol. The reaction mixture was heated under reflux conditions for 1 hour. It is concentrated and the crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to yield 1.52 g (82% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.05(t，3H)，1.95(s，3H)，3.08(dd，1H)，3.18(dd，1H)，3.91(s，2H)，3.97(q，2H)，5.02(t，1H)，6.85(dd，1H)，6.97(dd，1H)，7.33(dd，1H)，7.41(d，1H)，7.44(d，1H)，7.58(d，1H)，11.2(s，1H)。

LC-MS (method 4): r_t1.59 minutes; ms (esipos): 440[ M + H ] M/z]⁺。

Example 40A

3- (4-chlorophenyl) -3- { 5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propionic acid ethyl ester

2.0 mg (0.03 mmol) of copper powder are added to 2.21 g (3.08 mmol) of the 64% pure compound from example 19A in 23 ml of pyridine and 6 ml of ethanol. The reaction mixture was heated under reflux conditions for 1 hour. It is concentrated and the crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to yield 1.29 g (82% of theory) of the title compound having a purity of 79%.

LC-MS (method 3): r_t2.54 minutes; ms (esipos): 406[ M + H ] M/z]⁺。

Example 41A

3- (4-chloro-2-methylphenyl) -3- {7- [ (ethylsulfanyl) methyl ] -1H-indol-3-yl } propionic acid ethyl ester

849 mg (5.49 mmol) of 4-chloro-2-methylbenzaldehyde, 791 mg (5.49 mmol) of Meldrum's acid and 30.1 mg (0.26 mmol) of D, L-proline are added to a solution of 1.00 g (5.23 mmol) of the compound from example 10A in 44 ml of acetonitrile. The reaction mixture was stirred at room temperature overnight. It was concentrated, the residue taken up in ether and the precipitate separated off and discarded. Concentration yielded 2.70 g of the crude product, of which 2.40 g were introduced 9.5 ml of pyridine and 2.5 ml of ethanol, and 0.9 mg (14. mu. mol) of copper powder was added. The reaction mixture was heated under reflux conditions for 1 hour. It is concentrated and the residue is taken up in ethyl acetate, washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered through silica gel and concentrated. 950 mg of the crude product were obtained and introduced into 14.2 ml of pyridine and 3.7 ml of ethanol, and 1.3 mg (21. mu. mol) of copper powder was added. The reaction mixture was heated under reflux conditions for 1 hour. It is concentrated and the residue is taken up in ethyl acetate, washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered through silica gel and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to yield 620 mg of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.04(t，3H)，1.15(t，3H)，2.38(q，2H)，2.44(s，3H)，2.99(dd，1H)，3.11(dd，1H)，3.91-3.99(m，4H)，4.81(t，1H)，6.84(t，1H)，6.93(d，1H)，7.11-7.18(m，2H)，7.19-7.25(m，3H)，11.0(s，1H)。

LC-MS (method 3): r_t2.73 minutes; ms (esipos): 416[ M + H ] M/z]⁺。

Example 42A

3- (4-chloro-2-methylphenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propanoic acid ethyl ester

1.44 g (9.31 mmol) of 4-chloro-2-methylbenzaldehyde, 1.34 g (9.31 mmol) of Meldrum's acid and 48.7 mg (0.42 mmol) of D, L-proline are added to a solution of 1.50 g (8.46 mmol) of the compound from example 8A in 70 ml of acetonitrile. The reaction mixture was stirred at room temperature overnight. It is concentrated, the residue taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. 3.43 g of the crude product were obtained and introduced into 53 ml of pyridine and 14 ml of ethanol and 4.8 mg (75. mu. mol) of copper powder were added. The reaction mixture was heated under reflux conditions for 1 hour. It is concentrated and the residue is taken up in ethyl acetate, washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered through silica gel and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 1.68 g (49% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.04(t，3H)，1.94(s，3H)，2.44(s，3H)，2.99(dd，1H)，3.11(dd，1H)，3.87-4.00(m，4H)，4.81(t，1H)，6.85(t，1H)，6.93(d，1H)，7.11-7.18(m，2H)，7.19-7.26(m，3H)，11.0(s，1H)。

LC-MS (method 3): r_t2.63 minutes; ms (esipos): m/z is 402[ M + H [ ]]⁺。

Example 43A

3- (4-fluoro-2-methylphenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propanoic acid ethyl ester

614 mg (4.44 mmol) of 4-fluoro-2-methylbenzaldehyde, 640 mg (4.44 mmol) of Meldrum's acid and 24.4 mg (0.21 mmol) of D, L-proline are added to a solution of 750 mg (4.23 mmol) of the compound from example 8A in 35 ml of acetonitrile. The reaction mixture was stirred at room temperature overnight. A further 35 ml of acetonitrile was added and the mixture was stirred at room temperature for two days. It was concentrated and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid). 860 mg of product were obtained and introduced into 15 ml of pyridine and 5.2 ml of ethanol and 1.2 mg (19. mu. mol) of copper powder was added. The reaction mixture was heated under reflux conditions for 2 hours. It is concentrated and the crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 607 mg (37% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.04(t，3H)，1.94(s，3H)，2.45(s，3H)，2.98(dd，1H)，3.10(dd，1H)，3.91(s，2H)，3.96(q，2H)，4.81(t，1H)，6.85(t，1H)，6.88(dd，1H)，6.92(d，1H)，7.00(dd，1H)，7.16(d，1H)，7.19(d，1H)，7.24(dd，1H)，11.0(s，1H)。

LC-MS (method 5): r_t2.80 minutes; ms (esipos): 386[ M + H ] M/z ]⁺。

Example 44A

3- [ 2-fluoro-4- (trifluoromethyl) phenyl ] -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propionic acid ethyl ester

1.54 g (8.00 mmol) of 2-fluoro-4- (trifluoromethyl) benzaldehyde, 1.15 g (8.00 mmol) of Meldrum's acid and 44 mg (0.38 mmol) of D, L-proline are added to a solution of 1.50 g (7.62 mmol) of the compound from example 8A in 62 ml of acetonitrile. The reaction mixture was stirred at room temperature overnight. Concentration thereof yielded 4.47 g of crude product, which was introduced with 48 ml of pyridine and 12 ml of ethanol, and 4 mg (63. mu. mol) of copper powder was added. The reaction mixture was heated under reflux conditions for 1 hour. It is concentrated and the crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 2.74 g (82% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.04(t，3H)，1.93(s，3H)，3.21-3.25(m，2H)，3.91(s，2H)，3.97(q，2H)，4.99(t，1H)，6.88(t，1H)，6.94(d，1H)，7.29(d，1H)，7.39(d，1H)，7.48(d，1H)，7.58-7.68(m，2H)，11.1(s，1H)。

LC-MS (method 5): r_t2.89 minutes; ms (esipos): 440[ M + H ] M/z]⁺。

Example 45A

3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } -3- (naphthalen-2-yl) propionic acid ethyl ester

1.2 mg (0.02 mmol) of copper powder are added to 882 mg (1.92 mmol) of the compound from example 20A in 15 ml of pyridine and 5 ml of ethanol. The reaction mixture was heated under reflux conditions for 2 hours. It is concentrated and the crude product is purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) and preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to yield 635 mg (82% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.02(t，3H)，1.92(s，3H)，3.17(dd，1H)，3.26(dd，1H)，3.88-3.99(m，2H)，3.90(s，2H)，4.80(t，1H)，6.80(t，1H)，6.90(d，1H)，7.31(d，1H)，7.38-7.51(m，4H)，7.75-7.87(m，3H)，7.90(s，1H)，11.0(s，1H)。

LC-MS (method 4): r_t1.52 min; ms (esipos): 404[ M + H ] M/z]⁺。

Example 46A

4- (4-chlorophenyl) -4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butanoic acid ethyl ester

1.75 ml of concentrated sulfuric acid are added to 1.00 g (2.82 mmol) of the compound from example 36 in 25 ml of ethanol. The reaction mixture was heated under reflux conditions for 24 hours. After cooling, the reaction mixture was added to saturated aqueous sodium bicarbonate, extracted with dichloromethane, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient, addition of 0.1% formic acid). 0.45 g (39% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.15(t，3H)，1.94(s，3H)，2.17-2.44(m，4H)，3.91(s，2H)，4.01(q，2H)，4.13-4.19(m，1H)，6.84(t，1H)，6.92(d，1H)，7.25(d，1H)，7.29-7.36(m，5H)，11.0(s，1H)。

LC-MS (method 5): r_t2.93 minutes; ms (esipos): m/z is 402[ M + H [ ]]⁺。

Example 47A

3- (4-chlorophenyl) -3- { 6-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propionic acid ethyl ester

23 mg (0.36 mmol) of copper powder are added to 3.31 g (7.16 mmol) of the compound from example 21A in 13 ml of pyridine and 3 ml of ethanol. The reaction mixture was heated at reflux for 4 hours, then the pyridine was removed in vacuo. The residue was taken up in ethyl acetate, silica gel was added and the mixture was concentrated. The crude product-silica gel mixture was previously purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 5/1 → 3/1) and the product was purified again by preparative HPLC (acetonitrile/water gradient). 2.38 g (82% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.05(t，3H)，1.98(s，3H)，3.04(dd，1H)，3.15(dd，1H)，3.92-4.00(m，4H)，4.62(t，1H)，6.76(dd，1H)，7.24(dd，1H)，7.27-7.31(m，2H)，7.35-7.40(m，3H)，11.13(s，1H)。

HPLC (method 2): r_t5.06 minutes; ms (esineg): 404[ M-H ] M/z]^-。

Example 48A

3- { 6-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } -3- [4- (trifluoromethyl) phenyl ] propionic acid ethyl ester

The title compound was prepared starting from 3.82 g (7.71 mmol) of the compound from example 22A in analogy to the synthesis of the compound from example 47A. 3.05 g (90% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.03(t，3H)，1.98(s，3H)，3.08-3.24(m，2H)，3.91-4.00(m，4H)，4.72(t，1H)，6.77(dd，1H)，7.28(dd，1H)，7.42(s，1H)，7.57-7.63(m，4H)，11.17(s，1H)。

HPLC (method 2): r_t5.11 minutes; ms (esineg): 438[ M-H ] M/z]^-。

Example 49A

3- (1-Benzothien-5-yl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propionic acid ethyl ester

The title compound was prepared starting from 1.73 g (71% purity, 3.72 mmol) of the compound from example 23A in analogy to the synthesis of the compound from example 47A. 1.23 g (81% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.03(t，3H)，1.92(s，3H)，3.11(dd，1H)，3.22(dd，1H)，3.90(s，2H)，3.91-4.00(m，2H)，4.75(t，1H)，6.81(t，1H)，6.90(d，1H)，7.27(d，1H)，7.34-7.39(m，3H)，7.69(d，1H)，7.82-7.86(m，2H)，10.96(s，1H)。

HPLC (method 2): r_t5.02 minutes; ms (esipos): 410[ M + H ] M/z]⁺。

Example 50A

3- (2-bromo-1, 3-thiazol-5-yl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propanoic acid ethyl ester

19 mg (0.29 mmol) of copper powder are added to 3.57 g (81% pure, 5.87 mmol) of the compound from example 24A in 15 ml of pyridine and 8 ml of ethanol. The reaction mixture was heated at reflux for 5 hours, and then the copper was filtered off through celite. The filtrate was concentrated, the residue was stirred with diethyl ether/dichloromethane and the precipitated solid was filtered off. The filtrate was concentrated and purified by preparative HPLC (acetonitrile/water gradient). 1.24 g (46% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.08(t，3H)，1.95(s，3H)，3.20(d，2H)，3.92(s，2H)，4.01(q，2H)，4.97(t，1H)，6.89-6.99(m，2H)，7.35-7.40(m，2H)，7.61(s，1H)，11.09(s，1H)。

LC-MS (method 3): r_t2.28 min; ms (esipos): 439[ M + H ] M/z]⁺。

Example 51A

3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } -3- [4- (trifluoromethyl) phenyl ] propyl methanesulfonate

0.06 ml (0.45 mmol) of triethylamine and 3.3 mg (0.03 mmol) of 4-N, N-dimethylaminopyridine are added to 101 mg (0.27 mmol) of the compound from example 1 in 5.5 ml of dichloromethane. The mixture was stirred at room temperature for 15 minutes, then 0.03 ml (0.40 mmol) of methanesulfonyl chloride was added. The reaction mixture was stirred at room temperature for 2 hours, then diluted with dichloromethane, washed with 1N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient, addition of 0.1% formic acid) gives 101 mg (83% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.94(s，3H)，2.40-2.50(m，1H)，2.55-2.69(m，1H)，3.11(s，3H)，3.92(s，2H)，4.10-4.22(m，2H)，4.44(t，1H)，6.86(t，1H)，6.93(d，1H)，7.31(d，1H)，7.45(d，1H)，7.58-7.66(m，4H)，11.1(s，1H)。

LC-MS (method 3): r_t2.35 min; ms (esipos): 458[ M + H ] M/z]⁺。

Example 52A

3- (4-chlorophenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propyl methanesulfonate

4.06 ml (29.1 mmol) of triethylamine and 209 mg (1.71 mmol) of 4-N, N-dimethylaminopyridine are added to 5.93 g (17.1 mmol) of the compound from example 2 in 345 ml of dichloromethane. The mixture was stirred at room temperature for 15 minutes, then 2.0 ml (25.7 mmol) of methanesulfonyl chloride was added. The reaction mixture was stirred at room temperature for 2 hours, then diluted with dichloromethane, washed with 1N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 6.90 g (95% of theory) of the title compound are obtained and reacted further without purification.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.94(s，3H)，2.35-2.44(m，1H)，2.50-2.62(m，1H)，3.11(s，3H)，3.91(s，2H)，4.08-4.19(m，2H)，4.33(t，1H)，6.85(t，1H)，6.93(d，1H)，7.29(d，1H)，7.30-7.34(m，2H)，7.36-7.41(m，3H)，11.0(s，1H)。

LC-MS (method 5): r_t2.70 minutes; ms (esipos): 424[ M + H ] M/z]⁺。

Example 53A

3- (4-chlorophenyl) -3- {7- [ (ethylsulfanyl) methyl ] -1H-indol-3-yl } propyl methanesulfonate

0.27 ml (1.96 mmol) of triethylamine and 14.1 mg (0.12 mmol) of 4-N, N-dimethylaminopyridine are added to 415 mg (1.15 mmol) of the compound from example 3 in 23 ml of dichloromethane. The mixture was stirred at room temperature for 15 minutes, then 0.13 ml (1.73 mmol) of methanesulfonyl chloride was added. The reaction mixture was stirred at room temperature for 4 hours, then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient, addition of 0.1% formic acid) gives 520 mg (100% of theory) of the title compound.

LC-MS (method 3): r_t2.43 minutes; ms (esipos): 438[ M + H ] M/z]⁺。

Example 54A

3- (4-chloro-2-fluorophenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propyl methanesulfonate

1.1 ml (7.77 mmol) of triethylamine and 55.8 mg (0.46 mmol) of 4-N, N-dimethylaminopyridine are added to 1.66 g (4.57 mmol) of the compound from example 4 in 93 ml of dichloromethane. The mixture was stirred at room temperature for 15 minutes, then 0.5 ml (6.85 mmol) of methanesulfonyl chloride was added. The reaction mixture was stirred at room temperature for 4 hours, then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 1.94 g (96% of theory) of the title compound.

LC-MS (method 3): r_t2.35 min; ms (esipos): 442[ M + H ] M/z]⁺。

Enantiomer 54A-1:

1.48 g (4.07 mmol) of enantiomer 4-1 were reacted in analogy to the synthesis of the compound from example 54A. 1.88 g (100% of theory) of the corresponding enantiomer of the title compound were obtained as crude product, which was reacted without purification.

Example 55A

3- (4-chloro-2-fluorophenyl) -2-methyl-3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propyl methanesulfonate

0.04 ml (0.27 mmol) of triethylamine and 1.9 mg (0.02 mmol) of 4-N, N-dimethylaminopyridine are added to 60 mg (0.16 mmol) of the compound from example 5 in 4 ml of dichloromethane. The mixture was stirred at room temperature for 15 minutes, then 0.02 ml (0.24 mmol) of methanesulfonyl chloride was added. The reaction mixture was stirred at RT overnight, then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate, filtered and concentrated. 70 mg (97% of theory) of the title compound are obtained as a mixture of diastereomers, which is reacted without further purification.

LC-MS (method 5): r_t2.73 and 2.81 minutes; ms (esipos): 456[ M + H ] M/z ]⁺。

Example 56A

3- (4-chloro-2-fluorophenyl) -3- { 5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propyl methanesulfonate

0.35 ml (2.54 mmol) of triethylamine and 18.2 mg (0.15 mmol) of 4-N, N-dimethylaminopyridine are added to 570 mg (1.49 mmol) of the compound from example 6 in 40 ml of dichloromethane. The mixture was stirred at room temperature for 15 minutes, then 0.17 ml (2.24 mmol) of methanesulfonyl chloride was added. The reaction mixture was stirred at RT overnight, then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate, filtered and concentrated. 670 mg (98% of theory) of the title compound are obtained.

LC-MS (method 3): r_t2.37 minutes; ms (esipos): 460[ M + H ] M/z]⁺。

Example 57A

3- (2, 4-dichlorophenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propyl methanesulfonate

1.1 ml (7.93 mmol) of triethylamine and 57.0 mg (0.47 mmol) of 4-N, N-dimethylaminopyridine are added to 1.77 g (4.66 mmol) of the compound from example 7 in 95 ml of dichloromethane. The mixture was stirred at room temperature for 15 minutes, then 0.5 ml (7.00 mmol) of methanesulfonyl chloride was added. The reaction mixture was stirred at room temperature for 4 hours, then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 1.98 g (93% of theory) of the title compound.

LC-MS (method 3): r_t2.45 minutes; ms (esipos): 458[ M + H ] M/z]⁺。

Example 58A

3- (2, 4-dichlorophenyl) -3- { 5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propyl methanesulfonate

0.6 ml (4.48 mmol) of triethylamine and 32.2 mg (0.26 mmol) of 4-N, N-dimethylaminopyridine are added to 1.05 g (2.64 mmol) of the compound from example 8 in 53 ml of dichloromethane. The mixture was stirred at room temperature for 15 minutes, then 0.3 ml (3.95 mmol) of methanesulfonyl chloride was added. The reaction mixture was stirred at room temperature for 4 hours, then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate, filtered and concentrated. 1.36 g (97% of theory) of the title compound are obtained, which is converted without further purification.

LC-MS (method 4): r_t1.47 minutes; ms (esipos): m/z 476[ M + H ]]⁺。

Example 59A

3- (4-chlorophenyl) -3- { 5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propyl methanesulfonate

0.3 ml (2.28 mmol) of triethylamine and 16.4 mg (0.13 mmol) of 4-N, N-dimethylaminopyridine are added to 488 mg (1.34 mmol) of the compound from example 9 in 27 ml of dichloromethane. The mixture was stirred at room temperature for 15 minutes, then 0.16 ml (2.01 mmol) of methanesulfonyl chloride was added. The reaction mixture was stirred at room temperature for 4 hours, then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate, filtered and concentrated. 445 mg (71% of theory) of the title compound are obtained, which are reacted without further purification.

LC-MS (method 6): r_t2.59 min; ms (esipos): 442[ M + H ] M/z]⁺。

Example 60A

3- (4-chloro-2-methylphenyl) -3- {7- [ (ethylsulfanyl) methyl ] -1H-indol-3-yl } propyl methanesulfonate

The title compound was prepared starting from 250 mg (0.67 mmol) of the compound from example 10 in analogy to the synthesis of the compound from example 54A. 308 mg (100% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.15(t，3H)，2.25-2.42(m，2H)，2.39(q，2H)，2.42(s，3H)，3.11(s，3H)，3.92-4.01(m，2H)，4.10-4.24(m，2H)，4.51(t，1H)，6.86(t，1H)，6.94(d，1H)，7.16(dd，1H)，7.21(d，1H)，7.23-7.30(m，3H)，11.0(s，1H)。

LC-MS (method 3): r_t2.51 minutes; ms (esipos): 452[ M + H ] M/z]⁺。

Example 61A

3- (4-chloro-2-methylphenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propyl methanesulfonate

The title compound was prepared starting from 1.24 g (3.46 mmol) of the compound from example 11 in analogy to the synthesis of the compound from example 54A. 1.41 g (93% of theory) of the title compound are obtained.

LC-MS (method 3): r_t2.40 minutes; ms (esipos): 438[ M + H ] M/z]⁺。

Example 62A

3- (4-fluoro-2-methylphenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propyl methanesulfonate

0.17 ml (1.24 mmol) of triethylamine and 8.9 mg (0.07 mmol) of 4-N, N-dimethylaminopyridine are added to 250 mg (0.73 mmol) of the compound from example 12 in 15 ml of dichloromethane. The mixture was stirred at room temperature for 15 minutes, then 0.09 ml (1.09 mmol) of methanesulfonyl chloride was added. The reaction mixture was stirred at room temperature for 2 hours and then diluted with dichloromethane, washed with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 294 mg (96% of theory) of the title compound are obtained.

LC-MS (method 3): r_t2.28 min; ms (esipos): 422[ M + H ] M/z]⁺。

Example 63A

3- [ 2-fluoro-4- (trifluoromethyl) phenyl ] -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propyl methanesulfonate

1.3 ml (9.41 mmol) of triethylamine and 67.6 mg (0.55 mmol) of 4-N, N-dimethylaminopyridine are added to 2.20 g (5.54 mmol) of the compound from example 13 in 112 ml of dichloromethane. The mixture was stirred at room temperature for 15 minutes and then 0.64 ml (8.30 mmol) of methanesulfonyl chloride was added. The reaction mixture was stirred at room temperature for 4 hours, then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate, filtered and concentrated. 2.66 g (94% of theory) of the title compound are obtained.

LC-MS (method 4): r_t1.44 minutes; ms (esipos): m/z 476[ M + H ]]⁺。

Example 64A

3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } -3- (naphthalen-2-yl) propyl methanesulfonate

0.16 ml (1.18 mmol) of triethylamine and 8.5 mg (0.07 mmol) of 4-N, N-dimethylaminopyridine are added to 250 mg (0.69 mmol) of the compound from example 14 in 15 ml of dichloromethane. The mixture was stirred at room temperature for 15 minutes and then 0.08 ml (1.04 mmol) of methanesulfonyl chloride was added. The reaction mixture was stirred at room temperature for 2 hours and then diluted with dichloromethane, washed with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 302 mg (99% of theory) of the title compound are obtained.

LC-MS (method 3): r_t2.35 min; ms (esipos): 440[ M + H ] M/z]⁺。

Example 65A

4- (4-chlorophenyl) -4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butyl methanesulfonate

0.14 ml (1.00 mmol) of triethylamine and 7.2 mg (0.06 mmol) of 4-N, N-dimethylaminopyridine are added to 212 mg (0.59 mmol) of the compound from example 15 in 12 ml of dichloromethane. The mixture was stirred at room temperature for 15 minutes and then 0.07 ml (0.88 mmol) of methanesulfonyl chloride was added. The reaction mixture was stirred at room temperature for 2 hours then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. 255 mg (98% of theory) of the title compound are obtained and reacted further without purification.

LC-MS (method 5): r_t2.74 minutes; ms (esipos): 438[ M + H ] M/z]⁺。

Example 66A

3- (4-chlorophenyl) -3- { 6-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propyl methanesulfonate

0.63 ml (4.53 mmol) of triethylamine, 0.04 g (0.35 mmol) of 4-N, N-dimethylaminopyridine and 0.3 ml (3.83 mmol) of methanesulfonyl chloride are added to 1.27 g (3.48 mmol) of the compound from example 16 in 43 ml of dichloromethane. The reaction mixture was stirred at room temperature for 2 hours and then diluted with ethyl acetate, washed with 1N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 1.55 g of the title compound are obtained as crude product and reacted further without purification.

LC-MS (method 4): r_t1.41 minutes; ms (esipos): 442[ M + H ] M/z]⁺。

Example 67A

3- { 6-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } -3- [4- (trifluoromethyl) phenyl ] propyl methanesulfonate

The title compound was prepared starting from 1.81 g (4.55 mmol) of the compound from example 17 in analogy to the synthesis of the compound from example 66A. 2.20 g of the title compound are obtained as crude product and reacted further without purification.

LC-MS (method 4): r_t1.44 minutes; ms (esipos): m/z 476[ M + H ]]⁺。

Example 68A

3- (1-benzothien-5-yl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propyl methanesulfonate

The title compound was prepared starting from 640 mg (1.74 mmol) of the compound from example 18 in analogy to the synthesis of the compound from example 66A. 768 mg of the title compound are obtained as crude product and reacted further without purification.

LC-MS (method 4): r_t1.39 minutes; ms (esipos): 446[ M + H ] M/z]⁺。

Example 69A

3- (2-bromo-1, 3-thiazol-5-yl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propyl methanesulfonate

0.25 ml (1.77 mmol) of triethylamine, 15 mg (0.12 mmol) of 4-N, N-dimethylaminopyridine and 0.1 ml (1.30 mmol) of methanesulfonyl chloride are added to 470 mg (1.18 mmol) of the compound from example 19 in 20 ml of dichloromethane. The reaction mixture was stirred at room temperature for 1 hour, then diluted with dichloromethane, washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (mobile phase: acetonitrile-water gradient) to yield 512 mg (91% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.95(s，3H)，2.44-2.64(m，2H)，3.12(s，3H)，3.94(s，2H)，4.13-4.23(m，2H)，4.69(t，1H)，6.92(t，1H)，6.98(d，1H)，7.36-7.42(m，2H)，7.68(s，1H)，11.13(s，1H)。

LC-MS (method 4): r_t1.26 minutes; ms (esipos): m/z 475[ M + H ]]⁺。

Example 70A

2-methyl-3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } -3- [4- (trifluoromethyl) phenyl ] propyl methanesulfonate

The title compound was prepared starting from 566 mg (1.44 mmol) of the compound from example 20 in analogy to the synthesis of the compound from example 69A. 622 mg (92% of theory) of the title compound are obtained as a mixture of diastereomers.

LC-MS (method 6): r_t2.64/2.69 min; ms (esineg): 470[ M-H ] M/z]^-。

Example 71A

3- (4-chlorophenyl) -2-methyl-3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propyl methanesulfonate

The title compound was prepared starting from 202 mg (0.56 mmol) of the compound from example 21 in analogy to the synthesis of the compound from example 69A. 221 mg (90% of theory) of the title compound are obtained as a mixture of diastereomers.

LC-MS (method 3): r_t2.37/2.43 min; ms (esineg): m/z 436[ M-H ]]^-。

Example 72A

2-Cyanocyclopropanecarboxylic acid ethyl ester [ racemic trans isomer ]

40.2 g (291 mmol) of potassium carbonate are introduced into 89 ml of DMF at room temperature, 9.6 ml (146 mmol) of acrylonitrile, 15.5 ml (146 mmol) of ethyl chloroacetate and 1.96 g (8.61 mmol) of benzyltriethylammonium chloride are added and the mixture is stirred at room temperature for 3 days. Water was added, the mixture was extracted with ether, the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by vacuum distillation. 6.50 g (30% of theory) of the title compound (boiling range: 63-66 ℃ C./0.9 mbar) and 1.41 g (7%) of the corresponding cis-isomer (boiling range: 85-89 ℃ C./0.9 mbar) were obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.21(t，3H)，1.39(ddd，1H)，1.57(ddd，1H)，2.20(ddd，1H)，2.41(ddd，1H)，4.11(q，2H)。

GC-MS (method 7): r_t3.00 min; ms (eipos): 139[ M ] M/z]⁺。

Example 73A

2-cyano-N-methoxy-N-methylcyclopropanecarboxamide [ racemic trans isomer ]

6.50 g (46.7 mmol) of the compound from example 72A are introduced into 20 ml of methanol at room temperature, 46.7 ml (46.7 mmol) of 1N aqueous sodium hydroxide solution are added and the mixture is stirred at room temperature for 2 hours. Concentrated hydrochloric acid was then added until the pH was 2, the mixture was extracted with diethyl ether, the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was taken up in 8.5 ml (117 mmol) of thionyl chloride and stirred at 65 ℃ for 4 hours. Cooled and then concentrated, and the residue was taken up twice in ether and concentrated again each time. The residue was introduced into 17 ml of dichloromethane, 3.43 g (35.1 mmol) of N, O-dimethylhydroxylamine hydrochloride and 9.8 ml (70.3 mmol) of triethylamine were added, and the mixture was stirred at room temperature overnight. Water was added, the phases were separated, extracted twice with dichloromethane, the combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: dichloromethane/methanol 9/1) to yield 1.72 g (24% of theory) of the title compound.

¹H-NMR(400MHz，CDCl₃)：δ＝1.43(ddd，1H)，1.46-1.53(m，1H)，1.93(ddd，1H)，2.75-2.82(m，1H)，3.20(s，3H)，4.78(s，2H)。

Example 74A

2- [ (4-chlorophenyl) carbonyl ] cyclopropanecarbonitrile [ racemic trans isomer ]

3.5 ml (3.50 mmol) of a 1N solution of chlorophenylmagnesium bromide in diethyl ether are introduced at room temperature under argon into 5 ml of THF, a solution of 490 mg (3.18 mmol) of the compound from example 73A in 5 ml of tetrahydrofuran is added and the mixture is heated under reflux for 2 hours. Saturated aqueous ammonium chloride solution was added, extraction was performed twice with diethyl ether, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. 714 mg of the title compound were obtained in 54% purity (59% of theory) and the reaction was carried out without further purification.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.52(ddd，1H)，1.68(ddd，1H)，2.34(ddd，1H)，3.71(ddd，1H)，7.64-7.69(m，2H)，8.11-8.16(m，2H)。

GC-MS (method 7): r_t6.16 minutes; ms (eipos): 205[ M/z ]]⁺。

Example 75A

2- [1- (4-chlorophenyl) -1-hydroxyethyl ] cyclopropanecarbonitrile [ trans-diastereomer mixture ]

714 mg of the 54% pure compound from example 74A (1.89 mmol) are introduced into 7 ml of diethyl ether at room temperature, 0.94 ml (2.83 mmol) of a 3N solution of methylmagnesium bromide in diethyl ether are added and the mixture is stirred at room temperature overnight. The reaction mixture was added to a saturated, ice-cooled aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient) to yield 257 mg (55% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.96-1.07(m，1H)，1.13-1.20(m，0.4H)，1.21-1.27(m，0.6H)，1.44(s，1.2H)，1.50-1.56(m，0.4H)，1.52(s，1.8H)，1.67-1.73(m，0.6H)，1.97-2.04(ddd，1H)，5.21(s，0.6H)，5.23(s，0.4H)，7.35-7.43(m，2.4H)，7.49-7.55(m，1.6H)。

Example 76A

1-cyclopropyl-5-fluoro-2, 3-dihydro-1H-inden-1-ol

2.00 g (13.3 mmol) of 5-fluoro-1-indanone are introduced into 50 ml of diethyl ether at room temperature, 40 ml (20.0 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran are added and the mixture is stirred at room temperature overnight. The reaction mixture was added to a saturated, ice-cooled aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to yield 2.22 g (87% of theory) of the title compound, which was reacted without further purification.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.24-0.36(m，4H)，1.00-1.09(m，1H)，1.97-2.05(m，1H)，2.08-2.16(m，1H)，2.70-2.80(m，1H)，2.83-2.92(m，1H)，4.79(s，1H)，6.94-7.07(m，2H)，7.28(dd，1H)。

LC-MS (method 3): r_t1.69 minutes; ms (esipos): m/z 175[ M-OH]⁺。

Example 77A

1-cyclopropyl-1- (4-fluorophenyl) ethanol

0.50 g (5.94 mmol) of acetylcyclopropane were dissolved in 5 ml of diethyl ether at 0 ℃ and 8.9 ml (8.91 mmol) of a 1N solution of 4-fluorophenylmagnesium bromide in tetrahydrofuran were slowly added dropwise. Stirring was carried out at 0 ℃ for 1 hour, then warming to RT, the reaction solution was mixed with water and ethyl acetate, and the phases were separated. The organic phase was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. The crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10/1) to yield 0.99 g (93% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.15-0.25(m，1H)，0.27-0.38(m，2H)，0.39-0.47(m，1H)，1.10-1.18(m，1H)，1.40(s，3H)，4.72(s，1H)，7.06-7.14(m，2H)，7.47-7.54(m，2H)。

GC-MS (method 7): r_t3.96 minutes.

Example 78A

1-cyclopropyl-1- (2, 4-difluorophenyl) ethanol

1.50 g (9.61 mmol) of 2 ', 4' -difluoroacetophenone were dissolved in 8 ml of diethyl ether at 0 ℃ and a solution of 38.4 ml (19.21 mmol) of magnesium cyclopropylbromide in tetrahydrofuran was slowly added dropwise. Stirring was carried out at 0 ℃ for 1 hour, then warming to RT, the reaction solution was mixed with water and ethyl acetate, and the phases were separated. The organic phase was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. The crude product is purified by preparative HPLC (mobile phase: acetonitrile-water gradient) to yield 0.63 g (33% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.10-0.19(m，1H)，0.22-0.34(m，2H)，0.45-0.54(m，1H)，1.26-1.35(m，1H)，1.51(s，3H)，4.93(s，1H)，6.98-7.05(m，1H)，7.05-7.17(m，1H)，7.55-7.64(m，1H)。

GC-MS (method 7): r_t3.61 min.

Example 79A

1- (4-chloro-2-fluorophenyl) -1-cyclopropylethanol

114.6 ml (57.31 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran are taken up in 23 ml of diethyl ether at 0 ℃ and 4.95 g (28.65 mmol) of 4 '-chloro-2' -fluoroacetophenone in 5 ml of diethyl ether are slowly added dropwise. Stirring was carried out at 0 ℃ for 1 hour, then warming to RT, the reaction solution was mixed with acetonitrile, water and a little celite, and the mixture was filtered through celite. This phase was separated from the filtrate and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. The crude product is purified by preparative HPLC (mobile phase: acetonitrile-water gradient) to yield 4.30 g (70% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.10-0.19(m，1H)，0.21-0.37(m，2H)，0.47-0.54(m，1H)，1.26-1.35(m，1H)，1.51(d，3H)，4.97(s，1H)，7.24(dd，1H)，7.32(dd，1H)，7.58(t，1H)。

MS(ESIpos)：m/z＝197[M-OH]⁺。

Example 80A

(4-fluorophenyl) [4- (trifluoromethyl) phenyl ] methanol

1.00 g (5.71 mmol) of 4-bromofluorobenzene are dissolved in 10 ml of tetrahydrofuran at-78 ℃. 2.2 ml (6.86 mmol) of a 1.6N solution of N-butyllithium in hexane were added, followed by stirring for 15 minutes, and then 1.26 g (6.86 mmol) of trifluoro-p-tolualdehyde dissolved in 10 ml of tetrahydrofuran were added dropwise. The mixture was stirred at-78 ℃ for 1 hour and then at room temperature for 1 hour. The reaction solution was mixed with water and dichloromethane, and the phases were separated. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered, and the solvent was removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile-water gradient). 1.02 g (66% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝5.82(d，1H)，6.15(d，1H)，7.14(t，2H)，7.41(dd，2H)，7.59(d，2H)，7.67(d，2H)。

LC-MS (method 5): r_t2.41 minutes; ms (esipos): m/z 271[ M + H ]]⁺。

Example 81A

(4-chlorophenyl) (4-fluorophenyl) methanol

The title compound was prepared starting from 6.00 g (34.29 mmol) of 4-bromofluorobenzene and 5.78 g (41.14 mmol) of 4-chlorobenzaldehyde in analogy to the synthesis of the compound from example 80A. 7.14 g (88% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝5.72(d，1H)，6.03(d，1H)，7.08-7.16(m，2H)，7.33-7.41(m，6H)。

LC-MS (method 5): r_t2.31 minutes; ms (esipos): m/z is 219[ M-OH]⁺。

Example 82A

(4-fluoro-2-methylphenyl) (4-fluorophenyl) methanol

1.00 g (5.29 mmol) of 2-bromo-5-fluorotoluene are dissolved in 10 ml of tetrahydrofuran at-78 ℃. 4.0 ml (6.35 mmol) of a 1.6N solution of N-butyllithium in hexane was added, followed by stirring for 15 minutes, and then 0.79 g (6.35 mmol) of p-fluorobenzaldehyde dissolved in 10 ml of tetrahydrofuran was added dropwise. The mixture was warmed to room temperature and subsequently stirred for 1 hour. The reaction solution was mixed with water and ethyl acetate, and the phases were separated. The aqueous phase was extracted three times with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution. The solvent was removed in vacuo and the crude product was purified by preparative HPLC (mobile phase: acetonitrile-water gradient). 0.56 g (43% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.19(s，3H)，5.81(d，1H)，5.86(d，1H)，6.94-7.04(m，2H)，7.09-7.16(m，2H)，7.25-7.32(m，2H)，7.43(dd，1H)。

LC-MS (method 3): r_t1.98 minutes; ms (esipos): m/z is 217[ M-OH]⁺。

Example 83A

(4-chloro-2-methylphenyl) (4-fluorophenyl) methanol

The title compound was prepared starting from 1.00 g (4.87 mmol) of 2-bromo-5-chlorotoluene and 0.72 g (5.84 mmol) of 4-fluorobenzaldehyde in analogy to the synthesis of the compound from example 80A. 0.64 g (52% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.17(s，3H)，5.81(d，1H)，5.91(d，1H)，7.09-7.16(m，2H)，7.19-7.22(m，1H)，7.24-7.31(m，3H)，7.46(d，1H)。

LC-MS (method 3): r_t2.15 minutes; ms (esipos): m/z 233[ M-OH]⁺。

Example 84A

(2, 4-difluorophenyl) (4-fluorophenyl) methanol

The title compound was prepared starting from 1.00 g (5.71 mmol) of 4-bromofluorobenzene and 0.97 g (6.86 mmol) of 2, 4-difluorobenzaldehyde in analogy to the synthesis of the compound from example 80A. 0.53 g (38% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝5.90(d，1H)，6.10(d，1H)，7.05-7.19(m，4H)，7.31-7.38(m，2H)，7.53-7.60(m，1H)。

LC-MS (method 4): r_t1.18 minutes; ms (esipos): m/z 221[ M-OH]⁺。

Example 85A

(4-chloro-2-fluorophenyl) (4-fluorophenyl) methanol

The title compound was prepared starting from 4.60 g (26.28 mmol) of 4-bromofluorobenzene and 5.00 g (31.53 mmol) of 4-chloro-2-fluorobenzaldehyde in analogy to the synthesis of the compound from example 80A. 4.45 g (66% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝5.90(d，1H)，6.15(d，1H)，7.10-7.17(m，2H)，7.28-7.38(m，4H)，7.57(t，1H)。

LC-MS (method 5): r_t2.41 minutes; ms (esipos): 237[ M-OH ] M/z]⁺。

Example 86A

7- [ (methylsulfonyl) methyl ] -1H-indole

36.7 g (149 mmol) of 70% m-chloroperbenzoic acid are added at 0 ℃ to 12.0 g (67.7 mmol) of the compound from example 8A in 800 ml of tetrahydrofuran and the mixture is stirred at room temperature for 15 minutes. 100 ml of saturated aqueous sodium sulfite solution was added, followed by extraction with ethyl acetate several times. The combined organic phases were washed 5 times with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. 11.0 g (75% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)δ＝11.2(s，1H)，7.57(d，1H)，7.41(t，1H)，7.14(d，1H)，7.03(t，1H)，6.48(dd，1H)，4.76(s，2H)，2.88(s，3H)。

LC-MS (method 9): r_t0.74 min; ms (esipos): 210[ M + H ] M/z]⁺。

Example 87A

5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indole

35.4 g (143 mmol) of 70% m-chloroperbenzoic acid are added in 5 parts at 0 ℃ to 14.0 g (71.7 mmol) of the compound from example 11A in 700 ml of tetrahydrofuran and the mixture is stirred at room temperature for 30 minutes. The reaction mixture was added to saturated aqueous sodium bicarbonate solution, the aqueous phase was extracted four times with dichloromethane, and the combined organic phases were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 15.7 g (84% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)δ＝11.3(s，1H)，7.50(t，1H)，7.35(dd，1H)，7.02(dd，1H)，6.48(dd，1H)，4.78(s，2H)，2.91(s，3H)。

LC-MS (method 6): r_t1.59 minutes; ms (esineg): 226[ M-H ] M/z]^-。

Example 88A

3-hydroxy-3- [4- (trifluoromethyl) phenyl ] butanoic acid ethyl ester

19.9 ml (31.89 mmol) of a 1.6N solution of N-butyllithium in hexane were added dropwise at 0 ℃ to a solution of 6.7 ml (31.89 mmol) of hexamethyldisilazane (Hexamethyidilazinan) in 50 ml of tetrahydrofuran, and the mixture was stirred for 15 minutes and then cooled to-78 ℃. 3.12 ml (31.89 mmol) of ethyl acetate were added, the mixture was stirred for 1 hour, and after addition of 5.00 g (26.57 mmol) of 4-trifluoromethylacetophenone, the mixture was dissolved in 20 ml of tetrahydrofuran and stirred for a further hour at-78 ℃. 1N hydrochloric acid was added to the reaction solution, and the phases were separated. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 8/2) to yield 7.14 g (97% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.62-7.70(m，4H)，5.49(s，1H)，3.90(q，2H)，2.78(q，2H)，1.55(s，3H)，1.00(t，3H)。

Example 89A

3- [4- (trifluoromethyl) phenyl ] butane-1, 3-diol

7.00 g (25.34 mmol) of the compound from example 88A dissolved in 150 ml of tetrahydrofuran are added dropwise to a 1N solution of 76.0 ml (76.0 mmol) of diisobutylaluminum hydride in dichloromethane in 250 ml of tetrahydrofuran and the reaction mixture is stirred at room temperature for 3 hours. After addition of 1N hydrochloric acid, the phases were separated, the aqueous phase was extracted with dichloromethane and the combined organic phases were washed with saturated aqueous sodium chloride solution. Dried over sodium sulfate and filtered, and then the solvent is removed in a rotary evaporator. The crude product was purified by flash chromatography on silica gel (mobile phase: dichloromethane/methanol gradient) to yield 5.55 g (91% purity, 85% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.61-7.69(m，4H)，5.22(s，1H)，4.36-4.41(m，1H)，3.37-3.47(m，1H)，3.17-3.26(m，1H)，1.93(t，2H)，1.44(s，3H)。

Example 90A

3- (4-chlorophenyl) -3-cyclopropyl-3-hydroxypropionic acid ethyl ester

13.8 ml (22.14 mmol) of a 1.6N solution of N-butyllithium in hexane are added dropwise at-20 ℃ to a solution of 4.7 ml (22.14 mmol) of hexamethyldisilazane in 17 ml of tetrahydrofuran, and the mixture is stirred at 0 ℃ for 30 minutes and then cooled again to-78 ℃. 2.17 ml (22.14 mmol) of ethyl acetate are added and the mixture is stirred for 30 minutes, after addition of 2.00 g (11.07 mmol) of 4-chlorophenyl cyclopropyl ketone, dissolved in 17 ml of tetrahydrofuran and stirred for a further hour at-78 ℃. The reaction solution was mixed with 1N hydrochloric acid and ethyl acetate, and the phases were separated. The organic phase is washed successively with 0.5N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. After purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient), the acetonitrile is removed in a rotary evaporator and the aqueous phase is extracted several times with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 2.54 g (99% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.50(d，2H)，7.34(d，2H)，4.90(s，1H)，3.88(q，2H)，2.92(d，1H)，2.78(d，1H)，1.34-1.43(m，1H)，1.00(t，3H)，0.48-0.56(m，1H)，0.13-0.39(m，3H)。

Example 91A

3- (2, 3-dihydro-1, 4-benzodi)En-6-yl) -3-hydroxybutyric acid ethyl ester

The title compound was prepared starting from 2.00 g (11.22 mmol) of 1, 4-benzodiazepineAlk-6-ylmethyl ketone and 4.74 ml (22.45 mmol) of ethyl acetate, in analogy to the synthesis of the compound from example 90A. 2.52 g (84% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)δ＝6.91(d，1H)，6.85(dd，1H)，6.74(d，1H)，5.12(s，1H)，4.20(s，4H)，3.94(q，2H)，2.65(s，2H)，1.48(s，3H)，1.06(t，3H)。

Example 92A

5- [ (4-chloro-2-methylphenyl) { 5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } methyl ] -2, 2-dimethyl-1, 3-dioxane-4, 6-dione

0.68 g (4.41 mmol) of 4-chloro-2-methylbenzaldehyde, 0.64 g (4.41 mmol) of Meldrum's acid and 24.0 mg (0.21 mmol) of D, L-proline are added to a solution of 1.00 g of the 82% pure compound (4.20 mmol) from example 11A in 35 ml of acetonitrile. The reaction mixture was stirred at room temperature overnight. It was concentrated and the residue taken up in ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. 2.40 g of the title compound were obtained and the reaction was carried out without further purification.

LC-MS (method 5): r_t3.03 minutes; ms (esineg): 474[ M-H ] M/z ]^-。

Example 93A

5- ([ 2-chloro-4- (trifluoromethyl) phenyl ] {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } methyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione

1.50 g (7.19 mmol) of 2-chloro-4- (trifluoromethyl) benzaldehyde, 1.04 g (7.19 mmol) of Meldrum's acid and 39.4 mg (0.34 mmol) of D, L-proline are added to a solution of 1.21 g (6.85 mmol) of the compound from example 8A in 57 ml of acetonitrile. The reaction mixture was stirred at room temperature overnight. It was concentrated and the residue was taken up in diethyl ether and concentrated again. 3.64 g (75% of theory, 72% purity) of the title compound are obtained, which is reacted without further purification.

LC-MS (method 4): r_t1.50 minutes; MS (ESIneg): m/z 510[ M-H ]]^-。

Example 94A

2, 2-dimethyl-5- [ (4-methylphenyl) {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } methyl ] -1, 3-dioxane-4, 6-dione

1.28 g (10.7 mmol) of 4-methylbenzaldehyde, 1.54 g (10.7 mmol) of Meldrum's acid and 58.0 mg (0.51 mmol) of D, L-proline are added to a solution of 2.00 g (10.2 mmol) of the compound from example 8A in 80 ml of acetonitrile. The reaction mixture was stirred at room temperature overnight. It was concentrated and the residue taken up in ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. 4.34 g of the title compound were obtained and the reaction was carried out without further purification.

LC-MS (method 5): r_t2.70 minutes; MS (ESIneg): 422[ M-H ] M/z]^-。

Example 95A

5- [ (4-chloro-3-fluorophenyl) {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } methyl ] -2, 2-dimethyl-1, 3-dioxane-4, 6-dione

1.34 g (8.46 mmol) of 4-chloro-3-fluorobenzaldehyde, 1.22 g (8.46 mmol) of Meldrum's acid and 0.05 g (0.42 mmol) of D, L-proline are added to a solution of 1.50 g (8.46 mmol) of the compound from example 8A in 12 ml of acetonitrile. The reaction mixture was stirred at room temperature overnight. The precipitated solid is filtered off with suction, washed with acetonitrile and dried under high vacuum. 2.42 g (98% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.62(s，3H)，1.85(s，3H)，1.96(s，3H)，3.95(q，2H)，5.31-5.42(m，2H)，6.88(t，1H)，6.97(d，1H)，7.12-7.19(m，3H)，7.33(d，1H)，7.45(t，1H)，11.1(s，1H)。

HPLC (method 2): r_t4.99 min; MS (ESIneg): 460[ M-H ] M/z]^-。

Example 96A

5- [ (4-chloro-2, 6-difluorophenyl) {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } methyl ] -2, 2-dimethyl-1, 3-dioxane-4, 6-dione

1.64 g (9.31 mmol) of 4-chloro-2, 4-difluorobenzaldehyde, 1.22 g (8.46 mmol) of Meldrum's acid and 0.05 g (0.42 mmol) of D, L-proline are added to a solution of 1.50 g (8.46 mmol) of the compound from example 8A in 12 ml of acetonitrile. The reaction mixture was stirred at room temperature overnight. The crude product is purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 1.61 g (36% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.71(s，3H)，1.89(s，3H)，1.95(s，3H)，3.92(s，2H)，5.03(d，1H)，5.33(d，1H)，6.88-6.98(m，2H)，7.23-7.32(m，4H)，11.0(s，1H)。

HPLC (method 2): r_t4.77 min; MS (ESIneg): m/z 478[ M-H ═]^-。

Example 97A

5- [ (2, 2-difluoro-1, 3-benzodioxol-5-yl) {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } methyl ] -2, 2-dimethyl-1, 3-dioxane-4, 6-dione

1.57 g (8.46 mmol) of 2, 2-difluoro-1, 3-benzodioxol-5-formaldehyde, 1.22 g (8.46 mmol) of Meldrum's acid and 0.05 g (0.42 mmol) of D, L-proline are added to a solution of 1.50 g (8.46 mmol) of the compound from example 8A in 12 ml of acetonitrile. The reaction mixture was stirred at room temperature overnight. The precipitated solid is filtered off with suction, washed with acetonitrile and dried under high vacuum. 2.67 g (91% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.61(s，3H)，1.85(s，3H)，1.96(s，3H)，3.95(q，2H)，5.29(d，1H)，5.39-5.44(m，1H)，6.87(t，1H)，6.97(d，1H)，7.11-7.35(m，5H)，11.1(s，1H)。

HPLC (method 1): r_t4.99 min; MS (ESIneg): m/z 488[ M-H ]]^-。

Example 98A

3- (4-chloro-2-methylphenyl) -3- { 5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propanoic acid ethyl ester

2.1 mg (34. mu. mol) of copper powder was added to a solution of 2.48 g of the compound from example 92A in 28 ml of pyridine and 8 ml of ethanol. The reaction mixture was heated under reflux conditions for 1 hour. It was concentrated and the crude product was purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient) to yield 0.69 g of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝11.1(s，1H)，7.22-7.29(m，3H)，7.15(dd，1H)，6.80-6.89(m，2H)，4.75(t，1H)，3.96(q，2H)，3.91(s，2H)，3.11(dd，1H)，2.99(dd，1H)，2.42(s，3H)，1.95(s，3H)，1.04(t，3H)。

LC-MS (method 3): r_t2.65 minutes; MS (ESIneg): 418[ M-H ] M/z]^-。

Example 99A

3- [ 2-chloro-4- (trifluoromethyl) phenyl ] -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propionic acid ethyl ester

2.8 mg (45. mu. mol) of copper powder was added to a solution of 3.64 g (about 5.12 mmol, 72% purity) of the compound from example 93A in 41 ml of pyridine and 10 ml of ethanol. The reaction mixture was heated under reflux overnight. It is concentrated and the crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to yield 1.34 g (57% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝11.1(s，1H)，7.84(s，1H)，7.58-7.66(m，2H)，7.37(d，1H)，7.28(d，1H)，6.95(d，1H)，6.88(t，1H)，5.19(t，1H)，3.98(q，2H)，3.91(s，2H)，3.21(dd，1H)，3.13(dd，1H)，1.94(s，3H)，1.05(t，3H)。

LC-MS (method 4): r_t1.62 minutes; MS (ESIpos): m/z is 456[M+H]⁺。

Example 100A

3- (4-Methylphenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propanoic acid ethyl ester

6.5 mg (102. mu. mol) of copper powder were added to a solution of 4.34 g of the compound from example 94A in 75 ml of pyridine and 20 ml of ethanol. The reaction mixture was heated under reflux conditions for 1 hour. It was concentrated and the crude product was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to yield 2.55 g of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝10.9(s，1H)，7.29(d，1H)，7.19-7.27(m，3H)，7.01-7.06(m，2H)，6.90(d，1H)，6.80-6.85(m，1H)，4.57(t，1H)，3.90-4.00(m，2H)，3.90(s，2H)，3.13(dd，1H)，3.00(dd，1H)，2.21(s，3H)，1.93(s，3H)，1.05(t，3H)。

LC-MS (method 3): r _t2.49 minutes; MS (ESIneg): 366[ M-H ] M/z]^-。

Example 101A

3- (4-chloro-3-fluorophenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propionic acid ethyl ester

17 mg (262. mu. mol) of copper powder were added to a solution of 2.42 g (5.24 mmol) of the compound from example 95A in 10 ml of pyridine and 2 ml of ethanol. The reaction mixture was heated under reflux conditions for 4 hours. It is concentrated and the crude product is purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 1.82 g (85% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.05(t，3H)，1.93(s，3H)，3.06-3.22(m，2H)，3.90(s，2H)，3.97(q，2H)，4.66(t，1H)，6.86(t，1H)，6.93(d，1H)，7.25(dd，1H)，7.33(d，1H)，7.36-7.46(m，3H)，11.0(s，1H)。

HPLC (method 1): r_t5.11 minutes; MS (ESIpos): 406[ M + H ] M/z]⁺。

Example 102A

3- (4-chloro-2, 6-difluorophenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propionic acid ethyl ester

11 mg (166. mu. mol) of copper powder were added to a solution of 1.60 g (3.33 mmol) of the compound from example 96A in 6 ml of pyridine and 1.3 ml of ethanol. The reaction mixture was heated under reflux conditions for 4 hours. It was concentrated and the crude product was purified first by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5/1) and then by preparative HPLC (mobile phase: acetonitrile/water gradient). 1.15 g (81% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.06(t，3H)，1.93(s，3H)，3.25-3.34(m，2H)，3.91(s，2H)，3.99(q，2H)，4.97(t，1H)，6.87-6.97(m，2H)，7.22-7.34(m，4H)，11.1(s，1H)。

HPLC (method 1): r_t4.97 min; MS (ESIpos): 424[ M + H ] M/z]⁺。

Example 103A

3- (2, 2-difluoro-1, 3-benzodioxol-5-yl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propanoic acid ethyl ester

17 mg (271. mu. mol) of copper powder were added to a solution of 2.66 g (5.43 mmol) of the compound from example 97A in 10 ml of pyridine and 2 ml of ethanol. The reaction mixture was heated under reflux conditions for 4 hours. It was concentrated and the crude product was purified first by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient) and then by preparative HPLC (mobile phase: acetonitrile/water gradient). 1.73 g (74% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.04(t，3H)，1.93(s，3H)，3.05-3.22(m，2H)，3.90(s，2H)，3.96(q，2H)，4.67(t，1H)，6.86(t，1H)，6.93(d，1H)，7.21-7.28(m，2H)，7.32-7.39(m，2H)，7.44(d，1H)，11.1(s，1H)。

HPLC (method 1): r_t5.09 minutes; MS (ESIpos): 434[ M + H ] M/z]⁺。

Example 104A

3- (4-chlorophenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butanoic acid ethyl ester

3.42 g (14.10 mmol) of ethyl 3- (4-chlorophenyl) -3-hydroxybutyrate (prepared analogously to the synthesis of example 88A starting from 4-chloroacetophenone and ethyl acetate) and 3.12 g (14.10 mmol) of indium (III) chloride are added to 2.50 g (14.10 mmol) of the compound from example 8A in 100 ml of toluene. The reaction mixture was stirred at 80 ℃ for 5 hours. After cooling to RT, the reaction solution was mixed with water and ethyl acetate and the solid was filtered off. The filtrate phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification of the crude product by flash chromatography on silica gel (mobile phase: dichloromethane/methanol 95/5) and then by preparative HPLC (mobile phase: acetonitrile/water gradient) gives 0.98 g (17% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.84(t，3H)，1.84(s，3H)，1.95(s，3H)，3.16(s，2H)，3.72-3.85(m，2H)，3.91(s，2H)，6.67-6.75(m，2H)，6.87(dd，1H)，7.26-7.31(m，5H)，11.0(s，1H)。

LC-MS (method 3): r_t2.60 minutes; MS (ESIpos): m/z 400[ M-H ]]^-。

Example 105A

3- (4-chlorophenyl) -3-cyclopropyl-3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propionic acid ethyl ester

700 mg (2.61 mmol) of the compound from example 90A and 576 mg (2.61 mmol) of indium (III) chloride are added to 462 mg (2.61 mmol) of the compound from example 8A in 11 ml of toluene. The reaction mixture was stirred at 80 ℃ for 5 hours. After cooling to RT, the solid was filtered off over silica gel and the solvent was removed in a rotary evaporator. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) gives 69 mg (6% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝-0.16--0.10(m，2H)，0.40-0.49(m，2H)，0.78(t，3H)，1.96(s，3H)，2.01-2.10(m，1H)，3.19(m，1H)，3.28-3.33(m，1H)，3.69-3.79(m，2H)，3.90(q，2H)，6.37(d，1H)，6.61(t，1H)，6.82(d，1H)，7.27-7.41(m，5H)，11.0(s，1H)。

HPLC (method 1): r_t5.11 minutes; MS (ESIpos): 428[ M + H ] M/z]⁺。

Example 106A

3- (2, 3-dihydro-1, 4-benzodi)En-6-yl) -3- {7- [ (methylsulfanyl) methyl]-1H-indol-3-yl } butyric acid ethyl ester

600 mg (2.25 mmol) of the compound from example 91A and 0.21 ml (2.70 mmol) of trifluoroacetic acid are added to 399 mg (2.25 mmol) of the compound from example 8A in 4 ml of dichloromethane. The reaction mixture was stirred at room temperature for 30 minutes. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) gives 576 mg (60% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.83(t，3H)，1.80(s，3H)，1.96(s，3H)，309(q，2H)，3.71-3.84(m，2H)，3.92(s，2H)，4.16(s，4H)，6.67-6.74(m，4H)，6.82(d，1H)，6.87(d，1H)，7.24(d，1H)，10.9(s，1H)。

HPLC (method 2): r_t4.69 minutes; MS (ESIpos): 426[ M + H ] M/z]⁺。

Example 107A

3- (4-chloro-2-methylphenyl) -3- { 5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propyl methanesulfonate

512 mg (1.36 mmol) of the compound from example 132 in 25 ml of dichloromethane are mixed with 0.32 ml (2.30 mmol) of triethylamine and 16.6 mg (0.13 mmol) of 4-N, N-dimethylaminopyridine and stirred at room temperature for 15 minutes. Then 0.16 ml (2.03 mmol) of methanesulfonyl chloride was added and the mixture was stirred at room temperature for 4 hours. It was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate, filtered and concentrated. 608 mg (98% of theory) of the title compound are obtained, which are reacted further directly without further purification.

LC-MS (method 4): r_t1.45 minutes; MS (ESIpos): 456[ M + H ] M/z]⁺。

Example 108A

3- [ 2-chloro-4- (trifluoromethyl) phenyl ] -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propyl methanesulfonate

560 mg (1.35 mmol) of the compound from example 133 are mixed with 0.32 ml (2.30 mmol) of triethylamine and 16.5 mg (0.14 mmol) of 4-N, N-dimethylaminopyridine in 22 ml of dichloromethane and stirred for 15 minutes at room temperature. Then 0.16 ml (2.03 mmol) of methanesulfonyl chloride was added and the mixture was stirred at room temperature for 4 hours. It was diluted with dichloromethane, washed with 1N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 664 mg (100% of theory) of the title compound are obtained, which is reacted further directly without further purification.

LC-MS (method 5): r_t2.84 minutes; MS (ESIpos): 492[ M + H ] M/z]⁺。

Example 109A

3- (4-methylphenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propyl methanesulfonate

1.77 g (5.44 mmol) of the compound from example 134 are mixed with 1.3 ml (9.25 mmol) of triethylamine and 66.4 mg (0.54 mmol) of 4-N, N-dimethylaminopyridine in 100 ml of dichloromethane and stirred for 15 minutes at room temperature. Then 0.63 ml (8.16 mmol) of methanesulfonyl chloride was added and the mixture was stirred at room temperature for 4 hours. It was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate, filtered and concentrated. 2.08 g (95% of theory) of the title compound are obtained, which are reacted further directly without further purification.

¹H-NMR(400MHz，DMSO-d₆)δ＝11.0(s，1H)，7.34(d，1H)，7.28(d，1H)，7.21-7.26(m，2H)，7.04-7.10(m，2H)，6.91(d，1H)，6.83(t，1H)，4.26(t，1H)，4.07-4.19(m，2H)，3.91(s，2H)，3.10(s，3H)，2.48-2.60(m，1H)，2.31-2.44(m，1H)，2.22(s，3H)，1.93(s，3H)。

LC-MS (method 3): r_t2.29 minutes; MS (ESIpos): 404[ M + H ] M/z]⁺。

Example 110A

3- (4-chloro-3-fluorophenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propyl methanesulfonate

0.52 ml (3.70 mmol) of triethylamine, 0.04 g (0.28 mmol) of 4-N, N-dimethylaminopyridine and 0.24 ml (3.13 mmol) of methanesulfonyl chloride are added to 1.03 g (2.84 mmol) of the compound from example 135 in 35 ml of dichloromethane. The reaction mixture was stirred at room temperature for 2 hours and then diluted with ethyl acetate, washed with 1N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 1.30 g of the title compound are obtained as crude product, which is reacted further without purification.

LC-MS (method 5): r_t2.68 minutes; MS (ESIneg): 440[ M-H ] M/z]^-。

Example 111A

3- (4-chloro-2, 6-difluorophenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propyl methanesulfonate

0.40 ml (2.89 mmol) of triethylamine, 0.03 g (0.22 mmol) of 4-N, N-dimethylaminopyridine and 0.194 ml (2.45 mmol) of methanesulfonyl chloride are added to 0.85 g (2.23 mmol) of the compound from example 136 in 28 ml of dichloromethane. The reaction mixture was stirred at room temperature for 2 hours and then diluted with ethyl acetate, washed with 1N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 1.05 g of the title compound are obtained as crude product, which is reacted further without purification.

LC-MS (method 9): r_t1.24 minutes; MS (ESIneg): 458[ M-H ] M/z]^-。

Example 112A

3- (2, 2-difluoro-1, 3-benzodioxol-5-yl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propyl methanesulfonate

0.49 ml (3.52 mmol) of triethylamine, 0.03 g (0.27 mmol) of 4-N, N-dimethylaminopyridine and 0.23 ml (2.98 mmol) of methanesulfonyl chloride are added to 1.06 g (2.71 mmol) of the compound from example 137 in 33 ml of dichloromethane. The reaction mixture was stirred at room temperature for 2 hours and then diluted with ethyl acetate, washed with 1N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 1.35 g of the title compound are obtained as crude product, which is reacted further without purification.

LC-MS (method 3): r_t2.38 minutes; MS (ESIneg): 468[ M-H ] M/z]^-。

Example 113A

3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } -3- [4- (trifluoromethyl) phenyl ] butyl methanesulfonate

0.07 ml (0.52 mmol) of triethylamine, 4 mg (0.03 mmol) of 4-N, N-dimethylaminopyridine and 0.03 ml (0.38 mmol) of methanesulfonyl chloride are added to 135 mg (0.34 mmol) of the compound from example 138 in 10 ml of dichloromethane. The reaction mixture was stirred at room temperature for 1 hour, water was added, and the solvent was removed in a rotary evaporator. The crude product is purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 118 mg (73% of theory) of the title compound.

LC-MS (method 4): r_t1.48 minutes; MS (ESIneg): 470[ M-H ] M/z]^-。

Example 114A

3- (4-chlorophenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butyl methanesulfonate

0.23 ml (1.65 mmol) of triethylamine, 13 mg (0.11 mmol) of 4-N, N-dimethylaminopyridine and 0.09 ml (1.21 mmol) of methanesulfonyl chloride are added to 395 mg (1.10 mmol) of the compound from example 139 in 30 ml of dichloromethane. The reaction mixture was stirred at room temperature for 1 hour, water was added, and the solvent was removed in a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 439 mg (73% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.70(s，3H)，1.97(s，3H)，2.50-2.72(m，2H)，3.04(s，2H)，3.88-4.08(m，4H)，6.69-6.77(m，2H)，6.89(dd，1H)，7.26-7.37(m，5H)，11.0(s，1H)。

LC-MS (method 4): r_t1.44 minutes; MS (ESIneg): m/z 436[ M-H ]]^-。

Example 115A

3- (4-chlorophenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } pentyl methanesulfonate

0.39 ml (2.81 mmol) of triethylamine, 23 mg (0.23 mmol) of 4-N, N-dimethylaminopyridine and 0.16 ml (2.06 mmol) of methanesulfonyl chloride are added to 700 mg (1.10 mmol) of the compound from example 140 in 50 ml of dichloromethane. The reaction mixture was stirred at room temperature for 1 hour, water was added, and the solvent was removed in a rotary evaporator. The crude product is purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 782 mg (92% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.63(t，3H)，1.97(s，3H)，2.04-2.17(m，1H)，2.18-2.30(m，1H)，2.46-2.64(m，2H)，3.03(s，3H)，3.77-3.87(m，1H)，3.91-4.02(m，1H)，3.93(s，2H)，6.59-6.71(m，2H)，6.87(d，1H)，7.24-7.34(m，4H)，7.40(d，1H)，11.0(s，1H)。

LC-MS (method 4): r_t1.49 minutes; MS (ESIneg): 450[ M-H ] M/z]^-。

Example 116A

3- (4-chlorophenyl) -3-cyclopropyl-3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propyl methanesulfonate

0.02 ml (0.02 mmol) of triethylamine, 2 mg (0.01 mmol) of 4-N, N-dimethylaminopyridine and 0.01 ml (0.14 mmol) of methanesulfonyl chloride are added to 47 mg (0.12 mmol) of the compound from example 141 in 1.5 ml of dichloromethane. The reaction mixture was stirred at room temperature for 2 hours and then diluted with ethyl acetate, washed with 1N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 57 mg of the title compound are obtained as crude product, which is reacted further without purification.

LC-MS (method 9): r_t1.32 minutes; MS (ESIneg): 462[ M-H ] M/z]^-。

Example 117A

3- (2, 3-dihydro-1, 4-benzodi)En-6-yl) -3- {7- [ (methylsulfanyl) methyl]-1H-indol-3-yl } butyl methanesulfonate

0.21 ml (1.50 mmol) of triethylamine, 14 mg (0.12 mmol) of 4-N, N-dimethylaminopyridine and 0.10 ml (1.27 mmol) of methanesulfonyl chloride are added to 443 mg (1.15 mmol) of the compound from example 142 in 14 ml of dichloromethane. The reaction mixture was stirred at room temperature for 2 hours and then diluted with ethyl acetate, washed with 1N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 532 mg of the title compound are obtained as crude product, which is reacted further without purification.

LC-MS (method 6): r_t2.37 minutes; MS (ESIneg): 460[ M-H ] M/z]^-。

Example 118A

5-chloro-1-cyclopropyl-2, 3-dihydro-1H-inden-1-ol

45 ml (22.5 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran are added at room temperature to a mixture of 2.50 g (15.0 mmol) of 5-chloro-2, 3-dihydro-1H-inden-1-one and 6-chloro-2, 3-dihydro-1H-inden-1-one in 56 ml of diethyl ether and the mixture is stirred at room temperature overnight. The reaction mixture was added to ice-water, the phases separated, the aqueous phase extracted with dichloromethane, the combined organic phases dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) and preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 71.0 mg (2% of theory) of a mixture of 5-chloro-1-cyclopropyl-2, 3-dihydro-1H-inden-1-ol and 6-chloro-1-cyclopropyl-2, 3-dihydro-1H-inden-1-ol.

¹H-NMR(400MHz，DMSO-d₆)4.91(s，0.3H)，4.86(s，0.7H)，2.81-2.93(m，1H)，2.69-2.81(m，1H)，2.07-2.15(m，1H)，1.95-2.05(m，1H)，1.00-1.10(m，1H)，0.23-0.44(m，4H)。

LC-MS (method 4): r_t1.19 minutes; MS (ESIpos): m/z 191[ M-OH]⁺。

Example 119A

6-chloro-1-cyclopropyl-2, 3-dihydro-1H-inden-1-ol

45 ml (22.5 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran are added at room temperature to a mixture of 2.50 g (15.0 mmol) of 5-chloro-2, 3-dihydro-1H-inden-1-one and 6-chloro-2, 3-dihydro-1H-inden-1-one in 56 ml of diethyl ether and the mixture is stirred at room temperature overnight. The reaction mixture was added to ice-water, the phases separated, the aqueous phase extracted with dichloromethane, the combined organic phases dried over magnesium sulfate, filtered and concentrated. The crude product is purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) and preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 152 mg (5% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：4.91(s，1H)，2.81-2.91(m，1H)，2.69-2.79(m，1H)，2.07-2.16(m，1H)，1.96-2.05(m，1H)，1.00-1.10(m，1H)，0.26-0.43(m，4H)。

LC-MS (method 4): r_t1.19 minutes; MS (ESIpos): m/z 191[ M-OH]⁺。

Example 120A

2, 2-difluoro-N-methoxy-N-methylcyclopropanecarboxamide

7.00 g (49.8 mmol) of 2, 2-difluorocyclopropanecarbonyl chloride (described in Journal of Fluorine Chemistry 1990, 49, 127-139) were mixed with 6.32 g (64.8 mmol) of N, O-dimethylhydroxylamine hydrochloride and 18.1 ml (130 mmol) of triethylamine in 100 ml of dichloromethane and stirred at room temperature overnight. Water was added to the reaction mixture, the phases were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated. 5.73 g (70% of theory) of the title compound are obtained, which is reacted without further purification.

¹H-NMR(400MHz，DMSO-d₆)δ＝3.72(s，3H)，3.16(s，3H)，3.05-3.19(m，1H)，1.85-1.99(m，2H)。

GC-MS (method 7): r_t2.32 minutes; MS (EIpos): 165[ M ] M/z]⁺。

Example 121A

2-chloro-N-methoxy-N, 4-dimethylbenzamide

1.25 g (6.61 mmol) of 2-chloro-4-methylbenzoyl chloride in 4 ml of dichloromethane are mixed with 0.84 g (8.60 mmol) of N, O-dimethylhydroxylamine hydrochloride and 2.4 ml (17.2 mmol) of triethylamine and stirred for 24 hours. Water and 1N hydrochloric acid were added to the reaction mixture, the phases were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to yield 1.10 g (78% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.35-7.41(m，1H)，7.22-7.28(m，2H)，3.44(s，3H)，3.27(s，3H)，2.31(s，3H)。

LC-MS (method 9): r_t0.87 min; MS (ESIpos): 214[ M + H ] M/z]⁺。

Example 122A

2- [4- (trifluoromethyl) benzoyl ] cyclopropanecarbonitrile [ racemic trans isomer ]

Under argon, a few drops of dibromoethane and a solution of 4.00 g (14.7 mmol) of 1-iodo-4- (trifluoromethyl) benzene in 10 ml of dry ether were added to 375 mg (15.4 mmol) of magnesium in 40 ml of dry ether, and the mixture was heated under reflux for 2 hours. After cooling, the reaction solution of the supernatant (uberstehend) is added dropwise under argon to 2.00 g (13.0 mmol) of the compound from example 73A in 50 ml of THF, and the mixture is stirred at room temperature overnight. The reaction solution was then added to a saturated aqueous ammonium chloride solution, the phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. Purification of the residue by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) gives 1.42 g (46% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝8.28-8.33(m，2H)，7.94-7.99(m，2H)，3.76(ddd，1H)，2.39(ddd，1H)，1.73(ddd，1H)，1.57(ddd，1H)。

GC-MS (method 7): r_t5.08 min; MS (EIpos): 239[ M ] M/z]⁺。

Example 123A

2- (2, 4-difluorobenzoyl) cyclopropanecarbonitrile [ racemic trans-isomer ]

Under argon, a few drops of dibromoethane followed by 5.00 g (25.9 mmol) of 2, 4-difluorobromobenzene (dissolved in 50 ml of diethyl ether) were added to 661 mg (27.2 mmol) of magnesium in 100 ml of dry diethyl ether. The mixture was heated under reflux for 2 hours. After cooling, the supernatant reaction solution was added dropwise under argon to a solution of 3.63 g (23.5 mmol) of the compound from example 73A in 80 ml of THF, and the mixture was stirred at room temperature overnight. The reaction solution was then added to a saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated. Purification of the residue by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) gives 2.15 g (44% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.95(dt，1H)，7.50(ddd，1H)，7.28(dt，1H)，3.30-3.39(m，1H)，2.37(ddd，1H)，1.72(ddd，1H)，1.55-1.63(m，1H)。

LC-MS (method 4): r_t1.03 minutes; MS (ESIpos): 208[ M + H ] M/z]⁺。

Example 124A

(4-chlorophenyl) (2, 2-difluorocyclopropyl) methanone

A solution of 2.00 g (12.1 mmol) of the compound from example 120A in 20 ml of THF is added under argon at room temperature to a solution of 2.87 g (13.3 mmol) of 1N chlorophenylmagnesium bromide in diethyl ether in 20 ml of THF, and the mixture is heated under reflux for 2 hours. The reaction mixture was added to saturated aqueous ammonium chloride solution and extracted twice with ether, and the combined organic phases were dried over magnesium sulfate and concentrated. 2.47 g (94% of theory) of the title compound are obtained, which is reacted without further purification.

¹H-NMR(400MHz，DMSO-d₆)δ＝8.06-8.10(m，2H)，7.65-7.70(m，2H)，4.03(ddd，1H)，2.20-2.30(m，1H)，2.03-2.14(m，1H)。

GC-MS (method 7): r_t4.41 minutes; MS (EIpos): 216[ M ] M/z]⁺。

Example 125A

(2-chloro-4-methylphenyl) (cyclopropyl) methanone

7.7 ml (7.65 mmol) of a 1N solution of cyclopropylmagnesium bromide in THF are added to 1.09 g (5.10 mmol) of the compound from example 121A in 19 ml of diethyl ether, and the mixture is stirred at room temperature overnight. A further 7.7 ml (7.65 mmol) of a 1N solution of cyclopropylmagnesium bromide in THF was added and the mixture was stirred at rt overnight. The reaction mixture was added to ice-water and extracted with dichloromethane, the organic phase was dried over magnesium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to yield 326 mg (33% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.39-7.45(m，2H)，7.34(dd，1H)，2.44-2.50(m，1H)，2.34(s，3H)，1.05-1.15(m，4H)。

LC-MS (method 9): r_t1.11 minutes; MS (ESIpos): 195[ M + H ] M/z]⁺。

Example 126A

2- (4-methylbenzoyl) cyclopropanecarbonitrile [ racemic trans isomer ]

A solution of 4.00 g (26.0 mmol) of the compound from example 73A in 10 ml of THF is added under argon at room temperature to a solution of 29 ml (28.5 mmol) of 1N p-tolylmagnesium bromide in THF in 70 ml of THF and the mixture is heated under reflux for 2 hours. The reaction mixture was added to a saturated aqueous ammonium chloride solution and extracted with ethyl acetate, and the organic phase was dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 95/5). 2.60 g (54% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)δ＝8.00-8.05(m，2H)，7.37-7.42(m，2H)，3.68(ddd，1H)，2.41(s，3H)，2.30(ddd，1H)，1.65(ddd，1H)，1.50(d，1H)。

GC-MS (method 7): r_t5.84 minutes; MS (EIpos): 185[ M ] M/z]⁺。

Example 127A

2- (2-chloro-4-fluorobenzoyl) cyclopropanecarbonitrile [ racemic trans isomer ]

A solution of 24.0 g (115 mmol) of 2-chloro-4-p-fluorobromobenzene in 20 ml of diethyl ether was added dropwise to 2.92 g (120 mmol) of magnesium turnings in 780 ml of diethyl ether, activated by addition of a few drops of dibromoethane, and the reaction mixture was heated under reflux overnight. The reaction solution is added dropwise under argon to a solution of 17.7 g (68.8 mmol) of the compound from example 73A in 300 ml of THF, and the reaction mixture is initially stirred at room temperature overnight and then under reflux for 8 hours. It was concentrated and taken up in ethyl acetate and saturated aqueous ammonium chloride solution, the phases were separated, the organic phase was washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to yield 2.20 g (14% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.86(dd，1H)，7.65(dd，1H)，7.42(dt，1H)，3.29-3.35(m，1H)，2.40(ddd，1H)，1.76(ddd，1H)，1.60(ddd，1H)。

GC-MS (method 7): r_t5.68 minutes; MS (EIpos): m/z 223[ M ]]⁺。

Examples128A

2- (4-chloro-2-methoxybenzoyl) cyclopropanecarbonitrile [ racemic trans isomer ]

A solution of 500 mg (2.26 mmol) of 2-bromo-4-chloroanisole in 5 ml of diethyl ether is added dropwise to 57.6 mg (2.37 mmol) of magnesium turnings in 10 ml of diethyl ether, the reaction mixture is activated by addition of a few drops of dibromoethane and heated at reflux overnight. The reaction solution is added dropwise under argon to a solution of 316 mg (2.05 mmol) of the compound from example 73A in 10 ml of THF and the reaction mixture is heated under reflux for 2 hours. It is diluted with ethyl acetate and the organic phase is washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 9/1) to yield 278 mg (58% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.55(d，1H)，7.35(d，1H)，7.14(dd，1H)，3.35(ddd，1H)，2.26(ddd，1H)，1.66(ddd，1H)，1.56(ddd，1H)。

GC-MS (method 7): r_t6.73 minutes; MS (EIpos): 235[ M ] M/z]⁺。

Example 129A

2- [ 2-fluoro-4- (trifluoromethyl) benzoyl ] cyclopropanecarbonitrile [ racemic trans isomer ]

2.6 ml (4.12 mmol) of a 1.6N solution of N-butyllithium in hexane are added dropwise at-78 ℃ to a solution of 1.00 g (4.12 mmol) of 1-bromo-2-fluoro-4- (trifluoromethyl) benzene in 8 ml of THF, and the mixture is stirred for 0.5 h. Then, a solution of 423 mg (2.74 mmol) of the compound from example 73A in 2 ml of THF is added at-78 ℃ and the mixture is warmed to RT and stirred at RT for 2 h. It is diluted with dichloromethane and the organic phase is washed with water and saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to yield 206 mg (29% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝8.02(t，1H)，7.95(d，1H)，7.77(d，1H)，3.36-3.43(m，1H)，2.43(ddd，1H)，1.78(ddd，1H)，1.64(ddd，1H)。

GC-MS (method 7): r_t4.66 minutes; MS (EIpos): 257[ M ] M/z]⁺。

Example 130A

2- (4-chloro-2-fluorobenzoyl) cyclopropanecarbonitrile [ racemic trans isomer ]

A 0.1N solution of 5.67 g (134 mmol) of lithium chloride and 0.7 ml of diisobutylaluminum hydride in THF is added to 6.50 g (268 mmol) of magnesium turnings in 30 ml of THF. The mixture was stirred for five minutes and cooled to 0 ℃, 22.4 g (107 mmol) of 1-bromo-4-chloro-2-fluorobenzene was added and the mixture was warmed to RT and stirred at RT overnight. The reaction solution is added dropwise under argon to a solution of 15.0 g (97.3 mmol) of the compound from example 73A in 10 ml of THF and the reaction mixture is heated under reflux for 2 hours. The reaction mixture was added to saturated aqueous ammonium chloride solution and extracted with dichloromethane, and the organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 95/5) to give 5.40 g (25% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.86(t，1H)，7.70(dd，1H)，7.48(dd，1H)，3.32-3.38(m，1H)，2.38(ddd，1H)，1.73(ddd，1.H)，1.60(ddd，1H)。

LC-MS (method 9): r_t1.01 minutes; MS (ESIneg):

example 131A

2- (2-fluoro-4-methylbenzoyl) cyclopropanecarbonitrile [ racemic trans isomer ]

16.5 ml (26.5 mmol) of a 1.6N solution of N-butyllithium in hexane are added dropwise at-78 ℃ to a solution of 5.00 g (26.5 mmol) of 4-bromo-3-fluorotoluene in 40 ml of THF, and the mixture is stirred for 0.5 h. Then, a solution of 2.72 g (17.6 mmol) of the compound from example 73A in 10 ml of THF is added at-78 ℃ and the mixture is warmed to room temperature and stirred at room temperature for 2 hours. Water was added, the mixture was concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid). 300 mg (9% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.40(t，1H)，7.26(d，1H)，7.20(d，1H)，3.29-3.37(m，1H)，2.40(s，3H)，2.35(ddd，1H)，1.70(ddd，1H)，1.57(ddd，1H)。

GC-MS (method 7): r_t5.68 minutes; MS (EIpos): m-z＝203[M]⁺。

Example 132A

2- { 1-hydroxy-1- [4- (trifluoromethyl) phenyl ] ethyl } cyclopropanecarbonitrile [ trans-diastereomer mixture ]

3.0 ml (9.09 mmol) of a 3N solution of methylmagnesium bromide in diethyl ether are added at room temperature to 1.45 g (6.06 mmol) of the compound from example 122A in 25 ml of diethyl ether, and the mixture is stirred at room temperature overnight. The reaction mixture was added to a saturated, ice-cooled aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to yield 1.40 g (90% of theory) of the diastereomeric mixture of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.67-7.77(m，4H)，5.37(s，0.4H)，5.35(s，0.6H)，2.03-2.11(m，1H)，1.75(dt，0.6H)，1.57(s，1.8H)，1.52-1.59(m，0.4H)，1.48(s，1.2H)1.28(ddd，0.4H)，1.19(dt，0.4H)，1.05(ddd，0.6H)，1.00(dt，0.6H)。

Example 133A

2- [1- (2, 4-difluorophenyl) -1-hydroxyethyl ] cyclopropanecarbonitrile [ trans-diastereomer mixture ]

5.2 ml (15.6 mmol) of a 3N solution of methylmagnesium bromide in diethyl ether are added at room temperature to 2.15 g (10.4 mmol) of the compound from example 123A in 50 ml of diethyl ether, and the mixture is stirred at room temperature overnight. The reaction mixture was added to a saturated, ice-cooled aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to yield 2.16 g (93% of theory) of the diastereomeric mixture of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.51-7.62(m，1H)，7.16-7.28(m，1H)，7.02-7.13(m，1H)，5.48(s，0.5H)，5.47(s，0.5H)，1.99-2.09(m，1H)，1.72-1.78(m，0.5H)，1.59(s，1.5H)，1.51(s，1.5H)，1.46-1.53(m，0.5H)，1.16-1.31(m，1H)，0.96-1.05(m，1H)。

LC-MS (method 9): r_t0.92, 0.93 min; ms (esineg): 222[ M-H ] M/z]^-。

Example 134A

1- (4-chlorophenyl) -1- (2, 2-difluorocyclopropyl) ethanol

5.7 ml (17.1 mmol) of a 3N solution of methylmagnesium bromide in diethyl ether are added at room temperature to 2.47 g (11.4 mmol) of the compound from example 124A in 40 ml of diethyl ether, and the mixture is stirred at room temperature overnight. The reaction mixture was added to a saturated, ice-cooled aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to give 2.09 g (78% of theory) of the diastereomeric mixture of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.49-7.56(m，2H)，7.36-7.42(m，1.8H)，7.11-7.28(m，0.2H)，5.38(s，0.1H)，5.36(s，0.9H)，2.14(ddd，0.9H)，2.01(ddd，0.1H)，1.58-1.69(m，1H)，1.43-1.56(m，4H)。

Example 135A

1-ethyl-5-fluoroindan-1-ol

292 ml (876 mmol) of a 3N solution of ethylmagnesium bromide in ether are added to 5.00 g (33.3 mmol) of 5-fluoroindan-1-one in 150 ml of ether at room temperature, and the mixture is stirred at room temperature overnight. The reaction mixture was added to a saturated, ice-cooled aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to give 5.70 g (94% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.24(dd，1H)，6.94-7.03(m，2H)，4.89(s，1H)，2.82-2.93(m，1H)，2.66-2.76(m，1H)，2.07-2.17(m，1H)，1.92-2.02(m，1H)，1.67-1.78(m，1H)，1.54-1.64(m，1H)，0.82(t，3H)。

Example 136A

1-cyclopropyl-1- [ 2-fluoro-4- (trifluoromethyl) phenyl ] ethanol

A few drops of dibromoethane followed by 6.30 g (52.1 mmol) of cyclopropyl bromide (dissolved in 20 ml of diethyl ether) were added under argon to 1.33 g (54.7 mmol) of magnesium in 90 ml of dry diethyl ether. The mixture was heated under reflux for 2 hours. After cooling, 21 ml (9.94 mmol) of the supernatant reaction solution were added dropwise to a solution of 850 mg (4.12 mmol) of 1- [ 2-fluoro-4- (trifluoromethyl) phenyl ] ethanone in 17 ml of diethyl ether under argon and the mixture was stirred at room temperature overnight. The reaction mixture was added to ice-water, the phases separated, the aqueous phase extracted with dichloromethane, the combined organic phases dried over magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient, addition of 0.1% triethylamine) to yield 157 mg (15% of theory) of the diastereomer mixture of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.80(t，1H)，7.53-7.61(m，2H)，5.11(s，1H)，1.55(s，1.5H)，1.54(s，1.5H)，1.30-1.40(m，1H)，0.51-0.59(m，1H)，0.32-0.40(m，1H)，0.23-0.31(m，1H)，0.11-0.20(m，1H)。

Example 137A

1-cyclopropyl-1- (4-methylphenyl) ethanol

27 ml (26.8 mmol) of a 1N solution of cyclopropylmagnesium bromide in THF are added at room temperature to 3.00 g (22.4 mmol) of 1- (4-methylphenyl) ethanone in 60 ml of diethyl ether, and the mixture is stirred at room temperature overnight. A further 11 ml (11.2 mmol) of a 1N solution of cyclopropylmagnesium bromide in THF was then added and the mixture was stirred at rt overnight. The reaction mixture was added to ice-water, the phases separated, the aqueous phase extracted with dichloromethane, the combined organic phases dried over magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient, addition of 0.1% triethylamine) to yield 491 mg (13% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.33-7.38(m，2H)，7.05-7.12(m，2H)，4.56(s，1H)，2.26(s，3H)，1.38(s，3H)，1.07-1.16(m，1H)，0.36-0.44(m，1H)，0.26-0.33(m，2H)，0.14-0.22(m，1H)。

Example 138A

1-cyclopropyl-1- (4-chlorophenyl) ethanol

1.50 g (9.70 mmol) of 4-chloroacetophenone were dissolved in 8 ml of diethyl ether at 0 ℃ and 38.8 ml (19.41 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran were slowly added dropwise. Stir at 0 ℃ for 1 hour, then warm to RT, add water and acetonitrile to the reaction solution, and filter the mixture through celite. The organic solvent was removed in a rotary evaporator and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution and the solvent was removed in vacuo. The crude product was purified twice by preparative HPLC (mobile phase: acetonitrile/water gradient). Acetonitrile was removed from the combined product phases in a rotary evaporator and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed again with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered, and the solvent was removed in vacuo. 1.37 g (72% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.15-0.25(m，1H)，0.27-0.39(m，2H)，0.40-0.49(m，1H)，1.08-1.18(m，1H)，1.39(s，3H)，4.78(s，1H)，7.35(d，2H)，7.50(d，2H)。

GC-MS (method 7): r_t4.96 minutes; DCI-MS (ESIpos): 179[ M-H ] M/z₂O+H]⁺。

Example 139A

1-cyclopropyl-1- [4- (trifluoromethyl) phenyl ] ethanol

The title compound was prepared in analogy to the synthesis of the compound from example 138A starting from 1.50 g (7.97 mmol) of 4' - (trifluoromethyl) acetophenone and 31.9 ml (15.95 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran. 1.27 g (69% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.16-0.25(m，1H)，0.30-0.40(m，2H)，0.45-0.54(m，1H)，1.13-1.22(m，1H)，1.45(s，3H)，4.91(s，1H)，7.65(d，2H)，7.71(d，2H)。

GC-MS (method 7): r_t3.88 minutes; DCI-MS (ESIpos): 213[ M-H ] M/z₂O+H]⁺。

Example 140A

1-cyclopropyl-1- (3-fluoro-4-methoxyphenyl) ethanol

The title compound was prepared in analogy to the synthesis of the compound from example 138A starting from 1.50 g (8.92 mmol) of 3-fluoro-4-methoxyacetophenone and 35.7 ml (17.8 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran. 1.38 g (74% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.15-0.24(m，1H)，0.26-0.37(m，2H)，0.37-0.46(m，1H)，1.07-1.17(m，1H)，1.38(s，3H)，3.81(s，3H)，4.69(s，1H)，7.07(t，1H)，7.19-7.29(m，2H)。

GC-MS (method 7): r_t5.27 min; ms (eipos): 210[ M ] M/z]⁺。

Example 141A

1- (1-benzothien-5-yl) -1-cyclopropylethanol

0.60 g (24.64 mmol) of magnesium turnings are dried by heating under argon, cooled to RT and 30 ml of tetrahydrofuran are added. 5.00 g (23.46 mmol) of 5-bromo-1-benzothiophene in 30 ml of tetrahydrofuran, and a trace amount of iodine were added to the mixture, which was stirred at room temperature for 30 minutes. 2.17 g (25.81 mmol) of acetylcyclopropane in 30 ml of tetrahydrofuran was added, followed by stirring for 2 hours. The reaction solution was mixed with water and acetonitrile, and the mixture was filtered through celite. The organic solvent was removed in a rotary evaporator and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered, and the solvent was removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). Acetonitrile was removed from the combined product phases in a rotary evaporator and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed again with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered, and the solvent was removed in vacuo. 2.39 g (46% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.15-0.26(m，1H)，0.31-0.41(m，2H)，0.43-0.52(m，1H)，1.17-1.27(m，1H)，1.47(s，3H)，4.75(s，1H)，7.43(d，1H)，7.52(dd，1H)，7.70(d，1H)，7.90(d，1H)，7.98(d，1H)。

GC-MS (method 7): r_t6.64 min; DCI-MS (ESIpos): m/z is 201[ M-H ═ M₂O+H]⁺。

Example 142A

1-cyclopropyl-1- (2, 3-dihydro-1, 4-benzodi)En-6-yl) ethanol

The title compound was prepared starting from 1.50 g (8.42 mmol) of 1, 4-benzodiazepineIn analogy to the synthesis of the compound from example 138A, alk-6-ylmethyl ketone and 33.7 ml (16.84 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran. 1.12 g (59% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.13-0.23(m，1H)，0.26-0.35(m，2H)，0.35-0.43(m，1H)，1.05-1.14(m，1H)，1.34(s，3H)，4.20(s，4H)，4.53(s，1H)，6.75(d，1H)，6.89-6.96(m，2H)。

GC-MS (method 7): r_t6.46 minutes; ms (eipos): 220[ M ] M/z]⁺。

Example 143A

1- (1, 3-benzodioxol-5-yl) -1-cyclopropylethanol

The title compound was prepared in analogy to the synthesis of the compound from example 138A starting from 1.50 g (9.14 mmol) of 3, 4- (methylenedioxy) acetophenone and 36.5 ml (18.28 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran. 1.32 g (70% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.14-0.23(m，1H)，0.27-0.36(m，2H)，0.36-0.45(m，1H)，1.07-1.15(m，1H)，1.36(s，3H)，4.60(s，1H)，5.96(s，2H)，6.81(d，1H)，6.98(dd，1H)，7.02(d，1H)。

HPLC (method 1): r_t3.84 min.

Example 144A

1-cyclopropyl-1- (2, 2-difluoro-1, 3-benzodioxol-5-yl) ethanol

The title compound was prepared starting from 0.75 g (3.75 mmol) of 1- (2, 2-difluoro-1, 3-benzodioxol-5-yl) ethanone and 15.0 ml (7.50 mmol) of a 0.5N solution of cyclopropyl magnesium bromide in tetrahydrofuran in analogy to the synthesis of the compound from example 138A. 0.67 g (74% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.15-0.24(m，1H)，0.28-0.40(m，2H)，0.42-0.50(m，1H)，1.11-1.20(m，1H)，1.41(s，3H)，4.86(s，1H)，7.27-7.35(m，2H)，7.47(d，1H)。

HPLC (method 1): r_t4.50 minutes; DCI-MS (ESIpos): 225[ M-OH ] M/z]⁺。

Example 145A

1-cyclopropyl-1- (4-chlorophenyl) propanol

The title compound was prepared in analogy to the synthesis of the compound from example 138A starting from 1.50 g (8.90 mmol) of 1- (4-chlorophenyl) propan-1-one and 35.6 ml (17.79 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran. 1.42 g (76% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.08-0.24(m，2H)，0.28-0.38(m，1H)，0.45-0.53(m，1H)，0.67(t，3H)，1.16-1.25(m，1H)，1.69-1.88(m，2H)，4.43(s，1H)，7.34(d，2H)，7.45(d，2H)。

GC-MS (method 7): r_t5.24 minutes; ms (eipos): 210[ M ] M/z]⁺。

Example 146A

3- (4-chloro-2-fluorophenyl) pentane-3-ol

The title compound was prepared in analogy to the synthesis of the compound from example 138A starting from 2.00 g (10.61 mmol) of methyl 4-chloro-2-fluorobenzoate and 31.8 ml (31.82 mmol) of a 1N solution of ethylmagnesium bromide in tetrahydrofuran. 1.27 g (55% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.64(t，6H)，1.65-1.75(m，1H)，1.81-1.93(m，1H)，4.85(s，1H)，7.23-7.32(m，2H)，7.58(t，1H)。

HPLC (method 1): r_t4.72 minutes; DCI-MS (EIpos): 210[ M + NH ] M/z₄]⁺。

Example 147A

Cyclopropyl (2, 4-dichlorophenyl) methanol

17 ml (8.57 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in THF are added at 0 ℃ to 1.00 g (5.71 mmol) of 2, 4-dichlorobenzaldehyde in 20 ml of diethyl ether, and the mixture is warmed to room temperature and stirred at room temperature overnight. The reaction mixture was added to water and ethyl acetate, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water) to yield 925 mg (74% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.59(d，1H)，7.54(d，1H)，7.44(dd，1H)，5.41(d，1H)，4.57-4.63(m，1H)，1.04-1.14(m，1H)，0.33-0.41(m，4H)。

Example 148A

Cyclopropyl [ 2-fluoro-4- (trifluoromethyl) phenyl ] methanol

31 ml (15.6 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in THF are added at 0 ℃ to 2.00 g (10.4 mmol) of 2-fluoro-4- (trifluoromethyl) benzaldehyde in 40 ml of diethyl ether, and the mixture is warmed to room temperature and stirred at room temperature overnight. The reaction mixture was added to water and ethyl acetate, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 95/5) to yield 1.68 g (69% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.77(t，1H)，7.57-7.63(m，2H)，5.52(d，1H)，4.41(dd，1H)，1.05-1.15(m，1H)，0.29-0.50(m，4H)。

GC-MS (method 7): r_t3.53 minutes; ms (eipos): 234[ M ] M/z]⁺。

Example 149A

Cyclopropyl [4- (trifluoromethyl) phenyl ] methanol

34 ml (17.2 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in THF are added at 0 ℃ to 2.00 g (11.5 mmol) of 4- (trifluoromethyl) benzaldehyde in 44 ml of diethyl ether, and the mixture is warmed to room temperature and stirred at room temperature overnight. The reaction mixture was added to water and ethyl acetate, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 95/5) to yield 1.77 g (71% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.65-7.70(m，2H)，7.58-7.62(m，2H)，5.38(d，1H)，4.07(dd，1H)，0.97-1.07(m，1H)，0.36-0.50(m，4H)。

GC-MS (method 7): r_t3.87 min; ms (eipos): 216[ M ] M/z]⁺。

Example 150A

[ 2-chloro-4- (trifluoromethyl) phenyl ] (cyclopropyl) methanol

84 ml (41.9 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in THF are added at 0 ℃ to 5.83 g (30.0 mmol) of 2-chloro-4- (trifluoromethyl) benzaldehyde in 117 ml of diethyl ether, and the mixture is warmed to room temperature and stirred at room temperature overnight. The reaction mixture was added to water and ethyl acetate, the phases were separated, the aqueous phase was extracted three times with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase toluene/ethyl acetate 95/5) to yield 5.00 g (61% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.81(d，1H)，7.69(s，1H)，7.56(d，1H)，5.53(d，1H)，4.09(dd，1H)，0.97-1.07(m，1H)，0.36-0.50(m，4H)。

Example 151A

(4-chloro-2-fluorophenyl) (cyclopropyl) methanol

1.00 g (6.31 mmol) of 4-chloro-2-fluorobenzaldehyde are introduced into 20 ml of diethyl ether at 0 ℃ and 19 ml (9.46 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in THF are added and the mixture is stirred at room temperature overnight. The reaction mixture was added to water, the phases separated, the aqueous phase extracted twice with ethyl acetate, the combined organic phases dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water) to yield 730 mg (58% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.55(t，1H)，7.34(dd，1H)，7.28(dd，1H)，5.38(d，1H)，4.31(dd，1H)，1.03-1.13(m，1H)，0.24-0.49(m，4H)。

LC-MS (method 9): r_t1.08 min; ms (esipos): m/z 183[ M-OH]⁺。

Example 152A

(2-chloro-4-methylphenyl) (cyclopropyl) methanol

51.3 mg (1.36 mmol) of sodium borohydride are added under argon to 320 mg (1.23 mmol) of the compound from example 125A in 5 ml of ethanol and 1 ml of ethyl acetate, and the mixture is stirred for 2 hours at 40 ℃. A further 46.6 mg (1.23 mmol) of sodium borohydride was then added and the mixture was stirred at 40 ℃ overnight. The reaction mixture was added to saturated aqueous ammonium chloride and diethyl ether, the phases were separated, the aqueous phase was extracted twice with diethyl ether, the combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated. 307 mg of the title compound were obtained, which was reacted without further purification.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.39(d，1H)，7.24(d，1H)，7.06(dd，1H)，5.26(d，1H)，4.58(dd，1H)，2.30(s，3H)，1.05-1.15(m，1H)，0.30-0.40(m，4H)。

LC-MS (method 9): r_t1.11 minutes; ms (esipos): 179[ M-O ] M/zH]⁺。

Example 153A

Cyclopropyl- (4-chlorophenyl) methanol

1.50 g (10.67 mmol) of 4-chlorobenzaldehyde are dissolved in 20 ml of diethyl ether at 0 ℃ and 32.0 ml (16.00 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran are slowly added dropwise. Stir at 0 ℃ for 1 hour, then warm to RT, add water and ethyl acetate to the reaction solution, and separate the phases. The organic phase was dried over sodium sulfate, the solid was filtered off, and the solvent was removed in vacuo. The crude product is purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 1.21 g (62% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.29-0.49(m，4H)，0.94-1.04(m，1H)，3.97(dd，1H)，5.25(d，1H)，7.36(d，2H)，7.40(d，2H)。

LC-MS (method 9): r_t0.95 min; ms (esipos): m/z is 165[ M-OH]⁺。

Example 154A

Cyclopropyl- (2, 4-difluorophenyl) methanol

The title compound was prepared in analogy to the synthesis of the compound from example 153A starting from 1.50 g (10.55 mmol) of 2, 4-difluorobenzaldehyde and 31.7 ml (15.83 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran. 0.33 g (17% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.22-0.49(m，4H)，1.03-1.14(m，1H)，4.29(dd，1H)，5.33(d，1H)，7.03-7.18(m，2H)，7.56(dd，1H)。

LC-MS (method 9): r_t0.90 min; ms (esipos): m/z 167[ M-OH]⁺。

Example 155A

Cyclopropyl- (2-chloro-4-fluorophenyl) methanol

The title compound was prepared in analogy to the synthesis of the compound from example 153A starting from 1.50 g (9.46 mmol) of 2-chloro-4-fluorobenzaldehyde and 28.4 ml (14.19 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran. 1.51 g (80% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.33-0.40(m，4H)，1.05-1.15(m，1H)，4.59(t，1H)，5.36(d，1H)，7.23(dt，1H)，7.35(dd，1H)，7.61(dd，1H)。

LC-MS (method 9): r_t0.99 min; ms (esipos): m/z 183[ M-OH]⁺。

Example 156A

(4-chloro-2, 6-difluorophenyl) (cyclopropyl) methanol

2.00 g (11.33 mmol) of 4-chloro-2, 6-difluorobenzaldehyde are dissolved at 0 ℃ in 15 ml of diethyl ether and 34.0 ml (16.99 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran are slowly added dropwise. After stirring at room temperature for 2 hours, the reaction solution was mixed with 1N hydrochloric acid and ethyl acetate, and the phases were separated. The aqueous phase was extracted three times with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution and the solvent was removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 1.20 g (48% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.04-0.12(m，1H)，0.33-0.48(m，2H)，0.53-0.62(m，1H)，1.31-1.42(m，1H)，4.06(dd，1H)，5.51(d，1H)，7.27-7.34(m，2H)。

LC-MS (method 6): r_t1.97 min; ms (esipos): m/z is 201[ M-OH]⁺。

Example 157A

Cyclopropyl (2, 2-difluoro-1, 3-benzodioxol-5-yl) methanol

The title compound was prepared starting from 3.50 g (18.81 mmol) of 2, 2-difluoro-5-formylbenzodioxolane and 56.4 ml (28.21 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran in analogy to the synthesis of the compound from example 156A. 1.59% (37% of theory) of the title compound is obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.31-0.49(m，4H)，3.99(dd，1H)，5.33(d，1H)，7.20(dd，1H)，7.32(d，1H)，7.38(d，1H)。

LC-MS (method 9): r_t1.00 min; ms (esipos): 211[ M-OH ] M/z]⁺。

Example 158A

2- [ hydroxy (4-methylphenyl) methyl ] cyclopropanecarbonitrile [ trans-diastereomer mixture ]

607 mg (16.0 mmol) of sodium borohydride are added under argon to 2.70 g (14.6 mmol) of the compound from example 126A in 60 ml of ethanol and 16 ml of ethyl acetate, and the mixture is stirred for 2 hours at 40 ℃. The reaction mixture was added to water and extracted with dichloromethane and the organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to give 2.56 g (94% of theory) of the diastereomer mixture of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.24-7.29(m，2H)，7.12-7.17(m，2H)，5.48(d，0.5H)，5.43(d，0.5H)，4.37(t，0.5H)，4.18(t，0.5H)，2.29(s，3H)，1.66-1.77(m，2H)，1.09-1.18(m，2H)。

Example 159A

(4-chlorophenyl) (2, 2-difluorocyclopropyl) methanol

336 mg (8.89 mmol) of sodium borohydride are added under argon to 1.75 g (8.08 mmol) of the compound from example 124A in 33 ml of ethanol and 9 ml of ethyl acetate, and the mixture is stirred for 1 hour at 40 ℃. The reaction mixture was added to saturated aqueous ammonium chloride and diethyl ether, the phases were separated, the aqueous phase was extracted twice with diethyl ether, the combined organic phases were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. 1.44 g (82% of theory) of the diastereomeric mixture of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.44-7.49(m，2H)，7.37-7.42(m，2H)，5.75(d，1H)，4.28(dd，1H)，1.90-2.03(m，1H)，1.33-1.54(m，2H)。

Example 160A

2- { hydroxy [4- (trifluoromethyl) phenyl ] methyl } cyclopropanecarbonitrile [ trans-diastereomer mixture ]

298 mg (7.88 mmol) of sodium borohydride are added under argon to 1.71 g (7.17 mmol) of the compound from example 122A in 30 ml of ethanol and 7 ml of ethyl acetate, and the mixture is stirred for 1 hour at 40 ℃. The reaction mixture was added to saturated aqueous ammonium chloride solution and ethyl acetate, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude product is purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to give 1.64 g (95% of theory) of the diastereomeric mixture of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.70-7.75(m，2H)，7.60-7.65(m，2H)，5.79(d，0.5H)，5.74(d，0.5H)，4.54(t，0.5H)，4.34(t，0.5H)，1.73-1.85(m，2H)，1.13-1.26(m，2H)。

Example 161A

2- [ (2-chloro-4-fluorophenyl) (hydroxy) methyl ] cyclopropanecarbonitrile [ trans-diastereomeric mixture ]

409 mg (10.8 mmol) of sodium borohydride are added under argon to 2.20 g (9.84 mmol) of the compound from example 127A in 180 ml of ethanol and 60 ml of ethyl acetate, and the mixture is stirred for 2 hours at 40 ℃. The reaction mixture was added to dichloromethane, the phases were separated and the organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to yield 1.52 g (69% of theory) of the diastereomer mixture of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.65(d，0.5H)，7.57(d，0.5H)，7.44(t，0.5H)，7.41(t，0.5H)，7.22-7.31(m，1H)，5.80(d，0.5H)，5.76(d，0.5H)，4.96(t，0.5H)，4.73(t，0.5H)，1.77-1.88(m，1.5H)，1.66-1.73(m，0.5H)，1.08-1.23(m，2H)。

LC-MS (method 4): r_t1.01 minutes; ms (esipos): m/z is 208[ M-OH]⁺。

Example 162A

2- [ (2, 4-difluorophenyl) (hydroxy) methyl ] cyclopropanecarbonitrile [ trans-diastereomer mixture ]

342 mg (9.03 mmol) of sodium borohydride are added under argon to 1.70 g (8.21 mmol) of the compound from example 123A in 35 ml of ethanol and 15 ml of ethyl acetate, and the mixture is stirred for 1 hour at 40 ℃. The reaction mixture was added to saturated aqueous ammonium chloride solution and ethyl acetate, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude product is purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 9/1) to yield 1.50 g (87% of theory) of the diastereomeric mixture of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.49-7.61(m，1H)，7.18-7.26(m，1H)，7.07-7.15(m，1H)，5.75(d，0.5H)，5.70(d，0.5H)，4.71(t，0.5H)，4.48(t，0.5H)，1.77-1.87(m，1.5H)，1.62-1.69(m，0.5H)，1.12-1.22(m，1.5H)，1.04-1.11(m，0.5H)。

Example 163A

2- [ (4-chloro-2-methoxyphenyl) (hydroxy) methyl ] cyclopropanecarbonitrile [ trans-diastereomer mixture ]

49.1 mg (1.30 mmol) of sodium borohydride are added under argon to 278 mg (1.18 mmol) of the compound from example 128A in 23 ml of ethanol and 10 ml of ethyl acetate, and the mixture is stirred for 1 hour at 40 ℃. The reaction mixture was added to saturated aqueous ammonium chloride solution and ethyl acetate, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over magnesium sulfate, filtered and concentrated. 190 mg (68% of theory) of the diastereomeric mixture of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.40(d，0.5H)，7.35(d，0.5H)，6.99-7.08(m，2H)，5.48(d，0.5H)，5.45(d，0.5H)，4.85(t，0.5H)，4.65(t，0.5H)，3.84(s，1.5H)，3.82(s，1.5H)，1.71-1.82(m，1H)，1.58-1.70(m，1H)，1.08-1.17(m，1H)，1.01-1.07(m，1H)。

Example 164A

2- { [ 2-fluoro-4- (trifluoromethyl) phenyl ] (hydroxy) methyl } cyclopropanecarbonitrile [ trans-diastereomer mixture ]

351 mg (9.28 mmol) of sodium borohydride are added under argon to 2.17 g (8.44 mmol) of the compound from example 129A in 38 ml of ethanol and 16 ml of ethyl acetate, and the mixture is stirred for 1 hour at 40 ℃. The reaction mixture was added to saturated aqueous ammonium chloride solution and ethyl acetate, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude product is purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 9/1) to yield 1.59 g (73% of theory) of the diastereomeric mixture of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.70-7.81(m，1H)，7.60-7.70(m，2H)，5.93(d，0.5H)，5.88(d，0.5H)，4.83(t，0.5H)，4.60(t，0.5H)，1.80-1.90(m，1.5H)，1.69-1.76(m，0.5H)，1.10-1.26(m，2H)。

Example 165A

2- [ (4-chloro-2-fluorophenyl) (hydroxy) methyl ] cyclopropanecarbonitrile [ trans-diastereomeric mixture ]

1.01 g (26.6 mmol) of sodium borohydride are added under argon to 5.40 g (24.1 mmol) of the compound from example 130A in 99 ml of ethanol and 25 ml of ethyl acetate, and the mixture is stirred for 45 minutes at 40 ℃. The reaction mixture was added to saturated aqueous ammonium chloride and diethyl ether, the phases were separated, the aqueous phase was extracted twice with diethyl ether, the combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated. 5.25 g (96% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.56(t，0.5H)，7.51(t，0.5H)，7.43(dd，0.5H)，7.40(dd，0.5H)，7.33(dd，0.5H)，7.31(dd，0.5H)，5.80(d，0.5H)，5.74(d，0.5H)，4.73(t，0.5H)，4.50(t，0.5H)，1.76-1.87(m，1.5H)，1.63-1.70(m，0.5H)，1.05-1.22(m，2H)。

Example 166A

2- [ (2-fluoro-4-methylphenyl) (hydroxy) methyl ] cyclopropanecarbonitrile [ trans-diastereomer mixture ]

61.0 mg (1.62 mmol) of sodium borohydride are added under argon to 300 mg (1.48 mmol) of the compound from example 131A in 30 ml of ethanol and 13 ml of ethyl acetate, and the mixture is stirred for 1 hour at 40 ℃. The reaction mixture was added to saturated aqueous ammonium chloride solution and ethyl acetate, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over magnesium sulfate, filtered and concentrated. 280 mg (92% of theory) of the diastereomeric mixture of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.40(t，0.5H)，7.36(t，0.5H)，6.96-7.05(m，2H)，5.62(d，0.5H)，5.58(d，0.5H)，4.70(t，0.5H)，4.48(t，0.5H)，1.74-1.84(m，1.5H)，1.58-1.65(m，0.5H)，1.10-1.20(m，1.5H)，1.03-1.10(m，0.5H)。

Example 167A

2- [ (4-chlorophenyl) (hydroxy) methyl ] cyclopropanecarbonitrile [ trans-diastereomer mixture ]

736 mg (19.5 mmol) of sodium borohydride are added under argon to 4.85 g (17.7 mmol) of the compound from example 74A in 73 ml of ethanol and 18 ml of ethyl acetate, and the mixture is stirred for 2 hours at 40 ℃. The reaction mixture was added to saturated aqueous ammonium chloride and diethyl ether, the phases were separated, the aqueous phase was extracted twice with diethyl ether, the combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated. The crude product is purified by flash chromatography on silica gel (mobile phase: toluene/ethanol 9/1) to yield 2.79 g (76% of theory) of a diastereomeric mixture of the title compound.

¹H-NMR(400MHz，DMSO-d₆)δ＝7.38-7.44(m，4H)，5.66(d，0.5H)，5.61(d，0.5H)，4.43(t，0.5H)，4.23(t，0.5H)，1.70-1.80(m，2H)，1.10-1.20(m，2H)。

Example 168A

3- (3, 5-Difluorophenoxy) propan-1-ol

2.77 g (69.18 mmol) of sodium hydride (60% in mineral oil) are dissolved in 80 ml of DMF. 7.50 g (57.65 mmol) of 3, 5-difluorophenol in 15 ml of DMF are added dropwise at 0 ℃ and, after the gas has decayed, the mixture is stirred at room temperature for 30 minutes. The solution was cooled to 0 ℃, 5.45 g (57.65 mmol) of 3-chloro-1-propanol in 15 ml of DMF was added, and the mixture was then stirred at 60 ℃ for 2 hours and at 75 ℃ for 16 hours. The precipitated salt was filtered off and the DMF was removed in a rotary evaporator. The residue was taken up in water and extracted twice with ether. The combined organic phases were washed successively with water, 1N aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered, and the solvent was removed in vacuo. The crude product is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient) to give 8.15 g (75% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆): δ is 1.84 (quintuple, 2H), 3.54(dd, 2H), 4.06(t, 2H), 4.57(t, 1H), 6.66-6.79(m, 3H).

LC-MS (method 4): r_t0.98 min.

Example 169A

3- (3, 5-Difluorophenoxy) propionic acid

At about-20 ℃, 17.22 g (172.18 mmol) of chromium (VI) oxide was contained in 1.2 l of acetone and 38 ml of water, and 19 ml of concentrated sulfuric acid was slowly added to the mixture. The mixture is stirred for 10 minutes and then 8.10 g (43.05 mmol) of the compound from example 168A in 400 ml of acetone are added dropwise over the course of 1 hour. The mixture was stirred at 0 ℃ for 1.5 hours. After addition of 90 ml of propan-2-ol, the reaction mixture was filtered through celite, the solvent was removed from the filtrate in vacuo, and the residue was taken up in 500 ml of diethyl ether. The solution was washed twice with saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was removed in vacuo. 11.36 g of the title compound are obtained, which is reacted further in the next stage without further purification.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.69(t，2H)，4.19(t，2H)，6.68-6.81(m，3H)，12.4(s，1H)。

LC-MS (method 6): r_t1.76 min; ms (esineg): m/z is 201[ M-OH]⁺。

Example 170A

5, 7-difluoro-2, 3-dihydro-4H-benzopyran-4-one

0.5 ml of DMF and 7.35 ml (84.29 mmol) of oxalyl chloride are slowly added dropwise at room temperature to a solution of 11.36 g (42.15 mmol) of the compound from example 169A in 400 ml of dichloromethane. After stirring at room temperature for 3 hours, the solvent was removed in a rotary evaporator and the residue was taken up again in 200 ml of dichloromethane. 6.74 g (50.57 mmol) of aluminum trichloride were added in portions to the reaction mixture, and the mixture was stirred for 1 hour. 150 ml of 2N hydrochloric acid and 200 ml of dichloromethane are added, the phases are separated and the aqueous phase is extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered, and the solvent was removed in vacuo. The crude product is purified by flash chromatography on silica gel (mobile phase: dichloromethane). 6.46 g (80% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.77(t，2H)，4.57(t，2H)，6.81-6.95(m，2H)。

GC-MS (method 7): r_t4.45 minutes; ms (eipos): 184[ M ] M/z]⁺。

Example 171A

5, 7-difluoro-4-methyl-3, 4-dihydro-2H-benzopyran-4-ol

2.00 g (10.86 mmol) of the compound from example 170A are dissolved in 40 ml of diethyl ether at 0 ℃ and 5.4 ml (16.29 mmol) of a 3N solution of methylmagnesium bromide in diethyl ether are slowly added dropwise. Stir at 0 ℃ for 1 hour, then warm to RT, add water and ether to the reaction solution and separate the phases. The aqueous phase was extracted with ether, the combined organic phases were dried over sodium sulfate and filtered, and the solvent was removed in vacuo. The crude product is purified by flash chromatography on silica gel (mobile phase: dichloromethane). 2.03 g (93% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.56(d，3H)，1.92-1.96(m，2H)，4.12-4.22(m，2H)，5.25(s，1H)，6.51(dt，1H)，6.64-6.72(m，1H)。

GC-MS (method 7): r_t3.88 minutes; ms (eipos): m/z is 200[ M%]⁺。

Example 172A

4-cyclopropyl-5, 7-difluoro-3, 4-dihydro-2H-benzopyran-4-ol

2.00 g (10.86 mmol) of the compound from example 170A are dissolved in 40 ml of diethyl ether at 0 ℃ and 32.6 ml (16.29 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran are slowly added dropwise. Stir at 0 ℃ for 1 hour, then warm to RT, add water and ether to the reaction solution and separate the phases. The aqueous phase was extracted with ether, the combined organic phases were dried over sodium sulfate and filtered, and the solvent was removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). Acetonitrile was removed from the combined product phases in a rotary evaporator and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered, and the solvent was removed in vacuo. 0.66 g (27% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.24-0.33(m，2H)，0.45-0.51(m，1H)，0.74-0.84(m，1H)，1.15-1.25(m，1H)，1.82-1.95(m，2H)，4.14-4.29(m，2H)，5.02(s，1H)，6.51(d，1H)，6.62-6.70(m，1H)。

Example 173A

4- [ (4-fluorophenyl) (hydroxy) methyl ] benzonitrile

5.00 g (28.57 mmol) of 4-bromobenzene are dissolved in 100 ml of tetrahydrofuran at-78 ℃. A1.6N solution of 21.4 ml (34.29 mmol) of N-butyllithium in hexane was added, followed by stirring for 15 minutes and then 4.50 g (34.29 mmol) of 4-cyanobenzaldehyde dissolved in 30 ml of tetrahydrofuran was added dropwise. The mixture was stirred at-78 ℃ for 1 hour, warmed to room temperature and then stirred for 1 hour. The reaction solution was mixed with water and ethyl acetate, and the phases were separated. The aqueous phase was extracted three times with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the solid was filtered. The solvent was removed in vacuo and the crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). Acetonitrile was removed from the product-containing fractions in a rotary evaporator and the aqueous residue was extracted with dichloromethane. Removal of the solvent gave 2.37 g (36% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝5.81(d，1H)，6.19(d，1H)，7.10-7.17(m，2H)，7.37-7.44(m，2H)，7.57(d，2H)，7.78(d，2H)。

LC-MS (method 9): r_t0.94 min; ms (esipos): 210[ M-OH ] M/z]⁺。

Example 174A

4- [ (4-chlorophenyl) (hydroxy) methyl ] benzonitrile

0.67 g (27.42 mmol) of magnesium turnings are dried by heating under argon, cooled to RT, and 30 ml of tetrahydrofuran and 2 ml of dibromoethane are added. At 0 deg.C, 5.00 g (26.12 mmol) of 4-chlorobromobenzene in 30 mL of tetrahydrofuran was slowly added to the mixture, and the mixture was stirred at room temperature for 30 minutes. 3.77 g (28.73 mmol) of 4-cyanobenzaldehyde in 30 ml of tetrahydrofuran was added, followed by stirring for 3 hours. THF was removed from the reaction solution in a rotary evaporator and the residue was taken up in dichloromethane. It was washed with 1N hydrochloric acid, dried over sodium sulfate and filtered, and the solvent was removed in vacuo. The precipitate which separated from the oily residue was filtered off, washed with diethyl ether and then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). Acetonitrile was removed from the product-containing fractions in a rotary evaporator and the aqueous residue was extracted with dichloromethane. Removal of the solvent gave 1.43 g (23% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝5.81(d，1H)，6.23(d，1H)，7.35-7.42(m，4H)，7.57(d，2H)，7.78(d，2H)。

LC-MS (method 5): r_t2.20 minutes; ms (esipos): 226[ M-OH ] M/z]⁺。

Example 175A

(4-chlorophenyl) (4-methoxyphenyl) methanol

5.00 g (26.12 mmol) of 4-chlorobromobenzene are dissolved in 100 ml of tetrahydrofuran at-78 ℃. 19.6 ml (31.34 mmol) of a 1.6N solution of N-butyllithium in hexane are added, followed by stirring for 15 minutes and then 4.27 g (31.34 mmol) of 4-methoxybenzaldehyde dissolved in 30 ml of tetrahydrofuran are added dropwise. The mixture was stirred at-78 ℃ for 1 hour, warmed to room temperature and then stirred for 1 hour. The reaction solution was mixed with water and ethyl acetate, and the phases were separated. The aqueous phase was extracted three times with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the solid was filtered. The solvent was removed in vacuo and the crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). Acetonitrile was removed from the product-containing fractions in a rotary evaporator and the aqueous residue was extracted with dichloromethane. Removal of the solvent gave 4.20 g (65% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝3.71(s，3H)，5.64(d，1H)，5.86(d，1H)，6.83-6.88(m，2H)，7.22-7.26(m，2H)，7.35(s，4H)。

LC-MS (method 3): r_t1.92 minutes; ms (esipos): m/z 231[ M-OH]⁺。

Example 176A

(4-chloro-3-fluorophenyl) (4-fluorophenyl) methanol

The title compound was prepared starting from 5.00 g (28.57 mmol) of 4-bromofluorobenzene and 5.44 g (34.29 mmol) of 3-fluoro-4-chlorobenzaldehyde in analogy to the synthesis of the compound from example 175A. 5.01 g (69% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝5.74(s，1H)，6.16(d，1H)，7.10-7.17(m，2H)，7.20(dd，1H)，7.36-7.44(m，3H)，7.51(t，1H)。

LC-MS (method 9): r_t1.11 minutes; DCI-MS (ESIpos): 237[ M-H ] M/z₂O+H]⁺。

Example 177A

(3-chloro-4-fluorophenyl) (4-chlorophenyl) methanol

The title compound was prepared starting from 5.00 g (26.12 mmol) of 4-chlorobromobenzene and 4.97 g (31.34 mmol) of 4-fluoro-3-chlorobenzaldehyde in analogy to the synthesis of the compound from example 175A. 5.57 g (77% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝5.74(d，1H)，6.17(d，1H)，7.31-7.42(m，6H)，7.55(d，1H)。

LC-MS (method 4): r_t1.34 minutes; ms (esipos): 253[ M-OH ] M/z]⁺。

Example 178A

(4-chloro-2, 6-difluorophenyl) (4-fluorophenyl) methanol

5.00 g (21.98 mmol) of 2-bromo-5-chloro-1, 3-dibromobenzene are dissolved in 100 ml of tetrahydrofuran at-78 ℃. 16.5 ml (26.38 mmol) of a 1.6N solution of N-butyllithium in hexane are added, followed by stirring for 15 minutes and then 3.27 g (26.38 mmol) of 4-fluorobenzaldehyde dissolved in 30 ml of tetrahydrofuran are added dropwise. The mixture was stirred at-78 ℃ for 1 hour, warmed to room temperature and subsequently stirred for 1 hour. The reaction solution was mixed with water and ethyl acetate, and the phases were separated. The aqueous phase was extracted three times with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the solid was filtered. The solvent was removed in vacuo and the crude product was purified twice by preparative HPLC (mobile phase: acetonitrile/water gradient) and once by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4/1). The solvent was removed from the product-containing fractions in a rotary evaporator and the aqueous residue was extracted with dichloromethane. Removal of the solvent gave 0.80 g (13% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝6.03(d，1H)，6.28(d，1H)，7.11-7.18(m，2H)，7.29-7.41(m，4H)。

LC-MS (method 4): r_t1.28 minutes; ms (esipos): m/z 255[ M-OH]⁺。

Example 179A

Bis (4-chloro-2-fluorophenyl) methanol

The title compound was prepared starting from 5.00 g (23.87 mmol) of 4-chloro-2-fluorobenzene and 4.54 g (28.65 mmol) of 4-chloro-2-fluorobenzaldehyde in analogy to the synthesis of the compound from example 175A. The difference is that the crude product is pre-separated by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient) before purification by preparative HPLC. 1.79 g (26% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝6.09(s，1H)，6.31(d，1H)，7.30(dd，2H)，7.34-7.40(m，2H)，7.45-7.53(m，2H)。

LC-MS (method 4): r_t1.38 minutes; ms (esipos): m/z 271[ M-OH]⁺。

Practice ofExample 180A

(4-chloro-2-fluorophenyl) (4-fluoro-2-methylphenyl) methanol

The title compound was prepared starting from 5.00 g (26.45 mmol) of 2-bromo-5-fluorotoluene and 5.03 g (31.74 mmol) of 4-chloro-2-fluorobenzaldehyde in analogy to the synthesis of the compound from example 175A. Except that the crude product was purified twice by preparative HPLC. 4.84 g (65% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.23(s，3H)，6.01(s，2H)，6.96-7.03(m，2H)，7.26-7.43(m，4H)。

LC-MS (method 4): r_t1.33 minutes; ms (esipos): 251[ M-OH ] M/z]⁺。

Example 181A

(4-chloro-2-fluorophenyl) (2, 4-difluorophenyl) methanol

The title compound was prepared starting from 5.00 g (25.91 mmol) of 2, 4-difluorobromobenzene and 4.93 g (31.09 mmol) of 4-chloro-2-fluorobenzaldehyde in analogy to the synthesis of the compound from example 175A. 3.34 g (47% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝6.19(d，1H)，6.38(d，1H)，6.99-7.07(m，2H)，7.30(dd，1H)，7.33-7.42(m，2H)，7.82(d，1H)。

LC-MS (method 4): r_t1.26 minutes; ms (esipos): m/z 255[ M-OH]⁺。

Example 182A

1- (4-chlorophenyl) -1- (4-fluorophenyl) ethanol

The title compound was prepared starting from 5.00 g (28.57 mmol) of 4-bromofluorobenzene and 4.86 g (31.43 mmol) of 4-chloroacetophenone in analogy to the synthesis of the compound from example 176A. The difference is that a preliminary separation by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 9/1) is carried out before the crude product is purified by preparative HPLC. 5.23 g (73% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.81(s，3H)，5.86(s，1H)，7.06-7.13(m，2H)，7.31-7.36(m，2H)，7.39-7.45(m，4H)。

LC-MS (method 3): r_t2.12 minutes; ms (esipos): m/z 233[ M-OH]⁺。

Example 183A

1- (4-chloro-2-fluorophenyl) -1- (4-fluorophenyl) ethanol

The title compound was prepared starting from 4.22 g (24.14 mmol) of 4-bromofluorobenzene and 5.00 g (28.97 mmol) of 4-chloro-2-fluoroacetophenone in analogy to the synthesis of the compound from example 176A. Except that the crude product was purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 9/1). 5.23 g (73% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.84(s，3H)，5.98(s，1H)，7.06-7.13(m，2H)，7.25(dd，1H)，7.29-7.38(m，3H)，7.77(t，1H)。

LC-MS (method 4): r_t1.32 minutes; ms (esipos): 251[ M-OH ] M/z]⁺。

Example 184A

1- [4- (trifluoromethyl) phenyl ] prop-2-en-1-ol

A solution of 75.0 g (431 mmol) of 4- (trifluoromethyl) benzaldehyde in 750 ml of diethyl ether is slowly added dropwise at room temperature under argon to a 1N solution of 517 ml (517 mmol) of vinyl magnesium bromide in tetrahydrofuran. After heating under reflux for 1 hour, the reaction mixture was added to saturated aqueous ammonium chloride solution and extracted with tert-butyl methyl ether. The organic phase was dried, filtered and concentrated. The crude product is purified by column chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate 9/1) to yield 87.0 g (100% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.67-7.71(m，2H)，7.54-7.58(m，2H)，5.95(ddd，1H)，5.74(d，1H)，5.30(d，1H)，5.18(t，1H)，5.10(d，1H)。

GC-MS (method 7): r_t3.10 minutes; ms (eipos): 202[ M ] M/z]⁺。

Example 185A

1- (2, 4-dichlorophenyl) prop-2-en-1-ol

A solution of 20.0 g (114 mmol) of 2, 4-dichlorobenzaldehyde in 200 ml of diethyl ether is slowly added dropwise at room temperature under argon to a 1N solution of 137 ml (137 mmol) of vinyl magnesium bromide in tetrahydrofuran. After heating under reflux for 1 hour, the reaction mixture was added to saturated aqueous ammonium chloride solution and diluted with ether and water. The phases were separated and the organic phase was washed twice with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5/1) to yield 18.8 g (81% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.52-7.57(m，2H)，7.44(dd，1H)，5.91(ddd，1H)，5.80(d，1H)，5.37(t，1H)，5.24(dt，1H)，5.10(dt，1H)。

Example 186A

1- [4- (trifluoromethyl) phenyl ] prop-2-en-1-one

A solution of 18.0 g (89.0 mmol) of the compound from example 184A in 360 ml of dichloromethane is added dropwise at room temperature to a solution of 45.3 g (107 mmol) of 1, 1, 1-triacetoxy-1, 1-dihydro-1, 2-benzidoxol-3 (1H) -one in 360 ml of dichloromethane. After stirring at room temperature for 1 hour, the reaction mixture was added to a mixture of saturated aqueous sodium bicarbonate and sodium thiosulfate and extracted three times with dichloromethane. The organic phase was dried, filtered and concentrated. 17.5 g (98% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.16-8.20(m，2H)，7.90-7.95(m，2H)，7.40(dd，1H)，6.40(dd，1H)，6.10(dd，1H)。

GC-MS (method 7): r_t2.88 minutes; ms (eipos): m/z is 200[ M%]⁺。

Example 187A

1- (2, 4-dichlorophenyl) prop-2-en-1-one

73.5 g (362 mmol) of the compound from example 185A are mixed with 105 g (1.21 mol) of activated manganese dioxide in 2.2 l of dichloromethane and heated at reflux for 20 hours. After 2 and 4 hours, a further 105 g (1.21 mol) of activated manganese dioxide were added in each case. Filtration through celite was done with suction, washing with dichloromethane and concentration yielded 57.0 g of a mixture consisting of the title compound and the compound from example 185A. 47.7 g (162 mmol) of potassium dichromate are added to 47.0 g of the mixture in 329 ml of 10% strength sulfuric acid, the mixture is cooled occasionally at 15-20 ℃ and the mixture is stirred for 1.5 hours. This was followed by addition of 400 ml of ethyl acetate, neutralization by addition of sodium bicarbonate, filtration through celite, washing with ethyl acetate, separation of the phases, drying of the organic phase and concentration. The crude product was purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 6/1) to yield 17.8 g (55%) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.77(d，1H)，7.52-7.59(m，2H)，6.75(dd，1H)，6.23(d，1H)，6.06(d，1H)。

GC-MS (method 7): r_t4.55 minutes; ms (eipos): m/z is 200[ M%]⁺。

Example 188A

2, 2-Difluorocyclopropyl) [4- (trifluoromethyl) phenyl ] methanone

10.0 g (50.0 mmol) of the compound from example 186A are stirred with 210 mg (5.00 mmol) of sodium fluoride at 110 ℃ under argon for 5 minutes, 25.0 g (99.9 mmol) of trimethylsilyl 2, 2-difluoro-2- (fluorosulfonyl) acetate are slowly added in small portions, and the mixture is stirred at 110 ℃ for 20 minutes. The reaction mixture was then mixed with saturated aqueous sodium bicarbonate and ethyl acetate, the phases were separated and the organic phase was dried and concentrated. The crude product is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4/1) to yield 6.80 g (54% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.22-8.27(m，2H)，7.93-7.98(m，2H)，4.08(ddd，1H)，2.24-2.34(m，1H)，2.07-2.18(m，1H)。

GC-MS (method 7): r_t3.15 minutes; ms (eipos): 250[ M ] M/z]⁺。

Example 189A

(2, 4-dichlorophenyl) (2, 2-difluorocyclopropyl) methanone

The title compound was prepared starting from 20.0 g (99.5 mmol) of the compound from example 187A in analogy to the synthesis of the compound from example 188A. 13.4 g (54% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.81(d，1H)，7.72(d，1H)，7.62(dd，1H)，3.70(ddd，1H)，2.24-2.34(m，1H)，2.08-2.19(m，1H)。

GC-MS (method 7): r_t4.83 minutes; ms (eipos): 250[ M ] M/z ]⁺。

Example 190A

(2, 2-Difluorocyclopropyl) [4- (trifluoromethyl) phenyl ] methanol

1.13 g (29.9 mmol) of sodium borohydride are added under argon to a solution of 6.80 g (27.2 mmol) of the compound from example 188A in 111 ml of ethanol and 29 ml of ethyl acetate, and the mixture is stirred at 40 ℃ for 1 hour. The reaction mixture was then added to ethyl acetate and saturated aqueous ammonium chloride and stirred for 10 minutes. The phases were separated and the organic phase was washed with saturated aqueous sodium chloride, dried and concentrated. The crude product is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4/1) to yield 2.50 g (37% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.65-7.74(m，3.4H)，7.61-7.65(m，0.3H)，7.50-7.54(m，0.3H)，5.89(d，0.85H)，5.55(d，0.15H)，4.55(dd，0.15H)，4.39(dd，0.85H)，1.96-2.06(m，1H)，1.43-1.55(m，2H)。

Example 191A

(2, 4-dichlorophenyl) (2, 2-difluorocyclopropyl) methanol

The title compound was prepared starting from 9.00 g (35.8 mmol) of the compound from example 189A in analogy to the synthesis of the compound from example 190A. 7.30 g (80% of theory) of diastereomer 1 of the title compound and 1.10 g (12% of theory) of diastereomer 2 of the title compound are obtained.

Diastereomer 191A-1:

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.69(d，1H)，7.59(d，1H)，7.49(dd，1H)，5.95(d，1H)，4.74(dd，1H)，2.07-2.19(m，1H)，1.48-1.58(m，1H)，1.28-1.38(m，1H)。

diastereomer 191A-2:

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.65(d，1H)，7.59(d，1H)，7.48(dd，1H)，5.83(d，1H)，4.74-4.80(m，1H)，2.04-2.16(m，1H)，1.61-1.71(m，1H)，1.50-1.60(m，1H)。

example 192A

(2, 2-Difluorocyclopropyl) [4- (trifluoromethyl) phenyl ] methyl acetate

0.23 ml (2.86 mmol) of pyridine are added dropwise to 2.40 g (9.52 mmol) of the compound from example 190A and 1.94 g (19.0 mmol) of acetic anhydride and the mixture is stirred at room temperature overnight. The reaction mixture was then added to ethyl acetate and saturated aqueous sodium bicarbonate. The phases are separated, the organic phase is concentrated and the crude product is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 6/1). 2.66 g (95% of theory) of the title compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.74-7.80(m，2H)，7.68-7.73(m，1.8H)，7.57-7.61(m，0.2H)，5.57(d，0.1H)，5.53(d，0.9H)，2.33-2.46(m，1H)，2.09(s，3H)，1.74-1.84(m，1H)，1.60-1.71(m，1H)。

Example 193A

(2, 4-dichlorophenyl) (2, 2-difluorocyclopropyl) methyl acetate

The title compound was prepared starting from 8.20 g (32.4 mmol) of a mixture of two diastereomers of the compound from example 191A, in analogy to the synthesis of the compound from example 192A. 7.70 g (81% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.64-7.68(m，2H)，7.51(dd，1H)，5.75(d，1H)，2.41-2.50(m，1H)，2.07(s，3H)，1.67-1.79(m，1H)，1.47-1.57(m，1H)。

Working examples are as follows:

example 1

3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } -3- [4- (trifluoromethyl) phenyl ] propan-1-ol

A solution of 215 mg (0.51 mmol) of the compound from example 25A is added dropwise at room temperature under argon to a 1.8 ml (1.80 mmol) solution of lithium aluminum hydride in tetrahydrofuran in 10 ml of tetrahydrofuran. The mixture was stirred at room temperature for 15 minutes, and then, while cooling with ice, 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient) gives 169 mg (87% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.94(s，3H)，2.10-2.20(m，1H)，2.28-2.38(m，1H)，3.30-3.42(m，2H)，3.91(s，2H)，4.43(t，1H)，4.50(t，1H)，6.83(t，1H)，6.91(d，1H)，7.27(d，1H)，7.35(d，1H)，7.52-7.57(m，2H)，7.58-7.62(m，2H)，11.0(s，1H)。

LC-MS (method 4): r_t1.33 minutes; ms (esipos): 380[ M + H ] M/z]⁺。

Example 2

3- (4-chlorophenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propan-1-ol

6.68 g (17.2 mmol) of the compound from example 29A in 100 ml of tetrahydrofuran are added dropwise at room temperature under argon to a 1N solution of 60 ml (60 mmol) of lithium aluminum hydride in 300 ml of tetrahydrofuran. The mixture was stirred at room temperature for 15 minutes, and then, while cooling with ice, 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient). 5.93 g (99% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.94(s，3H)，2.04-2.14(m，1H)，2.24-2.34(m，1H)，3.30-3.41(m，2H)，3.91(s，2H)，4.31(t，1H)，6.83(t，1H)，6.91(d，1H)，7.25(d，1H)，7.27-7.30(m，3H)，7.31-7.36(m，2H)，10.9(s，1H)。

LC-MS (method 5): r_t2.48 minutes; ms (esipos): 346[ M + H ] M/z]⁺。

Example 3

3- (4-chlorophenyl) -3- {7- [ (ethylsulfanyl) methyl ] -1H-indol-3-yl } propan-1-ol

A solution of 1.05 g of the compound from example 33A with a purity of 84% (2.19 mmol) in 20 ml of tetrahydrofuran is added dropwise under argon at room temperature to a 1N solution of 9.1 ml (9.1 mmol) of lithium aluminum hydride in tetrahydrofuran in 50 ml of tetrahydrofuran. The mixture was stirred at room temperature for 15 minutes, and then, while cooling with ice, 1N hydrochloric acid was added. The mixture was extracted with dichloromethane and the organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 0.95 g (94% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.15(t，3H)，2.04-2.14(m，1H)，2.24-2.34(m，1H)，2.38(q，2H)，3.29-3.42(m，2H)，3.91-3.99(m，2H)，4.31(t，1H)，4.48(t，1H)，6.83(t，1H)，6.92(d，1H)，7.23-7.36(m，6H)，10.9(s，1H)。

LC-MS (method 4): r_t1.36 minutes; ms (esipos): m/z is 360[ M + H ]]⁺。

Example 4

3- (4-chloro-2-fluorophenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propan-1-ol

A solution of 2.23 g (5.49 mmol) of the compound from example 34A in 20 ml of tetrahydrofuran is added dropwise at room temperature under argon to a 1N solution of 19.2 ml (19.2 mmol) of lithium aluminum hydride in 50 ml of tetrahydrofuran. The mixture was stirred at room temperature for 15 minutes, and then 1N hydrochloric acid was added. The mixture was extracted with dichloromethane and the organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 1.89 g (95% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.94(s，3H)，2.08-2.19(m，1H)，2.26-2.35(m，1H)，3.34-3.41(m，2H)，3.91(s，2H)，4.50(t，1H)，4.61(t，1H)，6.86(t，1H)，6.93(d，1H)，7.17(dd，1H)，7.24-7.30(m，2H)，7.33(dd，1H)，7.37(t，1H)，11.0(s，1H)。

LC-MS (method 5): r_t2.47 minutes; ms (esipos): 364[ M + H ] M/z]⁺。

Enantiomer 4-1:

2.20 g of enantiomer 34A-2 with 90% purity (4.88 mmol) were reacted in analogy to the synthesis of the compound from example 4. 1.50 g (85% of theory) of the enantiomer of the title compound were obtained.

[α]_D ²⁰53.0 deg., c 0.204 deg., chloroform

Example 5

3- (4-chloro-2-fluorophenyl) -2-methyl-3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propan-1-ol

A solution of 200 mg of the compound from example 36A with a purity of 90% (0.35 mmol) in 4 ml of tetrahydrofuran is added dropwise at room temperature under argon to a 1.2 ml (1.2 mmol) solution of lithium aluminum hydride in tetrahydrofuran in 2 ml of tetrahydrofuran. The mixture was stirred at room temperature for 15 minutes, and then 1N hydrochloric acid was added. The mixture was extracted with dichloromethane and the organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 66 mg (51% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.83(d，1.8H)，0.97(d，1.2H)，1.94(s，3H)，2.46-2.60(m，1H)，3.06-3.14(m，0.4H)，3.22-3.28(m，0.6H)，3.28-3.35(m，0.4H)，3.45-3.51(m，0.6H)，3.86-3.95(m，2H)，4.26-4.34(m，1H)，4.42-4.47(m，1H)，6.85-6.94(m，2H)，7.14-7.18(m，1H)，7.26-7.40(m，3H)，7.46(t，0.6H)，7.52(t，0.4H)，11.0(s，1H)。

LC-MS (method 3): r_t2.21 and 2.28 minutes; ms (esipos): 378[ M + H ] M/z]⁺。

Example 6

3- (4-chloro-2-fluorophenyl) -3- { 5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propan-1-ol

A solution of 1.1 g (2.57 mmol) of the compound from example 37A in 20 ml of tetrahydrofuran is added dropwise at room temperature under argon to a 1N solution of 9.0 ml (9.0 mmol) of lithium aluminum hydride in tetrahydrofuran in 50 ml of tetrahydrofuran. The mixture was stirred at room temperature for 15 minutes, and then 1N hydrochloric acid was added. The mixture was extracted with dichloromethane and the organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to yield 715 mg (73% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.95(s，3H)，2.09-2.19(m，1H)，2.25-2.35(m，1H)，3.33-3.42(m，2H)，3.91(s，2H)，4.50(t，1H)，4.55(t，1H)，6.83(dd，1H)，6.98(dd，1H)，7.19(dd，1H)，7.31-7.37(m，2H)，7.41(t，1H)，11.1(s，1H)。

LC-MS (method 3): r_t2.19 minutes; ms (esipos): 382[ M + H ] M/z]⁺。

Example 7

3- (2, 4-dichlorophenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propan-1-ol

A solution of 2.34 g (5.54 mmol) of the compound from example 38A in 20 ml of tetrahydrofuran is added dropwise at room temperature under argon to a 1N solution of 19.4 ml (19.4 mmol) of lithium aluminum hydride in tetrahydrofuran in 50 ml of tetrahydrofuran. The mixture was stirred at room temperature for 15 minutes, and then 1N hydrochloric acid was added. The mixture was extracted with dichloromethane and the organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 2.00 g (95% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.94(s，3H)，2.04-2.15(m，1H)，2.23-2.35(m，1H)，3.34-3.46(m，2H)，3.87-3.96(m，2H)，4.50(t，1H)，4.76(t，1H)，6.85(t，1H)，6.93(d，1H)，7.24(d，1H)，7.28-7.32(m，2H)，7.36(d，1H)，7.55(d，1H)，11.0(s，1H)。

LC-MS (method 4): r_t1.38 minutes; ms (esipos): 380[ M + H ] M/z]⁺。

Example 8

3- (2, 4-dichlorophenyl) -3- { 5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propan-1-ol

A solution of 1.48 g (3.36 mmol) of the compound from example 39A in 20 ml of tetrahydrofuran is added dropwise at room temperature under argon to a 1N solution of 11.8 ml (11.8 mmol) of lithium aluminum hydride in tetrahydrofuran in 50 ml of tetrahydrofuran. The mixture was stirred at room temperature for 15 minutes, and then 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate, filtered and concentrated. 1.32 g (99% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.96(s，3H)，2.05-2.15(m，1H)，2.24-2.35(m，1H)，3.34-3.45(m，2H)，3.87-3.96(m，2H)，4.51(t，1H)，4.71(t，1H)，6.83(dd，1H)，6.95(dd，1H)，7.32(dd，1H)，7.37-7.41(m，2H)，7.56(d，1H)，11.1(s，1H)。

LC-MS (method 4): r_t1.39 minutes; ms (esipos): 398[ M + H ] M/z]⁺。

Example 9

3- (4-chlorophenyl) -3- { 5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propan-1-ol

1.29 g of a solution of the compound from example 40A with a purity of 79% (2.52 mmol) in 30 ml of tetrahydrofuran are added dropwise at room temperature under argon to a 1N solution of 11.1 ml (11.1 mmol) of lithium aluminum hydride in tetrahydrofuran in 70 ml of tetrahydrofuran. The mixture was stirred at room temperature for 15 minutes, and then 1N hydrochloric acid was added. The mixture was extracted with dichloromethane and the organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 0.68 g (74% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.95(s，3H)，2.03-2.14(m，1H)，2.21-2.32(m，1H)，3.28-3.41(m，2H)，3.91(s，2H)，4.27(t，1H)，4.47(t，1H)，6.81(dd，1H)，6.99(dd，1H)，7.28-7.37(m，4H)，7.38(d，1H)，11.1(s，1H)。

LC-MS (method 6): r_t2.40 minutes; ms (esipos): 364[ M + H ] M/z]⁺

Example 10

3- (4-chloro-2-methylphenyl) -3- {7- [ (ethylsulfanyl) methyl ] -1H-indol-3-yl } propan-1-ol

A solution of 2.23 g (5.49 mmol) of the compound from example 41A in 20 ml of tetrahydrofuran is added dropwise at room temperature under argon to a 1N solution of 5.7 ml (5.7 mmol) of lithium aluminum hydride in tetrahydrofuran in 50 ml of tetrahydrofuran. The mixture was stirred at room temperature for 15 minutes, and then 1N hydrochloric acid was added. The mixture was extracted with dichloromethane and the organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to yield 458 mg (76% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.15(t，3H)，1.96-2.06(m，1H)，2.21-2.32(m，1H)，2.39(q，2H)，2.42(s，3H)，3.32-3.46(m，2H)，3.92-4.00(m，2H)，4.48-4.54(m，2H)，6.83(t，1H)，6.92(d，1H)，7.11(dd，1H)，7.15-7.22(m，4H)，10.9(s，1H)。

LC-MS (method 5): r_t2.64 min; ms (esipos): 374[ M + H ] M/z]⁺。

Example 11

3- (4-chloro-2-methylphenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propan-1-ol

The title compound was prepared starting from 1.62 g (4.03 mmol) of the compound from example 42A in analogy to the synthesis of the compound from example 4. 1.4 g (97% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.94(s，3H)，1.96-2.06(m，1H)，2.21-2.32(m，1H)，2.42(s，3H)，3.30-3.46(m，2H)，3.87-3.96(m，2H)，4.48-4.55(m，2H)，6.83(t，1H)，6.91(d，1H)，7.11(dd，1H)，7.15-7.22(m，4H)，10.9(s，1H)。

LC-MS (method 4): r_t1.35 minutes; ms (esipos): m/z is 360[ M + H ]]⁺。

Example 12

3- (4-fluoro-2-methylphenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propan-1-ol

A solution of 585 mg (1.52 mmol) of the compound from example 43A in 15 ml of tetrahydrofuran is added dropwise at room temperature under argon to a 1N solution of 5.3 ml (5.31 mmol) of lithium aluminum hydride in tetrahydrofuran in 30 ml of tetrahydrofuran. The mixture was stirred at room temperature for 15 minutes, and then, while cooling with ice, 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to yield 369 mg (71% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.94(s，3H)，1.96-2.07(m，1H)，2.21-2.32(m，1H)，2.43(s，3H)，3.29-3.46(m，2H)，3.88-3.96(m，2H)，4.46-4.54(m，2H)，6.83(t，1H)，6.86(dd，1H)，6.91(d，1H)，6.97(dd，1H)，7.17-7.23(m，3H)，10.9(s，1H)。

LC-MS (method 4): r_t1.28 minutes; ms (esipos): 344[ M + H ] M/z]⁺。

Example 13

3- [ 2-fluoro-4- (trifluoromethyl) phenyl ] -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propan-1-ol

A solution of 2.74 g (6.13 mmol) of the compound from example 44A in 20 ml of tetrahydrofuran is added dropwise at room temperature under argon to a 1N solution of 21.5 ml (21.5 mmol) of lithium aluminum hydride in tetrahydrofuran in 50 ml of tetrahydrofuran. Stirring is carried out at room temperature for 15 minutes, 1N hydrochloric acid is subsequently added, extraction is carried out with dichloromethane, the organic phase is dried over magnesium sulfate, filtered and concentrated. 2.47 g (99% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.94(s，3H)，2.14-2.24(m，1H)，2.31-2.41(m，1H)，3.33-3.46(m，2H)，3.92(s，2H)，4.50-4.56(m，1H)，4.72(t，1H)，6.87(t，1H)，6.93(d，1H)，7.29(d，1H)，7.34(d，1H)，7.47(d，1H)，7.56-7.63(m，2H)，11.0(s，1H)。

L-MS (method 4): r_t1.36 minutes; ms (esipos): 398[ M + H ] M/z]⁺。

Example 14

3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } -3- (naphthalen-2-yl) propan-1-ol

A solution of 600 mg (1.49 mmol) of the compound from example 45A in 15 ml of tetrahydrofuran is added dropwise at room temperature under argon to a 1N solution of 5.2 ml (5.2 mmol) of lithium aluminum hydride in tetrahydrofuran in 30 ml of tetrahydrofuran. Stirring was carried out at room temperature for 15 minutes, followed by addition of 1N hydrochloric acid while cooling with ice, extraction with ethyl acetate, drying of the organic phase with magnesium sulfate, filtration and concentration. 486 mg (90% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.92(s，3H)，2.19-2.29(m，1H)，2.33-2.44(m，1H)，3.35-3.45(m，2H)，3.87-3.95(m，2H)，4.45-4.50(m，2H)，6.79(t，1H)，6.88(d，1H)，7.31(d，1H)，7.35(d，1H)，7.39-7.48(m，3H)，7.75-7.87(m，4H)，10.9(s，1H)。

LC-MS (method 5): r_t2.48 minutes; ms (esipos): 362[ M + H ] M/z]⁺。

Example 15

4- (4-chlorophenyl) -4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butan-1-ol

A solution of 420 mg (1.05 mmol) of the compound from example 46A in 10 ml of tetrahydrofuran is added dropwise at room temperature under argon to a 1N solution of 3.7 ml (3.7 mmol) of lithium aluminum hydride in tetrahydrofuran in 20 ml of tetrahydrofuran. The mixture was stirred at room temperature for 15 minutes, and then, while cooling with ice, 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid). 243 mg (65% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.28-1.50(m，2H)，1.92-2.03(m，1H)，1.94(s，3H)，2.07-2.19(m，1H)，3.38-3.44(m，2H)，3.91(s，2H)，4.12(t，1H)，4.36(t，1H)，6.83(t，1H)，6.90(d，1H)，7.25-7.31(m，4H)，7.32-7.36(m，2H)，10.9(s，1H)。

LC-MS (method 4): r_t1.36 minutes; ms (esipos): m/z is 360[ M + H ]]⁺。

Example 16

3- (4-chlorophenyl) -3- { 6-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propan-1-ol

A solution of 2.33 g (5.7 mmol) of the compound from example 47A in 18 ml of tetrahydrofuran is added dropwise at room temperature to 20.1 ml (60.1 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran and 20 ml of tetrahydrofuran. The mixture was stirred at 60 ℃ for 1 hour, acetonitrile was added, and water was added to the solution while cooling with ice. The solid is filtered off from the suspension by suction, the filtrate is concentrated and the residue is purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 1.72 g (82% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.98(s，3H)，2.02-2.13(m，1H)，2.22-2.32(m，1H)，3.29-3.41(m，2H)，3.94(s，2H)，4.30(t，1H)，4.48(t，1H)，6.75(dd，1H)，7.22(dd，1H)，7.26-7.37(m，5H)，11.09(s，1H)。

LC-MS (method 3): r_t2.16 minutes; ms (esipos): 364[ M + H ] M/z]⁺。

Example 17

3- { 6-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } -3- [4- (trifluoromethyl) phenyl ] propan-1-ol

The title compound was prepared starting from 2.98 g (6.78 mmol) of the compound from example 48A in analogy to the synthesis of the compound from example 16. 2.47 g (92% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.98(s，3H)，2.07-2.18(m，1H)，2.26-2.38(m，1H)，3.29-3.43(m，2H)，3.95(s，2H)，4.42(t，1H)，4.51(t，1H)，6.76(t，1H)，7.24(dd，1H)，7.37(s，1H)，7.54(d，2H)，7.61(d，2H)，11.13(s，1H)。

LC-MS (method 3): r_t2.23 minutes; MS (ESIp)os)：m/z＝398[M+H]⁺。

Example 18

3- (1-benzothien-5-yl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propan-1-ol

The title compound was prepared starting from 1.17 g (2.87 mmol) of the compound from example 49A in analogy to the synthesis of the compound from example 16. 0.93 g (88% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.93(s，3H)，2.13-2.24(m，1H)，2.31-2.41(m，1H)，3.34-3.44(m，2H)，3.91(s，2H)，4.39-4.49(m，2H)，6.80(t，1H)，6.89(d，1H)，7.26-7.40(m，4H)，7.68(d，1H)，7.80-7.86(m，2H)，10.91(s，1H)。

LC-MS (method 4): r_t1.29 minutes; ms (esipos): 368[ M + H ] M/z]⁺。

Example 19

3- (2-bromo-1, 3-thiazol-5-yl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propan-1-ol

A solution of 1.19 g (2.71 mmol) of the compound from example 50A in 25 ml of tetrahydrofuran is added dropwise at room temperature to 8.13 ml (8.13 mmol) of a 1N solution of diisobutylaluminum hydride in heptane/tetrahydrofuran and 25 ml of tetrahydrofuran. The mixture was stirred at room temperature for 1 hour, and the solution was mixed with ethyl acetate, water and 1N hydrochloric acid. The phases were separated, the aqueous phase was extracted three times with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution. After this time, it was dried over sodium sulfate, the solid was removed by filtration and the solvent was removed from the crude product in vacuo. Purification of the residue by preparative HPLC (mobile phase: acetonitrile/water gradient) gives 0.73 g (68% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.95(s，3H)，2.12-2.35(m，2H)，3.35-3.45(m，2H)，3.93(s，2H)，4.57(t，1H)，4.68(t，1H)，6.90(t，1H)，6.96(d，1H)，7.31(d，1H)，7.36(d，1H)，7.59(s，1H)，11.05(s，1H)。

LC-MS (method 5): r_t2.16 minutes; ms (esipos): m/z ═ 397[ M + H ]]⁺。

Example 20

2-methyl-3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } -3- [4- (trifluoromethyl) phenyl ] propan-1-ol

The title compound was prepared starting from 0.97 g (2.23 mmol) of the compound from example 28A in analogy to the synthesis of the compound from example 19. 0.66 g (75% of theory) of the title compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.76-1.01(m，3H)，1.94(s，3H)，2.47-2.57(m，1H)，3.01-3.50(m，2H)，3.90(s，2H)，4.10-4.17(m，1H)，4.40-4.49(m，1H)，6.81-6.94(m，2H)，7.34-7.45(m，2H)，7.55-7.63(m，4H)，10.97(s，1H)。

LC-MS (method 4): r_t1.37/1.39 min; ms (esipos): 394[ M + H ] M/z]⁺。

Example 21

3- (4-chlorophenyl) -2-methyl-3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl) propan-1-ol

The title compound was prepared starting from 395 mg (0.98 mmol) of the compound from example 32A in analogy to the synthesis of the compound from example 19. 222 mg (63% of theory) of the title compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.76-0.99(m，3H)，1.94(s，3H)，2.40-3.48(m，3H)，3.90(s，2H)，4.00-4.06(m，1H)，4.37-4.46(m，1H)，6.81-6.93(m，2H)，7.23-7.42(m，6H)，10.93(s，1H)。

LC-MS (method 6): r_t2.40/2.45 min; ms (esipos): m/z is 360[ M + H ]]⁺。

Example 22

3- (4-chloro-2-fluorophenyl) -3- { 5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } propan-1-ol

60 mg (0.16 mmol) of the compound from example 6 are introduced into 2 ml of dichloromethane at 0 ℃, 79.4 mg (0.32 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 27 mg (42% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.10-2.20(m，1H)，2.25-2.35(m，1H)，2.91(s，3H)，3.32-3.42(m，2H)，4.51(t，1H)，4.57(t，1H)，4.70-4.78(m，2H)，6.99(dd，1H)，7.12(dd，1H)，7.20(dd，1H)，7.34(dd，1H)，7.39-7.45(m，2H)，11.2(s，1H)。

LC-MS (method 3): r_t1.78 minutes; ms (esipos): m/z 414[ M + H ]]⁺。

Example 23

3- (2, 4-dichlorophenyl) -3- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } propan-1-ol

100 mg (0.26 mmol) of the compound from example 7 are introduced into 15 ml of dichloromethane at 0 ℃, 130 mg (0.53 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. 2 ml of methanol are added, concentrated, the residue is taken up in dichloromethane and saturated aqueous sodium bicarbonate, the phases are separated, the organic phase is washed twice with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, the organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 50 mg (46% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.05-2.15(m，1H)，2.25-2.35(m，1H)，2.88(s，3H)，3.35-3.45(m，2H)，4.51(t，1H)，4.67-4.76(m，2H)，4.78(t，1H)，6.95(t，1H)，7.10(d，1H)，7.30(dd，1H)，7.33-7.40(m，3H)，7.56(d，1H)，11.1(s，1H)。

LC-MS (method 5): r_t2.17 minutes; ms (esipos): m/z 412[ M + H ═ M]⁺。

Example 24

3- (2, 4-dichlorophenyl) -3- { 5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } propan-1-ol

100 mg (0.25 mmol) of the compound from example 8 are introduced into 15 ml of dichloromethane at 0 ℃, 124 mg (0.50 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 51 mg (47% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.05-2.16(m，1H)，2.24-2.34(m，1H)，2.91(s，3H)，3.33-3.43(m，2H)，4.52(t，1H)，4.69-4.79(m，3H)，6.99(dd，1H)，7.08(dd，1H)，7.33(dd，1H)，7.40(d，1H)，7.46(s，1H)，7.57(d，1H)，11.2(s，1H)。

LC-MS (method 3): r_t1.89 minutes; ms (esipos): 430[ M + H ] M/z]⁺。

Example 25

3- (4-chlorophenyl) -3- { 5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } propan-1-ol

75.0 mg (0.21 mmol) of the compound from example 9 are introduced into 12 ml of dichloromethane at 0 ℃, 102 mg (0.41 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 42 mg (52% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.04-2.14(m，1H)，2.22-2.32(m，1H)，2.90(s，3H)，3.28-3.41(m，2H)，4.29(t，1H)，4.48(t，1H)，4.69-4.78(m，2H)，6.97(dd，1H)，7.13(dd，1H)，7.28-7.37(m，4H)，7.47(d，1H)，11.2(s，1H)。

LC-MS (method 6): r_t2.06 minutes; ms (esipos): 396[ M + H ] M/z]⁺。

Example 26

3- (4-chloro-2-methylphenyl) -3- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } propan-1-ol

100 mg (0.28 mmol) of the compound from example 11 are introduced into 15 ml of dichloromethane at 0 ℃, 137 mg (0.56 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. 2 ml of methanol are added, concentrated, the residue is taken up in dichloromethane and saturated aqueous sodium bicarbonate, the phases are separated, the organic phase is washed twice with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, the organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 40 mg (37% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.96-2.06(m，1H)，2.21-2.31(m，1H)，2.42(s，3H)，2.87(s，3H)，3.28-3.46(m，2H)，4.50-4.56(m，2H)，4.66-4.76(m，2H)，6.93(t，1H)，7.07-7.14(m，2H)，7.17-7.23(m，2H)，7.26-7.30(m，2H)，11.0(s，1H)。

LC-MS (method 5): r_t2.13 minutes; ms (esipos): 392[ M + H ] M/z]⁺。

Example 27

4- (4-chlorophenyl) -4- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } butan-1-ol

40 mg (0.11 mmol) of the compound from example 15 are introduced into 7 ml of dichloromethane at 0 ℃, 54.8 mg (0.22 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight and then under reflux for 15 minutes. 2 ml of methanol were added, the mixture was concentrated, the residue was taken up in dichloromethane and saturated aqueous sodium bicarbonate, the phases were separated, the organic phase was washed twice with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 20 mg (46% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.28-1.50(m，2H)，1.92-2.03(m，1H)，2.08-2.19(m，1H)，2.87(s，3H)，3.41(t，2H)，4.14(t，1H)，4.36(s，1H)，4.66-4.75(m，2H)，6.92(t，1H)，7.08(d，1H)，7.27-7.31(m，2H)，7.32-7.40(m，4H)，11.0(s，1H)。

LC-MS (method 8): r_t2.09 minutes; ms (esineg): 390[ M-H ] M/z]^-。

Example 28

3- (1-benzothien-5-yl) -3- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } propan-1-ol

100 mg (0.27 mmol) of the compound from example 18 are introduced at 0 ℃ into 19 ml of dichloromethane, 134 mg (0.54 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol were added and the solvent was removed in vacuo. The crude product was purified three times by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 23 mg (21% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.13-2.24(m，1H)，2.31-2.41(m，1H)，2.86(s，3H)，3.33-3.43(m，2H)，4.40-4.50(m，2H)，4.71(s，2H)，6.89(t，1H)，7.07(d，1H)，7.31-7.42(m，4H)，7.69(d，1H)，7.81-7.86(m，2H)，11.01(s，1H)。

HPLC (method 2): r_t4.16 minutes; ms (esipos): m/z 400[ M + H ]]⁺。

Example 29

3- (4-chlorophenyl) -2-methyl-3- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } propan-1-ol

The title compound was prepared starting from 57 mg (0.15 mmol) of the compound from example 21 in analogy to the synthesis of the compound from example 28. 46 mg (77% of theory) of the title compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.76-0.99(m，3H)，2.40-3.46(m，3H)，2.87(s，3H)，4.01-4.09(m，1H)，4.37-4.47(m，1H)，4.70(s，2H)，6.95(t，1H)，7.09(d，1H)，7.24-7.29(m，2H)，7.33-7.54(m，4H)，11.02(s，1H)。

LC-MS (method 4): r_t1.10/1.15 min; ms (esipos): 392[ M + H ] M/z]⁺。

Example 30

3- (4-chloro-2-fluorophenyl) -3- { 5-fluoro-7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } propan-1-ol

60 mg (0.16 mmol) of the compound from example 6 are introduced into 2 ml of dichloromethane at 0 ℃, 40.7 mg (0.17 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 29 mg (46% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.09-2.20(m，1H)，2.25-2.35(m，1H)，2.52-2.54(m，3H)，3.32-3.42(m，2H)，4.18-4.25(m，1H)，4.33-4.39(m，1H)，4.51(t，1H)，4.56(t，1H)，6.89(dd，1H)，7.07(d，1H)，7.20(dd，1H)，7.34(dd，1H)，7.38-7.44(m，2H)，11.2(s，1H)。

LC-MS (method 5): r_t2.02 minutes; ms (esipos): 398[ M + H ] M/z]⁺。

Example 31

3- (2, 4-dichlorophenyl) -3- {7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } propan-1-ol

75.9 mg (0.20 mmol) of the compound from example 7 are introduced into 11 ml of dichloromethane at 0 ℃, 49.2 mg (0.20 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. 2 ml of methanol are added, concentrated, the residue is taken up in dichloromethane and saturated aqueous sodium bicarbonate, the phases are separated, the organic phase is washed twice with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, the organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 50 mg (63% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.04-2.15(m，1H)，2.25-2.35(m，1H)，2.52(s，3H)，3.33-3.46(m，2H)，4.18-4.25(m，1H)，4.31-4.38(m，1H)，4.51(t，1H)，4.77(t，1H)，6.91(t，1H)，7.00(d，1H)，7.27-7.39(m，4H)，7.55(d，1H)，11.1(s，1H)。

LC-MS (method 5): r_t2.06 minutes; ms (esipos): 396[ M + H ] M/z]⁺。

Example 32

3- (2, 4-dichlorophenyl) -3- { 5-fluoro-7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } propan-1-ol

100 mg (0.25 mmol) of the compound from example 8 are introduced into 15 ml of dichloromethane at 0 ℃, 61.9 mg (0.25 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 91 mg (88% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.05-2.15(m，1H)，2.24-2.34(m，1H)，2.53-2.54(m，3H)，3.34-3.45(m，2H)，4.18-4.26(m，1H)，4.33-4.40(m，1H)，4.52(t，1H)，4.72(t，1H)，6.89(d，1H)，7.03(d，1H)，7.33(dd，1H)，7.39(d，1H)，7.44(s，1H)，7.56(d，1H)，11.2(s，1H)。

LC-MS (method 3): r_t1.76 min; ms (esipos): m/z 414[ M + H ]]⁺。

Example 33

3- (4-chlorophenyl) -3- { 5-fluoro-7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } propan-1-ol

75.0 mg (0.21 mmol) of the compound from example 9 are introduced into 12 ml of dichloromethane at 0 ℃, 50.8 mg (0.21 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase acetonitrile/water gradient, addition of 0.1% formic acid) to yield 25 mg (30% of theory) of the title compound contaminated with m-chlorobenzoic acid. It is taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated to give 23 mg (29% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.03-2.14(m，1H)，2.22-2.32(m，1H)，2.52-2.53(m，3H)，3.28-3.40(m，2H)，4.18-4.25(m，1H)，4.28(t，1H)，4.32-4.39(m，1H)，4.49(s，1H)，6.86(dd，1H)，7.05-7.09(m，1H)，7.28-7.37(m，4H)，7.45(s，1H)，11.2(s，1H)。

LC-MS (method 3): r_t1.61 minutes; ms (esipos): 380[ M + H ] M/z]⁺。

Example 34

4- (4-chlorophenyl) -4- {7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } butan-1-ol

40 mg (0.11 mmol) of the compound from example 15 are introduced into 7 ml of dichloromethane at 0 ℃, 27.4 mg (0.11 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. 2 ml of methanol are added, concentrated, the residue is taken up in dichloromethane and saturated aqueous sodium bicarbonate, the phases are separated, the organic phase is washed twice with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, the organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 33 mg (79% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.28-1.50(m，2H)，1.92-2.03(m，1H)，2.09-2.19(m，1H)，2.51(s，3H)，3.38-3.44(m，2H)，4.14(t，1H)，4.19-4.24(m，1H)，4.29-4.38(m，2H)，6.88(t，1H)，6.98(d，1H)，7.25-7.31(m，2H)，7.32-7.36(m，4H)，11.1(s，1H)。

LC-MS (method 6): r_t1.97 min; ms (esipos): m/z 376[ M + H ═ M]⁺。

Example 35

4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } -4- [4- (trifluoromethyl) phenyl ] butanenitrile

28.5 g (0.44 mmol) of potassium cyanide are added to 100 mg (0.22 mmol) of the compound from example 51A in 5 ml of DMF. The mixture was stirred at 80 ℃ for 2 hours and then concentrated, the residue taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient, addition of 0.1% formic acid) gives 77 mg (91% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.94(s，3H)，2.31-2.39(m，1H)，2.41-2.46(m，2H)，2.47-2.55(m，1H)，3.92(s，2H)，4.35(t，1H)，6.86(t，1H)，6.94(d，1H)，7.30(d，1H)，7.44(d，1H)，7.57-7.61(m，2H)，7.62-7.65(m，2H)，11.1(s，1H)。

LC-MS (method 4): r_t1.43 minutes; ms (esipos): 389[ M + H ═ M/z]⁺。

Example 36

4- (4-chlorophenyl) -4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butanenitrile

2.12 g (32.5 mmol) of potassium cyanide are added to 6.90 g (16.3 mmol) of the compound from example 52A in 345 ml of DMF. The mixture was stirred at 80 ℃ for 4 hours and then concentrated, the residue taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient). 5.05 g (87% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.94(s，3H)，2.25-2.34(m，1H)，2.38-2.48(m，3H)，3.91(s，2H)，4.20-4.26(m，1H)，6.85(t，1H)，6.93(d，1H)，7.28(d，1H)，7.30-7.34(m，2H)，7.35-7.41(m，3H)，11.0(s，1H)。

LC-MS (method 3): r_t2.31 minutes; ms (esipos): 355[ M + H ] M/z]⁺。

Example 37

4- (4-chlorophenyl) -4- {7- [ (ethylsulfanyl) methyl ] -1H-indol-3-yl } butanenitrile

152 mg (2.33 mmol) of potassium cyanide are added to 510 mg (1.16 mmol) of the compound from example 53A in 7 ml of DMF. The mixture was stirred at 80 ℃ for 2 h, after cooling, water was added, the mixture was extracted with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid). 222 mg (52% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.15(t，3H)，2.25-2.34(m，1H)，2.35-2.48(m，5H)，3.96(s，2H)，4.20-4.26(m，1H)，6.85(t，1H)，6.94(d，1H)，7.28(d，1H)，7.30-7.35(m，2H)，7.36-7.40(m，3H)，11.0(s，1H)。

LC-MS (method 4): r_t1.48 minutes; ms (esipos): m/z 369[ M + H ]]⁺。

Example 38

4- (4-chloro-2-fluorophenyl) -4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butanenitrile

572 mg (8.78 mmol) of potassium cyanide are added to 1.94 g (4.39 mmol) of the compound from example 54A in 26 ml of DMF. The mixture is stirred at 80 ℃ for 2 hours and then concentrated and the crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 1.30 g (79% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.94(s，3H)，2.24-2.38(m，1H)，2.45-2.51(m，3H)，3.92(s，2H)，4.51-4.57(m，1H)，6.89(t，1H)，6.95(d，1H)，7.20(dd，1H)，7.28(d，1H)，7.36-7.43(m，3H)，11.1(s，1H)。

LC-MS (method 5): r_t2.70 minutes; ms (esipos): m/z 373[ M + H ]]⁺。

Enantiomer 38-1:

554 mg (8.51 mmol) of potassium cyanide were added to 1.88 g (4.25 mmol) of enantiomer 54A-1 in 95 ml of DMF. The mixture was stirred at 80 ℃ for 2 hours and then concentrated, the residue taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid). 727 mg (46% of theory) of the corresponding enantiomer of the title compound were obtained.

Example 39

4- (4-chloro-2-fluorophenyl) -3-methyl-4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butanenitrile

16.2 mg (0.25 mmol) of potassium cyanide are added to 70 mg (0.12 mmol) of the compound from example 55A in 3 ml of DMSO. The mixture was stirred at 80 ℃ for 4 hours and then concentrated, the residue taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid). 33.4 mg (69% of theory) of the title compound are obtained as a mixture of diastereomers.

¹H-MR(400MHz，DMSO-d₆)：δ＝0.97(d，1.8H)，1.09(d，1.2H)，1.93-1.95(m，3H)，2.31(dd，0.4H)，2.46-2.55(m，1H)，2.65(dd，0.6H)，2.86-2.97(m，1H)，3.87-3.95(m，2H)，4.25-4.33(m，1H)，6.89-6.97(m，2H)，7.18-7.24(m，1H)，7.32-7.37(m，1H)，7.39-7.45(m，1.4H)，7.50-7.63(m，1.6H)，11.0(s，0.4H)，11.0(s，0.6H)。

LC-MS (method 3): r_t2.46 and 2.51 minutes; ms (esipos): m/z 387[ M + H ]]⁺。

[α]_D ²⁰48.0 deg., c 0.196 deg., chloroform

Example 40

4- (4-chloro-2-fluorophenyl) -4- { 5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butanenitrile

190 mg (2.91 mmol) of potassium cyanide and 8.9 mg (0.07 mmol) of 4-N, N-dimethylaminopyridine are added to 670 mg (1.46 mmol) of the compound from example 56A in 40 ml of DMSO. The mixture was stirred at 80 ℃ for 2 hours and then concentrated, the residue taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to yield 522 mg (92% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.95(s，3H)，2.25-2.37(m，1H)，2.44-2.52(m，3H)，3.92(s，2H)，4.44-4.50(m，1H)，6.85(dd，1H)，7.01(dd，1H)，7.22(dd，1H)，7.39(dd，1H)，7.41-7.47(m，2H)，11.2(s，1H)。

LC-MS (method 5): r_t2.76 min; ms (esipos): 391[ M + H ] M/z]⁺。

EXAMPLE 41

4- (2, 4-dichlorophenyl) -4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butanenitrile

563 mg (8.64 mmol) of potassium cyanide are added to 1.98 g (4.32 mmol) of the compound from example 57A in 26 ml of DMF. The mixture is stirred at 80 ℃ for 2 hours and then concentrated and the crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 1.42 g (84% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.95(s，3H)，2.21-2.31(m，1H)，2.41-2.58(m，3H)，3.88-3.96(m，2H)，4.67-4.76(m，1H)，6.88(t，1H)，6.95(d，1H)，7.25(d，1H)，7.33(dd，1H)，7.38(d，1H)，7.42(s，1H)，7.60(d，1H)，11.1(s，1H)。

LC-MS (method 3): r_t2.51 minutes; ms (esipos): 389[ M + H ═ M/z]⁺。

Example 42

4- (2, 4-dichlorophenyl) -4- { 5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butanenitrile

1.36 g (2.86 mmol) of the compound from example 58A and 372 mg (5.71 mmol) of potassium cyanide are dissolved in 65 ml of DMSO and stirred at 120 ℃ overnight. The mixture was concentrated and the residue taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to yield 790 mg (68% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.96(s，3H)，2.20-2.33(m，1H)，2.41-2.53(m，3H)，3.88-3.96(m，2H)，4.66(t，1H)，6.86(dd，1H)，6.97(dd，1H)，7.35(dd，1H)，7.43(d，1H)，7.49(d，1H)，7.61(d，1H)，11.2(s，1H)。

LC-MS (method 5): r_t2.87 min; ms (esipos): 407[ M + H ] M/z]⁺。

Example 43

4- (4-chlorophenyl) -4- { 5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butanenitrile

445 mg (1.01 mmol) of the compound from example 59A and 131 mg (2.01 mmol) of potassium cyanide are dissolved in 23 ml of DMF and stirred at 80 ℃ for three days. The mixture was concentrated and the residue taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to yield 102 mg (27% of theory) of the title compound. 180 mg (0.47 mmol) of 3- [ 3-chloro-1- (4-chlorophenyl) propyl ] -5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indole are furthermore obtained.

LC-MS (method 4): r_t1.59 minutes; ms (esipos): 382[ M + H ] M/z]⁺。

180 mg (0.47 mmol) of 3- [ 3-chloro-1- (4-chlorophenyl) propyl ] -5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indole and 61.3 mg (0.94 mmol) of potassium cyanide are dissolved in 11 ml of DMSO and stirred at 120 ℃ overnight. The mixture was concentrated and the residue taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to yield a further 140 mg (80% of theory) of the title compound, whereby the overall yield of the title compound is 242 mg (64% of theory).

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.95(s，3H)，2.24-2.34(m，1H)，2.36-2.49(m，3H)，3.91(s，2H)，4.19(t，1H)，6.83(dd，1H)，7.04(dd，1H)，7.31-7.41(m，4H)，7.48(d，1H)，11.2(s，1H)。

LC-MS (method 4): r_t1.42 minutes; ms (esipos): m/z 373[ M + H ]]⁺。

Example 44

4- (4-chloro-2-methylphenyl) -4- {7- [ (ethylsulfanyl) methyl ] -1H-indol-3-yl } butanenitrile

86.4 mg (1.33 mmol) of potassium cyanide are added to 300 mg (0.66 mmol) of the compound from example 60A in 4 ml of DMF. Stirring was carried out at 80 ℃ for 2 hours, then water was added, extraction was carried out with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to yield 207 mg (81% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.16(t，3H)，2.14-2.27(m，1H)，2.39(q，2H)，2.42(s，3H)，2.43-2.52(m，3H)，3.92-4.01(m，2H)，4.44(t，1H)，6.87(t，1H)，6.95(d，1H)，7.16(dd，1H)，7.20-7.29(m，4H)，11.0(s，1H)。

LC-MS (method 4): r_t1.52 min; ms (esipos): 383[ M + H ] M/z]⁺。

Example 45

4- (4-chloro-2-methylphenyl) -4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butanenitrile

419 mg (6.44 mmol) of potassium cyanide are added to 1.41 g (3.22 mmol) of the compound from example 61A in 20 ml of DMF. The mixture was stirred at 80 ℃ for 2 h and then concentrated and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to give 987 mg (83% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.94(s，3H)，2.14-2.27(m，1H)，2.36-2.52(m，3H)，2.43(s，3H)，3.88-3.96(m，2H)，4.44(t，1H)，6.87(t，1H)，6.94(d，1H)，7.16(dd，1H)，7.21-7.29(m，4H)，11.0(s，1H)。

LC-MS (method 3): r_t2.45 minutes; ms (esipos): m/z 369[ M + H ]]⁺。

Example 46

4- (4-fluoro-2-methylphenyl) -4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butanenitrile

90.8 mg (1.40 mmol) of potassium cyanide are added to 294 mg (0.70 mmol) of the compound from example 62A in 15 ml of DMF. The mixture was stirred at 80 ℃ for 4 hours and then concentrated, the residue taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 188 mg (77% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.95(s，3H)，2.15-2.25(m，1H)，2.36-2.48(m，3H)，2.43(s，3H)，3.88-3.96(m，2H)，4.41-4.46(m，1H)，6.87(t，1H)，6.89-6.96(m，2H)，7.01(dd，1H)，7.22-7.30(m，3H)，11.0(s，1H)。

LC-MS (method 4): r_t1.40 minutes; ms (esipos): 353[ M + H ] M/z]⁺。

Example 47

4- [ 2-fluoro-4- (trifluoromethyl) phenyl ] -4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butanenitrile

726 mg (11.1 mmol) of potassium cyanide are added to 2.65 g (5.57 mmol) of the compound from example 63A in 128 ml of DMF. The mixture was stirred at 80 ℃ for 2 hours and then concentrated, the residue taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. 1.46 g of the title compound are obtained with a purity of 85% (55% of theory).

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.94(s，3H)，2.32-2.41(m，1H)，2.43-2.60(m，3H)，3.92(s，2H)，4.61-4.67(m，1H)，6.90(t，1H)，6.95(d，1H)，7.30(d，1H)，7.44(d，1H)，7.51(d，1H)，7.60-7.66(m，2H)，11.1(s，1H)。

LC-MS (method 3): r_t2.45 minutes; ms (esipos): 407[ M + H ] M/z]⁺。

Example 48

4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } -4- (naphthalen-2-yl) butanenitrile

97.5 mg (1.50 mmol) of potassium cyanide are added to 329 mg (0.75 mmol) of the compound from example 64A in 15 ml of DMF. The mixture was stirred at 80 ℃ for 4 hours and then concentrated, the residue taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 181 mg (65% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.92(s，3H)，2.39-2.59(m，4H)，3.87-3.95(m，2H)，4.37-4.42(m，1H)，6.82(t，1H)，6.91(d，1H)，7.34(d，1H)，7.41-7.50(m，4H)，7.79-7.85(m，2H)，7.88(d，1H)，7.92(s，1H)，11.0(s，1H)。

LC-MS (method 3): r_t2.39 minutes; ms (esipos): 371[ M + H ] M/z]⁺。

Example 49

5- (4-chlorophenyl) -5- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } valeronitrile

91.9 mg (1.41 mmol) of potassium cyanide are added to 309 mg (0.71 mmol) of the compound from example 65A in 5 ml of DMF. The mixture was stirred at 80 ℃ for 2 hours, then concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid). The DMF was removed by holding the crude product in dichloromethane, washing twice with water and saturated aqueous sodium chloride, drying over magnesium sulfate, filtering and concentrating. 134 mg (52% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.41-1.63(m，2H)，1.94(s，3H)，2.00-2.11(m，1H)，2.16-2.27(m，1H)，2.50-2.56(m，2H)，3.91(s，2H)，4.20(t，1H)，6.84(t，1H)，6.92(d，1H)，7.26-7.33(m，4H)，7.34-7.38(m，2H)，11.0(s，1H)。

LC-MS (method 5): r_t＝2.78 minutes; ms (esipos): m/z 369[ M + H ]]⁺。

Example 50

4- (4-chlorophenyl) -4- { 6-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butanenitrile

0.46 g (7.01 mmol) of potassium cyanide are added to 1.55 g (3.50 mmol) of the compound from example 66A in 32 ml of DMF. The mixture was stirred at 80 ℃ for 3 hours, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The combined organic phases were dried over sodium sulfate, the solid was filtered off and the solvent was removed. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 1.00 g (77% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.98(s，3H)，2.21-2.49(m，4H)，3.95(s，2H)，4.19-4.25(m，1H)，6.78(dd，1H)，7.25(dd，1H)，7.29-7.46(m，5H)，11.19(s，1H)。

HPLC (method 1): r_t5.03 minutes; ms (esineg): 371[ M-H ] M/z]^-。

Example 51

4- { 6-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } -4- [4- (trifluoromethyl) phenyl ] butanenitrile

The title compound was prepared starting from 2.20 g (4.62 mmol) of the compound from example 67A in analogy to the synthesis of the compound from example 50. 1.66 g (88% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.98(s，3H)，2.28-2.48(m，4H)，3.95(s，2H)，4.33(t，1H)，6.78(dd，1H)，7.28(dd，1H)，7.48(s，1H)，7.59(d，2H)，7.64(d，2H)，11.23(s，1H)。

HPLC (method 1): r_t5.06 minutes; ms (esineg): 405[ M-H ] M/z]^-。

Example 52

4- (1-benzothien-5-yl) -4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butanenitrile

The title compound was prepared starting from 768 mg (1.72 mmol) of the compound from example 68A in analogy to the synthesis of the compound from example 50. 494 mg (76% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.93(s，3H)，2.32-2.56(m，4H)，3.91(s，2H)，4.34(t，1H)，6.83(t，1H)，6.91(d，1H)，7.28-7.44(m，4H)，7.71(d，1H)，7.85-7.90(m，2H)，11.02(s，1H)。

HPLC (method 1): r_t4.97 min; ms (esineg): m/z 375[ M-H ]]^-。

Example 53

4- (2-bromo-1, 3-thiazol-5-yl) -4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butanenitrile

14 mg (0.21 mmol) of potassium cyanide are added to 50 mg (0.11 mmol) of the compound from example 69A in 1 ml of DMF. The mixture was stirred at 80 ℃ for 5 hours, water was added to the reaction solution, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, the solid was filtered off and the solvent was removed. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 38 mg (89% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.96(s，3H)，2.32-2.53(m，4H)，3.93(s，2H)，4.60(t，1H)，6.92(t，1H)，6.98(d，1H)，7.36-7.42(m，2H)，7.68(s，1H)，11.15(s，1H)。

LC-MS (method 5): r_t2.40 minutes; ms (esipos): 406[ M + H ] M/z]⁺。

Example 54

3-methyl-4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } -4- [4- (trifluoromethyl) phenyl ] butanenitrile

The title compound was prepared starting from 620 mg (1.32 mmol) of the compound from example 70A in analogy to the synthesis of the compound from example 53 but using dimethylsulfoxide as solvent. 492 mg (93% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.91-1.13(m，3H)，1.95(s，3H)，2.17-2.70(m，2H)，2.87-2.99(m，1H)，3.90(s，2H)，4.06-4.12(m，1H)，6.86-6.96(m，2H)，7.44-7.70(m，6H)，11.04-11.11(s，1H)。

LC-MS (method 6): r_t2.68 minutes; ms (esipos): m/z 403[ M + H ]]⁺。

Example 55

4- (4-chlorophenyl) -3-methyl-4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butanenitrile

The title compound was prepared starting from 215 mg (0.49 mmol) of the compound from example 71A in analogy to the synthesis of the compound from example 53 but using dimethylsulfoxide as solvent. 177 mg (98% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.91-1.11(m，3H)，1.93(s，3H)，2.16-2.69(m，2H)，2.79-2.91(m，1H)，3.90(s，2H)，3.95-4.01(m，1H)，6.86-6.95(m，2H)，7.27-7.34(m，2H)，7.42-7.52(m，4H)，11.00-11.07(s，1H)。

LC-MS (method 4): r_t1.44/1.46 min; ms (esineg): 367[ M-H ] M/z]^-。

Example 56

4- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } -4- [4- (trifluoromethyl) phenyl ] butanenitrile

100 mg (0.26 mmol) of the compound from example 35 are introduced into 20 ml of dichloromethane at 0 ℃, 159 mg (0.64 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient, addition of 0.1% formic acid) to yield 51 mg (47% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.29-2.48(m，4H)，2.88(s，3H)，4.36(t，1H)，4.72(s，2H)，6.96(t，1H)，7.11(d，1H)，7.42(d，1H)，7.53(d，1H)，7.57-7.61(m，2H)，7.62-7.66(m，2H)，11.2(s，1H)。

LC-MS (method 5): r_t2.40 minutes; ms (esipos): 421[ M + H ] M/z]⁺。

The enantiomers were purified by preparative HPLC on chiral phase [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x20 mm; eluent: isohexane/isopropanol 6: 4; flow rate: 20 ml/min; temperature: 22 ℃; UV detection: 230 nm ] separation. The separated enantiomer was again purified by preparative HPLC on the achiral phase (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid):

enantiomer 56-1:

R_tafter 6.86 minutes [ column: daicel AD-H, 5 micron, 250 mm x4.6 mm; eluent: isohexane/isopropanol 6: 4; flow rate: 1.0 ml/min; temperature: 23 ℃; UV detection: 230 nm]；

Yield: 7.1 mg.

Enantiomer 56-2:

R_t7.71 min [ column: daicel AD-H, 5 micron, 250 mm x4.6 mm; eluent: isohexane/isopropanol 6: 4; flow rate: 1.0 ml/min; temperature: 22 ℃; UV detection: 230 nm]。

Yield: 9.6 mg.

Example 57

4- (4-chlorophenyl) -4- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } butanenitrile

3.00 g (8.45 mmol) of the compound from example 36 are introduced into 600 ml of dichloromethane at 0 ℃, 2.08 g (8.45 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. 20 ml of methanol were added, the mixture was extracted with water and saturated aqueous sodium bicarbonate solution, the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 205 mg (6% of theory) of the title compound.

¹H-MR(400MHz，DMSO-d₆)：δ＝2.25-2.35(m，1H)，2.38-2.48(m，3H)，2.87(s，3H)，4.22-4.28(m，1H)，4.71(s，2H)，6.95(t，1H)，7.11(d，1H)，7.31-7.35(m，2H)，7.36-7.42(m，3H)，7.47(d，1H)，11.1(s，1H)。

LC-MS (method 4): r_t1.21 minutes; ms (esipos): m/z 387[ M + H ]]⁺。

The enantiomers were purified by preparative HPLC on chiral phase [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x20 mm; eluent: isohexane/isopropanol 3: 7; flow rate: 25 ml/min; temperature: 26 ℃; UV detection: 230 nm ] separation. The separated enantiomer was again purified by preparative HPLC on the achiral phase (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid):

enantiomer 57-1:

R_tafter 6.93 minutes [ column: daicel AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/isopropanol 1: 1; flow rate: 1.0 ml/min; temperature: RT; UV detection: 230 nm]；

Yield: 50 mg.

Enantiomer 57-2:

R_tafter 7.82 minutes [ column: daicel AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/isopropanol 1: 1; flow rate: 1.0 ml/min; temperature: RT; UV detection: 230 nm]；

Yield: 54 mg.

Example 58

4- (4-chlorophenyl) -4- {7- [ (ethylsulfonyl) methyl ] -1H-indol-3-yl } butanenitrile

83.0 mg (0.23 mmol) of the compound from example 37 are introduced into 13 ml of dichloromethane at 0 ℃, 111 mg (0.45 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 43.5 mg (48% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.19(t，3H)，2.25-2.35(m，1H)，2.36-2.48(m，3H)，3.02(q，2H)，4.22-4.28(m，1H)，4.66-4.75(m，2H)，6.94(t，1H)，7.10(d，1H)，7.31-7.35(m，2H)，7.36-7.41(m，3H)，7.47(d，1H)，11.1(s，1H)。

LC-MS (method 3): r_t2.03 minutes; ms (esipos): 401[ M + H ] M/z]⁺。

Example 59

4- (4-chloro-2-fluorophenyl) -4- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } butanenitrile

660 mg (1.77 mmol) of the compound from example 38 are introduced into 99 ml of dichloromethane at 0 ℃, 873 mg (3.54 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. 20 ml of methanol are added, the concentrated residue is taken up in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, the organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 620 mg (87% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.25-2.39(m，1H)，2.45-2.51(m，3H)，2.88(s，3H)，4.52-4.58(m，1H)，4.72(s，2H)，6.98(t，1H)，7.13(d，1H)，7.21(dd，1H)，7.36-7.43(m，3H)，7.45-7.48(m，1H)，11.2(s，1H)。

LC-MS (method 5): r_t2.31 minutes; ms (esipos): 405[ M + H ] M/z]⁺。

Enantiomer 59-1:

600 mg (1.61 mmol) of enantiomer 38-1 were introduced into 20 ml of dichloromethane at 0 ℃, 813 mg (3.30 mmol) of 70% m-chloroperbenzoic acid were added, and the mixture was stirred at room temperature overnight. The concentrated residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 450 mg (69% of theory) of the corresponding enantiomer of the title compound.

[α]_D ²⁰45.9 deg., c 0.505, chloroform

Example 60

4- (4-chloro-2-fluorophenyl) -3-methyl-4- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } butanenitrile

30.0 mg (0.08 mmol) of the compound from example 39 are introduced into 2 ml of dichloromethane at room temperature, 39.2 mg (0.16 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. 1 ml of methanol was added and the concentrated residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to give 9 mg (28% of theory) of diastereomer 60-1 and 16.1 mg (50% of theory) of diastereomer 60-2 of the title compound.

Diastereomer 60-1:

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.08(d，3H)，2.32(dd，1H)，2.48-2.55(m，1H)，2.87(s，3H)，2.86-2.98(m，1H)，4.29(d，1H)，4.71(s，2H)，7.01(t，1H)，7.12(d，1H)，7.22(dd，1H)，7.35(dd，1H)，7.51-7.56(m，2H)，7.60(t，1H)，11.2(s，1H)。

LC-MS (method 3): r_t2.02 minutes; ms (esipos): m/z 419[ M + H ]]⁺。

Diastereomer 60-2:

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.97(d，3H)，2.45-2.54(m，1H)，2.64(dd，1H)，2.87(s，3H)，2.84-2.95(m，1H)，4.31(d，1H)，4.71(s，2H)，7.01(t，1H)，7.13(d，1H)，7.21(dd，1H)，7.35(dd，1H)，7.50-7.60(m，3H)，11.2(s，1H)。

LC-MS (method 3): r_t2.10 minutes; ms (esipos): m/z 419[ M + H ]]⁺。

Example 61

4- (4-chloro-2-fluorophenyl) -4- { 5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } butanenitrile

80.0 mg (0.21 mmol) of the compound from example 40 are introduced at 0 ℃ into 5 ml of dichloromethane, 103 mg (0.42 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. Methanol was added and the concentrated residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 46 mg (53% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.26-2.38(m，1H)，2.44-2.52(m，3H)，2.91(s，3H)，4.45-4.51(m，1H)，4.75(s，2H)，7.01(dd，1H)，7.15(dd，1H)，7.23(dd，1H)，7.39(dd，1H)，7.45(t，1H)，7.54(d，1H)，11.3(s，1H)。

LC-MS (method 5): r_t2.38 minutes; ms (esipos): 423[ M + H ] M/z]⁺。

Example 62

4- (2, 4-dichlorophenyl) -4- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } butanenitrile

200 mg (0.51 mmol) of the compound from example 41 are introduced into 30 ml of dichloromethane at 0 ℃, 253 mg (1.03 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. 2 ml of methanol were added, and after concentration, the residue was taken up in dichloromethane and saturated aqueous sodium bicarbonate solution, and the phases were separated. The organic phase was washed twice with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 136 mg (63% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.20-2.32(m，1H)，2.41-2.56(m，3H)，2.88(s，3H)，4.68-4.77(m，3H)，6.98(t，1H)，7.13(d，1H)，7.31-7.40(m，3H)，7.50(s，1H)，7.61(d，1H)，11.2(s，1H)。

LC-MS (method 4): r_t1.28 minutes; ms (esipos): 421[ M + H ] M/z]⁺。

The enantiomers were purified by preparative HPLC on chiral phase [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x20 mm; eluent: isohexane/isopropanol 7: 3; flow rate: 20 ml/min; temperature: RT; UV detection: 230 nm ] separation. The separated enantiomer was again purified by preparative HPLC on the achiral phase (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid):

Enantiomer 62-1:

R_t18.55 min [ column: daicel AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/isopropanol 4: 1; flow rate: 1.0 ml/min; temperature: RT; UV detection: 230 nm]；

Enantiomer 62-2:

R_t20.07 min [ column: daicel AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/isopropanol 4: 1; flow rate: 1.0 ml/min; temperature: RT; UV detection: 230 nm]。

Example 63

4- (2, 4-dichlorophenyl) -4- { 5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } butanenitrile

590 mg (1.45 mmol) of the compound from example 42 are introduced into 85 ml of dichloromethane at 0 ℃, 714 mg (2.90 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 520 mg (82% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.22-2.35(m，1H)，2.40-2.53(m，3H)，2.92(s，3H)，4.67(t，1H)，4.71-4.80(m，2H)，7.02(dd，1H)，7.12(dd，1H)，7.36(dd，1H)，7.44(d，1H)，7.56(d，1H)，7.61(d，1H)，11.3(s，1H)。

LC-MS (method 5): r_t2.48 minutes; ms (esipos): 439[ M + H ] M/z]⁺。

Example 64

4- (4-chlorophenyl) -4- { 5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } butanenitrile

140 mg (0.38 mmol) of the compound from example 43 are introduced into 22 ml of dichloromethane at 0 ℃, 185 mg (0.75 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 122 mg (80% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.24-2.35(m，1H)，2.36-2.49(m，3H)，2.90(s，3H)，4.21(t，1H)，4.69-4.78(m，2H)，6.99(dd，1H)，7.19(dd，1H)，7.31-7.42(m，4H)，7.57(d，1H)，11.3(s，1H)。

LC-MS (method 5): r_t2.34 minutes; ms (esipos): 405[ M + H ] M/z]⁺。

Example 65

4- (4-chloro-2-methylphenyl) -4- {7- [ (ethylsulfonyl) methyl ] -1H-indol-3-yl } butanenitrile

73.0 mg (0.19 mmol) of the compound from example 44 are introduced into 11 ml of dichloromethane at 0 ℃, 94.0 mg (0.38 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. Methanol was added, concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to give 38.0 mg (48% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.19(t，3H)，2.15-2.27(m，1H)，2.38-2.50(m，3H)，2.42(s，3H)，3.02(q，2H)，4.45(t，1H)，4.67-4.76(m，2H)，6.96(t，1H)，7.11(d，1H)，7.17(dd，1H)，7.25(s，1H)，7.26(d，1H)，7.32-7.37(m，2H)，11.1(s，1H)。

LC-MS (method 3): r_t2.12 minutes; ms (esipos): 415[ M + H ] M/z]⁺。

Example 66

4- (4-chloro-2-methylphenyl) -4- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } butanenitrile

200 mg (0.54 mmol) of the compound from example 45 are introduced at 0 ℃ into 30 ml of dichloromethane, 267 mg (1.08 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. 2 ml of methanol are added, concentrated, the residue is taken up in dichloromethane, washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, the organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 87 mg (40% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.15-2.28(m，1H)，2.39-2.54(m，3H)，2.42(s，3H)，2.88(s，3H)，4.45(t，1H)，4.68-4.77(m，2H)，6.97(t，1H)，7.12(d，1H)，7.17(dd，1H)，7.25(s，1H)，7.26(d，1H)，7.33-7.37(m，2H)，11.1(s，1H)。

LC-MS (method 4): r_t1.26 minutes; ms (esipos): 401[ M + H ] M/z]⁺。

The enantiomers were purified by preparative HPLC on chiral phase [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x20 mm; eluent: isohexane/isopropanol 4: 1; flow rate: 20 ml/min; temperature: RT; UV detection: 230 nm ] separation. The separated enantiomer was again purified by preparative HPLC on the achiral phase (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid):

enantiomer 66-1:

R_t6.92 min [ column: daicel AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/isopropanol 3: 2; flow rate: 1.0 ml/min; temperature: RT; UV detection: 230 nm]；

Enantiomer 66-2:

R_t7.52 min [ column: daicel AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/isopropanol 3: 2; flow rate: 1.0 ml/min; temperature: RT; UV detection: 230 nm]。

Example 67

4- (4-fluoro-2-methylphenyl) -4- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } butanenitrile

50 mg (0.14 mmol) of the compound from example 46 are introduced into 10 ml of dichloromethane at 0 ℃, 69.9 mg (0.28 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 4 hours and then under reflux for 15 minutes. 2 ml of methanol were added, concentrated and the residue taken up in dichloromethane and saturated aqueous sodium bicarbonate and the phases separated. The organic phase was washed twice with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 24.6 mg (45% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.16-2.28(m，1H)，2.37-2.49(m，3H)，2.43(s，3H)，2.88(s，3H)，4.42-4.48(m，1H)，4.67-4.76(m，2H)，6.90-6.99(m，2H)，7.02(dd，1H)，7.11(d，1H)，7.27(dd，1H)，7.33-7.37(m，2H)，11.1(s，1H)。

LC-MS (method 5): r_t2.24 minutes; ms (esipos): 385M + H]⁺。

Example 68

4- [ 2-fluoro-4- (trifluoromethyl) phenyl ] -4- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } butanenitrile

100 mg of the 85% pure compound from example 47 (0.21 mmol) are introduced into 14 ml of dichloromethane at 0 ℃, 118 mg (0.48 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. The concentrated residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 65 mg (71% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.32-2.42(m，1H)，2.45-2.60(m，3H)，2.88(s，3H)，4.62-4.68(m，1H)，4.73(s，2H)，6.99(t，1H)，7.13(d，1H)，7.42(d，1H)，7.49-7.54(m，2H)，7.61-7.66(m，2H)，11.2(s，1H)。

LC-MS (method 4): r_t1.26 minutes; ms (esipos): 439[ M + H ] M/z]⁺。

Example 69

4- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } -4- (naphthalen-2-yl) butanenitrile

50 mg (0.14 mmol) of the compound from example 48 are introduced into 10 ml of dichloromethane at 0 ℃, 66.5 mg (0.27 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 4 hours and then under reflux for 15 minutes. 2 ml of methanol are added, concentrated, the residue is taken up in dichloromethane and saturated aqueous sodium bicarbonate, the phases are separated, the organic phase is washed twice with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, the organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 30 mg (55% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.40-2.60(m，4H)，2.86(s，3H)，4.38-4.44(m，1H)，4.67-4.75(m，2H)，6.92(t，1H)，7.09(d，1H)，7.42-7.54(m，5H)，7.79-7.85(m，2H)，7.88(d，1H)，7.93(s，1H)，11.1(s，1H)。

LC-MS (method 5): r_t2.34 minutes; ms (esipos): m/z 403[ M + H ]]⁺。

Example 70

5- (4-chlorophenyl) -5- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } valeronitrile

50 mg (0.14 mmol) of the compound from example 49 are introduced into 9 ml of dichloromethane at 0 ℃, 66.8 mg (0.27 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight and then under reflux for 15 minutes. 2 ml of methanol are added, concentrated, the residue is taken up in dichloromethane and saturated aqueous sodium bicarbonate, the phases are separated, the organic phase is washed twice with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, the organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 30 mg (55% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.41-1.63(m，2H)，2.00-2.11(m，1H)，2.16-2.26(m，1H)，2.50-2.57(m，2H)，2.87(s，3H)，4.22(t，1H)，4.67-4.76(m，2H)，6.84(t，1H)，7.10(d，1H)，7.29-7.34(m，2H)，7.34-7.41(m，4H)，11.1(s，1H)。

LC-MS (method 5): r_t2.36 minutes; ms (esipos): 401[ M + H ] M/z]⁺。

Example 71

4- (4-chlorophenyl) -4- { 6-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } butanenitrile

0.66 g (1.77 mmol) of the compound from example 50 are introduced into 120 ml of dichloromethane at 0 ℃, 1.09 g (4.43 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 3 hours. 2 ml of methanol were added and the mixture was extracted with water and saturated aqueous sodium bicarbonate. The phases were separated, the combined organic phases were dried over sodium sulfate and filtered, and the solvent was removed from the residue in vacuo. The crude product was initially purified by preparative HPLC (mobile phase: acetonitrile/water gradient) followed by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 3/2). 317 mg (44% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.21-2.49(m，4H)，2.95(s，3H)，4.21-4.28(m，1H)，4.73(s，2H)，6.86(dd，1H)，7.31-42(m，5H)，7.41(m，1H)，11.24(s，1H)。

HPLC (method 2): r_t4.52 min; ms (esineg): 422[ M-H ] M/z]^-。

Example 72

4- { 6-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } -4- [4- (trifluoromethyl) phenyl ] butanenitrile

0.95 g (2.35 mmol) of the compound from example 51 are introduced at 0 ℃ into 160 ml of dichloromethane, 1.45 g (5.88 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 3 hours. 2 ml of methanol was added, and the mixture was extracted with water, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The phases were separated and the solvent was removed from the organic phase in vacuo. The crude product was initially purified by preparative HPLC (mobile phase: acetonitrile/water gradient) followed by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 1/1). 483 mg (47% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.29-2.48(m，4H)，2.95(s，3H)，4.36(t，1H)，4.73(s，2H)，6.87(dd，1H)，7.42(dd，1H)，7.55(s，1H)，7.59(d，2H)，7.65(d，2H)，11.29(s，1H)。

HPLC (method 2): r_t4.58 minutes; ms (esipos): 439[ M + H ] M/z]⁺。

Example 73

4- (1-benzothien-5-yl) -4- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } butanenitrile

The title compound was prepared starting from 284 mg (0.75 mmol) of the compound from example 52 in analogy to the synthesis of the compound from example 72. 409 mg (54% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.23-2.52(m，4H)，2.86(s，3H)，4.36(t，1H)，4.71(s，2H)，6.92(dd，1H)，7.09(d，1H)，7.33-7.44(m，3H)，7.49-7.52(m，1H)，7.72(d，1H)，7.85-7.91(m，2H)，11.11(s，1H)。

HPLC (method 2): r_t4.46 minutes; DCI-MS (ESIpos): m/z is 409[ M + H%]⁺。

Example 74

4- (2-bromo-1, 3-thiazol-5-yl) -4- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } butanenitrile

125 mg (0.31 mmol) of the compound from example 53 are introduced into 15 ml of dichloromethane at 0 ℃, 152 mg (0.62 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was initially purified by preparative HPLC (mobile phase: acetonitrile/water gradient) followed by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 1/1) to give a slightly impure product. 119 mg (85% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.31-2.53(m，4H)，2.89(s，3H)，4.62(t，1H)，4.74(s，2H)，7.02(t，1H)，7.16(d，1H)，7.46-7.53(m，2H)，7.69(s，1H)，11.24(s，1H)。

LC-MS (method 3): r_t1.61 minutes; ms (esineg): 436[ MH ] m/z]^-。

Example 75

3-methyl-4- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } -4- [4- (trifluoromethyl) phenyl ] butanenitrile

335 mg (0.83 mmol) of the compound from example 54 are introduced at 0 ℃ into 40 ml of dichloromethane, 410 mg (1.67 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was taken up in a little acetonitrile. The solid containing the product was filtered off and the filtrate was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). The product-containing fractions were combined, taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic phase was dried over sodium sulfate, the solid filtered off and the solvent removed to yield 336 mg (93% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.91-1.13(m，3H)，2.18-2.69(m，2H)，2.87(s，2H)，2.87-2.96(m，2H)，4.08-4.15(m，1H)，4.70(s，2H)，6.99(t，1H)，7.12(d，1H)，7.57-7.70(m，6H)，11.14-11.20(s，1H)。

LC-MS (method 4): r_t1.26/1.29 min; ms (esipos): 435[ M + H ] M/z]⁺。

Example 76

4- (4-chlorophenyl) -3-methyl-4- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } butanenitrile

The title compound was prepared starting from 160 mg (0.43 mmol) of the compound from example 55 in analogy to the synthesis of the compound from example 74. 160 mg (92% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.91-1.11(m，3H)，2.17-2.68(m，2H)，2.79-2.90(m，4H)，3.97-4.06(m，1H)，4.70(s，2H)，6.98(t，1H)，7.11(d，1H)，7.31(t，2H)，7.45(d，2H)，7.53-7.61(m，2H)，11.10-11.16(s，1H)。

LC-MS (method 5): r_t2.33/2.40 min; ms (esineg): m/z 399[ M-H ]]^-。

Example 77

4- {7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } -4- [4- (trifluoromethyl) phenyl ] butanenitrile

25 mg (64. mu. mol) of the compound from example 35 were introduced into 5 ml of dichloromethane at 0 ℃, 16 mg (64. mu. mol) of 70% m-chloroperbenzoic acid were added and the mixture was stirred at room temperature overnight. The concentrated residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient, addition of 0.1% formic acid) to yield 24 mg (92% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.30-2.40(m，1H)，2.41-2.47(m，2H)，2.48-2.52(m，1H)，2.52(s，3H)，4.19-4.25(m，1H)，4.32-4.39(m，2H)，6.92(t，1H)，7.01(d，1H)，7.35-7.40(m，1H)，7.51(s，1H)，7.56-7.61(m，2H)，7.62-7.66(m，2H)，11.2(s，1H)。

LC-MS (method 4): r_t1.18 minutes; ms (esipos): 405[ M + H ] M/z]⁺。

Example 78

4- (4-chlorophenyl) -4- {7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } butanenitrile

The title compound is prepared starting from 85.0 mg (0.24 mmol) of the compound from example 36 in analogy to the synthesis of the compound from example 77 and is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient with addition of 0.1% formic acid) to yield 86 mg (97% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.25-2.35(m，1H)，2.38-2.48(m，3H)，2.51(s，3H)，4.19-4.28(m，2H)，4.34(dd，1H)，6.91(t，1H)，7.00(d，1H)，7.30-7.40(m，5H)，7.46(s，1H)，11.2(s，1H)。

LC-MS (method 5): r_t2.20 minutes; ms (esipos): 371[ M + H ] M/z]⁺。

Diastereomers were purified by preparative HPLC on chiral phase [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x20 mm; eluent: isohexane/isopropanol 1: 1; flow rate: 15 ml/min; temperature: 30 ℃; UV detection: 220 nm ] separation:

diastereomer 78-1:

R_t14.17 min [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4.6 mm; eluent: isohexane/ethanol 1: 1; flow rate: 1.0 ml/min; temperature: 30 ℃; UV detection: 220 nm]；

Diastereomer 78-2:

R_t15.40 min [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4.6 mm; eluent: isohexane/ethanol 1: 1; flow rate: 1.0 ml/min; temperature: 30 ℃; UV detection: 220 nm]；

Diastereomer 78-3:

R_t16.85 min [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4.6 mm; eluent: isohexane/ethanol 1: 1; flow rate: 1.0 ml/min; temperature: 30 ℃; UV detection: 220 nm ]；

Diastereomer 78-4:

R_t20.10 min [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4.6 mm; eluent: isohexane/ethanol 1: 1; flow rate: 1.0 ml/min; temperature: 30 ℃; UV detection: 220 nm]。

Example 79

4- (4-chloro-2-fluorophenyl) -4- {7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } butanenitrile

200 mg (0.54 mmol) of the compound from example 38 are introduced into 30 ml of dichloromethane at 0 ℃, 132 mg (0.54 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. 2 ml of methanol are added, concentrated, the residue is taken up in dichloromethane, washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 107 mg (51% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.25-2.37(m，1H)，2.45-2.51(m，3H)，2.52(s，3H)，4.19-4.26(m，1H)，4.32-4.39(m，1H)，4.51-4.57(m，1H)，6.94(t，1H)，7.02(d，1H)，7.20(d，1H)，7.32-7.42(m，3H)，7.45(d，1H)，11.2(s，1H)。

LC-MS (method 4): r_t1.17 minutes; ms (esipos): 389[ M + H ═ M/z]⁺。

Example 80

4- (4-chloro-2-fluorophenyl) -4- { 5-fluoro-7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } butanenitrile

80.0 mg (0.21 mmol) of the compound from example 40 are introduced into 5 ml of dichloromethane at 0 ℃, 53.0 mg (0.22 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. Methanol was added, concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to give 58.8 mg (71% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.25-2.39(m，1H)，2.44-2.52(m，3H)，2.52-2.54(m，3H)，4.19-4.25(m，1H)，4.34-4.40(m，1H)，4.45-4.51(m，1H)，6.91(dd，1H)，7.10(d，1H)，7.23(dd，1H)，7.39(dd，1H)，7.41-7.47(m，1H)，7.51-7.54(m，1H)，11.3(s，1H)。

LC-MS (method 6): r_t2.20 minutes; ms (esipos): 407[ M + H ] M/z]⁺。

Example 81

4- (2, 4-dichlorophenyl) -4- {7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } butanenitrile

200 mg (0.51 mmol) of the compound from example 41 are introduced into 30 ml of dichloromethane at 0 ℃, 127 mg (0.51 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. 2 ml of methanol are added, concentrated, the residue is taken up in dichloromethane, washed twice with saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution, and the organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 99 mg (48% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.20-2.32(m，1H)，2.41-2.58(m，3H)，2.52(s，3H)，4.19-4.26(m，1H)，4.32-4.39(m，1H)，4.69-4.76(m，1H)，6.94(t，1H)，7.02(d，1H)，7.30-7.35(m，2H)，7.35-7.39(m，1H)，7.48(d，1H)，7.60(d，1H)，11.2(s，1H)。

LC-MS (method 4): r_t1.24 minutes; ms (esipos): 405[ M + H ] M/z]⁺。

Example 82

4- (2, 4-dichlorophenyl) -4- { 5-fluoro-7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } butanenitrile

100 mg (0.25 mmol) of the compound from example 42 are introduced into 14 ml of dichloromethane at 0 ℃, 60.5 mg (0.25 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 80 mg (76% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.21-2.34(m，1H)，2.42-2.55(m，3H)，2.53(s，3H)，4.19-4.26(m，1H)，4.34-4.40(m，1H)，4.66(t，1H)，6.91(dd，1H)，7.03-7.08(m，1H)，7.36(dd，1H)，7.42(dd，1H)，7.55(d，1H)，7.61(d，1H)，11.3(s，1H)。

LC-MS (method 5): r_t2.35 min; ms (esipos): 423[ M + H ] M/z]⁺。

Example 83

4- (4-chlorophenyl) -4- { 5-fluoro-7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } butanenitrile

64.0 mg (0.17 mmol) of the compound from example 43 are introduced into 10 ml of dichloromethane at 0 ℃, 42.3 mg (0.17 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 54 mg (79% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.24-2.34(m，1H)，2.36-2.49(m，3H)，2.52-2.53(m，3H)，4.18-4.25(m，2H)，4.32-4.39(m，1H)，6.88(dd，1H)，7.10-7.15(m，1H)，7.31-7.41(m，4H)，7.55(d，1H)，11.3(s，1H)。

LC-MS (method 5): r_t2.22 minutes; ms (esipos): 389[ M + H ═ M/z]⁺。

Example 84

4- (4-chloro-2-methylphenyl) -4- {7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } butanenitrile

The title compound was prepared in analogy to the synthesis of the compound from example 79 starting from 200 mg (0.54 mmol) of the compound from example 45. 146 mg (70% of theory) of the title compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.15-2.27(m，1H)，2.38-2.52(m，3H)，2.42(s，3H)，2.52(s，3H)，4.19-4.26(m，1H)，4.31-4.39(m，1H)，4.45(t，1H)，6.93(t，1H)，7.01(d，1H)，7.16(dd，1H)，7.23-7.27(m，2H)，7.30(d，1H)，7.33-7.36(m，1H)，11.2(s，1H)。

LC-MS (method 4): r_t1.21 minutes; ms (esipos): 385M + H]⁺。

Example 85

4- (4-fluoro-2-methylphenyl) -4- {7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } butanenitrile

50 mg (0.14 mmol) of the compound from example 46 are introduced into 10 ml of dichloromethane at room temperature, 35.0 mg (0.14 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 4 hours. 2 ml of methanol are added, concentrated, the residue is taken up in dichloromethane and saturated aqueous sodium bicarbonate, the phases are separated, the organic phase is washed twice with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, the organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 24.6 mg (47% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.15-2.25(m，1H)，2.36-2.49(m，3H)，2.43(s，3H)，2.52(s，3H)，4.18-4.26(m，1H)，4.31-4.38(m，1H)，4.44(t，1H)，6.89-6.96(m，2H)，6.99-7.04(m，2H)，7.23-7.35(m，3H)，11.1(s，1H)。

LC-MS (method 3): r_t1.76 min; ms (esipos): m/z 369[ M + H ]]⁺。

Example 86

4- [ 2-fluoro-4- (trifluoromethyl) phenyl ] -4- {7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } butanenitrile

100 mg of the 85% pure compound from example 47 (0.21 mmol) are introduced into 14 ml of dichloromethane at 0 ℃, 59.1 mg (0.24 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 62 mg (71% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.32-2.42(m，1H)，2.43-2.60(m，3H)，2.52(s，3H)，4.20-4.26(m，1H)，4.32-4.38(m，1H)，4.62-4.67(m，1H)，6.95(t，1H)，7.03(d，1H)，7.37(d，1H)，7.49-7.53(m，2H)，7.59-7.66(m，2H)，11.2(s，1H)。

LC-MS (method 4): r_t1.21 minutes; ms (esipos): 423[ M + H ] M/z]⁺。

Example 87

5- (4-chlorophenyl) -5- {7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } valeronitrile

While cooling with ice, 50 mg (0.14 mmol) of the compound from example 49 was introduced into 9 ml of dichloromethane, 33.4 mg (0.14 mmol) of 70% m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature overnight. 2 ml of methanol were added, the concentrated residue was taken up in dichloromethane and saturated aqueous sodium bicarbonate solution, the phases were separated, the organic phase was washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 33 mg (63% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.41-1.63(m，2H)，2.00-2.11(m，1H)，2.16-2.26(m，1H)，2.50-2.56(m，2H)，2.51(s，3H)，4.19-4.25(m，2H)，4.31-4.37(m，1H)，6.89(t，1H)，6.99(d，1H)，7.29-7.33(m，2H)，7.33-7.40(m，4H)，11.1(s，1H)。

LC-MS (method 6): r_t2.17 minutes; ms (esipos): 385M + H]⁺。

Example 88

4- (4-chlorophenyl) -4- { 6-fluoro-7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } butanenitrile

300 mg (0.80 mmol) of the compound from example 50 are introduced into 55 ml of dichloromethane at 0 ℃, 198 mg (0.80 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added, and the mixture was extracted with water, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The phases were separated and the solvent was removed from the organic phase in vacuo. The crude product was initially purified by preparative HPLC (mobile phase: acetonitrile/water gradient) followed by flash chromatography on silica gel (mobile phase: ethyl acetate). 197 mg (63% of theory) of the title compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.21-2.48(m，4H)，2.55(s，3H)，4.20-4.36(m，3H)，6.84(dd，1H)，7.30-7.40(m，5H)，7.47(s，1H)，11.28(s，1H)。

HPLC (method 2): r_t4.52 min; ms (esipos): 389[ M + H ═ M/z]⁺。

Example 89

4- { 6-fluoro-7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } -4- [4- (trifluoromethyl) phenyl ] butanenitrile

The title compound was prepared starting from 557 mg (1.37 mmol) of the compound from example 51 in analogy to the synthesis of the compound from example 88. 412 mg (71% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.28-2.49(m，4H)，2.58(s，3H)，4.27-4.38(m，3H)，6.85(dd，1H)，7.36(dd，1H)，7.53(s，1H)，7.58(d，2H)，7.64(d，2H)，11.32(s，1H)。

HPLC (method 2): r_t4.47 minutes; ms (esipos): 423[ M + H ] M/z]⁺。

Example 90

4- (1-benzothien-5-yl) -4- {7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } butanenitrile

157 mg (0.42 mmol) of the compound from example 52 are introduced at 0 ℃ into 28 ml of dichloromethane, 102 mg (0.42 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol and a little ethyl acetate were added, and the mixture was extracted with water, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The phases were separated and the solvent was removed from the organic phase in vacuo. The crude product is purified by preparative HPLC (mobile phase: acetonitrile/water gradient) and 141 mg (86% of theory) of the title compound are provided as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.31-2.53(m，7H)，4.19-4.26(dd，1H)，4.30-4.39(m，2H)，6.88(t，1H)，6.98(d，1H)，7.33-7.42(m，3H)，7.49(s，1H)，7.71(d，1H)，7.84-7.91(m，2H)，11.14(s，1H)。

HPLC (method 2): r_t4.32 minutes; ms (esipos): 393[ M + H ] M/z]⁺。

Example 91

3-methyl-4- {7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } -4- [4- (trifluoromethyl) phenyl ] butanenitrile

150 mg (0.37 mmol) of the compound from example 54 are introduced into 20 ml of dichloromethane at 0 ℃, 92 mg (0.37 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 150 mg (96% of theory) of the title compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.91-1.13(m，3H)，2.18-2.70(m，5H)，2.86-2.98(m，1H)，4.08-4.14(m，1H)，4.18-4.38(m，2H)，6.93-7.03(m，2H)，7.53-7.69(m，6H)，11.16-11.23(s，1H)。

LC-MS (method 4): r_t1.21/1.24 min; ms (esipos): m/z 419[ M + H ]]⁺。

Example 92

2- [1- (4-chlorophenyl) -1- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } ethyl ] cyclopropanecarbonitrile [ trans-diastereomer mixture ]

150 mg (0.68 mmol) of the compound from example 75A and 120 mg (0.68 mmol) of the compound from example 8A are introduced into 4 ml of dichloromethane at 0 ℃ to which 157 mg (0.71 mmol) of indium (III) chloride are added and the mixture is stirred at room temperature for 1 hour and under reflux for 0.5 hour. After cooling, 0.05 ml (0.68 mmol) of trifluoroacetic acid was added and the mixture was stirred under reflux for 5 minutes. It was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 117 mg (45% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：0.84(ddd，0.6H)，0.97(ddd，0.4H)，1.26-1.36(m，1H)，1.37-1.43(m，0.4H)，1.49-1.56(m，0.6H)，1.54(s，1.2H)，1.55(s，1.8H)，1.97(s，1.8H)，1.98(s，1.2H)，2.28-2.36(m，1H)，3.88-3.99(m，2H)，6.53(d，0.6H)，6.60(d，0.4H)，6.65-6.73(m，1H)，6.85-6.91(m，1H)，7.25-7.39(m，5H)，11.1(s，1H)。

LC-MS (method 3): r_t2.52 min; ms (esineg): m/z 379[ M-H ═]^-。

Example 93

3- (1-cyclopropyl-5-fluoro-2, 3-dihydro-1H-inden-1-yl) -7- [ (methylsulfanyl) methyl ] -1H-indole

200 mg (0.78 mmol) of the compound from example 76A with a purity of 75% and 152 mg (0.86 mmol) of the compound from example 8A are introduced at 0 ℃ into 3.8 ml of dichloromethane, 0.07 ml (0.94 mmol) of trifluoroacetic acid are added and the mixture is stirred at 0 ℃ for 4 hours. It is diluted with dichloromethane and saturated aqueous ammonium chloride solution is added, the phases are separated, the aqueous phase is extracted with dichloromethane, the combined organic phases are dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 175 mg (64% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝-0.26--0.19(m，1H)，-0.01-0.09(m，1H)，0.41-0.52(m，2H)，1.46-1.55(m，1H)，1.96(s，3H)，2.14(ddd，1H)，2.54-2.62(m，1H)，2.87-3.04(m，2H)，3.87-3.97(m，2H)，6.67-6.74(m，3H)，6.79-6.90(m，2H)，7.11(dd，1H)，7.28(d，1H)，10.9(s，1H)。

LC-MS (method 4): r_t1.63 minutes; ms (esineg): 350[ M-H ] M/z]^-。

Example 94

3- (1-cyclopropyl-5-fluoro-2, 3-dihydro-1H-inden-1-yl) -5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indole

633 mg (2.47 mmol) of the compound from example 76A with a purity of 75% and 530 mg (2.71 mmol) of the compound from example 11A are introduced at 0 ℃ into 12 ml of dichloromethane, 0.23 ml (2.96 mmol) of trifluoroacetic acid are added and the mixture is stirred at 0 ℃ for 4 hours. It is diluted with dichloromethane and saturated aqueous ammonium chloride solution is added, the phases are separated, the aqueous phase is extracted with dichloromethane, the combined organic phases are dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 570 mg (63% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝-0.26--0.19(m，1H)，0.00-0.06(m，1H)，0.41-0.52(m，2H)，1.46-1.54(m，1H)，1.97(s，3H)，2.09-2.18(m，1H)，2.42-2.54(m，1H)，2.88-3.01(m，2H)，3.88-3.97(m，2H)，6.30(dd，1H)，6.71(dd，1H)，6.78(dd，1H)，6.82-6.88(m，1H)，7.13(dd，1H)，7.36-7.38(m，1H)，11.0(s，1H)。

LC-MS (method 3): r_t2.76 min; ms (esineg): 368[ M-H ] M/z]^-。

Example 95

3- [ 1-cyclopropyl-1- (4-fluorophenyl) ethyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

559 mg (3.10 mmol) of the compound from example 77A and 0.26 ml (3.39 mmol) of trifluoroacetic acid are added to 500 mg (2.82 mmol) of the compound from example 8A in 12 ml of dichloromethane. The reaction mixture was stirred at room temperature for 30 minutes, then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) gives 361 mg (38% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.04-0.13(m，1H)，0.15-0.26(m，1H)，0.36-0.55(m，2H)，1.50(s，3H)，1.52-1.62(m，1H)，1.98(s，3H)，3.87-3.98(m，2H)，6.56-6.68(m，2H)，6.84(d，1H)，7.04(t，2H)，7.27-7.37(m，3H)，10.93(s，1H)。

LC-MS (method 3): r_t2.68 minutes; ms (esineg): 338[ M-H ] M/z]^-。

Example 96

3- [ 1-cyclopropyl-1- (2, 4-difluorophenyl) ethyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 500 mg (2.82 mmol) of the compound from example 8 and 615 mg (3.10 mmol) of the compound from example 78A in analogy to the synthesis of the compound from example 95. 227 mg (94% purity, 21% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.12-0.19(m，2H)，0.44-0.53(m，2H)，1.58(s，3H)，1.57-1.67(m，1H)，1.97(s，3H)，3.91(s，2H)，6.53(d，1H)，6.64(t，1H)，6.83(d，1H)，6.93-7.01(m，1H)，7.06-7.13(m，1H)，7.24(d，1H)，7.75-7.84(m，1H)，10.91(s，1H)。

HPLC (method 2): r_t5.31 min; ms (esineg): 356[ M-H ] M/z]^-。

Example 97

3- [1- (4-chloro-2-fluorophenyl) -1-cyclopropylethyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 3.00 g (16.92 mmol) of the compound from example 8 and 4.00 g (18.62 mmol) of the compound from example 79A in analogy to the synthesis of the compound from example 95. With the difference that the reaction mixture was stirred at 0 ℃ for 2 hours and then warmed to room temperature. 1.54 g (24% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.14-0.19(m，2H)，0.45-0.52(m，2H)，1.57(s，3H)，1.59-1.67(m，1H)，1.97(s，3H)，3.91(s，2H)，6.55(d，1H)，6.65(t，1H)，6.84(d，1H)，7.16(dd，1H)，7.25(s，1H)，7.31(dd，1H)，7.78(t，1H)，10.93(s，1H)。

HPLC (method 1): r_t5.59 min; ms (esineg): 374[ M-H ] M/z]^-。

Example 98

3- [1- (4-chloro-2-fluorophenyl) -1-cyclopropylethyl ] -5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 500 mg (2.56 mmol) of the compound from example 8 and 605 mg (2.82 mmol) of the compound from example 79A in analogy to the synthesis of the compound from example 95. With the difference that the reaction mixture was stirred at 0 ℃ for 2 hours and then warmed to room temperature. 67 mg (7% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.09-0.20(m，2H)，0.44-0.54(m，2H)，1.56(s，3H)，1.56-1.66(m，1H)，1.98(s，3H)，3.91(s，2H)，6.17(dd，1H)，6.75(dd，1H)，7.20(dd，1H)，7.31-7.38(m，2H)，7.80(t，1H)，11.08(s，1H)。

HPLC (method 1): r_t5.48 minutes; ms (esineg): 390[ M-H ] M/z ]^-。

Example 99

3- { (4-fluorophenyl) [4- (trifluoromethyl) phenyl ] methyl } -7- [ (methylsulfanyl) methyl ] -1H-indole

503 mg (1.86 mmol) of the compound from example 80A and 75 mg (0.34 mmol) of indium (III) chloride are added to 300 mg (1.69 mmol) of the compound from example 8 in 15 ml of toluene. The reaction mixture was stirred at 80 ℃ for 5 hours, a further 187 mg (0.85 mmol) of indium (III) chloride were added and the mixture was stirred again for a further 5 hours. After cooling to RT, the reaction solution was mixed with water and ethyl acetate and the solid was filtered off. The filtrate phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) gives 107 mg (15% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.96(s，3H)，3.94(s，2H)，5.84(s，1H)，6.74(s，1H)，6.84(t，1H)，6.96(d，1H)，7.03(d，1H)，7.10-7.18(m，2H)，7.24-7.31(m，2H)，7.45(d，2H)，7.67(d，2H)，11.04(s，1H)。

LC-MS (method 5): r_t3.11 minutes; ms (esipos): 430[ M + H ] M/z]⁺。

Example 100

3- [ (4-chlorophenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

2.94 g (12.41 mmol) of the compound from example 81A and 2.50 g (11.28 mmol) of indium (III) chloride are added to 2.00 g (11.28 mmol) of the compound from example 8 in 100 ml of toluene. The reaction mixture was stirred at 80 ℃ for 3 hours. After cooling to RT, the reaction solution was mixed with water and ethyl acetate and the solid was filtered off. The filtrate phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) gives 0.83 g (19% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.96(s，3H)，3.94(s，2H)，5.72(s，1H)，6.70(s，1H)，6.83(t，1H)，6.95(d，1H)，7.01(d，1H)，7.09-7.16(m，2H)，7.21-7.29(m，4H)，7.33-7.38(m，2H)，11.00(s，1H)。

LC-MS (method 4): r_t1.65 minutes; ms (esineg): 394[ M-H ] M/z]^-。

Example 101

3- [ (4-fluoro-2-methylphenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

509 mg (2.17 mmol) of the compound from example 82A and 437 mg (1.97 mmol) of indium (III) chloride are added to 350 mg (1.97 mmol) of the compound from example 8 in 15 ml of toluene. The reaction mixture was stirred at 80 ℃ for 5 hours. After cooling to RT, the reaction solution was mixed with water and ethyl acetate and the solid was filtered off. The filtrate phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) gives 174 mg (22% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.97(s，3H)，2.26(s，3H)，3.94(d，2H)，5.78(s，1H)，6.54(s，1H)，6.80-6.93(m，3H)，6.95(d，1H)，7.00(d，1H)，7.05(dd，1H)，7.09-7.22(m，4H)，10.96(s，1H)。

LC-MS (method 5): r_t3.06 minutes; ms (esineg): 392[ M-H ] M/z]^-。

Example 102

3- [ (4-chloro-2-methylphenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 380 mg (2.14 mmol) of the compound from example 8 and 591 mg (2.36 mmol) of the compound from example 83A in analogy to the synthesis of the compound from example 101. 307 mg (35% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.97(s，3H)，2.26(s，3H)，3.94(d，2H)，5.79(s，1H)，6.53-6.56(m，1H)，6.80-6.88(m，2H)，6.96(d，1H)，7.00(d，1H)，7.09-7.22(m，5H)，7.28(d，1H)，10.98(s，1H)。

LC-MS (method 3): r_t2.89 minutes; ms (esineg): 408[ M-H ] M/z]^-

Example 103

3- [ (2, 4-difluorophenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 350 mg (1.97 mmol) of the compound from example 8 and 470 mg (1.97 mmol) of the compound from example 84A in analogy to the synthesis of the compound from example 101. 191 mg (24% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.96(s，3H)，3.94(s，2H)，5.88(s，1H)，6.69(s，1H)，6.85(t，1H)，6.94-7.17(m，6H)，7.19-7.28(m，3H)，11.04(s，1H)。

LC-MS (method 5): r_t3.00 min; ms (esineg): 396[ M-H ] M/z]^-。

Example 104

3- [ (4-chloro-2-fluorophenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 1.50 g (8.46 mmol) of the compound from example 8 and 2.15 g (8.46 mmol) of the compound from example 85A in analogy to the synthesis of the compound from example 101. However, the difference is that stirring was carried out at 80 ℃ for 3 hours. 0.66 g (19% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.96(s，3H)，3.94(s，2H)，5.89(s，1H)，6.70(d，1H)，6.82-6.88(m，1H)，6.97(d，1H)，7.00-7.09(m，2H)，7.11-7.18(m，2H)，7.20-7.27(m，3H)，7.42(dd，1H)，11.04(s，1H)。

LC-MS (method 6): r_t2.99 min; ms (esineg): m/z 412[ M-H ═ M]^-。

Example 105

3- [ (4-chloro-2-fluorophenyl) (4-fluorophenyl) methyl ] -5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 500 mg (2.56 mmol) of the compound from example 9 and 652 mg (2.56 mmol) of the compound from example 85A in analogy to the synthesis of the compound from example 101. 197 mg (18% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.97(s，3H)，3.94(s，2H)，5.87(s，1H)，6.74(dd，1H)，6.81(d，1H)，6.85-6.89(m，1H)，7.05(t，1H)，7.11-7.18(m，2H)，7.20-7.26(m，3H)，7.42(dd，1H)，11.19(s，1H)。

LC-MS (method 3): r_t2.85 minutes; ms (esineg): 430[ M-H ] M/z]^-。

Example 106

2- [1- (4-chlorophenyl) -1- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } ethyl ] cyclopropanecarbonitrile [ trans-diastereomer mixture ]

112 mg (0.29 mmol) of the compound from example 92 are introduced into 20 ml of dichloromethane at 0 ℃, 145 mg (0.59 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. Methanol was added and the concentrated residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to give 62 mg (51% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：0.85(ddd，0.6H)，0.97(ddd，0.4H)，1.27-1.42(m，1.4H)，1.52-1.58(m，0.6H)，1.55(s，1.8H)，1.56(s，1.2H)，2.29-2.39(m，1H)，2.91(s，3H)，4.68-4.78(m，2H)，6.65(d，0.6H)，6.71(d，0.4H)，6.75-6.83(m，1H)，7.03-7.08(m，1H)，7.25-7.29(m，0.8H)，7.30-7.37(m，3.2H)，7.45-7.48(m，1H)，11.2(s，1H)。

LC-MS (method 4): r_t1.27 minutes; ms (esineg): m/z 411[ M-H ]]^-。

Example 107

3- (1-cyclopropyl-5-fluoro-2, 3-dihydro-1H-inden-1-yl) -7- [ (methylsulfonyl) methyl ] -1H-indole

240 mg (0.68 mmol) of the compound from example 93 are introduced into 40 ml of dichloromethane at 0 ℃, 354 mg (1.43 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. 2 ml of methanol are added, concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 92 mg (35% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝-0.27--0.19(m，1H)，0.00-0.07(m，1H)，0.42-0.52(m，2H)，1.47-1.55(m，1H)，2.16(ddd，1H)，2.55-2.62(m，1H)，2.90(s，3H)，2.87-3.07(m，2H)，4.68-4.77(m，2H)，6.70(dd，1H)，6.77-6.86(m，3H)，7.02-7.08(m，1H)，7.12(dd，1H)，7.36-7.38(m，1H)，11.0(s，1H)。

LC-MS (method 4): r_t1.41 minutes; ms (esineg): 382[ M-H ] M/z]^-。

The enantiomers were purified by preparative HPLC on chiral phase [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x20 mm; eluent: isohexane/isopropanol 4: 1; flow rate: 20 ml/min; temperature: RT; UV detection: 230 nm ]. The separated enantiomer was again purified by preparative HPLC on the achiral phase (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid):

enantiomer 107-1:

R_t4.63 min [ column: daicel AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/isopropanol 3: 2; flow rate: 1.0 ml/min; temperature: RT; UV detection: 230 nm]；

Yield: 28.7 mg.

Enantiomer 107-2:

R_t4.95 min [ column: daicel AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/isopropanol 3: 2; flow rate: 1.0 ml/min; temperature: RT; UV detection: 230 nm]；

Yield: 25.0 mg.

Example 108

3- (1-cyclopropyl-5-fluoro-2, 3-dihydro-1H-inden-1-yl) -5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indole

80.0 mg (0.22 mmol) of the compound from example 94 are introduced at 0 ℃ into 6 ml of dichloromethane, 109 mg (0.44 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. Methanol was added and the concentrated residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 36.1 mg (42% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝-0.26--0.19(m，1H)，-0.01-0.06(m，1H)，0.42-0.53(m，2H)，1.45-1.55(m，1H)，2.11-2.19(m，1H)，2.44-2.54(m，1H)，2.93(s，3H)，2.90-3.00(m，2H)，4.71-4.80(m，2H)，6.42(dd，1H)，6.70(dd，1H)，6.82-6.88(m，1H)，6.94(dd，1H)，7.14(dd，1H)，7.47(d，1H)，11.1(s，1H)。

LC-MS (method 3): r_t2.36 minutes; ms (esineg): m/z 400[ M-H ]]^-。

Example 109

3- [ 1-cyclopropyl-1- (4-fluorophenyl) ethyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

107 mg (0.31 mmol) of the compound from example 95 are introduced into 21 ml of dichloromethane at 0 ℃, 155 mg (0.63 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 106 mg (91% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.04-0.25(m，2H)，0.36-0.56(m，2H)，1.51(s，3H)，1.52-1.63(m，1H)，2.91(s，3H)，4.72(s，2H)，6.66-6.79(m，2H)，6.98-7.10(m，3H)，7.23-7.35(m，2H)，7.44(d，1H)，11.02(s，1H)。

HPLC (method 2): r_t4.81 minutes; ms (esipos): 372[ M + H ] M/z]⁺。

The enantiomers were purified by preparative HPLC on chiral phase [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x20 mm; eluent: isohexane/isopropanol 7: 3; flow rate: 25 ml/min; temperature: 24 ℃; UV detection: 230 nm ] separation. The separated enantiomers were again purified by preparative HPLC on the achiral phase (mobile phase: acetonitrile/water gradient):

enantiomer 109-1:

R_t4.42 min [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/isopropanol 1: 1; flow rate: 1 ml/min; temperature: 24 ℃; UV detection: 230 nm ]；

Yield: 25.8 mg.

Enantiomer 109-2:

R_t4.96 min [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/isopropanol 1: 1; flow rate: 1 ml/min; temperature: 24 ℃; UV detection: 230 nm]；

Yield: 23.7 mg.

Example 110

3- [ 1-cyclopropyl-1- (2, 4-difluorophenyl) ethyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared starting from 91 mg (0.26 mmol) of the compound from example 96 in analogy to the synthesis of the compound from example 109. 71 mg (72% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.12-0.21(m，2H)，0.44-0.53(m，2H)，1.58(s，3H)，1.60-1.68(m，1H)，2.89(s，3H)，4.71(s，2H)，6.64(d，1H)，6.73(t，1H)，6.92-7.04(m，2H)，7.12(dt，1H)，7.34(s，1H)，7.75-7.84(m，1H)，11.01(s，1H)。

HPLC (method 2): r_t5.31 min; ms (esineg): m/z 388[ M-H ]]^-

Example 111

3- [1- (4-chloro-2-fluorophenyl) -1-cyclopropylethyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

1.42 g (3.80 mmol) of the compound from example 97 are introduced into 260 ml of dichloromethane at 0 ℃, 1.87 g (7.60 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 10 ml of methanol was added and the solvent was removed in vacuo. The residue was taken up in ethyl acetate and washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The solvent was removed in vacuo. The crude product is purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 1.23 g (80% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.13-0.21(m，2H)，0.45-0.53(m，2H)，1.57(s，3H)，1.59-1.68(m，1H)，2.89(s，3H)，4.71(s，2H)，6.67(d，1H)，6.75(t，1H)，7.02(d，1H)，7.17(dd，1H)，7.27-7.37(m，2H)，7.78(t，1H)，11.03(s，1H)。

HPLC (method 2): r_t4.99 min; DCI-MS (ESIpos): 406[ M + H ] M/z]⁺。

The enantiomers were purified by preparative HPLC on chiral phase [ column: daicel Chiralpak IA, 5 microns, 250 mm x20 mm; eluent: isohexane/isopropanol 7: 3; flow rate: 20 ml/min; temperature: 24 ℃; UV detection: 260 nm ] separation. The separated enantiomers were again purified by preparative HPLC on the achiral phase (mobile phase: acetonitrile/water gradient):

enantiomer 111-1:

R_t5.42 min [ column: daicel Chiralpak IA, 5 microns, 250 mm x4 mm; eluent: isohexane/isopropanol 1: 1; flow rate: 1 ml/min; temperature: 24 ℃; UV detection: 230 nm]；

Yield: 540.4 mg.

Enantiomer 111-2:

R_t5.90 min [ column: daicel Chiralpak IA, 5 microns, 250 mm x4 mm; eluent: isohexane/isopropanol 1: 1; flow rate:1 ml/min; temperature: 24 ℃; UV detection: 230 nm]；

Yield: 534.7 mg.

Example 112

3- [1- (4-chloro-2-fluorophenyl) -1-cyclopropylethyl ] -5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared starting from 58 mg (0.15 mmol) of the compound from example 98 in analogy to the synthesis of the compound from example 111. 57 mg (86% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.10-0.20(m，2H)，0.45-0.55(m，2H)，1.56(s，3H)，1.58-1.67(m，1H)，2.92(s，3H)，4.74(s，2H)，6.31(dd，1H)，6.91(dd，1H)，7.20(dd，1H)，7.35(dd，1H)，7.44(d，1H)，7.80(t，1H)，11.18(s，1H)。

HPLC (method 1): r_t5.00 min; ms (esineg): 422[ M-H ] M/z]^-。

Example 113

3- { (4-fluorophenyl) [4- (trifluoromethyl) phenyl ] methyl } -7- [ (methylsulfonyl) methyl ] -1H-indole

52 mg (0.12 mmol) of the compound from example 99 are introduced into 12 ml of dichloromethane at 0 ℃, 60 mg (0.24 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 38 mg (68% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.89(s，3H)，4.75(s，2H)，5.87(s，1H)，6.82(s，1H)，6.94(t，1H)，7.10-7.18(m，4H)，7.24-7.31(m，2H)，7.45(d，2H)，7.68(d，2H)，11.13(s，1H)。

LC-MS (method 4): r_t1.47 minutes; ms (esipos): 462[ M + H ] M/z]⁺。

Example 114

3- [ (4-chlorophenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

0.83 g (2.10 mmol) of the compound from example 100 are introduced into 150 ml of dichloromethane at 0 ℃, 1.03 g (4.19 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 0.70 g (78% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.89(s，3H)，4.74(s，2H)，5.75(s，1H)，6.78(s，1H)，6.93(t，1H)，7.09-7.16(m，4H)，7.22-7.28(m，4H)，7.34-7.38(m，2H)，11.09(s，1H)。

LC-MS (method 3): r _t2.39 minutes; ms (esineg): m/z 426[ M-H ]]^-。

The enantiomers were purified by preparative HPLC on chiral phase [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x20 mm; eluent: isohexane/ethanol 7: 3; flow rate: 20 ml/min; temperature: 24 ℃; UV detection: 230 nm ] separation. The separated enantiomers were again purified by preparative HPLC on the achiral phase (mobile phase: acetonitrile/water gradient):

enantiomer 114-1:

R_t12.89 min [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/ethanol 7: 3; flow rate: 1 ml/min; temperature: 24 ℃; UV detection: 230 nm]；

Yield: 217.0 mg.

Enantiomer 114-2:

R_tafter 13.91 minutes [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/ethanol 7: 3; flow rate: 1 ml/min; temperature: 24 ℃; UV detection: 230 nm]；

Yield: 186.0 mg.

Example 115

3- [ (4-fluoro-2-methylphenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

65 mg (0.17 mmol) of the compound from example 101 are introduced at 0 ℃ into 8 ml of dichloromethane, 81 mg (0.33 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 63 mg (88% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.27(s，3H)，2.89(s，3H)，4.74(s，2H)，5.80(s，1H)，6.63(s，1H)，6.82-6.95(m，3H)，7.05(dd，1H)，7.09-7.22(m，6H)，11.05(s，1H)。

LC-MS (method 3): r_t2.37 minutes; ms (esineg): 424[ M-H ] M/z]^-。

The enantiomers were purified by preparative HPLC on chiral phase [ column: daicel Chiralpak IA, 5 microns, 250 mm x20 mm; eluent: isohexane/ethanol 6: 4; flow rate: 20 ml/min; temperature: 24 ℃; UV detection: 230 nm ] separation. The separated enantiomers were again purified by preparative HPLC on the achiral phase (mobile phase: acetonitrile/water gradient):

enantiomer 115-1:

R_t5.09 min [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/ethanol 5: 5; flow rate: 1 ml/min; temperature: 24 ℃; UV detection: 230 nm]；

Yield: 15 mg.

Enantiomer 115-2:

R_t5.62 min [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/ethanol 5: 5; flow rate: 1 ml/min; temperature: 24 ℃; UV detection: 230 nm]；

Yield: 15 mg.

Example 116

3- [ (4-chloro-2-methylphenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

130 mg (0.32 mmol) of the compound from example 102 are introduced into 15 ml of dichloromethane at 0 ℃, 156 mg (0.63 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 106 mg (76% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.26(s，3H)，2.89(s，3H)，4.74(s，2H)，5.81(s，1H)，6.64(s，1H)，6.85(d，1H)，6.93(t，1H)，7.10-7.22(m，7H)，7.28(d，1H)，11.07(s，1H)。

LC-MS (method 3): r_t2.50 minutes; ms (esineg): 440[ M-H ] M/z]^-。

enantiomer 116-1:

R_t5.38 min [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/ethanol 5: 5; flow rate: 1 ml/min; temperature: 24 ℃; UV detection: 230 nm]；

Yield: 48.0 mg.

Enantiomer 116-2:

R_tafter 6.15 min [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/ethanol 5: 5; flow rate: 1 ml/min; temperature: 24 ℃; UV detection: 230 nm]；

Yield: 39.0 mg.

Example 117

3- [ (2, 4-difluorophenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

75 mg (0.19 mmol) of the compound from example 103 are introduced at 0 ℃ into 14 ml of dichloromethane, 93 mg (0.34 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 49 mg (60% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.90(s，3H)，4.75(s，2H)，5.90(s，1H)，6.77-6.79(m，1H)，6.94(t，1H)，6.97-7.10(m，2H)，7.11-7.18(m，4H)，7.20-7.27(m，3H)，11.13(s，1H)。

LC-MS (method 3): r_t2.31 minutes; ms (esineg): 428[ M-H ] M/z]^-。

Example 118

3- [ (4-chloro-2-fluorophenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

335 mg (0.81 mmol) of the compound from example 104 are introduced at 0 ℃ into 25 ml of dichloromethane, 93 mg (0.34 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was taken up in acetonitrile, the remaining solid was filtered off and the filtrate was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 286 mg (79% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.90(s，3H)，4.75(s，2H)，5.91(s，1H)，6.79(d，1H)，6.95(t，1H)，7.04(t，1H)，7.11-7.18(m，4H)，7.20-7.27(m，3H)，7.42(dd，1H)，11.14(s，1H)。

LC-MS (method 4): r_t1.46 minutes; ms (esineg): m/z 444[ M-H ]]^-。

The enantiomers were purified by preparative HPLC on chiral phase [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x20 mm; eluent: isohexane/ethanol 6: 4; flow rate: 20 ml/min; temperature: 24 ℃; UV detection: 230 nm ] separation. The separated enantiomers were again purified by preparative HPLC on the achiral phase (mobile phase: acetonitrile/water gradient):

enantiomer 118-1:

R_tafter 6.20 min [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/ethanol 5: 5; flow rate: 1 ml/min; temperature: 24 ℃; UV detection: 230 nm ]；

Enantiomer 118-2:

R_tafter 6.96 min [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/ethanol 5: 5; flow rate: 1 ml/min; temperature: 24 ℃; UV detection: 230 nm]。

Example 119

3- [ (4-chloro-2-fluorophenyl) (4-fluorophenyl) methyl ] -5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indole

110 mg (0.26 mmol) of the compound from example 105 are introduced at 0 ℃ into 12 ml of dichloromethane, 126 mg (0.51 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 96 mg (81% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.93(s，3H)，4.78(s，2H)，5.89(s，1H)，6.87-6.92(m，2H)，7.00-7.07(m，2H)，7.12-7.19(m，2H)，7.20-7.26(m，3H)，7.42(dd，1H)，11.27(s，1H)。

LC-MS (method 5): r_t2.82 minutes; ms (esineg): 462[ M-H ] M/z]^-。

Example 120

3- (1-cyclopropyl-5-fluoro-2, 3-dihydro-1H-inden-1-yl) -7- [ (methylsulfinyl) methyl ] -1H-indole

62.0 mg (0.18 mmol) of the compound from example 93 are introduced into 10 ml of dichloromethane at 0 ℃, 43.5 mg (0.18 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. 2 ml of methanol are added and the concentrated residue is purified by preparative HPLC (RP 18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to give 48 mg (74% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝-0.26--0.20(m，1H)，-0.01-0.06(m，1H)，0.42-0.52(m，2H)，1.47-1.55(m，1H)，2.12-2.19(m，1H)，2.53-2.54(m，3H)，2.52-2.61(m，1H)，2.88-3.05(m，2H)，4.18-4.27(m，1H)，4.31-4.39(m，1H)，6.70(dd，1H)，6.73-6.77(m，2H)，6.78-6.85(m，1H)，6.91-6.96(m，1H)，7.12(dd，1H)，7.35-7.37(m，1H)，11.0-11.1(m，1H)。

LC-MS (method 4): r_t1.35 minutes; ms (esineg): 366[ M-H ] M/z]^-。

Example 121

3- (1-cyclopropyl-5-fluoro-2, 3-dihydro-1H-inden-1-yl) -5-fluoro-7- [ (methylsulfinyl) methyl ] -1H-indole

80.0 mg (0.22 mmol) of the compound from example 94 are introduced at 0 ℃ into 6 ml of dichloromethane, 56.1 mg (0.23 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. Methanol was added, concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to give 43.6 mg (52% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝-0.26--0.19(m，1H)，-0.01-0.06(m，1H)，0.42-0.53(m，2H)，1.46-1.55(m，1H)，2.10-2.19(m，1H)，2.44-2.54(m，1H)，2.54-2.56(m，3H)，2.90-3.04(m，2H)，4.18-4.27(m，1H)，4.33-4.42(m，1H)，6.34-6.39(m，1H)，6.71(dd，1H)，6.81-6.88(m，2H)，7.14(dd，1H)，7.45(d，1H)，11.1(d，1H)。

LC-MS (method 4): r_t1.36 minutes; ms (esineg): 384[ M-H ] M/z]^-。

Example 122

3- [ 1-cyclopropyl-1- (4-fluorophenyl) ethyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

The title compound was prepared starting from 273 mg (0.81 mmol) of the compound from example 95 in analogy to the synthesis of the compound from example 91. 213 mg (73% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.04-0.13(m，1H)，0.16-0.25(m，1H)，0.36-0.56(m，2H)，1.50(s，3H)，1.53-1.63(m，1H)，2.55(s，3H)，4.21(dd，1H)，4.35(dd，1H)，6.65(d，1H)，6.71(t，1H)，6.91(d，1H)，7.05(t，2H)，7.28-7.35(m，2H)，7.42(d，1H)，11.05(s，1H)。

HPLC (method 2): r_t4.67 minutes; ms (esineg): m/z 354[ M-H ]]^-。

Diastereomers and enantiomers were separated by preparative HPLC on the chiral phase [ first column: DaicelChiralcel OJ-H, 5 microns, 250 mm x20 mm; eluent: isohexane/isopropanol 93: 7; flow rate: 25 ml/min; temperature: 24 ℃; UV detection: 230nml. second column: DaicelChiralpak AD-H, 5 microns, 250 mm x20 mm; eluent: Milli-Q water/ethanol 93: 7; flow rate: 25 ml/min; temperature: 24 ℃; UV detection: 230nm ] separation. The separated enantiomers were again purified by preparative HPLC on the achiral phase (mobile phase: acetonitrile/water gradient):

Isomer 122-1:

R_t9.84 min [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/ethanol 9: 1; flow rate: 1 ml/min; temperature: 24 ℃; UV detection: 260 nm]；

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.03-0.13(m，1H)，0.15-0.25(m，1H)，0.36-0.57(m，2H)，1.51(s，3H)，1.53-1.63(m，1H)，2.55(s，3H)，4.23(d，1H)，4.34(d，1H)，6.61-6.75(m，2H)，6.92(d，1H)，7.04(t，2H)，7.31(dd，2H)，7.42(d，1H)，11.05(s，1H)。

Isomer 122-2:

R_t8.31 min [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/ethanol 9: 1; flow rate: 1 ml/min; temperature: 24 ℃; UV detection: 260 nm]。

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.04-0.13(m，1H)，0.16-0.25(m，1H)，0.37-0.55(m，2H)，1.50(s，3H)，1.53-1.62(m，1H)，2.55(s，3H)，4.12(d，1H)，4.37(d，1H)，6.65(d，1H)，6.71(t，1H)，6.91(d，1H)，7.05(t，2H)，7.28-7.35(m，2H)，7.42(d，1H)，11.04(s，1H)。

Isomer 122-3:

R_t8.86 min [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/ethanol 9: 1; flow rate: 1 ml/min; temperature: 24 ℃; UV detection: 260 nm]。

Isomer 122-4:

R_t10.30 min [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/ethanol 9: 1; flow rate: 1 ml/min; temperature: 24 ℃; UV detection: 260 nm]。

Example 123

3- [ 1-cyclopropyl-1- (2, 4-difluorophenyl) ethyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

The title compound was prepared starting from 217 mg (94% purity, 0.61 mmol) of the compound from example 96 in analogy to the synthesis of the compound from example 91. 212 mg (99% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.12-0.20(m，2H)，0.45-0.52(m，2H)，1.58(s，3H)，1.59-1.68(m，1H)，2.54(s，3H)，4.20(dd，1H)，4.34(dd，1H)，6.59(d，1H)，6.69(t，1H)，6.90(d，1H)，6.93-7.01(m，1H)，7.10(dt，1H)，7.32(s，1H)，7.76-7.85(m，1H)，11.04(s，1H)。

HPLC (method 1): r_t4.64 min; DCI-MS (ESIpos): 374[ M + H ] M/z]⁺。

Example 124

3- [1- (4-chloro-2-fluorophenyl) -1-cyclopropylethyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

100 mg (0.27 mmol) of the compound from example 97 are introduced at 0 ℃ into 18 ml of dichloromethane, 66 mg (0.27 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solvent was removed in vacuo. The residue was taken up in ethyl acetate and washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The solvent was removed in vacuo. The crude product is purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 86 mg (83% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.13-0.20(m，2H)，0.45-0.53(m，2H)，1.58(s，3H)，1.59-1.68(m，1H)，2.55(s，3H)，4.20(dd，1H)，4.34(dd，1H)，6.62(d，1H)，6.71(t，1H)，6.91(d，1H)，7.16(dt，1H)，7.29-7.35(m，2H)，7.78(dt，1H)，11.05(s，1H)。

HPLC (method 2): r_t4.85 minutes; ms (esineg): m/z 388[ M-H ]]^-。

Example 125

3- { (4-fluorophenyl) [4- (trifluoromethyl) phenyl ] methyl } -7- [ (methylsulfinyl) methyl ] -1H-indole

75 mg (0.18 mmol) of the compound from example 99 are introduced into 25 ml of dichloromethane at 0 ℃, 43 mg (0.18 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was purified twice by preparative HPLC (mobile phase: acetonitrile/water gradient). 65 mg (84% of theory) of the title compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.54(s，3H)，4.24(d，1H)，4.37(d，1H)，5.86(s，1H)，6.81(s，1H)，6.90(t，1H)，7.03(d，1H)，7.08-7.18(m，3H)，7.24-7.31(m，2H)，7.45(d，2H)，7.67(d，2H)，11.15(s，1H)。

LC-MS (method 4): r_t1.42 minutes; ms (esineg): m/z 444[ M-H ]]^-。

Example 126

3- [ (4-chlorophenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

110 mg (0.28 mmol) of the compound from example 100 are introduced into 20 ml of dichloromethane at 0 ℃, 68 mg (0.28 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 93 mg (81% of theory) of the title compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.54(s，3H)，4.23(d，1H)，4.37(d，1H)，5.74(s，1H)，6.77(s，1H)，6.89(t，1H)，7.02(d，1H)，7.06-7.16(m，3H)，7.21-7.28(m，4H)，7.34-7.38(m，2H)，11.11(s，1H)。

LC-MS (method 3): r_t2.28 min; ms (esineg): 410[ M-H ] M/z]^-。

Example 127

3- [ (4-fluoro-2-methylphenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

65 mg (0.17 mmol) of the compound from example 101 are introduced at 0 ℃ into 8 ml of dichloromethane, 41 mg (0.17 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 67 mg (99% of theory) of the title compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.26(s，3H)，2.54(s，3H)，4.23(dd，1H)，4.37(dd，1H)，5.80(s，1H)，6.62(s，1H)，6.82-6.94(m，3H)，6.98-7.23(m，7H)，11.07(s，1H)。

LC-MS (method 4): r_t1.38 minutes; ms (esineg): 408[ M-H ] M/z]^-。

Example 128

3- [ (4-chloro-2-methylphenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

130 mg (0.32 mmol) of the compound from example 102 are introduced at 0 ℃ into 15 ml of dichloromethane, 78 mg (0.32 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 129 mg (96% of theory) of the title compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.26(s，3H)，2.53(s，3H)，4.24(dd，1H)，4.37(dd，1H)，5.81(s，1H)，6.63(s，1H)，6.85(d，1H)，6.89(t，1H)，7.02(d，1H)，7.08(d，1H)，7.10-7.22(m，5H)，7.28(d，1H)，11.09(s，1H)。

LC-MS (method 3): r_t2.38 minutes; ms (esineg): 424[ M-H ] M/z]^-。

Example 129

3- [ (2, 4-difluorophenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

75 mg (0.19 mmol) of the compound from example 103 are introduced at 0 ℃ into 14 ml of dichloromethane, 47 mg (0.19 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 74 mg (95% of theory) of the title compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.54(s，3H)，4.24(dd，1H)，4.38(dd，1H)，5.89(s，1H)，6.77(s，1H)，6.90(t，1H)，6.97-7.17(m，6H)，7.20-7.27(m，3H)，11.15(s，1H)。

LC-MS (method 3): r_t2.17 minutes; ms (esineg): m/z 412[ M-H ═ M]^-

Example 130

3- [ (4-chloro-2-fluorophenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

70 mg (0.17 mmol) of the compound from example 104 are introduced into 10 ml of dichloromethane at 0 ℃, 42 mg (0.17 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 76 mg (99% of theory) of the title compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.54(s，3H)，4.24(dd，1H)，4.38(dd，1H)，5.90(s，1H)，6.78(s，1H)，6.90(t，1H)，7.01-7.18(m，3H)，7.19-7.20(m，5H)，7.42(dd，1H)，11.14(s，1H)。

LC-MS (method 3): r_t2.31 minutes; ms (esineg): 428[ M-H ] M/z]^-。

Example 131

3- [ (4-chloro-2-fluorophenyl) (4-fluorophenyl) methyl ] -5-fluoro-7- [ (methylsulfinyl) methyl ] -1H-indole

50 mg (0.12 mmol) of the compound from example 105 are introduced at 0 ℃ into 6 ml of dichloromethane, 29 mg (0.12 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 45 mg (87% of theory) of the title compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.53(s，3H)，4.24(dd，1H)，4.40(dd，1H)，5.88(s，1H)，6.81-6.95(m，3H)，7.04(dt，1H)，7.11-7.18(m，2H)，7.20-7.26(m，3H)，7.42(dd，1H)，11.28(s，1H)。

LC-MS (method 5): r_t2.70 minutes; ms (esineg): 446[ M-H ] M/z]^-。

Example 132

3- (4-chloro-2-methylphenyl) -3- { 5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propan-1-ol

A solution of 690 mg (1.64 mmol) of the compound from example 98A in 10 ml of THF is added dropwise at room temperature under argon to a solution of 5.8 ml (5.75 mmol) of 1N lithium aluminum hydride in THF in 20 ml of THF. 1N hydrochloric acid was then added, the mixture was extracted with ethyl acetate, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 0.60 g (97% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.1(s，1H)，7.18-7.28(m，3H)，7.13(dd，1H)，6.87(dd，1H)，6.82(dd，1H)，4.50(t，1H)，4.46(t，1H)，3.87-3.96(m，2H)，3.32-3.45(m，2H)，2.39(s，3H)，2.19-2.29(m，1H)，1.06-2.05(m，1H)，1.96(s，3H)。

LC-MS (method 5): r_t2.59 min; ms (esipos): 378[ M + H ] M/z]⁺。

Example 133

3- [ 2-chloro-4- (trifluoromethyl) phenyl ] -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propan-1-ol

A solution of 1.30 g (2.85 mmol) of the compound from example 99A in 20 ml of THF is added dropwise at room temperature under argon to a solution of 10 ml (9.98 mmol) of 1N lithium aluminum hydride in THF in 80 ml of THF. 1N hydrochloric acid is then added, the mixture is extracted with dichloromethane, the organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 0.73 g (61% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.0(s，1H)，7.81(s，1H)，7.56-7.62(m，2H)，7.36(d，1H)，7.25(d，1H)，6.93(d，1H)，6.86(t，1H)，4.88(t，1H)，4.53(t，1H)，3.88-3.96(s，2H)，3.35-3.49(m，2H)，2.29-2.40(m，1H)，2.08-2.20(m，1H)，1.94(s，3H)。

LC-MS (method 4): r_t1.43 minutes; ms (esipos): m/z 414[ M + H ]]⁺.

Example 134

3- (4-methylphenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propan-1-ol

A solution of 2.41 g (6.57 mmol) of the compound from example 100A in 20 ml of THF is added dropwise at room temperature under argon to a solution of 23 ml (23.0 mmol) of 1N lithium aluminum hydride in THF in 80 ml of THF. 1N hydrochloric acid is then added, the mixture is extracted with dichloromethane, the organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 1.77 g (83% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝10.9(s，1H)，7.22-7.28(m，2H)，7.16-7.21(m，2H)，7.01-7.06(m，2H)，6.89(d，1H)，6.81(t，1H)，4.42(t，1H)，4.23(t，1H)，3.91(s，2H)，3.32-3.39(m，2H)，2.22-2.32(m，1H)，2.21(s，3H)，2.03-2.14(m，1H)，1.93(s，3H)。

LC-MS (method 4): r_t1.29 minutes; ms (esipos): 326[ M + H ] M/z]⁺。

Example 135

3- (4-chloro-3-fluorophenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propan-1-ol

A solution of 1.74 g (4.28 mmol) of the compound from example 101A in 7 ml of tetrahydrofuran is added dropwise at room temperature under argon to a 1N solution of 15.0 ml (15.05 mmol) of lithium aluminum hydride in tetrahydrofuran in 20 ml of tetrahydrofuran. The mixture was stirred at 60 ℃ for 1 hour then water and acetonitrile were added and the suspension was filtered through celite. The solvent was removed in a rotary evaporator and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 1.36 g (87% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.94(s，3H)，2.08-2.17(m，1H)，2.23-2.34(m，1H)，3.27-3.42(m，2H)，3.91(s，2H)，4.35(t，1H)，4.49(t，1H)，6.85(t，1H)，6.92(d，1H)，7.20(dd，1H)，7.27-7.38(m，3H)，11.0(s，1H)。

HPLC (method 1): r_t4.63 minutes; ms (esineg): 462[ M-H ] M/z]^-。

Example 136

3- (4-chloro-2, 6-difluorophenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propan-1-ol

A solution of 1.09 g (2.56 mmol) of the compound from example 102A in 6 ml of tetrahydrofuran is added dropwise at room temperature under argon to a 1N solution of 9.0 ml (9.0 mmol) of lithium aluminum hydride in tetrahydrofuran in 12 ml of tetrahydrofuran. The mixture was stirred at 60 ℃ for 1 hour then water and acetonitrile were added and the suspension was filtered through celite. The solvent was removed in a rotary evaporator and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 0.88 g (90% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.93(s，3H)，2.22-2.46(m，2H)，3.33-3.51(m，2H)，3.91(s，2H)，4.53(t，1H)，4.74(t，1H)，6.85-6.96(m，2H)，7.22-7.32(m，4H)，11.0(s，1H)。

HPLC (method 1): r_t4.55 minutes; ms (esineg): 380[ M-H ] M/z]^-。

Example 137

3- (2, 2-difluoro-1, 3-benzodioxol-5-yl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propan-1-ol

1.67 g (3.86 mmol) of the compound from example 103A in 8 ml of tetrahydrofuran are added dropwise at room temperature under argon to a 1N solution of 13.5 ml (13.5 mmol) of lithium aluminum hydride in tetrahydrofuran in 16 ml of tetrahydrofuran. The mixture was stirred at 60 ℃ for 1 hour then water and acetonitrile were added and the suspension was filtered through celite. The solvent was removed in a rotary evaporator and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 1.39 g (92% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.94(s，3H)，2.07-2.17(m，1H)，2.24-2.35(m，1H)，3.28-3.42(m，2H)，3.91(s，2H)，4.36(t，1H)，4.48(t，1H)，6.84(t，1H)，6.92(d，1H)，7.18(dd，1H)，7.25(d，1H)，7.29-7.36(m，3H)，11.0(s，1H)。

HPLC (method 2): r_t4.65 minutes; ms (esineg): 390[ M-H ] M/z]^-。

Example 138

3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } -3- [4- (trifluoromethyl) phenyl ] butan-1-ol

1.59 g (91% purity, approx. 6.77 mmol) of the compound from example 89A and 1.50 g (6.77 mmol) of indium (III) chloride are added to 1.20 g (6.77 mmol) of the compound from example 8A in 29 ml of toluene. The reaction mixture was stirred at 80 ℃ for 5 hours. After cooling to RT, the reaction solution was mixed with water and ethyl acetate and the solid was filtered off. The filtrate phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) gives 0.14 g (5% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.69(s，3H)，1.97(s，3H)，2.26-2.53(m，2H)，3.10-3.21(m，1H)，3.21-3.29(m，1H)，3.93(s，2H)，4.33(t，1H)，6.66-6.73(m，2H)，6.87(dd，1H)，7.33(d，1H)，7.47(d，2H)，7.60(d，2H)，11.0(s，1H)。

LC-MS (method 9): r_t1.20 minutes; ms (esipos): 392[ M + H ] M/z]⁺。

Example 139

3- (4-chlorophenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butan-1-ol

A solution of 740 mg (1.84 mmol) of the compound from example 104A in 20 ml of tetrahydrofuran is added dropwise at room temperature under argon to a 1N solution of 5.5 ml (5.5 mmol) of diisobutylaluminum hydride in dichloromethane in 20 ml of tetrahydrofuran. The mixture was stirred at room temperature for 2 hours, then water and dichloromethane were added and the phases were separated. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 437 mg (66% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.64(s，3H)，1.97(s，3H)，2.20-2.44(m，2H)，3.10-3.30(m，2H)，3.92(s，2H)，4.30(t，1H)，6.66-6.74(m，2H)，6.87(d，1H)，7.23-7.30(m，5H)，10.9(s，1H)。

LC-MS (method 5): r_t2.52 min; ms (esipos): m/z is 360[ M + H ]]⁺。

Example 140

3- (4-chlorophenyl) -3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } pent-1-ol

3.04 g (14.10 mmol) of 3- (4-chlorophenyl) pentane-1, 3-diol (prepared analogously to the syntheses of examples 88A and 89A, starting from 1- (4-chlorophenyl) propane-1-one and ethyl acetate) and 3.12 g (14.10 mmol) of indium (III) chloride are added to 2.50 g (14.10 mmol) of the compound from example 8A in 60 ml of toluene. The reaction mixture was stirred at 80 ℃ for 5 hours. After cooling to RT, the reaction solution was mixed with water and ethyl acetate and the solid was filtered off over celite. The filtrate phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) gives 2.13 g (40% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.61(t，3H)，1.97(s，3H)，1.98-2.38(m，4H)，2.98-3.09(m，1H)，3.12-3.22(m，1H)，3.92(s，2H)，4.27(t，1H)，6.59-6.68(m，2H)，6.85(dd，1H)，7.22-7.34(m，5H)，10.9(s，1H)。

LC-MS (method 4): r_t1.38 minutes; ms (esineg): 372[ M-H ] M/z]^-。

Example 141

3- (4-chlorophenyl) -3-cyclopropyl-3- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } propan-1-ol

A solution of 62 mg (0.15 mmol) of the compound from example 105A in 0.5 ml of tetrahydrofuran is added dropwise at room temperature under argon to a 1N solution of 0.51 ml (0.51 mmol) of lithium aluminum hydride in tetrahydrofuran in 1 ml of tetrahydrofuran. The mixture was stirred at 60 ℃ for 1 hour and then mixed with water and acetonitrile, and the suspension was filtered through celite. The solvent was removed in a rotary evaporator and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 52 mg (93% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝-0.20--0.10(m，2H)，0.34-0.49(m，2H)，1.63-1.72(m，1H)，1.98(s，3H)，2.27-2.50(m，2H)，3.13-3.23(m，1H)，3.23-3.32(m，1H)，3.94(q，2H)，4.30(t，1H)，6.44(d，1H)，6.64(t，1H)，6.85(d，1H)，7.23(d，2H)，7.29(d，2H)，7.38(d，1H)，11.0(s，1H)。

LC-MS (method 4): r_t1.42 minutes; ms (esineg): 384[ M-H ] M/z]^-。

Example 142

3- (2, 3-dihydro-1, 4-benzodi)En-6-yl) -3- {7- [ (methylsulfanyl) methyl]-1H-indol-3-yl } butan-1-ol

A solution of 625 mg (1.47 mmol) of the compound from example 106A in 3 ml of tetrahydrofuran is added dropwise at room temperature under argon to a 1N solution of 5.14 ml (5.14 mmol) of lithium aluminum hydride in tetrahydrofuran in 6 ml of tetrahydrofuran. The mixture was stirred at 60 ℃ for 1 hour and then mixed with water and acetonitrile, and the suspension was filtered through celite. The solvent was removed in a rotary evaporator and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 491 mg (87% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，3H)，1.97(s，3H)，2.15-2.25(m，1H)，2.29-2.40(m，1H)，3.09-3.29(m，2H)，3.92(s，2H)，4.16(s，4H)，4.25(t，1H)，6.63-6.73(m，4H)，6.83(d，1H)，6.87(d，1H)，7.21(d，1H)，10.9(s，1H)。

HPLC (method 1): r_t4.28 min; DCI-MS (ESIpos): m/z 383[ M-H ═₂O+NH₄]⁺。

Example 143

3- (4-chlorophenyl) -3- {7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } pent-1-ol

60 mg (0.16 mmol) of the compound from example 140 are introduced at 0 ℃ into 6 ml of dichloromethane, 40 mg (0.16 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The crude product is purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 62 mg (99% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.61(t，3H)，1.99-2.11(m，1H)，2.13-2.27(m，2H)，2.29-2.39(m，1H)，2.50(s，3H)，2.99-3.09(m，1H)，3.11-3.22(m，1H)，4.22(dd，1H)，4.27(t，1H)，4.35(dd，1H)，6.65-6.73(m，2H)，6.91(dd，1H)，7.24(d，2H)，7.29(d，2H)，7.40(d，1H)，11.1(s，1H)。

LC-MS (method 3): r_t1.73 minutes; ms (esineg): m/z 388[ M-H ]]^-。

Example 144

3- (4-chloro-2-fluorophenyl) -3- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } propan-1-ol

33.2 mg (0.12 mmol) of 60% m-chloroperbenzoic acid are added to 40.0 mg (0.11 mmol) of the compound from example 4 in 5 ml of dichloromethane and the mixture is stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 16.2 mg (37% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.1(s，1H)，7.31-7.40(m，4H)，7.18(dd，1H)，7.11(d，1H)，6.96(t，1H)，4.67-4.76(m，2H)，4.62(t，1H)，4.51(t，1H)，3.34-3.43(m，2H)，2.88(s，3H)，2.27-2.38(m，1H)，2.09-2.20(m，1H)。

LC-MS (method 3): r_t1.73 minutes; ms (esipos): 396[ M + H ] M/z]⁺。

Example 145

3- (4-chloro-2-methylphenyl) -3- {7- [ (ethylsulfonyl) methyl ] -1H-indol-3-yl } propan-1-ol

106 mg (0.43 mmol) of 70% m-chloroperbenzoic acid were added to 80.0 mg (0.21 mmol) of the compound from example 10 in 12 ml of dichloromethane and the mixture was stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 45 mg (51% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.0(s，1H)，7.26-7.30(m，2H)，7.22(d，1H)，7.19(d，1H)，7.12(dd，1H)，7.08(d，1H)，6.92(t，1H)，4.66-4.76(m，2H)，4.49-4.56(m，2H)，3.32-3.46(m，2H)，3.02(q，2H)，2.42(s，3H)，2.21-2.32(m，1H)，1.96-2.07(m，1H)，1.19(t，3H)。

LC-MS (method 3): r _t1.87 min; ms (esipos): 406[ M + H ] M/z]⁺。

Example 146

3- (2, 2-difluoro-1, 3-benzodioxol-5-yl) -3- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } propan-1-ol

140 mg (0.36 mmol) of the compound from example 137 are introduced into 24 ml of dichloromethane at 0 ℃, 176 mg (0.72 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvent was removed in a rotary evaporator. The crude product is purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 43 mg (28% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.07-2.18(m，1H)，2.24-2.35(m，1H)，2.87(s，3H)，3.27-3.42(m，2H)，4.38(t，1H)，4.49(t，1H)，4.71(s，2H)，6.94(t，1H)，7.10(d，1H)，7.18(d，1H)，7.26(d，1H)，7.34-7.46(m，3H)，11.0(s，1H)。

HPLC (method 1): r_t4.19 minutes; DCI-MS (ESIpos): 424[ M + H ] M/z]⁺。

Example 147

3- (4-chlorophenyl) -3- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } pent-1-ol

2.12 g (5.67 mmol) of the compound from example 140 are introduced into 150 ml of dichloromethane at 0 ℃, 2.80 g (11.34 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 15 ml of methanol was added and the solution was concentrated. The crude product is purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 1.76 g (77% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.61(t，3H)，1.99-2.11(m，1H)，2.13-2.27(m，2H)，2.29-2.39(m，1H)，2.89(s，3H)，2.99-3.09(m，1H)，3.11-3.22(m，1H)，4.28(t，1H)，4.72(s，2H)，6.69-6.77(m，2H)，7.02(dd，1H)，7.24(d，2H)，7.29(d，2H)，7.42(d，1H)，11.0(s，1H)。

LC-MS (method 3): r_t1.86 minutes; ms (esineg): 404[ M-H ] M/z]^-。

Example 148

3- (4-chloro-2-methylphenyl) -3- { 5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } propan-1-ol

53.5 mg (0.22 mmol) of 70% m-chloroperbenzoic acid are added at 0 ℃ to 40.0 mg (0.11 mmol) of the compound from example 132 in 3 ml of dichloromethane and the mixture is stirred at room temperature overnight. 2 ml of methanol are added and the concentrated residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 24.0 mg (55% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.2(s，1H)，7.33-7.35(m，1H)，7.19-7.24(m，2H)，7.14(dd，1H)，6.95-7.03(m，2H)，4.70-4.80(m，2H)，4.48(t，1H)，3.30-3.44(m，3H)，2.91(s，3H)，2.39(s，3H)，2.17-2.30(m，1H)，1.96-2.07(m，1H)。

LC-MS (method 6): r_t2.15 minutes; ms (esipos): 410[ M + H ] M/z]⁺。

Example 149

4- (4-chloro-2-methylphenyl) -4- { 5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butanenitrile

174 mg (2.67 mmol) of potassium cyanide and 8.1 mg (0.07 mmol) of 4-N, N-dimethylaminopyridine are added to 608 mg (1.33 mmol) of the compound from example 107A in 30 ml of DMSO. The mixture was stirred at 120 ℃ for 2 hours and then concentrated, the residue taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to yield 154 mg (30% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.2(s，1H)，7.34-7.36(m，1H)，7.24-7.30(m，2H)，7.18(dd，1H)，6.95(dd，1H)，6.84(dd，1H)，4.38(t，1H)，3.87-3.97(m，2H)，2.37-2.48(m，3H)，2.40(s，3H)，2.13-2.26(m，1H)，1.96(s，3H)。

LC-MS (method 3): r_t2.47 minutes; ms (esipos): m/z 387[ M + H ]]⁺。

Example 150

4- [ 2-chloro-4- (trifluoromethyl) phenyl ] -4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butanenitrile

176 mg (2.70 mmol) of potassium cyanide and 8.2 mg (0.07 mmol) of 4-N, N-dimethylaminopyridine are added to 664 mg (1.35 mmol) of the compound from example 108A in 29 ml of DMSO. The mixture was stirred at 120 ℃ for 1 hour and then concentrated, the residue taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to yield 460 mg (81% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.2(s，1H)，7.86(s，1H)，7.58-7.65(m，2H)，7.47(d，1H)，7.27(d，1H)，6.96(d，1H)，6.89(t，1H)，4.85(t，1H)，3.89-3.97(m，2H)，2.43-2.62(m，3H)，2.24-2.38(m，1H)，1.95(s，3H)。

LC-MS (method 9): r_t1.33 minutes; ms (esipos): 423[ M + H ] M/z]⁺。

Example 151

4- (4-methylphenyl) -4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butanenitrile

671 mg (10.3 mmol) of potassium cyanide and 31.5 mg (0.26 mmol) of 4-N, N-dimethylaminopyridine are added to 2.08 g (5.15 mmol) of the compound from example 109A in 112 ml of DMSO. The mixture was stirred at 120 ℃ for 1 hour and then concentrated, the residue taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 1.92 g (99% of theory) of the title compound.

LC-MS (method 3): r_t2.34 minutes; ms (esipos): m/z 335[ M + H]⁺。

Example 152

4- (4-chloro-3-fluorophenyl) -4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butanenitrile

0.38 g (5.90 mmol) of potassium cyanide are added to 1.30 g (2.95 mmol) of the compound from example 110A in 27 ml of DMSO. The mixture was stirred at 80 ℃ for 3 hours, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The combined organic phases were freed of solvent and the crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 0.95 g (86% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.94(s，3H)，2.28-2.51(m，4H)，3.92(s，2H)，4.24-4.30(m，1H)，6.87(t，1H)，6.94(d，1H)，7.24(dd，1H)，7.34(d，1H)，7.42(dt，2H)，7.47(t，1H)，11.1(s，1H)。

HPLC (method 1): r_t4.91 min; DCI-MS (ESIpos): m/z 373[ M + H ]]⁺。

Example 153

4- (4-chloro-2, 6-difluorophenyl) -4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butanenitrile

0.30 g (4.57 mmol) of potassium cyanide are added to 1.05 g (2.28 mmol) of the compound from example 111A in 21 ml of DMSO. The mixture was stirred at 80 ℃ for 3 hours, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The combined organic phases were freed of solvent and the crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 0.74 g (83% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.94(s，3H)，2.40-2.63(m，4H)，3.92(s，2H)，4.59-4.66(m，1H)，6.91(t，1H)，6.95(d，1H)，7.26(d，1H)，7.28-7.37(m，3H)，11.1(s，1H)。

HPLC (method 2): r_t4.78 minutes; DCI-MS (ESIpos): 391[ M + H ] M/z]⁺。

Example 154

4- (2, 2-difluoro-1, 3-benzodioxol-5-yl) -4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butanenitrile

0.37 g (5.76 mmol) of potassium cyanide are added to 1.35 g (2.88 mmol) of the compound from example 112A in 26 ml of DMSO. The mixture was stirred at 80 ℃ for 3 hours, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The combined organic phases were freed of solvent and the crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 0.90 g (78% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.94(s，3H)，2.29-2.51(m，4H)，3.92(s，2H)，4.24-4.31(m，1H)，6.87(t，1H)，6.94(d，1H)，7.22(dd，1H)，7.29(d，1H)，7.35(d，1H)，7.42(s，2H)，11.1(s，1H)。

HPLC (method 1): r_t4.89 minutes; DCI-MS (ESIpos): 401[ M + H ] M/z]⁺。

Example 155

4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } -4- [4- (trifluoromethyl) phenyl ] valeronitrile

33 mg (0.50 mmol) of potassium cyanide are added to 118 mg (0.25 mmol) of the compound from example 113A in 1.5 ml of DMSO. The mixture was stirred at 80 ℃ for 4 hours, water and dichloromethane were added to the reaction solution, and the phases were separated. The organic phase was extracted with dichloromethane and the combined organic phases were freed of solvent. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 62 mg (62% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.68(s，3H)，1.97(s，3H)，2.07-2.18(m，1H)，2.20-2.31(m，1H)，2.47-2.64(m，2H)，3.94(q，2H)，6.72(d，2H)，6.90(t，1H)，7.40(d，1H)，7.49(d，2H)，7.62(d，2H)，11.1(s，1H)。

LC-MS (method 9): r_t1.29 minutes; ms (esineg): 401[ M-H ] M/z]^-。

Example 156

4- (4-chlorophenyl) -4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } valeronitrile

128 mg (1.96 mmol) of potassium cyanide are added to 430 mg (0.98 mmol) of the compound from example 114A in 8 ml of DMSO. The mixture was stirred at 80 ℃ for 8 hours, water and dichloromethane were added to the reaction solution, and the phases were separated. The organic phase was extracted with dichloromethane and the combined organic phases were freed of solvent. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 280 mg (77% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.64(s，3H)，1.97(s，3H)，2.07-2.29(m，2H)，2.43-2.59(m，2H)，3.93(q，2H)，6.69-6.75(m，2H)，6.89(dd，1H)，7.25-7.36(m，5H)，11.1(s，1H)。

LC-MS (method 3): r_t2.46 minutes; ms (esineg): 367[ M-H ] M/z]^-。

Example 157

4- (4-chlorophenyl) -4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } hexanenitrile

223 mg (3.43 mmol) of potassium cyanide are added to 775 mg (1.71 mmol) of the compound from example 115A in 12 ml of DMSO. The mixture was stirred at 80 ℃ for 12 hours, water and dichloromethane were added to the reaction solution, and the phases were separated. The organic phase was extracted with dichloromethane and the combined organic phases were freed of solvent. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 551 mg (84% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.59(t，3H)，1.97(s，3H)，1.96-2.23(m，2H)，2.43-2.53(m，2H)，3.93(s，2H)，6.60(d，1H)，6.67(t，1H)，6.87(d，1H)，7.24-7.33(m，4H)，7.40(d，1H)，11.1(s，1H)。

LC-MS (method 4): r_t1.51 minutes; ms (esineg): m/z 381[ M-H ]]^-。

Example 158

4- (4-chlorophenyl) -4-cyclopropyl-4- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } butanenitrile

16 mg (0.25 mmol) of potassium cyanide are added to 57 mg (0.12 mmol) of the compound from example 116A in 1 ml of DMSO. The mixture was stirred at 80 ℃ for 16 h, water was added to the reaction solution and the crude product was purified directly by preparative HPLC (mobile phase: acetonitrile/water gradient). 29 mg (60% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝-0.20--0.12(m，2H)，0.38-0.51(m，2H)，1.62-1.71(m，1H)，1.97(s，3H)，2.12-2.34(m，2H)，2.49-2.64(m，2H)，3.93(s，2H)，6.40(d，1H)，6.65(t，2H)，6.86(d，1H)，7.25(d，2H)，7.31(d，2H)，7.47(d，1H)，11.1(s，1H)。

LC-MS (method 4): r_t1.55 minutes; ms (esineg): 393[ M-H ] M/z]^-。

Example 159

4- (2, 3-dihydro-1, 4-benzodi)En-6-yl) -4- {7- [ (methylsulfanyl) methyl]-1H-indol-3-yl } valeronitrile

150 mg (2.30 mmol) of potassium cyanide are added to 530 mg (1.15 mmol) of the compound from example 117A in 10 ml of DMSO. The mixture was stirred at 80 ℃ for 16 hours, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The combined organic phases were freed of solvent and the crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 328 mg (73% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.59(s，3H)，1.97(s，3H)，2.05-2.25(m，2H)，2.36-2.52(m，2H)，3.93(q，2H)，4.17(s，4H)，6.66-6.75(m，4H)，6.82(d，1H)，6.89(d，1H)，7.29(d，1H)，11.0(s，1H)。

HPLC (method 2): r_t4.55 minutes; DCI-MS (ESIpos): 393[ M + H ] M/z]⁺。

Example 160

4- (4-chloro-3-fluorophenyl) -4- {7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } butanenitrile

300 mg (0.81 mmol) of the compound from example 152 are introduced into 55 ml of dichloromethane at 0 ℃, 198 mg (0.81 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvent was removed in a rotary evaporator. The crude product is purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 266 mg (85% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.29-2.56(m，7H)，4.18-4.39(m，3H)，6.93(t，1H)，7.01(d，1H)，7.24(d，1H)，7.38-7.52(m，4H)，11.2(s，1H)。

HPLC (method 1): r_t4.31 min; DCI-MS (ESIpos): 389[ M + H ═ M/z]⁺。

Example 161

4- (4-chloro-2, 6-difluorophenyl) -4- {7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } butanenitrile

231 mg (0.59 mmol) of the compound from example 153 are introduced into 40 ml of dichloromethane at 0 ℃, 198 mg (0.81 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred for 2 hours at 0 ℃. 2 ml of methanol was added and the solution was concentrated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvent was removed in a rotary evaporator. The crude product is purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 171 mg (71% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.40-2.64(m，7H)，4.22(d，1H)，4.35(d，1H)，4.60-4.67(m，1H)，6.97(t，1H)，7.02(d，1H)，7.32(d，3H)，7.43(s，1H)，11.2(s，1H)。

HPLC (method 1): r_t4.25 minutes; DCI-MS (ESIpos): 407[ M + H ] M/z]⁺。

Example 162

4- (2, 2-difluoro-1, 3-benzodioxol-5-yl) -4- {7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } butanenitrile

272 mg (0.68 mmol) of the compound from example 154 are introduced into 46 ml of dichloromethane at 0 ℃, 167 mg (0.68 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvent was removed in a rotary evaporator. The crude product is purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 236 mg (81% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.27-2.57(m，7H)，4.18-4.38(m，3H)，6.93(t，1H)，7.01(d，1H)，7.22(d，1H)，7.29(d，1H)，7.38-7.50(m，3H)，11.2(s，1H)。

HPLC (method 2): r_t4.44 minutes; DCI-MS (ESIpos): 417[ M + H ] M/z]⁺。

Example 163

4- (4-chlorophenyl) -4- {7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } hexanenitrile

120 mg (0.31 mmol) of the compound from example 157 are introduced at 0 ℃ into 12 ml of dichloromethane, 77 mg (0.31 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The crude product is purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 120 mg (96% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.59(t，3H)，1.96-2.24(m，4H)，2.41-2.58(m，5H)，4.16-4.25(m，1H)，4.36(d，1H)，6.66(d，1H)，6.72(t，1H)，6.94(d，1H)，7.26(d，2H)，7.31(d，2H)，7.48(d，1H)，11.2(s，1H)。

LC-MS (method 4): r_t1.24 minutes; ms (esineg): m/z ═ 397[ M-H ]]^-。

Example 164

4- (4-chloro-2-methylphenyl) -4- { 5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } butanenitrile

87.5 mg (0.36 mmol) of 70% m-chloroperbenzoic acid are added at 0 ℃ to 67.0 mg (0.17 mmol) of the compound from example 149 in 5 ml of dichloromethane and the mixture is stirred at room temperature overnight. Methanol was added, concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to give 36.6 mg (51% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.3(s，1H)，7.43(d，1H)，7.29(d，1H)，7.26(d，1H)，7.19(dd，1H)，7.10(dd，1H)，7.00(dd，1H)，4.70-4.80(m，2H)，4.39(t，1H)，2.91(s，3H)，2.36-2.48(m，3H)，2.39(s，3H)，2.15-2.28(m，1H)。

LC-MS (method 5): r_t2.43 minutes; ms (esipos): m/z 419[ M + H ]]⁺。

Example 165

4- [ 2-chloro-4- (trifluoromethyl) phenyl ] -4- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } butanenitrile

406 mg (1.65 mmol) of 70% m-chloroperbenzoic acid are added at 0 ℃ to 348 mg (0.82 mmol) of the compound from example 150 in 6 ml of dichloromethane and the mixture is stirred at room temperature overnight. It is diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and concentrated, and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 200 mg (53% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.2(s，1H)，7.87(s，1H)，7.59-7.66(m，2H)，7.55(d，1H)，7.39(d，1H)，7.14(d，1H)，6.99(t，1H)，4.84(t，1H)，4.69-4.78(m，2H)，2.89(s，3H)，2.44-2.60(m，3H)，2.26-2.38(m，1H)。

LC-MS (method 4): r_t1.33 minutes; ms (esipos): 455[ M + H ] M/z]⁺。

Example 166

4- (4-methylphenyl) -4- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } butanenitrile

251 mg (1.02 mmol) of 70% m-chloroperbenzoic acid are added to 200 mg (0.60 mmol) of the compound from example 151 in 10 ml of dichloromethane and the mixture is stirred at room temperature overnight. 2 ml of methanol were added, concentrated and the residue taken up in dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 48.0 mg (22% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.1(s，1H)，7.42(d，1H)，7.39(d，1H)，7.20-7.25(m，2H)，7.06-7.11(m，3H)，6.94(t，1H)，4.71(s，2H)，4.18(t，1H)，2.86(s，3H)，2.35-2.48(m，3H)，2.23-2.32(m，1H)，2.23(s，3H)。

LC-MS (method 4): r_t1.21 minutes; ms (esipos): 367[ M + H ] M/z]⁺。

Example 167

4- (4-chloro-3-fluorophenyl) -4- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } butanenitrile

300 mg (0.81 mmol) of the compound from example 152 are introduced into 55 ml of dichloromethane at 0 ℃, 198 mg (0.81 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvent was removed in a rotary evaporator. The crude product is purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 266 mg (85% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.29-2.49(m，4H)，2.88(s，3H)，4.26-4.32(m，1H)，4.72(s，2H)，6.97(t，1H)，7.12(d，1H)，7.24(dd，1H)，7.41-7.52(m，4H)，11.2(s，1H)。

HPLC (method 1): r_t4.42 minutes; ms (esipos): 405[ M + H ] M/z]⁺。

Example 168

4- (4-chloro-2, 6-difluorophenyl) -4- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } butanenitrile

461 mg (1.18 mmol) of the compound from example 153 were introduced into 80 ml of dichloromethane at 0 ℃, 581 mg (2.36 mmol) of 70% m-chloroperbenzoic acid were added and the mixture was stirred for 2 hours at 0 ℃. 2 ml of methanol was added and the solution was concentrated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvent was removed in a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to give 342 mg (68% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.40-2.64(m，4H)，2.88(s，3H)，4.61-4.67(m，1H)，4.73(s，2H)，7.01(t，1H)，7.13(d，1H)，7.29-7.39(m，3H)，7.45(s，1H)，11.2(s，1H)。

HPLC (method 1): r_t4.33 minutes; DCI-MS (ESIpos): 440[ M + NH ] M/z₄]⁺。

Example 169

4- (2, 2-difluoro-1, 3-benzodioxol-5-yl) -4- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } butanenitrile

544 mg (1.36 mmol) of the compound from example 154 are introduced at 0 ℃ into 93 ml of dichloromethane, 670 mg (2.72 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvent was removed in a rotary evaporator. The crude product is purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 352 mg (60% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.29-2.49(m，3H)，2.88(s，3H)，4.26-4.32(m，1H)，4.72(s，2H)，6.97(t，1H)，7.12(d，1H)，7.23(dd，1H)，7.29(d，1H)，7.43(d，1H)，7.45-7.51(m，2H)，11.1(s，1H)。

HPLC (method 2): r_t4.34 minutes; DCI-MS (ESIpos): m/z 450[ M + NH ]₄]⁺。

The enantiomers were purified by preparative HPLC on chiral phase [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x20 mm; eluent: isohexane/isopropanol 1: 1; flow rate: 20 ml/min; temperature: 24 ℃; UV detection: 230 nm ] separation. The separated enantiomers were again purified by preparative HPLC on the achiral phase (mobile phase: acetonitrile/water gradient):

enantiomer 169-1：

R_t5.86 min [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/isopropanol 1: 1; flow rate: 1 ml/min; temperature: 24 ℃; UV detection: 230 nm]；

Enantiomer 169-2:

R_t6.85 min [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/isopropanol 1: 1; flow rate: 1 ml/min; temperature: 24 ℃; UV detection: 230 nm]。

Example 170

4- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } -4- [4- (trifluoromethyl) phenyl ] valeronitrile

45 mg (0.11 mmol) of the compound from example 155 are introduced at 0 ℃ into 5 ml of dichloromethane, 55 mg (0.22 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to give 43 mg (89% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.68(s，3H)，2.08-2.35(m，2H)，2.46-2.63(m，2H)，2.90(s，3H)，4.73(s，2H)，6.78-6.84(m，2H)，7.07(dd，1H)，7.46-7.52(m，3H)，7.63(d，2H)，11.2(s，1H)。

LC-MS (method 4): r_t1.28 minutes; ms (esipos): 435[ M + H ] M/z]⁺。

Example 171

4- (4-chlorophenyl) -4- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } valeronitrile

180 mg (0.49 mmol) of the compound from example 156 are introduced into 20 ml of dichloromethane at 0 ℃, 241 mg (0.98 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 185 mg (95% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.64(s，3H)，2.06-2.29(m，2H)，2.43-2.60(m，2H)，2.89(s，3H)，4.73(s，2H)，6.77-6.85(m，2H)，7.07(dd，1H)，7.24-7.33(m，4H)，7.44(d，1H)，11.2(s，1H)。

LC-MS (method 5): r_t2.40 minutes; ms (esineg): m/z 399[ M-H ]]^-。

The enantiomers were purified by preparative HPLC on chiral phase [ column: a chiral silica phase based on the selector poly (N-methacryloyl-L-leucine dicyclopropylmethylamide), 5 microns, 250 mm x 20 mm; eluent: isohexane/ethyl acetate 4: 6; flow rate: 20 ml/min; temperature: 24 ℃; UV detection: 260 nm ] separation. The separated enantiomers were again purified by preparative HPLC on the achiral phase (mobile phase: acetonitrile/water gradient):

enantiomer 171-1:

R_t4.06 min [ column: a chiral silica gel phase based on the selector poly (N-methacryloyl-L-leucine dicyclopropylmethylamide), 5 microns, 250 mm x4 mm; eluent: isohexane/ethyl acetate 3: 7; flow rate: 1.5 ml/min; temperature: 24 ℃; UV detection: 260 nm ]；

Yield: 54.0 mg.

Enantiomer 171-2:

R_t4.83 min [ column: a chiral silica gel phase based on the selector poly (N-methacryloyl-L-leucine dicyclopropylmethylamide), 5 microns, 250 mm x4 mm; eluent: isohexane/ethyl acetate 3: 7; flow rate: 1.5 ml/min; temperature: 24 ℃; UV detection: 260 nm]；

Yield: 55.0 mg.

Example 172

4- (4-chlorophenyl) -4- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } hexanenitrile

380 mg (0.99 mmol) of the compound from example 157 are introduced at 0 ℃ into 40 ml of dichloromethane, 489 mg (1.99 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to give 377 mg (92% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.59(t，3H)，1.97-2.24(m，4H)，2.42-2.56(m，2H)，2.88(s，3H)，4.72(q，2H)，6.70(d，1H)，6.76(t，1H)，7.04(d，1H)，7.26(d，2H)，7.32(d，2H)，7.50(d，1H)，11.2(s，1H)。

LC-MS (method 4): r_t1.29 minutes; ms (esineg): 413[ M-H ] M/z]^-。

The enantiomers were purified by preparative HPLC on chiral phase [ column: a chiral silica gel phase based on the selector poly (N-methacryloyl-L-isoleucine-3-pentylamide), 5 microns, 250 mm x20 mm; eluent: isohexane/ethyl acetate 4: 6; flow rate: 20 ml/min; temperature: 24 ℃; UV detection: 260 nm ] separation. The separated enantiomers were again purified by preparative HPLC on the achiral phase (mobile phase: acetonitrile/water gradient):

Enantiomer 172-1:

R_t3.70 min [ column: a chiral silica gel phase based on the selector poly (N-methacryloyl-L-isoleucine-3-pentylamide), 5 microns, 250 mm x4 mm; eluent: isohexane/ethyl acetate 3: 7; flow rate: 1.5 ml/min; temperature: 24 ℃; UV detection: 260 nm]；

Yield: 102 mg.

Enantiomer 172-2:

R_t4.86 min [ column: a chiral silica gel phase based on the selector poly (N-methacryloyl-L-isoleucine-3-pentylamide), 5 microns, 250 mm x4 mm; eluent: isohexane/ethyl acetate 3: 7; flow rate: 1.5 ml/min; temperature: 24 ℃; UV detection: 260 nm]；

Yield: 95 mg.

Example 173

4- (4-chlorophenyl) -4-cyclopropyl-4- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } butanenitrile

23 mg (0.06 mmol) of the compound from example 158 are introduced into 4 ml of dichloromethane at 0 ℃, 29 mg (0.12 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred for 2 hours at 0 ℃.1 ml of methanol was added and the solution was concentrated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvent was removed in a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to give 21 mg (82% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝-0.22--0.12(m，2H)，0.38-0.53(m，2H)，1.63-1.73(m，1H)，2.12-2.34(m，2H)，2.49-2.65(m，2H)，2.89(s，3H)，4.72(q，2H)，6.51(d，1H)，6.74(t，1H)，7.03(d，1H)，7.24(d，2H)，7.31(d，2H)，7.57(s，1H)，11.2(s，1H)。

HPLC (method 1): r_t4.52 min; DCI-MS (ESIpos): 427[ M + H ] M/z]⁺。

Example 174

4- (2, 3-dihydro-1, 4-benzodi)En-6-yl) -4- {7- [ (methylsulfonyl) methyl]-1H-indol-3-yl } valeronitrile

185 mg (0.47 mmol) of the compound from example 159 are introduced at 0 ℃ into 32 ml of dichloromethane, 232 mg (0.94 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvent was removed in a rotary evaporator. The crude product is purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 128 mg (64% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，3H)，2.08-2.25(m，2H)，2.36-2.53(m，2H)，2.89(s，3H)，4.17(s，4H)，4.72(s，2H)，6.65-6.75(m，3H)，6.82(t，1H)，6.92(d，1H)，7.06(d，1H)，7.38(d，1H)，11.1(s，1H)。

HPLC (method 2): r_t4.13 minutes; ms (esipos): 425[ M + H ] M/z]⁺。

Example 175

3- (5-chloro-1-cyclopropyl-2, 3-dihydro-1H-inden-1-yl) -7- [ (methylsulfanyl) methyl ] -1H-indole

0.03 ml (0.40 mmol) of trifluoroacetic acid are added at 0 ℃ to 70.0 mg (0.34 mmol) of the compound from example 118A and 65.4 mg (0.37 mmol) of the compound from example 8A in 1.6 ml of dichloromethane, and the mixture is stirred at 0 ℃ for 4 hours. It is diluted with dichloromethane and saturated aqueous ammonium chloride solution is added, the phases are separated, the aqueous phase is extracted with dichloromethane, the combined organic phases are dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 48.8 mg (40% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝10.9(s，1H)，7.35(d，1H)，7.29(d，1H)，7.07(dd，1H)，6.88(dd，1H)，6.68-6.74(m，3H)，3.87-3.97(m，2H)，2.88-3.04(m，2H)，2.52-2.60(m，1H)，2.08-2.16(m，1H)，1.96(s，3H)，1.46-1.56(m，1H)，0.41-0.53(m，2H)，0.00-0.07(m，1H)，-0.24--0.17(m，1H)。

LC-MS (method 9): r_t1.49 minutes; ms (esineg): 366[ M-H ] M/z]^-。

Example 176

3- (6-chloro-1-cyclopropyl-2, 3-dihydro-1H-inden-1-yl) -7- [ (methylsulfanyl) methyl ] -1H-indole

70.0 mg (0.34 mmol) of the compound from example 119A and 65.4 mg (0.37 mmol) of the compound from example 8A are introduced at 0 ℃ into 1.6 ml of dichloromethane, 0.03 ml (0.40 mmol) of trifluoroacetic acid are added and the mixture is stirred at 0 ℃ for 4 hours. It is diluted with dichloromethane and saturated aqueous ammonium chloride solution is added, the phases are separated, the aqueous phase is extracted with dichloromethane, the combined organic phases are dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 52.4 mg (42% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝10.9(s，1H)，7.32(d，1H)，7.28(d，1H)，7.22(dd，1H)，6.89(dd，1H)，6.68-6.76(m，3H)，3.87-3.99(m，2H)，2.86-3.01(m，2H)，2.50-2.59(m，1H)，2.05-2.14(m，1H)，1.97(s，3H)，1.47-1.56(m，1H)，0.43-0.56(m，2H)，0.03-0.11(m，1H)，-0.18--0.11(m，1H)。

LC-MS (method 4): r_t1.68 minutes; ms (esineg): 366[ M-H ] M/z]^-。

Example 177

2- (1- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } -1- [4- (trifluoromethyl) phenyl ] ethyl) cyclopropanecarbonitrile [ trans-diastereomer mixture ]

0.02 ml (0.24 mmol) of trifluoroacetic acid and 43.3 mg (0.20 mmol) of indium (III) chloride are added at room temperature to 50.0 mg (0.20 mmol) of the compound from example 132A and 69.5 mg (0.39 mmol) of the compound from example 8A in 2 ml of dichloromethane, and the mixture is heated under reflux overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 9.0 mg (11% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.1(s，1H)，7.62-7.69(m，2H)，7.48-7.56(m，2H)，7.39-7.44(m，1H)，6.85-6.91(m，1H)，6.70(t，1H)，6.67(t，1H)，6.58(d，1H)，6.50(d，1H)，3.88-4.00(m，2H)，2.31-2.44(m，0.5H)，1.92-2.00(m，3.5H)，1.52-1.62(m，3.5H)，1.44-1.52(m，0.5H)，1.29-1.39(m，1H)，1.00-1.07(m，0.5H)，0.85-0.95(m，0.5H)。

LC-MS (method 9): r_t1.31 minutes; ms (esineg): 413[ M-H ] M/z]^-。

Example 178

2- [1- (2, 4-difluorophenyl) -1- {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } ethyl ] cyclopropanecarbonitrile [ trans-diastereomer mixture ]

0.08 ml (1.08 mmol) of trifluoroacetic acid and 218 mg (0.99 mmol) of indium (III) chloride are added at room temperature to 200 mg (0.90 mmol) of the compound from example 133A and 318 mg (1.79 mmol) of the compound from example 8A in 8 ml of dichloromethane, and the mixture is heated under reflux overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 128 mg (37% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.1(s，1H)，7.66-7.74(m，0.5H)，7.58-7.66(m，0.5H)，7.32(d，0.5H)，7.27(d，0.5H)，7.11-7.19(m，1H)，7.01-7.10(m，1H)，6.84-6.91(m，1H)，6.63-6.73(m，1H)，6.54(d，0.5H)，6.46(d，0.5H)，3.87-3.97(m，2H)，2.35-2.45(m，1H)，1.97(s，1.5H)，1.96(s，1.5H)，1.65(s，1.5H)，1.60(s，1.5H)，1.38-1.50(m，1H)，1.30-1.37(m，1H)，0.91-0.98(m，0.5H)，0.78-0.85(m，0.5H)。

LC-MS (method 4): r_t1.42 minutes; ms (esineg): m/z 381[ M-H ]]^-。

Example 179

2- [1- (4-chlorophenyl) -1- { 5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } ethyl ] cyclopropanecarbonitrile [ mixture of trans-diastereomers ]

367 mg (1.66 mmol) of indium (III) chloride and 0.12 ml (1.58 mmol) of trifluoroacetic acid are added at room temperature to 350 mg (1.58 mmol) of the compound from example 75A and 308 mg (1.58 mmol) of the compound from example 11A in 9 ml of dichloromethane, and the mixture is heated under reflux for 15 minutes. It was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 32.5 mg (5% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.2(s，1H)，7.44-7.48(m，1H)，7.25-7.40(m，4H)，6.76-6.83(m，1H)，6.26(dd，0.2H)，6.17(dd，0.8H)，3.87-3.99(m，2H)，2.28-2.39(m，1H)，1.99(s，0.6H)，1.98(s，2.4H)，1.50-1.57(m，3.8H)，1.27-1.43(m，1.2H)，0.95-1.03(m，0.2H)，0.78-0.86(m，0.8H)。

LC-MS (method 3): r_t2.50 minutes; ms (esineg): m/z ═ 397[ M-H ]]^-。

Example 180

3- [1- (4-chlorophenyl) -1- (2, 2-difluorocyclopropyl) ethyl ] -7- [ (methylsulfanyl) methyl ] -2, 3-dihydro-1H-indole

76.2 mg (0.43 mmol) of the compound from example 8A, dissolved in 1 ml of toluene, are added at room temperature to 190 mg (0.86 mmol) of indium (III) chloride and 100 mg (0.43 mmol) of the compound from example 134A in 1 ml of toluene, and the mixture is stirred for 2 hours at 80 ℃. A further 1.90 g (8.60 mmol) of indium (III) chloride are then added and the mixture is stirred at 80 ℃ for 1 hour. It is diluted with toluene and washed with water, the organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 16.0 mg (10% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.1(s，1H)，7.33-7.38(m，3H)，7.26-7.31(m，2H)，6.89(d，1H)，6.64-6.75(m，2H)，3.89-3.97(m，2H)，2.39-2.54(m，1H)，1.98(s，3H)，1.55-1.68(m，4H)，1.41-1.53(m，1H)。

LC-MS (method 5): r_t3.06 minutes; ms (esineg): 390[ M-H ] M/z]^-

Example 181

3- (1-ethyl-5-fluoro-2, 3-dihydro-1H-inden-1-yl) -7- [ (methylsulfanyl) methyl ] -1H-indole

515 mg (2.33 mmol) of indium (III) chloride and 0.17 ml (2.22 mmol) of trifluoroacetic acid are added at 0 ℃ to 400 mg (2.22 mmol) of the compound from example 135A and 393 mg (2.22 mmol) of the compound from example 8A in 12 ml of dichloromethane, and the mixture is stirred at room temperature for 1 hour. It was diluted with dichloromethane, washed with water, dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 33 mg (4% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝10.8(s，1H)，7.09(dd，1H)，6.98-7.06(m，3H)，6.87-6.95(m，2H)，6.78(t，1H)，3.86-3.96(m，2H)，2.88-3.03(m，2H)，2.46-2.55(m，1H)，2.15-2.27(m，2H)，1.98-2.10(m，1H)，1.95(s，3H)，0.78(t，3H)。

LC-MS (method 4): r_t1.62 minutes; ms (esineg): 338[ M-H ] M/z]^-。

Example 182

3- { 1-cyclopropyl-1- [ 2-fluoro-4- (trifluoromethyl) phenyl ] ethyl } -7- [ (methylsulfanyl) methyl ] -1H-indole

0.02 ml (0.24 mmol) of trifluoroacetic acid are added to 50.0 mg (0.20 mmol) of the compound from example 136A and 35.7 mg (0.20 mmol) of the compound from example 8A in 4 ml of dichloromethane, and the mixture is stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 10.0 mg (12% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.0(s，1H)，8.01(t，1H)，7.63(d，1H)，7.42(d，1H)，7.27-7.30(m，1H)，6.84(d，1H)，6.64(t，1H)，6.53(d，1H)，3.87-3.96(m，2H)，1.97(s，3H)，1.64-1.73(m，1H)，1.60(s，3H)，0.46-0.50(m，2H)，0.16-0.25(m，2H)。

LC-MS (method 9): r_t1.44 minutes; ms (esineg): 406[ M-H ] M/z]^-。

Example 183

3- [ 1-cyclopropyl-1- (4-methylphenyl) ethyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

0.23 ml (3.00 mmol) of trifluoroacetic acid are added to 885 mg (4.99 mmol) of the compound from example 8A and 440 mg (2.50 mmol) of the compound from example 137A in 44 ml of dichloromethane, and the mixture is stirred at room temperature overnight. The reaction mixture was concentrated in a rotary evaporator. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 87.4 mg (10% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝10.9(s，1H)，7.33(d，1H)，7.12-7.20(m，2H)，6.99-7.05(m，2H)，6.80-6.86(m，1H)，6.60-6.66(m，2H)，3.87-3.97(m，2H)，2.24(s，3H)，1.97(s，3H)，1.51-1.60(m，1H)，1.49(s，3H)，0.43-0.51(m，1H)，0.34-0.42(m，1H)，0.14-0.21(m，1H)，0.02-0.10(m，1H)。

LC-MS (method 9): r_t1.44 minutes; ms (esineg): m/z is 334[ M-H ]]^-。

Example 184

3- [1- (4-chlorophenyl) -1-cyclopropylethyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

600 mg (3.05 mmol) of the compound from example 138A and 0.28 ml (3.66 mmol) of trifluoroacetic acid are added to 541 mg (3.05 mmol) of the compound from example 8A in 4 ml of dichloromethane. The reaction mixture was stirred at room temperature for 30 minutes, and the crude product was then purified three times by preparative HPLC (mobile phase: acetonitrile/water gradient) and once by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10/1). 441 mg (41% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.05-0.15(m，1H)，0.17-0.25(m，1H)，0.37-0.54(m，2H)，1.49(s，3H)，1.52-1.61(m，1H)，1.98(s，3H)，3.92(q，2H)，6.60(d，1H)，6.66(t，1H)，6.85(d，1H)，7.26-7.37(m，5H)，10.9(s，1H)。

HPLC (method 1): r_t5.35 min; DCI-MS (ESIpos): 356[ M + H ] M/z]⁺。

Example 185

3- { 1-cyclopropyl-1- [4- (trifluoromethyl) phenyl ] ethyl } -7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 462 mg (2.61 mmol) of the compound from example 8A and 600 mg (2.61 mmol) of the compound from example 139A in analogy to the synthesis of the compound from example 184. 273 mg (27% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.11-0.19(m，1H)，0.22-0.30(m，1H)，0.41-0.57(m，2H)，1.51(s，3H)，1.57-1.67(m，1H)，1.98(s，3H)，3.93(q，2H)，6.58(d，1H)，6.65(t，1H)，6.85(d，1H)，7.40(d，1H)，7.53(d，2H)，7.61(d，2H)，11.0(s，1H)。

HPLC (method 1): r_t5.35 min; DCI-MS (ESIpos): 390[ M + H ] M/z]⁺。

Example 186

3- [ 1-cyclopropyl-1- (3-fluoro-4-methoxyphenyl) ethyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

100 mg (0.48 mmol) of the compound from example 140A and 0.04 ml (0.57 mmol) of trifluoroacetic acid are added to 84 mg (0.48 mmol) of the compound from example 8A in 2.5 ml of dichloromethane. The reaction mixture was stirred at room temperature for 30 minutes and the crude product was then purified directly by preparative HPLC (mobile phase: acetonitrile/water gradient). 63 mg (361% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.05-0.13(m，1H)，0.16-0.24(m，1H)，0.36-0.53(m，2H)，1.48(s，3H)，1.51-1.59(m，1H)，1.97(s，3H)，3.78(s，3H)，3.92(q，2H)，6.61-6.70(m，2H)，6.85(dd，1H)，6.98-7.07(m，3H)，7.33(d，1H)，10.9(s，1H)。

LC-MS (method 5): r_t2.94 minutes; ms (esineg): 368[ M-H ] M/z]^-

Example 187

3- [1- (1-benzothien-5-yl) -1-cyclopropylethyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

600 mg (2.75 mmol) of the compound from example 141A and 0.25 ml (3.30 mmol) of trifluoroacetic acid are added to 487 mg (2.75 mmol) of the compound from example 8A in 4 ml of dichloromethane. The reaction mixture was stirred at room temperature for 30 minutes, and the crude product was then purified twice by preparative HPLC (mobile phase: acetonitrile/water gradient) and once by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10/1). 404 mg (39% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.08-0.17(m，1H)，0.21-0.29(m，1H)，0.39-0.56(m，2H)，1.57(s，3H)，1.61-1.71(m，1H)，1.98(s，3H)，3.93(q，2H)，6.55-6.60(m，2H)，6.79-6.85(m，1H)，7.24(dd，1H)，7.37-7.42(m，2H)，7.67(d，1H)，7.79(d，1H)，7.91(d，1H)，11.0(s，1H)。

LC-MS (method 3): r_t2.76 min; ms (esineg): m/z 376[ M-H ═]^-。

Example 188

3- [ 1-cyclopropyl-1- (2, 3-dihydro-1, 4-benzodi)En-6-yl) ethyl]-7- [ (methylsulfanyl) methyl group]-1H-indoles

400 mg (1.82 mmol) of the compound from example 142A and 0.17 ml (2.18 mmol) of trifluoroacetic acid are added to 322 mg (1.82 mmol) of the compound from example 8A in 3 ml of dichloromethane. The reaction mixture was stirred at room temperature for 30 minutes, and the crude product was then purified twice by preparative HPLC (mobile phase: acetonitrile/water gradient) and recrystallized from acetonitrile. 184 mg (27% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.03-0.12(m，1H)，0.16-0.24(m，1H)，0.33-0.52(m，2H)，1.45(s，3H)，1.48-1.57(m，1H)，1.98(s，3H)，3.92(q，2H)，4.17(s，4H)，6.64-6.76(m，5H)，6.85(d，1H)，7.30(s，1H)，10.9(s，1H)。

HPLC (method 1): r_t4.98 minutes; ms (eipos): m/z 379[ M ═ M]⁺。

Example 189

3- [1- (1, 3-benzodioxol-5-yl) -1-cyclopropylethyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

600 mg (2.91 mmol) of the compound from example 143A and 0.27 ml (3.49 mmol) of trifluoroacetic acid are added to 516 mg (2.91 mmol) of the compound from example 8A in 4 ml of dichloromethane. The reaction mixture was stirred at room temperature for 30 minutes and the crude product was then purified twice by preparative HPLC (mobile phase: acetonitrile/water gradient). 377 mg (35% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.05-0.13(m，1H)，0.17-0.28(m，1H)，0.34-0.52(m，2H)，1.46(s，3H)，1.49-1.59(m，1H)，1.98(s，3H)，3.93(q，2H)，5.93(s，2H)，6.64-6.87(m，6H)，7.31(d，1H)，10.9(s，1H)。

HPLC (method 1): r_t4.91 min; DCI-MS (ESIpos): m/z is 365[ M + H ═ M]⁺。

Example 190

3- [ 1-cyclopropyl-1- (2, 2-difluoro-1, 3-benzodioxol-5-yl) ethyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 32 mg (0.18 mmol) of the compound from example 8A and 43 mg (0.18 mmol) of the compound from example 144A in analogy to the synthesis of the compound from example 186. 38 mg (53% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.10-0.18(m，1H)，0.21-0.30(m，1H)，0.39-0.55(m，2H)，1.48(s，3H)，1.53-1.63(m，1H)，1.98(s，3H)，3.93(q，2H)，6.61-6.71(m，2H)，6.86(d，1H)，7.14(dd，1H)，7.25(d，1H)，7.28(d，1H)，7.35(d，1H)，11.0(s，1H)。

HPLC (method 1): r_t5.39 minutes; DCI-MS (ESIpos): m/z is 402[ M + H [ ]]⁺。

Example 191

3- [1- (4-chlorophenyl) -1-cyclopropyl-propyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 84 mg (0.48 mmol) of the compound from example 8A and 100 mg (0.48 mmol) of the compound from example 145A in analogy to the synthesis of the compound from example 186. 38 mg (21% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝-0.22--0.13(m，2H)，0.34-0.47(m，2H)，0.68(t，3H)，1.61-1.71(m，1H)，1.97(s，3H)，2.11-2.32(m，2H)，3.92(q，2H)，6.41(d，1H)，6.61(t，1H)，6.83(d，1H)，7.23-7.31(m，4H)，7.37(d，1H)，11.0(s，1H)。

HPLC (method 1): r_t5.54 minutes; DCI-MS (ESIpos): 370[ M + H ] M/z]⁺。

Example 192

3- [3- (4-chloro-2-fluorophenyl) pentan-3-yl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

600 mg (2.77 mmol) of the compound from example 146A, 585 mg (2.64 mmol) of indium (III) chloride and 301 mg (2.64 mmol) of trifluoroacetic acid are added to 446 mg (2.52 mmol) of the compound from example 8A in 15 ml of dichloromethane. The reaction mixture was stirred at 80 ℃ for 1 hour. After cooling to RT, the reaction solution was mixed with dichloromethane and silica gel, and the solvent was removed in a rotary evaporator. The residue was purified twice by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient) and twice by preparative HPLC (mobile phase: acetonitrile/water gradient). 208 mg (22% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.59(t，6H)，1.97(s，3H)，2.11-2.26(m，4H)，3.92(s，2H)，6.62-6.68(m，2H)，6.84(dd，1H)，7.13(dd，1H)，7.24-7.30(m，2H)，7.55(t，1H)，10.9(s，1H)。

HPLC (method 2): r_t5.49 minutes; DCI-MS (ESIpos): m/z 376[ M + H ═ M]⁺。

Example 193

3- (5, 7-difluoro-4-methyl-3, 4-dihydro-2H-benzopyran-4-yl) -7- [ (methylsulfanyl) methyl ] -1H-indole

565 mg (2.82 mmol) of the compound from example 171A and 0.26 ml (3.39 mmol) of trifluoroacetic acid are added to 500 mg (2.82 mmol) of the compound from example 8A in 20 ml of dichloromethane. The reaction mixture was stirred at room temperature for 30 minutes, the solvent was removed in vacuo and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient) and subsequent flash chromatography on silica gel (mobile phase: dichloromethane). 632 mg (62% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.82-1.93(m，4H)，1.97(s，3H)，2.36-2.46(m，1H)，3.92(q，2H)，4.09-4.23(m，2H)，6.52-6.60(m，1H)，6.63-6.68(m，1H)，6.76(t，1H)，6.84(d，1H)，6.90(d，1H)，7.07(d，1H)，10.9(s，1H)。

LC-MS (method 9): r_t1.32 minutes; ms (esineg): m/z of 358[ ]M-H]^-。

Example 194

3- (4-cyclopropyl-5, 7-difluoro-3, 4-dihydro-2H-benzopyran-4-yl) -7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 450 mg (2.54 mmol) of the compound from example 8A and 574 mg (2.54 mmol) of the compound from example 172A in analogy to the synthesis of the compound from example 193. 80 mg (8% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.09-0.18(m，1H)，0.44-0.59(m，2H)，0.68-0.78(m，1H)，1.65-1.75(m，1H)，1.97(s，3H)，2.13-2.23(m，1H)，3.93(q，2H)，3.96-4.06(m，1H)，4.28-4.36(m，1H)，6.53-6.64(m，2H)，6.81(t，1H)，6.92(d，1H)，7.04(d，1H)，7.09(d，1H)，10.9(s，1H)。

LC-MS (method 9): r_t1.36 minutes; ms (esineg): 384[ M-H ] M/z]^-。

Example 195

2- [1- (2, 4-difluorophenyl) -1- { 5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } ethyl ] cyclopropanecarbonitrile [ trans-diastereomer mixture ]

273 mg (1.23 mmol) of indium (III) chloride and 0.1 ml (1.34 mmol) of trifluoroacetic acid are added to 250 mg (1.12 mmol) of the compound from example 11A and 437 mg (2.24 mmol) of the compound from example 133A in 44 ml of dichloromethane, and the mixture is stirred at room temperature overnight. The reaction mixture was concentrated in a rotary evaporator. The residue is purified by preparative HPLC (RP 18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 313 mg (69% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.2(s，1H)，7.68-7.76(m，0.6H)，7.59-7.67(m，0.4H)，7.41(d，0.6H)，7.35(d，0.4H)，7.14-7.21(m，1H)，7.05-7.13(m，1H)，6.75-6.82(m，1H)，6.19(d，0.4H)，6.08(d，0.6H)，3.87-3.97(m，2H)，2.36-2.46(m，1H)，1.98(s，1.2H)，1.97(s，1.8H)，1.63(s，1.8H)，1.57(s，1.2H)，1.39-1.51(m，1H)，1.31-1.38(m，1H)，0.93-1.01(m，0.4H)，0.75-0.82(m，0.6H)。

LC-MS (method 4): r_t1.42 minutes; ms (esineg): m/z 399[ M-H ]]^-。

Example 196

3- [1- (4-chlorophenyl) -1-cyclopropylethyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

131 mg (0.37 mmol) of the compound from example 184 are introduced into 25 ml of dichloromethane at 0 ℃, 91 mg (0.37 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvent was removed in a rotary evaporator. The crude product is purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 113 mg (83% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.05-0.14(m，1H)，0.17-0.26(m，1H)，0.38-0.55(m，2H)，1.49(s，3H)，1.52-1.62(m，1H)，2.55(d，3H)，4.21(t，1H)，4.35(t，1H)，6.65-6.74(m，2H)，6.92(d，1H)，7.26-7.33(m，4H)，7.43(s，1H)，11.1(s，1H)。

HPLC (method 2): r_t4.77 min; ms (esipos): 372[ M + H ] M/z]⁺。

Example 197

3- { 1-cyclopropyl-1- [4- (trifluoromethyl) phenyl ] ethyl } -7- [ (methylsulfinyl) methyl ] -1H-indole

The title compound was prepared starting from 76 mg (0.20 mmol) of the compound from example 185 in analogy to the synthesis of the compound from example 196. 42 mg (53% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.10-0.19(m，1H)，0.22-0.31(m，1H)，0.41-0.58(m，2H)，1.51(s，3H)，1.57-1.68(m，1H)，2.55(s，3H)，4.22(t，1H)，4.36(dd，1H)，6.64(d，1H)，6.71(t，1H)，6.92(d，1H)，7.47(s，1H)，7.53(d，2H)，7.61(d，2H)，11.1(s，1H)。

HPLC (method 2): r_t4.79 min; ms (esineg): 404[ M-H ] M/z]^-。

Example 198

3- [1- (4-chlorophenyl) -1-cyclopropyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

The title compound was prepared starting from 58 mg (0.16 mmol) of the compound from example 191 in analogy to the synthesis of the compound from example 196. 50 mg (82% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝-0.23--0.13(m，2H)，0.35-0.47(m，2H)，0.69(t，3H)，1.62-1.71(m，1H)，2.11-2.34(m，2H)，2.54(s，3H)，4.20(t，1H)，4.34(dd，1H)，6.47(dd，1H)，6.67(d，1H)，6.89(d，1H)，7.23-7.31(m，4H)，7.45(d，1H)，11.1(s，1H)。

HPLC (method 1): r_t4.94 minutes; ms (esineg): 384[ M-H ] M/z]^-。

Example 199

3- (5, 7-difluoro-4-methyl-3, 4-dihydro-2H-benzopyran-4-yl) -7- [ (methylsulfinyl) methyl ] -1H-indole

75 mg (0.21 mmol) of the compound from example 193 are introduced at 0 ℃ into 10 ml of dichloromethane, 51 mg (0.21 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient).

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.81-1.93(m，4H)，2.36-2.46(m，1H)，2.54(s，3H)，4.10-4.26(m，3H)，4.35(dd，1H)，6.51-6.59(m，1H)，6.63-6.69(m，1H)，6.82(t，1H)，6.88(d，1H)，6.96(dd，1H)，7.16(d，1H)，11.0(s，1H)。

LC-MS (method 9): r_t1.08 min; ms (esineg): 374[ M-H ] M/z]^-。

Example 200

3- [ 5-chloro-1-cyclopropyl-2, 3-dihydro-1H-inden-1-yl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

64.0 mg (0.26 mmol) of 70% m-chloroperbenzoic acid are added at 0 ℃ to 46.6 mg (0.13 mmol) of the compound from example 175 in 10 ml of dichloromethane and the mixture is stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 18 mg (35.5% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.0(s，1H)，7.35-7.39(m，2H)，7.03-7.09(m，2H)，6.78-6.84(m，2H)，6.71(d，1H)，4.68-4.77(m，2H)，2.92-3.08(m，2H)，2.90(s，3H)，2.51-2.60(m，1H)，2.10-2.18(m，1H)，1.47-1.56(m，1H)，0.42-0.54(m，2H)，0.00-0.07(m，1H)，-0.24--0.17(m，1H)。

LC-MS (method 4): r_t1.49 minutes; ms (esineg): 398[ M-H ] M/z]^-。

Example 201

3- (6-chloro-1-cyclopropyl-2, 3-dihydro-1H-inden-1-yl) -7- [ (methylsulfonyl) methyl ] -1H-indole

64.0 mg (0.26 mmol) of 70% m-chloroperbenzoic acid are added at 0 ℃ to 46.6 mg (0.13 mmol) of the compound from example 176 in 10 ml of dichloromethane and the mixture is stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 24.0 mg (47% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.0(s，1H)，7.37(d，1H)，7.33(d，1H)，7.22(dd，1H)，7.07(dd，1H)，6.79-6.85(m，2H)，6.69(d，1H)，4.68-4.79(m，2H)，2.91-3.01(m，2H)，2.90(s，3H)，2.51-2.60(m，1H)，2.07-2.15(m，1H)，1.48-1.57(m，1H)，0.44-0.58(m，2H)，0.03-0.10(m，1H)，-0.18--0.10(m，1H)。

LC-MS (method 9): r_t1.27 minutes; ms (esineg): 398[ M-H ] M/z]^-。

Example 202

2- (1- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } -1- [4- (trifluoromethyl) phenyl ] ethyl) cyclopropanecarbonitrile [ trans-diastereomer mixture ]

8.5 mg (0.04 mmol) of 70% m-chloroperbenzoic acid are added at 0 ℃ to 7.0 mg (0.02 mmol) of the compound from example 177 in 1 ml of dichloromethane and the mixture is stirred at room temperature for 1 hour. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 4.8 mg (64% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.2(s，1H)，7.63-7.70(m，2H)，7.47-7.56(m，3H)，7.06(t，1H)，6.74-6.83(m，1H)，6.70(d，0.5H)，6.62(d，0.5H)，4.68-4.79(m，2H)，2.91(s，3H)，2.34-2.45(m，1H)，1.55-1.65(m，3.5H)，1.43-1.50(m，0.5H)，1.29-1.40(m，1H)，1.00-1.07(m，0.5H)，0.80-0.95(m，0.5H)。

LC-MS (method 9): r_t1.13 minutes; ms (esineg): m/z 445[ M-H ]]^-。

Example 203

2- [1- (2, 4-difluorophenyl) -1- {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } ethyl ] cyclopropanecarbonitrile [ trans-diastereomer mixture ]

135 mg (0.55 mmol) of 70% m-chloroperbenzoic acid are added at 0 ℃ to 100 mg (0.26 mmol) of the compound from example 178 in 6 ml of dichloromethane and the mixture is stirred at room temperature for 1 hour. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 80.5 mg (74% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.2(s，1H)，7.66-7.74(m，0.5H)，7.58-7.66(m，0.5H)，7.40(d，0.5H)，7.36(d，0.5H)，7.12-7.19(m，2H)，7.01-7.10(m，1H)，6.73-6.82(m，1H)，6.66(d，0.5H)，6.58(d，0.5H)，4.66-4.77(m，2H)，2.89(s，3H)，2.36-2.46(m，1H)，1.64(s，1.5H)，1.61(s，1.5H)，1.45-1.52(m，0.5H)，1.38-1.44(m，0.5H)，1.31-1.38(m，1H)，0.91-0.99(m，0.5H)，0.79-0.87(m，0.5H)。

LC-MS (method 9): r_t1.06 minutes; ms (esineg): m/z ═413[M-H]^-。

In a similarly performed batch, a further 25.0 mg of the title compound were obtained as a diastereomer mixture, combined with the first stage.

Diastereomers and enantiomers were purified by preparative HPLC on chiral phase [ column: daicel ChiralpakAD-H, 5 microns, 250 mm x20 mm; eluent: isohexane/(isopropanol/methanol (1: 1)) 75: 25; flow rate: 20 ml/min; temperature: 24 ℃; UV detection: 230 nm ] separation. The separated enantiomers were again purified by preparative HPLC on the achiral phase (mobile phase: acetonitrile/water gradient):

enantiomer 203-1:

R_t14.37 minutes [ bar: daicel Chiralpak AD-H, 5 microns, 250 mm x4 mm; eluent: isopropanol/methanol (1: 1)/isohexane 25: 75; flow rate: 1 ml/min; temperature: 24 ℃; UV detection: 230 nm]。

¹H-NMR(400MHz，DMSO-d₆)δ＝11.2(s，1H)，7.66-7.74(m，1H)，7.40(d，1H)，7.15(t，1H)，7.01-7.10(m，2H)，6.76(t，1H)，6.58(d，1H)，4.66-4.76(m，2H)，2.89(s，3H)，2.36-2.44(m，1H)，1.64(s，3H)，1.49(dt，1H)，1.34(dt，1H)，0.79-0.87(m，1H)。

LC-MS (method 9): r_t1.04 min; ms (esineg): 413[ M-H ] M/z]^-。

Yield: 18.0 mg.

Example 204

2- [1- (4-chlorophenyl) -1- { 5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } ethyl ] cyclopropanecarbonitrile [ mixture of trans-diastereomers ]

247 mg (1.00 mmol) of 70% m-chloroperbenzoic acid are added at 0 ℃ to 200 mg (0.50 mmol) of the compound from example 179 in 6 ml of dichloromethane, and the mixture is stirred at room temperature overnight. 2 ml of methanol are added, concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 110 mg (48% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.3(s，1H)，7.53-7.57(m，1H)，7.24-7.40(m，4H)，6.91-6.99(m，1H)，6.40(dd，0.5H)，6.31(dd，0.5H)，4.70-4.81(m，2H)，2.94(s，3H)，2.29-2.40(m，1H)，1.51-1.60(m，3.5H)，1.27-1.43(m，1.5H)，0.95-1.03(m，0.5H)，0.80-0.87(m，0.5H)。

LC-MS (method 5): r_t2.47 minutes; ms (esineg): m/z 429[ M-H ]]^-。

Example 205

3- [1- (4-chlorophenyl) -1- (2, 2-difluorocyclopropyl) ethyl ] -7- [ (methylsulfonyl) methyl ] -2, 3-dihydro-1H-indole

15.1 mg (0.06 mmol) of 70% m-chloroperbenzoic acid are added to 12.0 mg (0.03 mmol) of the compound from example 180 in 1 ml of dichloromethane and the mixture is stirred at room temperature for 2 hours. Methanol was added, concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to give 6.0 mg (46% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.2(s，1H)，7.44(d，1H)，7.34-7.39(m，2H)，7.26-7.32(m，2H)，7.07(d，1H)，6.76-6.84(m，2H)，4.69-4.68(m，2H)，2.92(s，3H)，2.21-2.27(m，0.5H)，2.09-2.16(m，0.5H)，1.56-1.69(m，3.5H)，1.43-1.55(m，1H)，1.32-1.38(m，0.5H)。

LC-MS (method 6): r_t2.52 min; ms (esineg): 422[ M-H ] M/z]^-。

Example 206

3- (1-Ethyl-5-fluoro-2, 3-dihydro-1H-inden-1-yl) -7- [ (methylsulfonyl) methyl ] -1H-indole

27.5 mg (0.16 mmol) of 70% m-chloroperbenzoic acid are added to 27.0 mg (0.08 mmol) of the compound from example 181 in 2 ml of dichloromethane and the mixture is stirred at room temperature overnight. 2 ml of methanol are added, concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 3.6 mg (12% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝10.9(s，1H)，7.05-7.13(m，4H)，7.00-7.05(m，1H)，6.84-6.95(m，2H)，4.65-4.76(m，2H)，2.91-3.02(m，2H)，2.89(s，3H)，2.47-2.55(m，1H)，2.15-2.28(m，2H)，1.99-2.10(m，1H)0.79(t，3H)。

LC-MS (method 5): r_t2.67 minutes; ms (esineg): 370[ M-H ] M/z]^-。

Example 207

3- { 1-cyclopropyl-1- [ 2-fluoro-4- (trifluoromethyl) phenyl ] ethyl } -7- [ (methylsulfonyl) methyl ] -1H-indole

32.3 mg (0.13 mmol) of 70% m-chloroperbenzoic acid are added to 26.0 mg (0.06 mmol) of the compound from example 182 in 2 ml of dichloromethane and the mixture is stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 16 mg (57% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.1(s，1H)，8.01(t，1H)，7.63(d，1H)，7.42(d，1H)，7.38(d，1H)，7.02(d，1H)，6.74(t，1H)，6.64(d，1H)，4.67-4.77(m，2H)，2.89(s，3H)，1.65-1.75(m，1H)，1.60(s，3H)，0.47-0.57(m，2H)，0.16-0.26(m，2H)。

LC-MS (method 9): r_t1.27 minutes; ms (esineg): 438[ M-H ] M/z]^-。

Example 208

3- [ 1-cyclopropyl-1- (4-methylphenyl) ethyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

151 mg (0.61 mmol) of 70% m-chloroperbenzoic acid are added to 100 mg (0.30 mmol) of the compound from example 183 in 2 ml of dichloromethane and the mixture is stirred at room temperature overnight. It was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 52.9 mg (48% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆): δ is 11.0(s, 1H), 7.42(s, 1H), 7.13-7.18(m, 2H), 6.97-7.06(m, 3H), 6.70-6.74(m, 2H), 4.66-4.77(s, 2H), 2.90(s, 3H), 2.24(s, 3H), 1.50-1.60(m, 1H), 1.50(s, 3H), 0.44-0.52(m, 1H), 0.35-0.43(m, 1H), 0.14-0.22(m, 1H), 0.02-0.10(m, 1H). LC-MS (method 9): r_t1.23 minutes; ms (esineg): 366[ M-H ] M/z]^-。

Example 209

3- [1- (4-chlorophenyl) -1-cyclopropylethyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

261 mg (0.74 mmol) of the compound from example 184 are introduced into 50 ml of dichloromethane at 0 ℃, 361 mg (1.47 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvent was removed in a rotary evaporator. The crude product is purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 214 mg (75% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.05-0.14(m，1H)，0.17-0.26(m，1H)，0.38-0.55(m，2H)，1.49(s，3H)，1.52-1.62(m，1H)，2.91(s，3H)，4.72(q，2H)，6.69-6.79(m，2H)，7.03(d，1H)，7.26-7.33(m，4H)，7.44(d，1H)，11.0(s，1H)。

HPLC (method 2): r_t4.85 minutes; ms (esineg): 386[ M-H ] M/z]^-。

Example 210

3- { 1-cyclopropyl-1- [4- (trifluoromethyl) phenyl ] ethyl } -7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared starting from 153 mg (0.39 mmol) of the compound from example 185 in analogy to the synthesis of the compound from example 209. 63 mg (38% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.10-0.19(m，1H)，0.22-0.31(m，1H)，0.41-0.58(m，2H)，1.51(s，3H)，1.58-1.68(m，1H)，2.91(s，3H)，4.73(q，2H)，6.69(d，1H)，6.75(t，1H)，7.03(d，1H)，7.49(d，1H)，7.52(d，2H)，7.61(d，2H)，11.1(s，1H)。

HPLC (method 2): r_t4.88 minutes; ms (esineg): 420[ M-H ] M/z]^-。

Example 211

3- [ 1-cyclopropyl-1- (3-fluoro-4-methoxyphenyl) ethyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared starting from 282 mg (0.76 mmol) of the compound from example 186 in analogy to the synthesis of the compound from example 209. 215 mg (70% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.05-0.13(m，1H)，0.16-0.25(m，1H)，0.37-0.54(m，2H)，1.48(s，3H)，1.51-1.60(m，1H)，2.91(s，3H)，3.78(s，3H)，4.72(q，2H)，6.73-6.80(m，2H)，6.99-7.07(m，4H)，7.42(d，1H)，11.0(s，1H)。

HPLC (method 1): r_t4.58 minutes; DCI-MS (ESIpos): m/z 419[ M-NH ]₄]^-。

Example 212

3- [1- (1-benzothien-5-yl) -1-cyclopropylethyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared starting from 237 mg (0.63 mmol) of the compound from example 187 in analogy to the synthesis of the compound from example 209. 144 mg (56% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.08-0.17(m，1H)，0.21-0.29(m，1H)，0.40-0.58(m，2H)，1.58(s，3H)，1.62-1.71(m，1H)，2.91(s，3H)，4.73(q，2H)，6.64-6.72(m，2H)，7.00(dd，1H)，7.23(dd，1H)，7.40(d，1H)，7.48(d，1H)，7.68(d，1H)，7.79(d，1H)，7.91(d，1H)，11.0(s，1H)。

HPLC (method 2): r_t4.80 minutes; ms (esine): 408[ M-H ] M/z]^-。

Example 213

3- [ 1-cyclopropyl-1- (2, 3-dihydro-1, 4-benzodi) En-6-yl) ethyl]-7- [ (methylsulfonyl) methyl group]-1H-indoles

The title compound was prepared starting from 94 mg (0.25 mmol) of the compound from example 188 in analogy to the synthesis of the compound from example 209. 56 mg (55% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.03-0.12(m，1H)，0.16-0.25(m，1H)，0.33-0.43(m，1H)，0.43-0.53(m，1H)，1.45(s，3H)，1.48-1.58(m，1H)，2.91(s，3H)，4.17(s，4H)，4.72(q，2H)，6.67-6.84(m，5H)，7.02(d，1H)，7.39(s，1H)，11.0(s，1H)。

HPLC (method 1): r_t4.51 minutes; DCI-MS (ESIpos): m/z 429[ M-NH ]₄]^-。

Example 214

3- [1- (1, 3-benzodioxol-5-yl) -1-cyclopropylethyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared starting from 214 mg (0.59 mmol) of the compound from example 189 in analogy to the synthesis of the compound from example 209. 162 mg (69% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.05-0.14(m，1H)，0.17-0.26(m，1H)，0.35-0.54(m，2H)，1.47(s，3H)，1.50-1.59(m，1H)，2.90(s，3H)，4.72(q，2H)，5.94(s，2H)，6.72-6.84(m，5H)，7.03(dd，1H)，7.40(d，1H)，11.0(s，1H)。

HPLC (method 1): r_t4.48 minutes; DCI-MS (ESIpos): m/z ═ 397[ M + H ]]⁺。

Example 215

3- [ 1-cyclopropyl-1- (2, 2-difluoro-1, 3-benzodioxol-5-yl) ethyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared in analogy to the synthesis of the compound from example 209 starting from 33 mg (0.08 mmol) of the compound from example 190. 27 mg (76% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.10-0.19(m，1H)，0.22-0.31(m，1H)，0.40-0.57(m，2H)，1.49(s，3H)，1.54-1.64(m，1H)，2.91(s，3H)，4.73(s，2H)，6.73-6.81(m，2H)，7.04(dd，1H)，7.12(dd，1H)，7.25(d，1H)，7.29(d，1H)，7.45(d，1H)，11.1(s，1H)。

HPLC (method 1): r _t4.91 min; DCI-MS (ESIpos): 451[ M + H ] M/z]⁺。

Example 216

3- [1- (4-chlorophenyl) -1-cyclopropyl-propyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared starting from 116 mg (0.31 mmol) of the compound from example 191 in analogy to the synthesis of the compound from example 209. 98 mg (78% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝-0.23--0.13(m，2H)，0.35-0.48(m，2H)，0.68(t，3H)，1.62-1.72(m，1H)，2.11-2.34(m，2H)，2.89(s，3H)，4.72(s，2H)，6.52(d，1H)，6.71(t，1H)，7.00(d，1H)，7.25(d，2H)，7.29(d，2H)，7.47(s，1H)，11.1(s，1H)。

HPLC (method 1): r_t5.02 minutes; ms (esineg): m/z 400[ M-H ]]^-。

Example 217

3- [3- (4-chloro-2-fluorophenyl) pentan-3-yl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared starting from 162 mg (0.43 mmol) of the compound from example 192 in analogy to the synthesis of the compound from example 209. 164 mg (93% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.59(t，6H)，2.11-2.27(m，4H)，2.88(s，3H)，4.71(s，2H)，6.75(d，2H)，7.02(t，1H)，7.14(dd，1H)，7.28(dd，1H)，7.34(d，1H)，7.56(d，1H)，11.0(s，1H)。

HPLC (method 1): r_t5.00 min; ms (esineg): 406[ M-H ] M/z]^-。

Example 218

3- (5, 7-difluoro-4-methyl-3, 4-dihydro-2H-benzopyran-4-yl) -7- [ (methylsulfonyl) methyl ] -1H-indole

510 mg (1.42 mmol) of the compound from example 193 are introduced at 0 ℃ into 50 ml of dichloromethane, 700 mg (2.84 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 5 ml of methanol was added and the solution was extracted with saturated aqueous sodium bicarbonate. After removal of the solvent in a rotary evaporator, the crude product is purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 386 mg (70% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.83-1.93(m，4H)，2.36-2.46(m，1H)，2.90(s，3H)，4.10-4.24(m，2H)，4.72(q，2H)，6.51-6.59(m，1H)，6.63-6.69(m，1H)，6.86(t，1H)，6.93(d，1H)，7.07(d，1H)，7.18(d，1H)，11.0(s，1H)。

LC-MS (method 9): r_t1.13 minutes; ms (esineg): 390[ M-H ] M/z]^-。

Example 219

3- (4-cyclopropyl-5, 7-difluoro-3, 4-dihydro-2H-benzopyran-4-yl) -7- [ (methylsulfonyl) methyl ] -1H-indole

65 mg (0.17 mmol) of the compound from example 194 are introduced into 10 ml of dichloromethane at 0 ℃, 83 mg (0.34 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to give 48 mg (68% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.09-0.19(m，1H)，0.45-0.57(m，2H)，0.68-0.79(m，1H)，1.65-1.78(m，2H)，2.16-2.26(m，1H)，2.90(s，3H)，3.98-4.07(m，1H)，4.29-4.39(m，1H)，4.74(s，2H)，6.51-6.66(m，2H)，6.90(t，1H)，7.10(d，1H)，7.13-7.21(m，2H)，11.0(s，1H)。

LC-MS (method 9): r_t1.17 minutes; ms (esineg): m/z 416[ M-H ═ M]^-。

Example 220

2- [1- (2, 4-difluorophenyl) -1- { 5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } ethyl ] cyclopropanecarbonitrile [ trans-diastereomer mixture ]

63.1 mg (0.26 mmol) of 70% m-chloroperbenzoic acid are added to 50.0 mg (0.13 mmol) of the compound from example 195 in 5 ml of dichloromethane and the mixture is stirred at room temperature overnight. It was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 40.1 mg (74% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.2(s，1H)，7.68-7.76(m，0.6H)，7.59-7.67(m，0.4H)，7.50(d，0.6H)，7.45(d，0.4H)，7.14-7.22(m，1H)，7.04-7.13(m，1H)，6.90-6.98(m，1H)，6.32(d，0.4H)，6.23(d，0.6H)，4.69-4.79(m，2H)，2.92(s，3H)，2.38-2.47(m，1H)，1.62(s，1.8H)，1.58(s，1.2H)，1.47-1.53(m，0.6H)，1.40-1.46(m，0.4H)，1.32-1.39(m，1H)，0.94-1.02(m，0.4H)，0.76-0.85(m，0.6H)。

LC-MS (method 9): r_t1.17 minutes; ms (esineg): 431[ M-H ] M/z]^-。

Example 221

3- [ cyclopropyl (2, 4-dichlorophenyl) methyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

0.2 ml (2.76 mmol) of trifluoroacetic acid are added to 500 mg (2.30 mmol) of the compound from example 147A and 408 mg (2.30 mmol) of the compound from example 8A in 32 ml of dichloromethane, and the mixture is stirred at room temperature for 30 minutes. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 342 mg (35% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.0(s，1H)，7.57(d，1H)，7.45(d，1H)，7.37(d，1H)，7.33(dd，1H)，7.07(d，1H)，6.91(d，1H)，6.82(t，1H)，3.87-3.97(m，3H)，1.94(s，3H)，1.48-1.58(m，1H)，0.64-0.73(m，1H)，0.45-0.53(m，1H)，0.22-0.35(m，2H)。

LC-MS (method 9): r_t1.60 minutes; ms (esineg): 374[ M-H ] M/z]^-。

Example 222

3- { cyclopropyl [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl } -7- [ (methylsulfanyl) methyl ] -1H-indole

0.66 ml (8.61 mmol) of trifluoroacetic acid are added to 1.68 g (7.18 mmol) of the compound from example 148A and 1.27 g (7.18 mmol) of the compound from example 8A in 80 ml of dichloromethane, and the mixture is stirred at room temperature for 2 hours. It is concentrated and the residue is purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 98/2) and preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 80.0 mg (3% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.0(s，1H)，7.65(t，1H)，7.60(d，1H)，7.50(d，1H)，7.41(d，1H)，7.10(d，1H)，6.92(d，1H)，6.82(t，1H)，3.88-3.97(m，2H)，3.78(d，1H)，1.95(s，3H)，1.55-1.66(m，1H)，0.65-0.74(m，1H)，0.48-0.57(m，1H)，0.31-0.38(m，1H)，0.21-0.28(m，1H)。

LC-MS (method 9): r_t1.43 minutes; ms (esineg): 392[ M-H ] M/z]^-。

Example 223

3- { cyclopropyl [4- (trifluoromethyl) phenyl ] methyl } -7- [ (methylsulfanyl) methyl ] -1H-indole

0.76 ml (9.82 mmol) of trifluoroacetic acid are added to 1.77 g (8.19 mmol) of the compound from example 149A and 1.45 g (8.19 mmol) of the compound from example 8A in 91 ml of dichloromethane, and the mixture is stirred at room temperature for 2 hours. It is concentrated and the residue is purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 98/2) and preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to yield 890 mg (29% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.0(s，1H)，7.59-7.64(m，2H)，7.52-7.57(m，2H)，7.43(d，1H)，7.07(d，1H)，6.91(d，1H)，6.79(t，1H)，3.89-3.97(m，2H)，3.50(d，1H)，1.95(s，3H)，1.45-1.58(m，1H)，0.62-0.71(m，1H)，0.49-0.57(m，1H)，0.24-0.36(m，2H)。

LC-MS (method 4): r_t1.62 minutes; ms (esineg): 374[ M-H ] M/z]^-。

Example 224

3- { [ 2-chloro-4- (trifluoromethyl) phenyl ] (cyclopropyl) methyl } -7- [ (methylsulfanyl) methyl ] -1H-indole

2.6 ml (33.8 mmol) of trifluoroacetic acid are added to 7.07 g (28.2 mmol) of the compound from example 150A and 5.00 g (28.2 mmol) of the compound from example 8A in 620 ml of dichloromethane and the mixture is stirred at room temperature for 2 hours. It is concentrated and the residue is purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 98/2) and preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 960 mg (7% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.0(s，1H)，7.75(d，1H)，7.67(s，1H)，7.51(d，1H)，7.46(s，1H)，7.12(d，1H)，6.92(d，1H)，6.82(t，1H)，3.88-3.98(m，2H)，3.52(d，1H)，1.95(s，3H)，1.49-1.61(m，1H)，0.62-0.71(m，1H)，0.49-0.59(m，1H)，0.24-0.39(m，2H)。

LC-MS (method 9): r_t1.45 minutes; ms (esineg): 408[ M-H ] M/z]^-。

Example 225

3- [ (4-chloro-2-fluorophenyl) (cyclopropyl) methyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

0.13 ml (1.73 mmol) of trifluoroacetic acid are added to 256 mg (1.45 mmol) of the compound from example 8A and 290 mg (1.45 mmol) of the compound from example 151A in 20 ml of dichloromethane, and the mixture is stirred at room temperature for 2 hours. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 273 mg (51% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.0(s，1H)，7.31-7.43(m，3H)，7.19(d，1H)，7.08(d，1H)，6.91(d，1H)，6.81(t，1H)，3.87-3.97(m，2H)，3.69(d，1H)，1.95(s，3H)，1.49-1.61(m，1H)，0.62-0.72(m，1H)，0.46-0.55(m，1H)，0.27-0.35(m，1H)，0.18-0.26(m，1H)。

LC-MS (method 9): r_t1.45 minutes; ms (esineg): 358[ M-H ] M/z]^-。

Example 226

3- [ cyclopropyl (4-fluorophenyl) methyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

188 mg (1.13 mmol) of cyclopropyl (4-fluorophenyl) methanol and 0.10 ml (1.35 mmol) of trifluoroacetic acid are added to 200 mg (1.13 mmol) of the compound from example 8A in 13 ml of dichloromethane. The reaction mixture was stirred at room temperature for 15 minutes, the solvent was removed in vacuo and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 267 mg (73% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.19-0.33(m，2H)，0.46-0.56(m，1H)，0.58-0.67(m，1H)，1.41-1.52(m，1H)，1.95(s，3H)，3.40(d，1H)，3.92(s，2H)，6.78(t，1H)，6.89(d，1H)，7.02-7.09(m，3H)，7.30-7.39(m，3H)，11.0(s，1H)。

GC-MS (method 7): r_t9.72 minutes; ms (eipos): 325[ M ] M/z]⁺。

Example 227

3- [ (4-chlorophenyl) (cyclopropyl) methyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

515 mg (2.82 mmol) of the compound from example 153A and 0.26 ml (3.39 mmol) of trifluoroacetic acid are added to 500 mg (2.82 mmol) of the compound from example 8A in 20 ml of dichloromethane the reaction mixture is stirred at room temperature for 30 minutes, the solvent is removed in vacuo and the crude product is then purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 500 mg (50% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.20-0.33(m，2H)，0.46-0.56(m，1H)，0.59-0.68(m，1H)，1.41-1.53(m，1H)，1.95(s，3H)，3.40(d，1H)，3.92(s，2H)，6.78(t，1H)，6.89(d，1H)，7.05(d，1H)，7.27-7.36(m，4H)，7.38(d，1H)，11.0(s，1H)。

LC-MS (method 4): r_t1.61 minutes; ms (esineg): 340[ M-H ] M/z]^-。

Example 228

3- [ cyclopropyl (2, 4-difluorophenyl) methyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 300 mg (1.69 mmol) of the compound from example 8A and 312 mg (1.69 mmol) of the compound from example 154A in analogy to the synthesis of the compound from example 227. 170 mg (29% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.17-0.34(m，2H)，0.46-0.55(m，1H)，0.62-0.71(m，1H)，1.49-1.61(m，1H)，1.95(s，3H)，3.68(d，1H)，3.92(s，2H)，6.81(t，1H)，6.91(d，1H)，7.08(d，1H)，7.14(dt，1H)，7.35-7.45(m，2H)，11.0(s，1H)。

LC-MS (method 4): r_t1.56 minutes; ms (esineg): m/z is 342[ M-H [ ]]^-。

Example 229

3- [ (2-chloro-4-fluorophenyl) (cyclopropyl) methyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 500 mg (2.82 mmol) of the compound from example 8A and 566 mg (2.82 mmol) of the compound from example 155A in analogy to the synthesis of the compound from example 227. 394 mg (39% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.22-0.34(m，2H)，0.44-0.53(m，1H)，0.63-0.72(m，1H)，1.47-1.58(m，1H)，1.95(s，3H)，3.88-3.97(m，3H)，6.81(t，1H)，6.91(d，1H)，7.07(d，1H)，7.12(dt，1H)，7.34-7.40(m，2H)，7.47(dd，1H)，11.0(s，1H)。

LC-MS (method 9): r_t1.42 minutes; ms (esineg): 358[ M-H ] M/z]^-。

Example 230

3- [ (4-chloro-2, 6-difluorophenyl) (cyclopropyl) methyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

617 mg (2.82 mmol) of the compound from example 156A and 0.26 ml (3.39 mmol) of trifluoroacetic acid are added to 500 mg (2.82 mmol) of the compound from example 8A in 20 ml of dichloromethane. The reaction mixture was stirred at RT overnight, the solvent was removed in vacuo and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 155 mg (14% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.12-0.21(m，1H)，0.34-0.43(m，1H)，0.48-0.57(m，1H)，0.70-0.80(m，1H)，1.71-1.84(m，1H)，1.94(s，3H)，3.61(d，1H)，3.92(s，2H)，6.84(t，1H)，6.92(d，1H)，7.06(d，1H)，7.30(d，2H)，7.39(d，1H)，11.0(s，1H)。

LC-MS (method 4): r_t1.66 minutes; ms (esineg): m/z 376[ M-H ═]^-。

Example 231

3- [ cyclopropyl (2, 2-difluoro-1, 3-benzodioxol-5-yl) methyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 500 mg (2.82 mmol) of the compound from example 8A and 644 mg (2.82 mmol) of the compound from example 157A in analogy to the synthesis of the compound from example 227. Except that the mixture was stirred at room temperature for 45 minutes. 661 mg (60% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.21-0.35(m，2H)，0.46-0.56(m，1H)，0.60-0.69(m，1H)，1.45-1.56(m，1H)，1.95(s，3H)，3.42(d，1H)，3.92(s，2H)，6.80(t，1H)，6.90(d，1H)，7.10(d，1H)，7.16(dd，1H)，7.26(d，1H)，7.35(d，1H)，7.42(d，1H)，11.0(s，1H)。

LC-MS (method 4): r_t1.63 minutes; ms (esineg): 386[ M-H ] M/z]^-。

Example 232

3- [ (2-chloro-4-fluorophenyl) (cyclopropyl) methyl ] -5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 200 mg (1.02 mmol) of the compound from example 11A and 206 mg (1.02 mmol) of the compound from example 156A in analogy to the synthesis of the compound from example 227. 247 mg (64% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.19-0.37(m，2H)，0.45-0.54(m，1H)，0.63-0.72(m，1H)，1.48-1.59(m，1H)，1.96(s，3H)，3.68(d，1H)，3.92(s，2H)，6.76(dd，1H)，6.82(dd，1H)，7.15(dt，1H)，7.39(dt，1H)，7.42(d，1H)，7.51(dd，1H)，11.1(s，1H)。

LC-MS (method 9): r_t1.41 minutes; ms (esineg): m/z 376[ M-H ═]^-。

Example 233

3- [ [ (2-chloro-4-fluorophenyl) (cyclopropyl) methyl ] -6-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indole

514 mg (2.56 mmol) of the compound from example 156A and 0.24 ml (3.07 mmol) of trifluoroacetic acid are added to 500 mg (2.56 mmol) of the compound from example 9A in 4 ml of dichloromethane. The reaction mixture was stirred at room temperature for 30 minutes, and the crude product was then purified three times by preparative HPLC (mobile phase: acetonitrile/water gradient) and once by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10/1). 404 mg (41% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.21-0.35(m，2H)，0.44-0.53(m，1H)，0.64-0.74(m，1H)，1.46-1.57(m，1H)，1.99(s，3H)，3.91(d，1H)，3.95(s，2H)，6.75(dd，1H)，7.02(dd，1H)，7.14(dt，1H)，7.36-7.41(m，2H)，7.46(dd，1H)，11.1(s，1H)。

HPLC (method 1): r_t5.15 minutes; DCI-MS (ESIpos): 378[ M + H ] M/z]⁺。

Example 234

3- [ (4-chlorophenyl) (cyclopropyl) methyl ] -6-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 500 mg (2.56 mmol) of the compound from example 9A and 468 mg (2.56 mmol) of the compound from example 153A in analogy to the synthesis of the compound from example 233. 411 mg (44% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.20-0.32(m，2H)，0.46-0.55(m，1H)，0.60-0.68(m，1H)，1.40-1.50(m，1H)，1.99(s，3H)，3.39(d，1H)，3.96(s，2H)，6.71(dd，1H)，7.01(dd，1H)，7.27-7.35(m，4H)，7.41(d，1H)，11.1(s，1H)。

HPLC (method 1): r_t5.09 minutes; DCI-MS (ESIpos): m/z is 360[ M + H ]]⁺。

Example 235

3- [ (4-chlorophenyl) (cyclopropyl) methyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

100 mg (0.29 mmol) of the compound from example 227 are introduced at 0 ℃ into 15 ml of dichloromethane, 72 mg (0.29 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to give 135 mg of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.20-0.34(m，2H)，0.47-0.56(m，1H)，0.59-0.68(m，1H)，1.41-1.52(m，1H)，2.47-2.53(s，3H)，3.41(d，1H)，4.23(dd，1H)，4.35(dd，1H)，6.84(t，1H)，6.97(d，1H)，7.12(d，1H)，7.27-7.36(m，4H)，7.45(s，1H)，11.1(s，1H)。

LC-MS (method 9): r_t1.16 minutes; ms (esineg): 356[ M-H ] M/z]^-。

Example 236

3- [ cyclopropyl (2, 4-difluorophenyl) methyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

The title compound was prepared starting from 50 mg (0.15 mmol) of the compound from example 228 in analogy to the synthesis of the compound from example 235. 43 mg (82% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.18-0.36(m，2H)，0.46-0.56(m，1H)，0.62-0.72(m，1H)，1.49-1.61(m，1H)，2.52(s，3H)，3.69(d，1H)，4.23(dd，1H)，4.35(dd，1H)，6.87(t，1H)，6.94-7.02(m，2H)，7.11-7.19(m，2H)，7.36-7.45(m，2H)，11.1(s，1H)。

LC-MS (method 9): r_t1.12 minutes; ms (esineg): 358[ M-H ] M/z]^-。

Example 237

3- [ (2-chloro-4-fluorophenyl) (cyclopropyl) methyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

The title compound was prepared starting from 65 mg (0.18 mmol) of the compound from example 229 in analogy to the synthesis of the compound from example 235. 68 mg (100% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.22-0.35(m，2H)，0.44-0.54(m，1H)，0.63-0.73(m，1H)，1.47-1.58(m，1H)，2.52(s，3H)，3.95(d，1H)，4.22(dd，1H)，4.35(t，1H)，6.87(t，1H)，6.98(d，1H)，7.09-7.16(m，2H)，7.36-7.49(m，3H)，11.1(s，1H)。

LC-MS (method 9): r_t1.19 minutes; ms (esineg): 374[ M-H ] M/z]^-。

Example 238

3- [ (4-chloro-2, 6-difluorophenyl) (cyclopropyl) methyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

The title compound was prepared starting from 150 mg (0.25 mmol) of the compound from example 230 in analogy to the synthesis of the compound from example 235. 75 mg (77% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.12-0.22(m，1H)，0.35-0.44(m，1H)，0.48-0.57(m，1H)，0.70-0.80(m，1H)，1.71-1.83(m，1H)，2.51(s，3H)，3.62(d，1H)，4.23(dd，1H)，4.35(t，1H)，6.90(t，1H)，6.99(d，1H)，7.13(d，1H)，7.30(d，2H)，7.47(s，1H)，11.1(s，1H)。

LC-MS (method 9): r _t1.21 minutes; ms (esineg): 392[ M-H ] M/z]^-。

Example 239

3- [ cyclopropyl (2, 2-difluoro-1, 3-benzodioxol-5-yl) methyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

The title compound was prepared starting from 100 mg (0.26 mmol) of the compound from example 231 in analogy to the synthesis of the compound from example 235. 92 mg (88% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.21-0.36(m，2H)，0.47-0.56(m，1H)，0.60-0.69(m，1H)，1.45-1.55(m，1H)，2.53(s，3H)，3.44(d，1H)，4.23(dd，1H)，4.35(t，1H)，6.85(t，1H)，6.98(d，1H)，7.17(t，2H)，7.26(d，1H)，7.35(d，1H)，7.48(s，1H)，11.1(s，1H)。

LC-MS (method 9): r_t1.19 minutes; ms (esineg): m/z is 402[ M-H [ ]]^-。

Example 240

3- [ (4-chlorophenyl) (cyclopropyl) methyl ] -6-fluoro-7- [ (methylsulfinyl) methyl ] -1H-indole

The title compound was prepared starting from 119 mg (0.33 mmol) of the compound from example 234 in analogy to the synthesis of the compound from example 196. Except that stirring was carried out at 0 ℃ for 2 hours, followed by warming to RT. 92 mg (74% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.21-0.33(m，2H)，0.47-0.56(m，1H)，0.59-0.68(m，1H)，1.39-1.50(m，1H)，2.58(d，3H)，3.40(d，1H)，4.27-4.37(m，2H)，6.77(dd，1H)，7.06-7.12(m，1H)，7.28-7.35(m，4H)，7.44-7.47(m，1H)，11.2(s，1H)。

HPLC (method 1): r_t4.61 minutes; ms (esipos): m/z 376[ M + H ═ M]⁺。

Example 241

3- [ (2-chloro-4-fluorophenyl) (cyclopropyl) methyl ] -6-fluoro-7- [ [ (methylsulfinyl) methyl ] -1H-indole

The title compound was prepared starting from 115 mg (0.30 mmol) of the compound from example 233 in analogy to the synthesis of the compound from example 196. Except that stirring was carried out at 0 ℃ for 2 hours, followed by warming to RT. 85 mg (71% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.21-0.36(m，2H)，0.44-0.54(m，1H)，0.63-0.73(m，1H)，1.46-1.57(m，1H)，2.58(d，3H)，3.92(d，1H)，4.27-4.37(m，2H)，6.81(dd，1H)，7.07-7.17(m，2H)，7.37-7.49(m，3H)，11.2(s，1H)。

HPLC (method 1): r_t4.67 minutes; ms (esipos): 394[ M + H ] M/z]⁺。

Example 242

3- [ cyclopropyl (2, 4-dichlorophenyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

361 mg (1.46 mmol) of 70% m-chloroperbenzoic acid are added to 290 mg (0.77 mmol) of the compound from example 221 in 43 ml of dichloromethane and the mixture is stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 205 mg (65% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.1(s，1H)，7.57(d，1H)，7.43-7.47(m，2H)，7.33(dd，1H)，7.18(d，1H)，7.09(d，1H)，6.92(t，1H)，4.67-4.77(m，2H)，3.95(d，1H)，2.88(s，3H)，1.47-1.58(m，1H)，0.65-0.73(m，1H)，0.45-0.54(m，1H)，0.22-0.37(m，2H)。

LC-MS (method 9): r_t1.37 minutes; ms (esineg): 406[ M-H ] M/z]^-。

Example 243

3- { cyclopropyl [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl } -7- [ (methylsulfonyl) methyl ] -1H-indole

53.6 mg (0.22 mmol) of 70% m-chloroperbenzoic acid are added to 45.0 mg (0.11 mmol) of the compound from example 222 in 15 ml of dichloromethane and the mixture is stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 22.0 mg (45% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.1(s，1H)，7.65(t，1H)，7.60(d，1H)，7.48-7.53(m，2H)，7.22(d，1H)，7.10(d，1H)，6.92(t，1H)，4.67-4.77(m，2H)，3.79(d，1H)，2.89(s，3H)，1.55-1.67(m，1H)，0.65-0.74(m，1H)，0.49-0.58(m，1H)，0.32-0.40(m，1H)，0.21-0.29(m，1H)。

LC-MS (method 4): r _t1.44 minutes; ms (esineg): 424[ M-H ] M/z]^-。

Example 244

3- { cyclopropyl [4- (trifluoromethyl) phenyl ] methyl } -7- [ (methylsulfonyl) methyl ] -1H-indole

233 mg (0.95 mmol) of 70% m-chloroperbenzoic acid are added to 187 mg (0.50 mmol) of the compound from example 223 in 50 ml of dichloromethane and the mixture is stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 112 mg (55% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.1(s，1H)，7.60-7.64(m，2H)，7.52-7.57(m，2H)，7.51(d，1H)，7.18(d，1H)，7.08(d，1H)，6.88(t，1H)，4.67-4.77(m，2H)，3.52(d，1H)，2.89(s，3H)，1.47-1.58(m，1H)，0.63-0.71(m，1H)，0.49-0.57(m，1H)，0.25-0.37(m，2H)。

LC-MS (method 4): r_t1.41 minutes; ms (esineg): 406[ M-H ] M/z]^-。

Example 245

3- { [ 2-chloro-4- (trifluoromethyl) phenyl ] (cyclopropyl) methyl } -7- [ (methylsulfonyl) methyl ] -1H-indole

61.8 mg (0.25 mmol) of 70% m-chloroperbenzoic acid are added to 54.1 mg (0.13 mmol) of the compound from example 224 in 15 ml of dichloromethane and the mixture is stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 40.0 mg (69% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.1(s，1H)，7.83(s，1H)，7.70(d，1H)，7.64(d，1H)，7.48(d，1H)，7.20(d，1H)，7.10(d，1H)，6.92(t，1H)，4.67-4.77(m，2H)，4.03(d，1H)，2.89(s，3H)，1.53-1.64(m，1H)，0.67-0.76(m，1H)，0.47-0.56(m，1H)，0.33-0.41(m，1H)，0.25-0.33(m，1H)。

LC-MS (method 9): r_t1.29 minutes; ms (esineg): 440[ M-H ] M/z ]^-。

Example 246

3- [ (4-chloro-2-fluorophenyl) (cyclopropyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

250 mg (1.01 mmol) of 70% m-chloroperbenzoic acid are added to 192 mg (0.53 mmol) of the compound from example 225 in 30 ml of dichloromethane and the mixture is stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 123 mg (56% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.1(s，1H)，7.45(d，1H)，7.40(t1H)，7.35(dd，1H)，7.17-7.22(m，2H)，7.09(d，1H)，6.91(t，1H)，4.67-4.77(m，2H)，3.71(d，1H)，2.89(s，3H)，1.50-1.61(m，1H)，0.63-0.73(m，1H)，0.47-0.56(m，1H)，0.28-0.36(m，1H)，0.18-0.27(m，1H)。

LC-MS (method 9): r_t1.30 minutes; ms (esineg): 390[ M-H ] M/z]^-。

Example 247

3- [ (2-chloro-4-methylphenyl) (cyclopropyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

135 mg (0.61 mmol) of indium (III) chloride and 0.07 ml (0.92 mmol) of trifluoroacetic acid are added to 132 mg (0.61 mmol) of the compound from example 86A and 100 mg (0.51 mmol) of the compound from example 152A in 5 ml of dichloromethane, and the mixture is stirred at room temperature overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 29.0 mg (15% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.0(s，1H)，7.46(d，1H)，7.29(d，1H)，7.18-7.23(m，2H)，7.08(d，1H)，6.99(dd，1H)，6.90(t，1H)，4.67-4.77(m，2H)，3.92(d，1H)，2.89(s，3H)，2.20(s，3H)，1.49-1.59(m，1H)，0.63-0.73(m，1H)，0.43-0.51(m，1H)，0.23-0.34(m，2H)。

LC-MS (method 4): r_t1.43 minutes; ms (esineg): 386[ M-H ] M/z]^-。

Example 248

3- [ cyclopropyl (4-fluorophenyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

160 mg (0.49 mmol) of the compound from example 226 are introduced into 33 ml of dichloromethane at 0 ℃, 242 mg (0.49 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred for 2 hours at 0 ℃.2 ml of methanol was added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to give 118 mg (67% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.21-0.33(m，2H)，0.47-0.56(m，1H)，0.59-0.68(m，1H)，1.42-1.53(m，1H)，2.89(s，3H)，3.42(d，1H)，4.72(q，2H)，6.87(t，1H)，7.02-7.10(m，2H)，7.17(d，1H)，7.30-7.37(m，2H)，7.45(d，1H)，11.1(s，1H)。

LC-MS (method 9): r_t1.15 minutes; ms (esineg): 356[ M-H ] M/z]^-。

Example 249

3- [ (4-chlorophenyl) (cyclopropyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

350 mg (1.20 mmol) of the compound from example 227 are introduced at 0 ℃ into 40 ml of dichloromethane, 505 mg (1.20 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 5 ml of methanol was added and the solution was concentrated. The crude product is purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 243 mg (63% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.21-0.34(m，2H)，0.47-0.56(m，1H)，0.60-0.69(m，1H)，1.41-1.52(m，1H)，2.89(s，3H)，3.42(d，1H)，4.72(s，2H)，6.88(t，1H)，7.07(d，1H)，7.17(d，1H)，7.30(d，2H)，7.38(d，2H)，7.47(s，1H)，11.1(s，1H)。

LC-MS (method 9): r _t1.21 minutes; ms (esineg): 372[ M-H ] M/z]^-。

Example 250

3- [ cyclopropyl (2, 4-difluorophenyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared starting from 80 mg (0.23 mmol) of the compound from example 228 in analogy to the synthesis of the compound from example 249. 62 mg (66% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.18-0.35(m，2H)，0.47-0.56(m，1H)，0.63-0.72(m，1H)，1.50-1.621(m，1H)，2.89(s，3H)，3.69(d，1H)，4.72(q，1H)，6.91(t，1H)，6.98(dt，1H)，7.09(d，1H)，7.11-7.22(m，2H)，7.37-7.47(m，2H)，11.1(s，1H)。

LC-MS (method 9): r_t1.17 minutes; ms (esineg): 374[ M-H ] M/z]^-。

Example 251

3- [ (2-chloro-4-fluorophenyl) (cyclopropyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared starting from 285 mg (0.79 mmol) of the compound from example 229 in analogy to the synthesis of the compound from example 249. Except that the reaction solution was washed with a saturated aqueous sodium bicarbonate solution and then purified. 219 mg (71% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.22-0.36(m，2H)，0.45-0.54(m，1H)，0.64-0.73(m，1H)，1.48-1.59(m，1H)，2.89(s，3H)，3.95(d，1H)，4.72(q，2H)，6.91(t，1H)，7.06-7.21(m，3H)，7.39(dd，1H)，7.42-7.49(m，2H)，11.1(s，1H)。

LC-MS (method 9): r_t1.23 minutes; ms (esineg): 390[ M-H ] M/z]^-。

Example 252

3- [ (4-chloro-2, 6-difluorophenyl) (cyclopropyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

104 mg (0.48 mmol) of the compound from example 156A and 0.04 ml (0.57 mmol) of trifluoroacetic acid are added to 100 mg (0.48 mmol) of the compound from example 86A in 4 ml of dichloromethane. The reaction mixture was stirred at room temperature for 45 minutes, the solvent was removed in vacuo and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 100 mg (51% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.13-0.22(m，1H)，0.36-0.44(m，1H)，0.48-0.58(m，1H)，0.70-0.80(m，1H)，1.72-1.83(m，1H)，2.88(s，3H)，3.62(d，1H)，4.73(q，2H)，6.94(t，1H)，7.10(d，1H)，7.18(d，1H)，7.30(d，2H)，7.48(d，1H)，11.1(s，1H)。

LC-MS(method 9): r_t1.25 minutes; ms (esineg): 408[ M-H ] M/z]^-

Example 253

3- [ cyclopropyl (2, 2-difluoro-1, 3-benzodioxol-5-yl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared starting from 500 mg (1.29 mmol) of the compound from example 231 in analogy to the synthesis of the compound from example 249. Except that the reaction solution was washed with a saturated aqueous sodium bicarbonate solution and then purified. 311 mg (57% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.22-0.36(m，2H)，0.47-0.56(m，1H)，0.61-0.70(m，1H)，1.45-1.56(m，1H)，2.89(s，3H)，3.44(d，1H)，4.72(q，2H)，6.89(t，1H)，7.08(d，1H)，7.16(dd，1H)，7.22(d，1H)，7.26(d，1H)，7.36(d，1H)，7.49(d，1H)，11.1(s，1H)。

LC-MS (method 4): r_t1.42 minutes; ms (esineg): 418[ M-H ] M/z]^-。

Example 254

3- [ (4-chlorophenyl) (cyclopropyl) methyl ] -5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indole

64 mg (0.35 mmol) of the compound from example 153A and 0.03 ml (0.42 mmol) of trifluoroacetic acid are added to 80 mg (0.35 mmol) of the compound from example 87A in 2.5 ml of dichloromethane. The reaction mixture was stirred at room temperature for 45 minutes, the solvent was removed in vacuo and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 110 mg (80% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.21-0.31(m，2H)，0.48-0.55(m，1H)，0.60-0.68(m，1H)，1.42-1.52(m，1H)，2.92(s，3H)，3.40(d，1H)，4.75(q，2H)，6.88-6.99(m，2H)，7.29-7.37(m，4H)，7.55(d，1H)，11.2(s，1H)。

LC-MS (method 9): r_t1.22 minutes; ms (esineg): 390[ M-H ] M/z ]^-。

Example 255

3- [ (2-chloro-4-fluorophenyl) (cyclopropyl) methyl ] -5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared starting from 180 mg (0.48 mmol) of the compound from example 232 in analogy to the synthesis of the compound from example 249. 145 mg (74% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.19-0.28(m，1H)，0.30-0.38(m，1H)，0.46-0.54(m，1H)，0.64-0.72(m，1H)，1.49-1.60(m，1H)，2.92(s，3H)，3.87(d，1H)，4.75(q，2H)，6.90(dd，1H)，6.98(dd，1H)，7.16(dt，1H)，7.40(dd，1H)，7.48-7.54(m，2H)，11.2(s，1H)。

LC-MS (method 9): r_t1.24 minutes; ms (esineg): 408[ M-H ] M/z]^-。

Example 256

3- [ (4-chloro-2, 6-difluorophenyl) (cyclopropyl) methyl ] -5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indole

96 mg (0.44 mmol) of the compound from example 156A and 0.04 ml (0.53 mmol) of trifluoroacetic acid are added to 100 mg (0.44 mmol) of the compound from example 87A in 3 ml of dichloromethane. The reaction mixture was stirred at room temperature for 45 minutes, the solvent was removed in vacuo and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 162 mg (86% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.12-0.21(m，1H)，0.38-0.48(m，1H)，0.48-0.57(m，1H)，0.69-0.79(m，1H)，1.70-1.83(m，1H)，2.91(s，3H)，3.59(d，1H)，4.75(q，2H)，6.89(dd，1H)，6.99(dd，1H)，7.33(d，2H)，7.56(d，1H)，11.2(s，1H)。

LC-MS (method 4): r_t1.46 minutes; ms (esineg): m/z 426[ M-H ]]^-。

Example 257

3- [ cyclopropyl (2, 2-difluoro-1, 3-benzodioxol-5-yl) methyl ] -5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indole

100 mg (0.44 mmol) of the compound from example 157A and 0.04 ml (0.53 mmol) of trifluoroacetic acid are added to 100 mg (0.44 mmol) of the compound from example 87A in 5 ml of dichloromethane. The reaction mixture was stirred at room temperature for 45 minutes, the solvent was removed in vacuo and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 151 mg (78% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.21-0.34(m，2H)，0.47-0.55(m，1H)，0.60-0.69(m，1H)，1.46-1.57(m，1H)，2.92(s，3H)，3.42(d，1H)，4.75(s，2H)，6.97(dd，1H)，7.01(dd，1H)，7.17(dd，1H)，7.28(d，1H)，7.38(d，1H)，7.58(d，1H)，11.2(s，1H)。

LC-MS (method 9): r_t1.22 minutes; ms (esineg): m/z 436[ M-H ]]^-。

Example 258

3- [ (4-chlorophenyl) (cyclopropyl) methyl ] -6-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared starting from 238 mg (0.66 mmol) of the compound from example 234 in analogy to the synthesis of the compound from example 209. 144 mg (55% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.22-0.33(m，2H)，0.47-0.56(m，1H)，0.60-0.68(m，1H)，1.40-1.51(m，1H)，2.96(s，3H)，3.41(d，1H)，4.74(s，2H)，6.79(dd，1H)，7.15(dd，1H)，7.28-7.36(m，4H)，7.47(d，1H)，11.2(s，1H)。

HPLC (method 1): r_t4.66 minutes; ms (esipos): 392[ M + H ] M/z]⁺。

Example 259

3- [ (2-chloro-4-fluorophenyl) (cyclopropyl) methyl ] -6-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared starting from 230 mg (0.61 mmol) of the compound from example 233 in analogy to the synthesis of the compound from example 249. Except that stirring was carried out at 0 ℃ for 2 hours, followed by warming to RT. 166 mg (66% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.21-0.37(m，2H)，0.45-0.54(m，1H)，0.64-0.73(m，1H)，1.47-1.58(m，1H)，2.96(s，3H)，3.92(d，1H)，4.74(s，2H)，6.84(dd，1H)，7.10-7.19(m，2H)，7.39(dd，1H)，7.42-7.50(m，2H)，11.2(s，1H)。

HPLC (method 1): r_t4.71 minutes; ms (esipos): 410[ M + H ] M/z]⁺。

Example 260

2- [ { 5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } (4-methylphenyl) methyl ] cyclopropanecarbonitrile [ trans-diastereomer mixture ]

130 mg (0.59 mmol) of indium (III) chloride and 0.05 ml (0.64 mmol) of trifluoroacetic acid are added to 104 mg (0.53 mmol) of the compound from example 11A and 100 mg (0.53 mmol) of the compound from example 158A in 6 ml of dichloromethane, and the mixture is stirred under reflux for 1 hour. It was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 39.6 mg (20% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.1(s，1H)，7.21-7.25(m，2H)，7.09-7.13(m，2H)，6.75-6.83(m，2H)，3.87-3.95(m，2H)，3.52(d，1H)，2.21-2.31(m，4H)，1.95(s，3H)，1.63-1.69(m，1H)，1.35-1.41(m，1H)，1.00-1.06(m，1H)。

LC-MS (method 9): r_t1.25 minutes; ms (esineg): m/z 363[ M-H ═]^-。

Example 261

3- [ (4-chlorophenyl) (2, 2-difluorocyclopropyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

In three parallel batches, 3.08 g (13.9 mmol) of indium (III) chloride and 1.6 ml (20.9 mmol) of trifluoroacetic acid in each case were added to 2.54 g (11.6 mmol) of the compound from example 159A and 2.92 g (13.9 mmol) of the compound from example 86A in 125 ml of 1, 2-dichloroethane in each case, and the mixture was heated under reflux overnight. It is diluted with dichloromethane in each case, the three batches are combined and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered through kieselguhr and concentrated. The residue was purified by preparative SFC (ethylpyridine column; mobile phase: carbon dioxide/methanol gradient; 150 bar; 35 ℃) to yield 995 mg (7% of theory) of the title compound as a mixture of diastereomers.

The enantiomers were purified by preparative HPLC on chiral phase [ column: a chiral silica phase based on the selector poly (N-methacryloyl-L-isoleucine-3-pentylamide), 10 microns, 250 mm x 20 mm; eluent: linear gradient isohexane/ethyl acetate 9: 1 → 2: 8 over 27 min; flow rate: 25.0 ml/min; temperature: RT; UV detection: 265 nm ]. 173 mg of enantiomer 261-1 and 154 mg of enantiomer 261-2 were obtained.

Enantiomer 261-1:

R_t4.32 min [ column: a chiral silica gel phase based on the selector poly (N-methacryloyl-L-isoleucine-3-pentylamide), 10 microns, 250 mm x4.6 mm; eluent: isohexane/ethyl acetate 6: 4; flow rate: 2.0 ml/min; temperature: RT; UV detection: 265 nm]。

1H-NMR(400MHz，DMSO-d₆)：δ＝11.1(s，1H)，7.45(d，1H)，7.41-7.45(m，2H)，7.31-7.36(m，2H)，7.24(d，1H)，7.11(d，1H)，6.92(t，1H)，4.68-4.78(m，2H)，3.94(d，1H)，2.90(s，3H)，2.51-2.65(m，1H)，1.56-1.68(m，1H)，1.32-1.42(m，1H)。

LC-MS (method 9): r_t1.15 minutes; ms (esineg): 408[ M-H ] M/z]-。

Enantiomer 261-2:

R_t5.11 min [ column: a chiral silica gel phase based on the selector poly (N-methacryloyl-L-isoleucine-3-pentylamide), 10 microns, 250 mm x4.6 mm; eluent: isohexane/ethyl acetate 2: 8; flow rate: 2.0 ml/min; temperature: RT; UV detection: 265 nm]。

1H-NMR(400MHz，DMSO-d₆)：δ＝11.1(s，1H)，7.55(d，1H)，7.30-7.38(m，4H)，7.26(d，1H)，7.10(d，1H)，6.91(t，1H)，4.67-4.77(m，2H)，3.98(d，1H)，2.89(s，3H)，2.51-2.64(m，1H)，1.67-1.78(m，1H)，1.25-1.37(m，1H)。

LC-MS (method 9): r_t1.16 minutes; ms (esineg): 408[ M-H ] M/z ]^-。

Example 262

3- [ (4-chlorophenyl) (2, 2-difluorocyclopropyl) methyl ] -5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indole

97.1 mg (0.44 mmol) of indium (III) chloride and 0.05 ml (0.07 mmol) of trifluoroacetic acid are added to 80.0 mg (0.37 mmol) of the compound from example 159A and 100 mg (0.44 mmol) of the compound from example 87A in 4 ml of 1, 2-dichloroethane, and the mixture is heated under reflux overnight. It is concentrated, the residue taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 6.0 mg (4% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.3(s，1H)，7.64(d，0.5H)，7.55(d，0.5H)，7.32-7.47(m，4H)，6.96-7.09(m，2H)，4.70-4.80(m，2H)，3.97(d，0.5H)，3.92(d，0.5H)，2.93(s，3H)，2.56-2.66(m，1H)，1.56-1.77(m，1H)，1.26-1.38(m，1H)。

LC-MS (method 9): r_t1.17 minutes; ms (esineg): m/z 426[ M-H ]]^-。

Example 263

2- [ { 5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } (4-methylphenyl) methyl ] cyclopropanecarbonitrile [ trans-diastereomer mixture ]

3.63 g (16.4 mmol) of indium (III) chloride and 1.9 ml (24.6 mmol) of trifluoroacetic acid are added under argon to 4.23 g (16.4 mmol) of the compound from example 87A and 2.56 g (13.7 mmol) of the compound from example 158A in 300 ml of 1, 2-dichloroethane, and the mixture is stirred under reflux for 4 hours. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 3.16 g (49% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.2(s，1H)，7.57(d，1H)，7.18-7.26(m，2H)，7.06-7.14(m，2H)，6.89-7.01(m，2H)，4.69-4.80(m，2H)，3.57(d，0.5H)，3.54(d，0.5H)，2.92(d，1.5H)，2.91(d，1.5H)，2.22-2.32(m，1H)，2.26(d，1.5H)，2.24(d，1.5H)，1.61-1.70(m，1H)，1.35-1.42(m，0.5H)，1.24-1.31(m，0.5H)，1.00-1.08(m，1H)。

LC-MS (method 9): r_t1.06, 1.08 min; ms (esineg): 395[ M-H ] M/z]^-。

Example 264

2- [ (4-methylphenyl) {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } methyl ] cyclopropanecarbonitrile [ trans-diastereomer mixture ]

195 mg (0.88 mmol) of indium (III) chloride and 0.11 ml (1.44 mmol) of trifluoroacetic acid are added under argon to 168 mg (0.80 mmol) of the compound from example 86A and 150 mg (0.80 mmol) of the compound from example 158A in 9 ml of dichloromethane, and the mixture is heated under reflux for 1 hour. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 100 mg (33% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.11(s，0.5H)，11.09(s，0.5H)，7.48(s，1H)，7.16-7.25(m，3H)，7.05-7.12(m，3H)，6.89(t，0.5H)，6.88(t，0.5H)，4.67-4.78(m，2H)，3.60(d，0.5H)，3.57(d，0.5H)，2.89(d，1.5H)，2.88(d，1.5H)，2.20-2.32(m，1H)，2.25(d，1.5H)，2.23(d，1.5H)，1.70(dt，0.5H)，1.64(dt，0.5H)，1.39(dt，0.5H)，1.27(dt，0.5H)，1.01-1.10(m，1H)。

LC-MS (method 9): r_t1.04, 1.06 minutes; ms (esineg): m/z 377[ M-H ═ M]^-。

Example 265

2- ({7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } [4- (trifluoromethyl) phenyl ] methyl) cyclopropanecarbonitrile [ trans-diastereomer mixture ]

1.05 g (4.75 mmol) of indium (III) chloride and 0.55 ml (7.12 mmol) of trifluoroacetic acid are added to 954 mg (3.96 mmol) of the compound from example 160A and 1.02 g (4.75 mmol) of the compound from example 86A in 60 ml of 1, 2-dichloroethane, and the mixture is heated under reflux overnight. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 197 mg (12% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.20(s，0.5H)，11.18(s，0.5H)，7.54-7.71(m，5H)，7.23(d，0.5H)，7.21(d，0.5H)，7.12(d，0.5H)，7.10(d，0.5H)，6.92(t，0.5H)，6.91(t，0.5H)，4.68-4.79(m，2H)，3.77(d，0.5H)，3.75(d，0.5H)，2.90(s，1.5H)，2.89(s，1.5H)，2.31-2.42(m，1H)，1.77-1.84(m，0.5H)，1.69-1.76(m，0.5H)，1.39-1.46(m，0.5H)，1.28-1.34(m，0.5H)，1.06-1.18(m，1H)。

LC-MS (method 9): r_t1.09, 1.11 minutes; ms (esineg): 431[ M-H ] M/z]^-。

The enantiomers were initially purified by preparative HPLC on chiral phases [ column: daicel ChiralpakAD-H, 5 microns, 250 mm x20 mm; eluent: isohexane/isopropanol 1: 1; flow rate: 20 ml/min; temperature: RT; UV detection: 230 nm ], and then separated by separation with an equal RP18 of acetonitrile/water 1: 1.

Enantiomer 265-1:

R_t5.54 min [ column: daicel AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/isopropanol 1: 1; flow rate: 1.0 ml/min; temperature: RT; UV detection: 230 nm]。

R_t7.99 min [ column: reprosil C18, 10 μm, 250 mm x 4.6 mm; eluent: acetonitrile/water 1: 1; flow rate: 1.0 ml/min; temperature: RT; UV detection: 210 nm]。

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.2(s，1H)，7.66-7.71(m，2H)，7.58-7.62(m，2H)，7.56(d，1H)，7.21(d，1H)，7.10(d，1H)，6.91(t，1H)，4.67-4.77(m，2H)，3.75(d，1H)，2.89(s，3H)，2.31-2.41(m，1H)，1.81(dt，1H)，1.43(dt，1H)，1.10(ddd，1H)。

Yield: 12.0 mg.

Example 266

2- [ (2-chloro-4-fluorophenyl) { 5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } methyl ] cyclopropanecarbonitrile [ trans-diastereomeric mixture ]

1.62 g (7.31 mmol) of indium (III) chloride and 0.92 ml (12.0 mmol) of trifluoroacetic acid are added under argon to 1.89 g (6.65 mmol) of the compound from example 87A with a purity of 80% and 1.50 g (6.65 mmol) of the compound from example 161A in 75 ml of 1, 2-dichloroethane, and the mixture is heated under reflux overnight. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative SFC HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to yield 1.65 g (57% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.30(s，0.5H)，11.28(s，0.5H)，7.68(dd，0.5H)，7.61(dd，0.5H)，7.52(d，0.5H)，7.46(d，0.5H)，7.44(dd，0.5H)，7.41(dd，0.5H)，7.26(dt，0.5H)，7.21(dt，0.5H)，6.97-7.07(m，2H)，4.70-4.80(m，2H)，4.07(d，0.5H)，4.04(d，0.5H)，2.93(s，1.5H)，2.92(s，1.5H)，2.36-2.45(m，1H)，1.88-1.94(m，0.5H)，1.54-1.60(m，0.5H)，1.38-1.45(m，0.5H)，1.27-1.34(m，0.5H)，1.19-1.26(m，0.5H)，0.94-1.01(m，0.5H)。

LC-MS (method 9): r_t1.08, 1.10 minutes; ms (esineg): m/z 433[ M-H ═]^-。

The enantiomers were purified by preparative HPLC on chiral phase [ column: chiral silica phase based on the selector poly (N-methacryloyl-L-isoleucine-3-pentylamide), 10 microns, 250 mm x 20 mm; eluent: a step gradient isohexane/ethyl acetate 1: 9(15.7 min) → 0: 100(6 min); flow rate: 80.0 ml/min; temperature: RT; UV detection: 265 nm ].

Enantiomer 266-1:

R_t3.62 min [ column: a chiral silica gel phase based on the selector poly (N-methacryloyl-L-isoleucine-3-pentylamide), 10 microns, 250 mm x4.6 mm; eluent: ethyl acetate; flow rate: 2.0 ml/min; temperature: RT; UV detection: 265 nm]。

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.3(s，1H)，7.68(dd，1H)，7.46(d，1H)，7.44(dd，1H)，7.26(dt，1H)，7.05(dd，1H)，7.00(dd，1H)，4.70-4.80(m，2H)，4.04(d，1H)，2.92(s，3H)，2.36-2.46(m，1H)，1.54-1.60(m，1H)，1.38-1.45(m，1H)，1.19-1.26(m，1H)。

LC-MS (method 4): r_t1.26 minutes; ms (esineg): m/z 433[ M-H ═]^-。

Yield: 240 mg.

Example 267

2- [ (2, 4-difluorophenyl) { 5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } methyl ] cyclopropanecarbonitrile [ trans-diastereomer mixture ]

96.9 mg (0.44 mmol) of indium (III) chloride and 0.06 ml (0.72 mmol) of trifluoroacetic acid are added under argon to 113 mg (0.40 mmol) of the compound from example 87A with a purity of 80% and 100 mg (0.48 mmol) of the compound from example 162A in 4 ml of dichloromethane and the mixture is heated under reflux for 1 hour. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 69.0 mg (41% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.28(s，0.5H)，11.26(s，0.5H)，7.48-7.62(m，2H)，7.14-7.23(m，1H)，6.97-7.13(m，3H)，4.69-4.80(m，2H)，3.88(d，0.5H)，3.85(d，0.5H)，2.93(s，1.5H)，2.92(s，1.5H)，2.36-2.46(m，1H)，1.80-1.87(m，0.5H)，1.58-1.64(m，0.5H)，1.37-1.44(m，0.5H)，1.28-1.35(m，0.5H)，1.14-1.21(m，0.5H)，0.95-1.02(m，0.5H)。

LC-MS (method 6): r_t2.19, 2.22 minutes; ms (esineg): 417[ M-H ] M/z]^-。

Example 268

2- [ (4-chloro-2-methoxyphenyl) { 5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } methyl ] cyclopropanecarbonitrile [ trans-diastereomer mixture ]

104 mg (0.47 mmol) of indium (III) chloride and 0.05 ml (0.70 mmol) of trifluoroacetic acid are added under argon to 93.0 mg (0.39 mmol) of the compound from example 163A and 121 mg (0.47 mmol) of the 88% pure compound from example 87A in 5 ml of 1, 2-dichloroethane, and the mixture is heated under reflux for 2 hours. The reaction mixture was added to a saturated aqueous ammonium chloride solution, then extracted with dichloromethane, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to give 35.0 mg (20% of theory) of diastereomer 1 and 31.3 mg (18% of theory) of diastereomer 2 of the title compound.

Diastereomer 268-1:

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.2(s，1H)，7.50(d，1H)，7.31(d，1H)，7.08(d，1H)，6.93-7.00(m，3H)，4.69-4.79(m，2H)，3.93(d，1H)，3.84(s，3H)，2.92(s，3H)，2.29-2.36(m，1H)，1.51(dt，1H)，1.36(dt，1H)，1.10(ddd，1H)。

LC-MS (method 9): r_t1.09 minutes; ms (esineg): m/z 445[ M-H ]]^-。

Diastereomer 268-2:

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.2(s，1H)，7.52(d，1H)，7.27(d，1H)，7.06(d，1H)，6.91-7.02(m，3H)，4.70-4.80(m，2H)，3.95(d，1H)，3.84(s，3H)，2.92(s，3H)，2.29-2.36(m，1H)，1.75(dt，1H)，1.25(dt，1H)，0.94(ddd，1H)。

LC-MS (method 9): r_t1.11 minutes; ms (esineg): m/z 445[ M-H ] ]^-。

Example 269

2- [ (4-chloro-2-methoxyphenyl) {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } methyl ] cyclopropanecarbonitrile [ trans-diastereomer mixture ]

104 mg (0.47 mmol) of indium (III) chloride and 0.05 ml (0.70 mmol) of trifluoroacetic acid are added under argon to 93.0 mg (0.39 mmol) of the compound from example 163A and 112 mg (0.47 mmol) of the 88% pure compound from example 86A in 5 ml of 1, 2-dichloroethane, and the mixture is heated under reflux for 2 hours. The reaction mixture was added to a saturated aqueous ammonium chloride solution, then extracted with dichloromethane, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to give 30.5 mg (18% of theory) of diastereomer 1 and 28.0 mg (17% of theory) of diastereomer 2 of the title compound.

Diastereomer 269-1:

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.1(s，1H)，7.43(d，1H)，7.24(d，1H)，7.19(d，1H)，7.07-7.11(m，2H)，6.95(dd，1H)，6.91(t，1H)，4.67-4.76(m，2H)，4.01(d，1H)，3.85(s，3H)，2.89(s，3H)，2.25-2.34(m，1H)，1.53(dt，1H)，1.38(dt，1H)，1.06(ddd，1H)。

LC-MS (method 9): r_t1.07 min; ms (esineg): m/z 427[ M-H ═]^-。

Diastereomer 269-2:

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.1(s，1H)，7.44(d，1H)，7.21(d，1H)，7.19(d，1H)，7.10(d，1H)，7.06(d，1H)，6.88-6.95(m，2H)，4.67-4.77(m，2H)，4.03(d，1H)，3.85(s，3H)，2.89(s，3H)，2.25-2.34(m，1H)，1.72(dt，1H)，1.25(dt，1H)，0.97(ddd，1H)。

LC-MS (method 9): r_t1.10 minutes; ms (esineg): m/z 445[ M-H ]]^-。

Example 270

2- [ (2, 4-difluorophenyl) {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } methyl ] cyclopropanecarbonitrile [ trans-diastereomer mixture ]

116 mg (0.53 mmol) of indium (III) chloride and 0.07 ml (0.86 mmol) of trifluoroacetic acid are added under argon to 100 mg (0.48 mmol) of the compound from example 86A and 120 mg (0.57 mmol) of the compound from example 162A in 5 ml of dichloromethane, and the mixture is stirred under reflux for 1 hour. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 29.0 mg (15% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.17(s，0.5H)，11.15(s，0.5H)，7.43-7.57(m，2H)，7.15-7.29(m，2H)，6.99-7.14(m，2H)，6.95(t，0.5H)，6.94(t，0.5H)，4.67-4.78(m，2H)，3.92(d，0.5H)，3.89(d，0.5H)，2.90(s，1.5H)，2.89(s，1.5H)，2.34-2.44(m，1H)，1.80-1.86(m，0.5H)，1.60-1.66(m，0.5H)，1.39-1.46(m，0.5H)，1.28-1.35(m，0.5H)，1.12-1.19(m，0.5H)，0.97-1.04(m，0.5H)。

LC-MS (method 4): r_t1.18, 1.20 minutes; ms (esineg): m/z 399[ M-H ]]^-。

Example 271

2- ({ 5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } [ 2-fluoro-4- (trifluoromethyl) phenyl ] methyl) cyclopropanecarbonitrile [ trans-diastereomer mixture ]

1.63 g (7.35 mmol) of indium (III) chloride and 0.85 ml (11.0 mmol) of trifluoroacetic acid are added to 1.59 g (6.13 mmol) of the compound from example 164A and 1.90 g (7.35 mmol) of the compound from example 87A in 100 ml of 1, 2-dichloroethane, and the mixture is heated at reflux overnight. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 763 mg (27% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.35(s，0.5H)，11.32(s，0.5H)，7.84(t，0.5H)，7.76(t，0.5H)，7.53-7.68(m，3H)，7.13(dd，0.5H)，7.09(dd0.5H)，7.03(dd，0.5H)，7.00(dd，0.5H)，4.70-4.81(m，2H)，3.99(d，0.5H)，3.97(d，0.5H)，2.93(s，1.5H)，2.92(s，1.5H)，2.44-2.53(m，1H)，1.86-1.93(m，0.5H)，1.63-1.70(m，0.5H)，1.38-1.45(m，0.5H)，1.30-1.37(m，0.5H)，1.18-1.25(m，0.5H)，0.98-1.06(m，0.5H)。

LC-MS (method 6): r_t2.41, 2.46 minutes; ms (esineg): m/z 467[ M-H ═]^-。

The mixture of diastereomers was separated by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to give 91.9 mg of diastereomer 1 of the title compound.

Diastereomer 271-1:

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.3(s，1H)，7.84(t，1H)，7.60-7.67(m，2H)，7.55(d，1H)，7.13(dd，1H)，7.00(dd，1H)，4.70-4.79(m，2H)，3.97(d，1H)，2.92(s，3H)，2.44-2.53(m，1H)，1.63-1.70(m，1H)，1.38-1.45(m，1H)，1.18-1.25(m，1H)。

LC-MS (method 9): r_t1.10 minutes; ms (esineg): m/z 467[ M-H ═]^-。

The enantiomers were purified by preparative HPLC on chiral phase [ column: chiral silica phase based on the selector poly (N-methacryloyl-L-isoleucine-3-pentylamide), 10 μm, 250 mm x20 mm; eluent: a step gradient of isohexane/ethyl acetate 4: 6(30 min) → 3: 7(30 min) → 0: 100(15 min); flow rate: 80.0 ml/min; temperature: RT; UV detection: 265 nm ].

Enantiomer 271-1-1:

R_t7.14 min [ column: a chiral silica gel phase based on the selector poly (N-methacryloyl-L-isoleucine-3-pentylamide), 10 microns, 250 mm x4.6 mm; eluent: ethyl acetate; flow rate: 2.0 ml/min; temperature: RT; UV detection: 265 nm]。

Yield: 40.0 mg.

Example 272

2- ({ 5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } [4- (trifluoromethyl) phenyl ] methyl) cyclopropanecarbonitrile [ trans-diastereomer mixture ]

33.0 mg (0.15 mmol) of indium (III) chloride and 0.02 ml (0.22 mmol) of trifluoroacetic acid are added under argon to 30.0 mg (0.12 mmol) of the compound from example 160A and 41.4 mg (0.15 mmol) of the 82% pure compound from example 87A in 1 ml of 1, 2-dichloroethane, and the mixture is heated under reflux conditions for three days. It is concentrated, the residue taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to give 12.6 mg (23% of theory) of diastereomer 1 and 13.2 mg (24% of theory) of diastereomer 2 of the title compound.

Diastereomer 272-1:

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.3(s，1H)，7.67-7.72(m，2H)，7.59-7.66(m，3H)，6.98-7.05(m，2H)，4.70-4.79(m，2H)，3.72(d，1H)，2.92(s，3H)，2.35-2.44(m，1H)，1.76(dt，1H)，1.41(dt，1H)，1.06-1.13(m，1H)。

LC-MS (method 9): r_t1.10 minutes; ms (esineg): m/z 449[ M-H ]]^-。

Diastereomer 272-2:

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.3(s，1H)，7.63-7.68(m，3H)，7.56-7.61(m，2H)，6.96-7.03(m，2H)，4.71-4.81(m，2H)，3.74(d，1H)，2.93(s，3H)，2.37-2.45(m，1H)，1.73(dt，1H)，1.31(dt，1H)，1.06-1.14(m，1H)。

LC-MS (method 9): r_t1.12 minutes; ms (esineg): m/z 449[ M-H ]]^-。

Example 273

2- [ (4-chloro-2-fluorophenyl) { 5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } methyl ] cyclopropanecarbonitrile [ trans-diastereomeric mixture ]

471 mg (2.13 mmol) of indium (III) chloride and 0.25 ml (3.19 mmol) of trifluoroacetic acid are added under argon to 400 mg (1.77 mmol) of the compound from example 165A and 483 mg (2.13 mmol) of the compound from example 87A in 18 ml of dichloromethane, and the mixture is heated under reflux for 3 days. It is concentrated, the residue taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) and another separation of RP18 with acetonitrile/water 55: 45 to give 131 mg (17% of theory) of diastereomer 1 and 127 mg (17% of theory) of diastereomer 2 of the title compound.

Diastereomer 273-1:

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.3(s，1H)，7.58(t，1H)，7.52(d，1H)，7.40(dd，1H)，7.31(dd，1H)，7.07(dd，1H)，7.00(dd，1H)，4.70-4.79(m，2H)，3.87(d，1H)，2.92(s，3H)，2.38-2.47(m，1H)，1.62(dt，1H)，1.41(dt，1H)，1.18(ddd，1H)。

LC-MS (method 9): r_t1.08 min; ms (esineg): m/z 433[ M-H ═]^-。

The enantiomers were purified by preparative HPLC on chiral phase [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x20 mm; eluent: isohexane/(isopropanol/methanol (1: 1)) 6: 4; flow rate: 20 ml/min; temperature: RT; UV detection: 230 nm ] separation.

Enantiomer 273-1-2:

R_tafter 7.90 min [ column: daicel AD-H, 5 micron, 250 mm x 4 mm; eluent: isohexane/(ethanol/methanol 1/1) 1: 1; flow rate: 1.0 ml/min; temperature: RT; UV detection: 230 nm]。

Yield: 44.0 mg.

Diastereomer 273-2:

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.3(s，1H)，7.55(d，1H)，7.51(t，1H)，7.38(dd，1H)，7.26(dd，1H)，6.99-7.07(m，2H)，4.70-4.81(m，2H)，3.88(d，1H)，2.93(s，3H)，2.37-2.46(m，1H)，1.85(dt，1H)，1.32(dt，1H)，0.99(dt，1H)。

LC-MS (method 9): r_t1.11 minutes; ms (esineg): m/z 433[M-H]^-。

Example 274

2- [ (4-chloro-2-fluorophenyl) {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } methyl ] cyclopropanecarbonitrile [ trans-diastereomeric mixture ]

1.76 g (7.98 mmol) of indium (III) chloride and 0.92 ml (12.0 mmol) of trifluoroacetic acid are added under argon to 1.50 g (6.65 mmol) of the compound from example 165A and 1.67 g (7.98 mmol) of the compound from example 86A in 69 ml of dichloromethane and the mixture is heated under reflux conditions for three days. It is concentrated, the residue taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) and another separation with acetonitrile/water 1: 1 isocratic RP18 to give 283 mg (10% of theory) of diastereomer 1 and 145 mg (5% of theory) of diastereomer 2 of the title compound.

Diastereomer 274-1:

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.2(s，1H)，7.52(t，1H)，7.45(d，1H)，7.40(dd，1H)，7.25-7.31(m，2H)，7.11(d，1H)，6.95(t，1H)，4.67-4.77(m，2H)，3.91(d，1H)，2.88(s，3H)，2.35-2.44(m，1H)，1.64(dt，1H)，1.42(dt，1H)，1.17(dt，1H)。

LC-MS (method 9): r_t1.09 minutes; ms (esineg): 415[ M-H ] M/z]^-。

Diastereomer 274-2:

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.2(s，1H)，7.32-7.51(m，3H)，7.20-7.29(m，2H)，7.13(d，1H)，6.95(t，1H)，4.68-4.79(m，2H)，3.93(d，1H)，2.90(s，3H)，2.34-2.44(m，1H)，1.84(dt，1H)，1.31(dt，1H)，0.97-1.05(m，1H)。

LC-MS (method 9): r_t1.10 minutes; ms (esineg): m/z 433[ M-H ═]^-。

Example 275

2- [ (2-fluoro-4-methylphenyl) { 5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } methyl ] cyclopropanecarbonitrile [ trans-diastereomer mixture ]

347 mg (1.57 mmol) of indium (III) chloride and 0.18 ml (2.35 mmol) of trifluoroacetic acid are added under argon to 268 mg (1.31 mmol) of the compound from example 166A and 405 mg (1.57 mmol) of the compound from example 87A having a purity of 88% in 10 ml of 1, 2-dichloroethane, and the mixture is heated under reflux overnight. It is concentrated, the residue taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 358 mg (66% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.26(s，0.5H)，11.24(s，0.5H)，7.53(d，0.5H)，7.51(d，0.5H)，7.38(t，0.5H)，7.32(t，0.5H)，6.93-7.04(m，4H)，4.69-4.81(m，2H)，3.84(d，0.5H)，3.81(d，0.5H)，2.92(s，1.5H)，2.91(s，1.5H)，2.32-2.43(m，1H)，2.28(s，1.5H)，2.26(s，1.5H)，1.82(dt，0.5H)，1.57(dt，0.5H)，1.41(dt，0.5H)，1.30(dt，0.5H)，1.16(ddd，0.5H)，0.97(dt，0.5H)。

LC-MS (method 9): r_t1.09, 1.11 minutes; ms (esineg): 413[ M-H ] M/z ]^-。

Example 276

2- [ (4-chlorophenyl) {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } methyl ] cyclopropanecarbonitrile [ trans-diastereomer mixture ]

95.7 mg (0.43 mmol) of indium (III) chloride and 0.04 ml (0.49 mmol) of trifluoroacetic acid are added under argon to 83.3 mg (0.40 mmol) of the compound from example 167A and 100 mg (0.25 mmol) of the 53% pure compound from example 86A in 5 ml of dichloromethane and the mixture is heated under reflux for three days. It is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 41.0 mg (33% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.16(s，0.5H)，11.15(s，0.5H)，7.52(s，1H)，7.30-7.40(m，4H)，7.16-7.23(m，1H)，7.07-7.13(m，1H)，6.92(t，0.5H)，6.90(t，0.5H)，4.67-4.78(m，2H)，3.67(d，0.5H)，3.64(d，0.5H)，2.90(s，1.5H)，2.89(s，1.5H)，2.24-2.35(m，1H)，1.73-1.80(m，0.5H)，1.64-1.71(m，0.5H)，1.38-1.45(m，0.5H)，1.26-1.32(m，0.5H)，1.03-1.15(m，1H)。

LC-MS (method 9): r_t1.05, 1.08 min; ms (esineg): m/z ═ 397[ M-H ]]^-。

The enantiomers were purified by preparative HPLC on chiral phase [ column: daicel Chiralpak OD-H, 5 microns, 250 mm x20 mm; eluent: isohexane/(ethanol/methanol (1: 1)) 1: 1; flow rate: 20 ml/min; temperature: RT; UV detection: 230 nm ] separation.

Enantiomer 276-1:

R_tafter 11.19 min [ column: daicel OD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/(ethanol/methanol (1: 1)) 1: 1; flow rate: 1.0 ml/min; temperature: RT; UV detection: 230 nm ]。

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.1(s，1H)，7.52(s，1H)，7.34-7.41(m，4H)，7.18(d，1H)，7.09(d，1H)，6.90(d，1H)，4.67-4.77(m，2H)，3.64(d，1H)，2.89(s，3H)，2.24-2.34(m，1H)，1.77(dt，1H)，1.41(dt，1H)，1.03-1.15(m，1H)。

LC-MS (method 6): r_t2.20 minutes; ms (esineg): m/z ═ 397[ M-H ]]^-。

Yield: 45 mg.

Example 277

2- [ (4-chlorophenyl) { 5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } methyl ] cyclopropanecarbonitrile [ trans-diastereomer mixture ]

128 mg (0.58 mmol) of indium (III) chloride and 0.07 ml (0.87 mmol) of trifluoroacetic acid are added under argon to 100 mg (0.48 mmol) of the compound from example 167A and 149 mg (0.58 mmol) of the 88% pure compound from example 87A in 5 ml of 1, 2-dichloroethane, and the mixture is heated under reflux overnight. It is concentrated, the residue taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to yield 130 mg (65% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.29(s，0.5H)，11.27(s，0.5H)，7.60(d，1H)，7.32-7.42(m，4H)，6.94-7.02(m，2H)，4.70-4.81(m，2H)，3.64(d，0.5H)，3.61(d，0.5H)，2.93(d，1.5H)，2.92(d，1.5H)，2.27-2.38(m，1H)，1.65-1.76(m，1H)，1.36-1.44(m，0.5H)，1.26-1.33(m，0.5H)，1.03-1.11(m，1H)。

LC-MS (method 4): r_t1.24, 1.27 minutes; ms (esineg): 415[ M-H ] M/z]^-。

In a similarly performed batch and separation of the mixture of diastereomers by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) gave 410 mg of diastereomer 1 of the title compound.

Diastereomer 277-1:

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.3(s，1H)，7.61(d，1H)，7.35-7.42(m，4H)，6.94-7.01(m，2H)，4.70-4.81(m，2H)，3.61(d，1H)，2.92(d，3H)，2.27-2.36(m，1H)，1.69-1.76(m，1H)，1.36-1.43(m，1H)，1.03-1.10(m，1H)。

LC-MS (method 9): r_t1.08 min; ms (esineg): 415[ M-H ] M/z]^-。

The enantiomers were purified by preparative HPLC on chiral phase [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x20 mm; eluent: isohexane/(ethanol/methanol (1: 1) 1: 1; flow rate: 20 ml/min; temperature: RT; UV detection: 230 nm.) the separated enantiomer was again purified by preparative HPLC on the achiral phase (RP18 column; mobile phase: acetonitrile/water gradient, addition of 0.1% formic acid) to give 17.0 mg of enantiomer 277-1-1.

Enantiomer 277-1-1:

R_t13.48 min [ column: daicel AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/(ethanol/methanol (1: 1)) 1: 1; flow rate: 1.0 ml/min; temperature: RT; UV detection: 230 nm]。

Example 278

3- [ bis (4-fluorophenyl) methyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

1.24 g (5.64 mmol) of 4, 4' -difluorobenzhydrol (Difluorobenzohydrol) and 1.25 g (5.64 mmol) of indium (III) chloride are added to 1.00 g (5.64 mmol) of the compound from example 8A in 30 ml of toluene. The reaction mixture was stirred at 80 ℃ for 5 hours. After cooling to RT, the reaction solution was mixed with ethyl acetate and the solid was filtered off. The filtrate was mixed with water, the phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) gives 0.53 g (25% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.96(s，3H)，3.93(s，2H)，5.72(s，1H)，6.68(s，1H)，6.82(t，1H)，6.94(d，1H)，7.01(d，1H)，7.08-7.16(m，4H)，7.22-7.29(m，4H)，11.0(s，1H)。

LC-MS (method 4): r_t1.58 minutes; ms (esineg): 378[ M-H ] M/z]^-。

Example 279

3- [ bis (4-chlorophenyl) methyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 1.50 g (8.46 mmol) of the compound from example 8A and 2.14 g (8.46 mmol) of 4, 4' -dichlorobenzhydrol (dichlobenzohydrol) in analogy to the synthesis of the compound from example 278. 0.94 g (27% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.96(s，3H)，3.94(s，2H)，5.73(s，1H)，6.71(s，1H)，6.83(t，1H)，6.95(d，1H)，7.02(d，1H)，7.24(d，4H)，7.36(d，4H)，11.0(s，1H)。

LC-MS (method 4): r_t1.71 minutes; ms (esineg): 410[ M-H ] M/z]^-。

Example 280

4- [ (4-fluorophenyl) {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } methyl ] benzonitrile

The title compound was prepared starting from 750 mg (4.23 mmol) of the compound from example 8A and 961 mg (4.23 mmol) of the compound from example 173A in analogy to the synthesis of the compound from example 278. 276 mg (17% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.95(s，3H)，3.94(s，2H)，5.84(s，1H)，6.73(d，1H)，6.84(t，1H)，6.96(d，1H)，7.01(d，1H)，7.10-7.18(m，2H)，7.24-7.31(m，2H)，7.43(d，2H)，7.77(d，2H)，11.1(s，1H)。

LC-MS (method 3): r_t2.52 min; ms (esineg): 385M/z [ M-H ]]^-。

Example 281

4- [ (4-chlorophenyl) {7- [ (methylsulfanyl) methyl ] -1H-indol-3-yl } methyl ] benzonitrile

The title compound was prepared starting from 750 mg (4.23 mmol) of the compound from example 8A and 1.03 g (4.23 mmol) of the compound from example 174A in analogy to the synthesis of the compound from example 278. 248 mg (15% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.95(s，3H)，3.94(s，2H)，5.85(s，1H)，6.74(s，1H)，6.84(t，1H)，6.96(d，1H)，7.02(d，1H)，7.26(d，2H)，7.38(d，2H)，7.43(d，2H)，7.78(d，2H)，11.1(s，1H)。

LC-MS (method 5): r_t3.00 min; ms (esineg): 401[ M-H ] M/z]^-。

Example 282

3- [ (4-chlorophenyl) (4-methoxyphenyl) methyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 750 mg (4.23 mmol) of the compound from example 8A and 1.05 g (4.23 mmol) of the compound from example 175A in analogy to the synthesis of the compound from example 278. 262 mg (15% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.96(s，3H)，3.72(s，3H)，3.93(s，2H)，5.63(s，1H)，6.68(s，1H)，6.82(t，1H)，6.86(d，2H)，6.94(d，1H)，7.01(d，1H)，7.13(d，2H)，7.23(d，2H)，7.34(d，2H)，11.0(s，1H)。

LC-MS (method 9): r_t1.43 minutes; ms (esineg): 406[ M-H ] M/z]^-。

Example 283

3- [ (4-chloro-3-fluorophenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 750 mg (4.23 mmol) of the compound from example 8A and 1.08 g (4.23 mmol) of the compound from example 176A in analogy to the synthesis of the compound from example 278. 460 mg (26% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.95(s，3H)，3.94(s，2H)，5.77(s，1H)，6.76(d，1H)，6.84(t，1H)，6.96(d，1H)，7.03(d，1H)，7.01-7.17(m，3H)，7.20-7.32(m，3H)，7.51(t，1H)，11.0(s，1H)。

LC-MS (method 6): r_t2.94 minutes; ms (esineg): m/z 412[ M-H ═ M]^-。

Example 284

3- [ (3-chloro-4-fluorophenyl) (4-chlorophenyl) methyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 750 mg (4.23 mmol) of the compound from example 8A and 1.15 g (4.23 mmol) of the compound from example 177A in analogy to the synthesis of the compound from example 278. 483 mg (26% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.95(s，3H)，3.94(s，2H)，5.77(s，1H)，6.75(s，1H)，6.85(t，1H)，6.96(d，1H)，7.03(d，1H)，7.20-7.28(m，3H)，7.32-7.43(m，4H)，11.1(s，1H)。

LC-MS (method 4): r_t1.71 minutes; ms (esineg): 428[ M-H ] M/z]^-。

Example 285

3- [ (4-chloro-2, 6-difluorophenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 490 mg (2.76 mmol) of the compound from example 8A and 753 mg (2.76 mmol) of the compound from example 178A in analogy to the synthesis of the compound from example 278. 140 mg (12% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.96(s，3H)，3.95(s，2H)，5.98(s，1H)，6.84-6.91(m，2H)，6.98(d，1H)，7.04(d，1H)，7.08-7.15(m，2H)，7.21-7.27(m，2H)，7.37(d，2H)，11.1(s，1H)。

LC-MS (method 3): r_t2.84 minutes; ms (esineg): 430[ M-H ] M/z]^-。

Example 286

3- [ bis (4-chloro-2-fluorophenyl) methyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 750 mg (4.23 mmol) of the compound from example 8A and 1.22 g (4.23 mmol) of the compound from example 179A in analogy to the synthesis of the compound from example 278. 97 mg (5% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.97(s，3H)，3.95(s，2H)，6.04(s，1H)，6.77(s，1H)，6.88(t，1H)，6.96-7.08(m，4H)，7.23(dd，2H)，7.45(dd，2H)，11.1(s，1H)。

LC-MS (method 4): r_t1.75 minutes; ms (esineg): 446[ M-H ] M/z]^-。

Example 287

3- [ (4-chloro-2-fluorophenyl) (4-fluoro-2-methylphenyl) methyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 750 mg (4.23 mmol) of the compound from example 8A and 1.14 g (4.23 mmol) of the compound from example 180A in analogy to the synthesis of the compound from example 278. 554 mg (31% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.97(s，3H)，2.25(s，3H)，3.95(s，2H)，5.93(s，1H)，6.61(s，1H)，6.85(t，2H)，6.89-7.00(m，3H)，7.04(d，1H)，7.09(dd，1H)，7.22(dd，1H)，7.43(dd，1H)，11.1(s，1H)。

LC-MS (method 3): r_t2.92 minutes; ms (esineg): m/z 426[ M-H ]]^-。

Example 288

3- [ (4-chloro-2-fluorophenyl) (2, 4-difluorophenyl) methyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 750 mg (4.23 mmol) of the compound from example 8A and 1.15 g (4.23 mmol) of the compound from example 181A in analogy to the synthesis of the compound from example 278. The difference was that stirring was carried out at 80 ℃ for two days, then 0.33 ml (4.23 mmol) of trifluoroacetic acid was added and stirring was carried out for an additional 16 hours. 65 mg (75% purity, 3% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.97(s，3H)，3.96(s，2H)，6.13(s，1H)，6.86-6.93(m，2H)，6.97-7.21(m，6H)，7.37-7.44(m，2H)，11.2(s，1H)。

LC-MS (method 4): r_t1.65 minutes; ms (esineg): 430[ M-H ] M/z]^-。

Example 289

3- [1- (4-chlorophenyl) -1- (4-fluorophenyl) ethyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 1.00 g (5.64 mmol) of the compound from example 8A and 1.41 g (5.64 mmol) of the compound from example 182A in analogy to the synthesis of the compound from example 278. Except that stirring was carried out at 80 ℃ for only 4 hours. 1.31 g (56% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.98(s，3H)，2.15(s，3H)，3.93(s，2H)，6.62(d，1H)，6.73-6.79(m，2H)，6.92(dd，1H)，7.06-7.23(m，6H)，7.31-7.36(m，2H)，11.0(s，1H)。

LC-MS (method 4): r_t1.69 minutes; ms (esineg): 408[ M-H ] M/z ]^-。

Example 290

3- [1- (4-chloro-2-fluorophenyl) -1- (4-fluorophenyl) ethyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 1.00 g (5.64 mmol) of the compound from example 8A and 1.52 g (5.64 mmol) of the compound from example 183A in analogy to the synthesis of the compound from example 278. 0.95 g (39% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：6＝1.99(s，3H)，2.20(s，3H)，3.94(s，2H)，6.65(d，1H)，6.79(t，1H)，6.86-6.96(m，3H)，7.07-7.24(m，5H)，7.36(dd，1H)，11.0(s，1H)。

LC-MS (method 5): r_t3.23 minutes; ms (esineg): m/z 426[ M-H ]]^-。

Example 291

3- [ (4-chlorophenyl) (4-fluorophenyl) methyl ] -5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 500 mg (2.56 mmol) of the compound from example 11A and 667 mg (2.56 mmol) of the compound from example 81A in analogy to the synthesis of the compound from example 278. Except that stirring was carried out at 80 ℃ for only 4 hours to obtain 535 mg (50% of theory) of the target compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.97(s，3H)，3.93(s，2H)，5.71(s，1H)，6.72(dd，1H)，6.81(s，1H)，6.85(dd，1H)，7.10-7.17(m，2H)，7.21-7.29(m，4H)，7.34-7.39(m，2H)，11.1(s，1H)。

LC-MS (method 5): r_t3.14 minutes; ms (esineg): m/z 412[ M-H ═ M]^-。

Example 292

5-fluoro-3- [ (4-fluoro-2-methylphenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 500 mg (2.56 mmol) of the compound from example 11A and 733 mg (2.56 mmol) of the compound from example 82A in analogy to the synthesis of the compound from example 278. Except that stirring was carried out at 80 ℃ for only 4 hours. 428 mg (39% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.98(s，3H)，2.26(s，3H)，3.94(q，2H)，5.76(s，1H)，6.64(s，1H)，6.71(dd，2H)，6.82-6.95(m，3H)，7.05(dd，1H)，7.09-7.22(m，4H)，11.1(s，1H)。

LC-MS (method 4): r_t1.63 minutes; ms (esineg): 410[ M-H ] M/z]^-。

Example 293

3- [ (4-chloro-2-methylphenyl) (4-fluorophenyl) methyl ] -5-fluoro-7- [ (methylsulfanyl) methyl ] -1H-indole

The title compound was prepared starting from 500 mg (2.56 mmol) of the compound from example 11A and 706 mg (2.56 mmol) of the compound from example 83A in analogy to the synthesis of the compound from example 278. Except that stirring was carried out at 80 ℃ for only 4 hours. 616 mg (56% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.98(s，3H)，2.25(s，3H)，3.94(q，2H)，5.77(s，1H)，6.65(s，1H)，6.72(dd，2H)，6.82-6.89(m，2H)，7.10-7.20(m，5H)，7.28(dd，1H)，11.1(s，1H)。

LC-MS (method 4): r_t1.70 minutes; ms (esineg): m/z 426[ M-H ]]^-。

Example 294 and example 295

390 mg (1.03 mmol) of the compound from example 278 are introduced at 0 ℃ into 40 ml of dichloromethane, 507 mg (2.06 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to give 40 mg (10% of theory) of example 294 as a mixture of diastereomers and 309 mg (73% of theory) of example 295.

Example 294

3- [ bis (4-fluorophenyl) methyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.53(s，3H)，4.24(d，1H)，4.37(d，1H)，5.73(s，1H)，6.76(d，1H)，6.88(t，1H)，7.01(d，1H)，7.06-7.16(m，5H)，7.22-7.28(m，3H)，11.1(s，1H)。

LC-MS (method 4): r_t1.32 minutes; ms (esineg): 394[ M-H ] M/z]^-。

Example 295

3- [ bis (4-fluorophenyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.89(s，3H)，4.74(s，2H)，5.74(s，1H)，6.77(d，1H)，6.92(t，1H)，7.09-7.16(m，6H)，7.22-7.28(m，4H)，11.1(s，1H)。

LC-MS (method 5): r_t2.63 minutes; ms (esineg): 410[ M-H ] M/z]^-。

Example 296

3- [ bis (4-chlorophenyl) methyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

200 mg (0.49 mmol) of the compound from example 279 are introduced into 20 ml of dichloromethane at 0 ℃, 120 mg (0.49 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 134 mg (65% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.53(s，3H)，4.24(d，1H)，4.37(d，1H)，5.74(s，1H)，6.79(d，1H)，6.89(t，1H)，7.02(d，1H)，7.09(d，1H)，7.23(d，4H)，7.36(d，4H)，11.1(s，1H)。

LC-MS (method 4): r_t1.47 minutes; ms (esineg): m/z 426[ M-H ]]^-。

Example 297

4- [ (4-fluorophenyl) {7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } methyl ] benzonitrile

The title compound was prepared in analogy to the synthesis of the compound from example 296 starting from 60 mg (0.16 mmol) of the compound from example 280. 61 mg (98% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.53(s，3H)，4.24(d，1H)，4.37(d，1H)，5.86(s，1H)，6.81(d，1H)，6.89(t，1H)，7.03(d，1H)，7.09(d，1H)，7.14(t，2H)，7.24-7.30(m，2H)，7.43(d，2H)，7.77(d，2H)，11.2(s，1H)。

LC-MS (method 4): r_t1.25 minutes; ms (esineg): 401[ M-H ] M/z]^-。

Example 298

4- [ (4-chlorophenyl) {7- [ (methylsulfinyl) methyl ] -1H-indol-3-yl } methyl ] benzonitrile

The title compound was prepared in analogy to the synthesis of the compound from example 296 starting from 60 mg (0.15 mmol) of the compound from example 281. 62 mg (99% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.53(s，3H)，4.24(d，1H)，4.37(d，1H)，5.86(s，1H)，6.82(d，1H)，6.90(t，1H)，7.03(d，1H)，7.09(d，1H)，7.25(d，2H)，7.38(d，2H)，7.43(d，2H)，7.78(d，2H)，11.2(s，1H)。

LC-MS (method 5): r_t2.47 minutes; ms (esineg): 417[ M-H ] M/z]^-。

Example 299

3- [ (4-chloro-3-fluorophenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

The title compound was prepared in analogy to the synthesis of the compound from example 296 starting from 75 mg (0.18 mmol) of the compound from example 283. 76 mg (98% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.53(s，3H)，4.24(dd，1H)，4.37(d，1H)，5.78(s，1H)，6.84(d，1H)，6.90(t，1H)，7.02(d，1H)，7.07-7.17(m，4H)，7.20-7.31(m，3H)，7.52(t，1H)，11.2(s，1H)。

LC-MS (method 9): r_t1.24 minutes; ms (esineg): 428[ M-H ] M/z]^-。

Example 300

3- [ (3-chloro-4-fluorophenyl) (4-chlorophenyl) methyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

The title compound was prepared starting from 100 mg (0.23 mmol) of the compound from example 284 in analogy to the synthesis of the compound from example 296. 102 mg (98% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.53(s，3H)，4.24(dd，1H)，4.38(d，1H)，5.79(s，1H)，6.83(s，1H)，6.90(t，1H)，7.03(d，1H)，7.10(d，1H)，7.19-7.23(m，3H)，7.32-7.43(m，4H)，11.2(s，1H)。

LC-MS (method 4): r_t1.47 minutes; ms (esineg): m/z 444[ M-H ]]^-。

Example 301

3- [ (4-chloro-2, 6-difluorophenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

The title compound was prepared in analogy to the synthesis of the compound from example 296 starting from 40 mg (0.09 mmol) of the compound from example 285. 38 mg (92% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.54(s，3H)，4.25(dd，1H)，4.39(dd，1H)，5.99(s，1H)，6.93(t，1H)，6.97(s，1H)，7.05(d，1H)，7.08-7.16(m，3H)，7.20-7.27(m，2H)，7.37(d，2H)，11.2(s，1H)。

LC-MS (method 3): r_t2.32 minutes; ms (esineg): 446[ M-H ] M/z]^-。

Example 302 and example 303

89 mg (0.20 mmol) of the compound from example 286 are introduced into 10 ml of dichloromethane at 0 ℃, 86 mg (0.35 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to give 46 mg (48% of theory) of example 302 as a mixture of diastereomers and 31 mg (34% of theory) of example 303.

Example 302

3- [ bis (4-chloro-2-fluorophenyl) methyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.54(s，3H)，4.25(d，1H)，4.39(d，1H)，6.05(s，1H)，6.85(s，1H)，6.93(t，1H)，7.00-7.08(m，3H)，7.13(d，1H)，7.24(d，2H)，7.45(d，2H)，11.2(s，1H)。

LC-MS (method 3): r _t2.47 minutes; ms (esineg): 462[ M-H ] M/z]^-。

Example 303

3- [ bis (4-chloro-2-fluorophenyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.91(s，3H)，4.76(s，2H)，6.06(s，1H)，6.86(s，1H)，6.97(t，1H)，7.03(t，2H)，7.17(t，2H)，7.24(dd，2H)，7.46(dd，2H)，11.2(s，1H)。

LC-MS (method 3): r_t2.59 min; ms (esineg): m/z 478[ M-H ═]^-。

Example 304

3- [ (4-chloro-2-fluorophenyl) (4-fluoro-2-methylphenyl) methyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

The title compound was prepared starting from 100 mg (0.23 mmol) of the compound from example 287 in analogy to the synthesis of the compound from example 296. 99 mg (95% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.24(s，3H)，2.54(s，3H)，4.24(dd，1H)，4.38(dd，1H)，5.94(s，1H)，6.69(d，1H)，6.82-6.97(m，4H)，7.02-7.14(m，3H)，7.22(dd，1H)，7.43(dd，1H)，11.2(s，1H)。

LC-MS (method 5): r_t2.76 min; ms (esineg): m/z 442[ M-H ]]^-。

Example 305 and example 306

60 mg (75% purity, 0.10 mmol) of the compound from example 288 were added to 6 ml of dichloromethane, 51 mg (0.21 mmol) of 70% m-chloroperbenzoic acid at 0 ℃ and the mixture was stirred at room temperature for 2 hours. 2 ml of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to give 40 mg (83% of theory) of example 305 as a diastereomer mixture and 10 mg (63% purity, 13% of theory) of example 306.

Example 305

3- [ (4-chloro-2-fluorophenyl) (2, 4-difluorophenyl) methyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.54(s，3H)，4.26(dd，1H)，4.40(dd，1H)，6.14(s，1H)，6.94(t，1H)，6.99(s，1H)，7.01-7.20(m，6H)，7.37-7.47(m，2H)，11.3(s，1H)。

LC-MS (method 4): r_t1.39 minutes; ms (esineg): 446[ M-H ] M/z]^-。

Example 306

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.91(s，3H)，4.77(s，2H)，6.14(s，1H)，6.94-7.07(m，3H)，7.09-7.20(m，5H)，7.37-7.46(m，2H)，11.2(s，1H)。

LC-MS (method 4): r_t1.45 minutes; ms (esineg): m/z ═462[M-H]^-。

Example 307

3- [1- (4-chlorophenyl) -1- (4-fluorophenyl) ethyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

The title compound was prepared starting from 300 mg (0.73 mmol) of the compound from example 289 in analogy to the synthesis of the compound from example 296. 193 mg (62% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.16(s，3H)，2.55(s，3H)，4.23(d，1H)，4.37(d，1H)，6.72(d，1H)，6.78-6.85(m，2H)，6.98(dd，1H)，7.07-7.14(m，2H)，7.15-7.22(m，4H)，7.34(d，2H)，11.1(s，1H)。

LC-MS (method 4): r_t1.45 minutes; ms (esineg): 424[ M-H ] M/z]^-。

Example 308

3- [1- (4-chloro-2-fluorophenyl) -1- (4-fluorophenyl) ethyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

The title compound was prepared starting from 300 mg (0.70 mmol) of the compound from example 290 in analogy to the synthesis of the compound from example 296. 258 mg (83% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.20(s，3H)，2.56(s，3H)，4.23(s，1H)，4.38(s，1H)，6.76(dd，1H)，6.84(t，1H)，6.88-6.96(m，2H)，7.00(d，1H)，7.07-7.25(m，5H)，7.36(dd，1H)，11.2(s，1H)。

LC-MS (method 3): r_t2.38 minutes; ms (esineg): m/z 442[ M-H ]]^-。

Example 309

3- [ (4-chlorophenyl) (4-fluorophenyl) methyl ] -5-fluoro-7- [ (methylsulfinyl) methyl ] -1H-indole

The title compound was prepared in analogy to the synthesis of the compound from example 296 starting from 100 mg (0.24 mmol) of the compound from example 291. 102 mg (98% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.54(s，3H)，4.23(d，1H)，4.38(d，1H)，5.72(s，1H)，6.81(dd，1H)，6.88-6.93(m，2H)，6.88-6.96(m，2H)，7.13(t，2H)，7.21-7.28(m，4H)，7.37(d，2H)，11.2(s，1H)。

LC-MS (method 5): r_t2.66 minutes; ms (esineg): 428[ M-H ] M/z]^-。

Example 310

5-fluoro-3- [ (4-fluoro-2-methylphenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfinyl) methyl ] -1H-indole

The title compound was prepared starting from 75 mg (0.18 mmol) of the compound from example 292 in analogy to the synthesis of the compound from example 296. 75 mg (96% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.26(s，3H)，2.54(s，3H)，4.23(dd，1H)，4.38(dd，1H)，5.78(s，1H)，6.72(s，1H)，6.77-6.95(m，4H)，7.06(dd，1H)，7.10-7.21(m，4H)，11.2(s，1H)。

LC-MS (method 3): r_t2.29 minutes; ms (esineg): m/z 426[ M-H ]]^-。

Example 311

The title compound was prepared starting from 120 mg (0.28 mmol) of the compound from example 293 in analogy to the synthesis of the compound from example 296. 114 mg (92% of theory) of the target compound are obtained as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.25(s，3H)，2.55(s，3H)，4.24(dd，1H)，4.39(dd，1H)，5.79(s，1H)，6.74(d，1H)，6.79-6.86(m，2H)，6.91(dt，1H)，7.10-7.21(m，5H)，7.28(d，1H)，11.2(s，1H)。

LC-MS (method 3): r_t2.42 minutes; ms (esineg): m/z 442[ M-H ]]^-。

Example 312

3- [ bis (4-chlorophenyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

680 mg (1.65 mmol) of the compound from example 279 are introduced into 40 ml of dichloromethane at 0 ℃, 813 mg (3.30 mmol) of 70% m-chloroperbenzoic acid are added and the mixture is stirred for 2 hours at 0 ℃. 2 ml of methanol was added and the solution was concentrated. The crude product is purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to yield 529 mg (72% of theory) of the title compound.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.89(s，3H)，4.74(s，2H)，5.76(s，1H)，6.79(d，1H)，6.93(t，1H)，7.13(d，2H)，7.24(d，4H)，7.36(d，4H)，11.1(s，1H)。

LC-MS (method 4): r_t1.51 minutes; ms (esineg): m/z 442[ M-H ]]^-。

Example 313

4- [ (4-fluorophenyl) {7- [ (methylsulfonyl) methyl ] -1H-indol-3-yl } methyl ] benzonitrile

The title compound was prepared starting from 170 mg (0.44 mmol) of the compound from example 280 in analogy to the synthesis of the compound from example 312. 155 mg (84% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.89(s，3H)，4.74(s，2H)，5.87(s，1H)，6.82(d，1H)，6.93(t，1H)，7.10-7.18(m，4H)，7.24-7.30(m，2H)，7.43(d，2H)，7.78(d，2H)，11.1(s，1H)。

LC-MS (method 9): r_t1.13 minutes; ms (esineg): 417[ M-H ] M/z]^-。

Example 314

3- [ (4-chlorophenyl) (4-methoxyphenyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared in analogy to the synthesis of the compound from example 312 starting from 150 mg (0.37 mmol) of the compound from example 282. 130 mg (80% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.89(s，3H)，3.72(s，3H)，4.73(s，2H)，5.65(s，1H)，6.76(s，1H)，6.84-6.95(m，3H)，7.09-7.16(m，4H)，7.23(d，2H)，7.34(d，2H)，11.1(s，1H)。

LC-MS (method 5): r_t2.70 minutes; ms (esineg): 438[ M-H ] M/z]^-。

Example 315

3- [ (4-chloro-3-fluorophenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared starting from 330 mg (0.80 mmol) of the compound from example 283 in analogy to the synthesis of the compound from example 312. 323 mg (91% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.89(s，3H)，4.75(s，2H)，5.79(s，1H)，6.85(d，1H)，6.94(t，1H)，7.07-7.18(m，5H)，7.20-7.31(m，3H)，7.52(t，1H)，11.1(s，1H)。

LC-MS (method 9): r_t1.27 minutes; ms (esineg): m/z 444[ M-H ]]^-。

Example 316

3- [ (3-chloro-4-fluorophenyl) (4-chlorophenyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared starting from 335 mg (0.78 mmol) of the compound from example 284 in analogy to the synthesis of the compound from example 312. 295 mg (82% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.89(s，3H)，4.75(s，2H)，5.79(s，1H)，6.84(s，1H)，6.94(t，1H)，7.14(dd，1H)，7.20-7.28(m，3H)，7.32-7.43(m，4H)，11.1(s，1H)。

LC-MS (method 4): r_t1.52 min; ms (esineg): 460[ M-H ] M/z]^-。

Example 317

3- [ (4-chloro-2, 6-difluorophenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared starting from 60 mg (0.14 mmol) of the compound from example 285 in analogy to the synthesis of the compound from example 312. 58 mg (90% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.90(s，3H)，4.76(s，2H)，6.00(s，1H)，6.94-7.00(m，2H)，7.08-7.18(m，4H)，7.20-7.26(m，2H)，7.37(d，2H)，11.2(s，1H)。

LC-MS (method 3): r_t2.44 minutes; ms (esineg): 462[ M-H ] M/z]^-。

enantiomer 317-1:

R_tafter 6.25 min [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/ethanol 1: 1; flow rate: 1 ml/min; temperature: 24 ℃; UV detection: 230 nm]；

Yield: 18.0 mg.

Enantiomer 317-2:

R_tafter 6.98 min [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/ethanol 1: 1; flow rate: 1 ml/min; temperature: 24 ℃; UV detection: 230 nm]。

Yield: 18.0 mg.

Example 318

3- [ (4-chloro-2-fluorophenyl) (4-fluoro-2-methylphenyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared starting from 410 mg (0.96 mmol) of the compound from example 287 in analogy to the synthesis of the compound from example 312. 427 mg (97% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.25(s，3H)，2.91(s，3H)，4.75(s，2H)，5.94(s，1H)，6.70(d，1H)，6.85(dd，1H)，6.89-6.98(m，3H)，7.09(dd，1H)，7.15(dd，2H)，7.22(dd，1H)，7.44(dd，1H)，11.1(s，1H)。

LC-MS (method 5): r_t2.89 minutes; ms (esineg): 458[ M-H ] M/z]^-。

Example 319

3- [1- (4-chlorophenyl) -1- (4-fluorophenyl) ethyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared starting from 900 mg (2.20 mmol) of the compound from example 289 in analogy to the synthesis of the compound from example 312. 939 mg (97% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.16(s，3H)，2.92(s，3H)，4.74(s，2H)，6.72(d，1H)，6.82-6.91(m，2H)，7.07-7.14(m，3H)，7.15-7.22(m，4H)，7.34(d，2H)，11.1(s，1H)。

LC-MS (method 4): r_t1.49 minutes; ms (esineg): 440[ M-H ] M/z]^-。

Example 320

3- [1- (4-chloro-2-fluorophenyl) -1- (4-fluorophenyl) ethyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared starting from 600 mg (1.40 mmol) of the compound from example 290 in analogy to the synthesis of the compound from example 312. 589 mg (91% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.21(s，3H)，2.92(s，3H)，4.75(s，2H)，6.76(d，1H)，6.85-6.94(m，2H)，6.85-6.94(m，2H)，6.99(d，1H)，7.07-7.15(m，3H)，7.15-7.24(m，3H)，7.37(dd，1H)，11.1(s，1H)。

LC-MS (method 3): r_t2.49 minutes; ms (esineg): 458[ M-H ] M/z]^-。

Example 321

3- [ (4-chlorophenyl) (4-fluorophenyl) methyl ] -5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared starting from 380 mg (0.92 mmol) of the compound from example 291 in analogy to the synthesis of the compound from example 312. 364 mg (89% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.92(s，3H)，4.77(s，2H)，5.73(s，1H)，6.87(dd，1H)，6.91(s，1H)，7.01(dd，1H)，7.14(t，2H)，7.21-7.28(m，4H)，7.37(d，2H)，11.2(s，1H)。

LC-MS (method 5): r_t2.78 minutes; ms (esineg): m/z 444[ M-H ]]^-。

The enantiomers were purified by preparative HPLC on chiral phase [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x20 mm; eluent: isohexane/ethanol 8: 2; flow rate: 20 ml/min; temperature: 24 ℃; UV detection: 230 nm ] separation. The separated enantiomers were again purified by preparative HPLC on the achiral phase (mobile phase: acetonitrile/water gradient):

enantiomer 321-1:

R_t7.14 min [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/ethanol 1: 1; flow rate: 1 ml/min; temperature: 24 ℃; UV detection: 230 nm]；

Yield: 107 mg.

Enantiomer 321-2:

R_tafter 7.66 minutes [ column: daicel Chiralpak AD-H, 5 microns, 250 mm x4 mm; eluent: isohexane/ethanol 1: 1; flow rate: 1 ml/min; temperature: 24 ℃; UV detection: 230 nm]。

Yield: 110 mg.

Example 322

5-fluoro-3- [ (4-fluoro-2-methylphenyl) (4-fluorophenyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared starting from 310 mg (0.75 mmol) of the compound from example 292 in analogy to the synthesis of the compound from example 312. 269 mg (81% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.26(s，3H)，2.93(s，3H)，4.77(s，2H)，5.79(s，1H)，6.74(s，1H)，6.81-6.95(m，3H)，7.01(dd，1H)，7.06(dd，1H)，7.10-7.21(m，4H)，11.2(s，1H)。

LC-MS (method 3): r_t2.42 minutes; ms (esineg): m/z 442[ M-H ]]^-。

Example 323

3- [ (4-chloro-2-methylphenyl) (4-fluorophenyl) methyl ] -5-fluoro-7- [ (methylsulfonyl) methyl ] -1H-indole

The title compound was prepared starting from 440 mg (1.03 mmol) of the compound from example 293 in analogy to the synthesis of the compound from example 312. 400 mg (85% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.25(s，3H)，2.93(s，3H)，4.78(s，2H)，5.79(s，1H)，6.75(d，1H)，6.83(d，1H)，6.87(dd，1H)，7.01(dd，1H)，7.10-7.21(m，5H)，7.28(d，1H)，11.2(s，1H)。

LC-MS (method 3): r_t2.54 minutes; ms (esineg): 458[ M-H ] M/z]^-。

Example 324

3- { (2, 2-Difluorocyclopropyl) [4- (trifluoromethyl) phenyl ] methyl } -7- [ (methylsulfonyl) methyl ] -1H-indole

2.05 g (9.27 mmol) of indium (III) chloride are added under argon and reflux to 2.50 g (8.50 mmol) of the compound from example 192A and 1.62 g (7.72 mmol) of the compound from example 86A in 31 ml of 1, 2-dichloroethane and the mixture is heated under reflux for 2.5 hours. An additional 2.00 g (9.04 mmol) of indium (III) chloride are added and the mixture is heated under reflux for a further 2 hours. After this time ethyl acetate and saturated aqueous sodium bicarbonate solution were added, the phases were separated, the organic phase was dried and concentrated. The residue was purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 1/1) and by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to give 13.0 mg (0.3% of theory) of the title compound as a mixture of diastereomers.

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.2(s，1H)，7.62-7.69(m，2.6H)，7.49-7.60(m，2.4H)，7.29(d，0.7H)，7.26(d，0.3H)，7.11(d，1H)，6.92(t，0.3H)，6.91(t，0.7H)，4.68-4.78(m，2H)，4.09(d，0.7H)，4.06(d，0.3H)，2.89(s，3H)，2.60-2.74(m，1H)，1.70-1.81(m，0.7H)，1.59-1.69(m，0.3H)，1.30-1.47(m，1H)。

LC-MS (method 9): r_t1.19 minutes; ms (esineg): m/z 442[ M-H ]]^-。

Example 325

3- [ (2, 4-dichlorophenyl) (2, 2-difluorocyclopropyl) methyl ] -7- [ (methylsulfonyl) methyl ] -1H-indole

1.64 g (7.39 mmol) of indium (III) chloride are added under argon and reflux to 2.00 g (6.78 mmol) of the compound from example 193A and 1.29 g (6.16 mmol) of the compound from example 86A in 20 ml of 1, 2-dichloroethane and the mixture is heated under reflux for 1.5 h. After this time ethyl acetate and saturated aqueous sodium bicarbonate solution were added, the phases were separated, the organic phase was dried and concentrated. The residue was purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 2/1 and 1/1) and by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to give 28.0 mg (1% of theory) of diastereomer 1 and 28.0 mg (1% of theory) of diastereomer 2 of the title compound.

Diastereomer 325-1:

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.2(s，1H)，7.62(d，1H)，7.58(d，1H)，7.37-7.43(m，2H)，7.25(d，1H)，7.13(d，1H)，6.96(t，1H)，4.68-4.78(m，2H)，4.42(d，1H)，2.89(s，3H)，2.63-2.76(m，1H)，1.62-1.73(m，1H)，1.21-1.31(m，1H)。

LC-MS (method 9): r_t1.23 minutes; ms (esipos): 444[ M + H ] M/z]⁺。

The enantiomers were purified by preparative HPLC on chiral phase [ column: daicel Chiralpak AS-H, 5 microns, 250 mm x20 mm; eluent: isohexane/isopropanol 1: 1; flow rate: 20 ml/min; temperature: RT; UV detection: 230 nm ] separation. 7.0 mg of enantiomer 325-1-1 and 7.0 mg of enantiomer 325-1-2 were obtained.

Enantiomer 325-1-1:

R_t7.58 min [ column: daicel Chiralpak AS, 10 microns, 250 mm x4.6 mm; eluent: isohexane/isopropanol 1: 1; flow rate: 1 ml/min; temperature: RT; UV detection: 230 nm]。

Enantiomer 325-1-2:

R_t9.55 min [ column: daicel Chiralpak AS, 10 microns, 250 mm x4.6 mm; eluent: isohexane/isopropanol 1: 1; flow rate: 1 ml/min; temperature: RT; UV detection: 230 nm]。

Diastereomer 325-2:

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.2(s，1H)，7.64(d，1H)，7.58(d，1H)，7.47(d，1H)，7.37-7.43(m，2H)，7.11(d，1H)，6.96(t，1H)，4.67-4.76(m，2H)，4.37(d，1H)，2.88(s，3H)，2.65-2.80(m，1H)，1.73-1.84(m，1H)，1.42-1.52(m，1H)。

LC-MS (method 9): r_t1.23 minutes; ms (esipos): m/z 442[ M-H ]]^-。

B. Evaluation of pharmacological Activity

Abbreviations:

DMEM Darber's modified eagle's medium

DNA deoxyribonucleic acid

FCS fetal calf serum

HEPES 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid

PCR polymerase chain reaction

Tris Tris (hydroxymethyl) methylamine

The advantageous pharmacological properties of the compounds of the invention can be shown in the following tests:

1. in vitro cell assay to determine inhibition of MR activity and MR selectivity compared to other steroid hormone receptors

The identification of antagonists of the human Mineralocorticoid Receptor (MR) and the quantification of the activity of the compounds described herein is carried out with the aid of recombinant cell lines. The cells were originally derived from Hamster Ovary epithelial cells (Chinese Hamster Ovary, CHO K1, ATCC: American Type culture Collection, VA 20108, USA).

A well-established chimera system in which the ligand-binding domain of the human steroid hormone receptor is fused to the DNA-binding domain of the yeast transcription factor GAL4 was used in this CHO K1 cell line. The GAL 4-steroid hormone receptor chimera thus produced was co-transfected into CHO cells with a reporter construct and stably expressed.

Cloning:

to generate the GAL 4-steroid hormone receptor chimera, the PCR-amplified ligand-binding domains of GAL 4-DNA-binding domain (amino acids 1-147) from vector (Vektor) pFC2-dbd (from Stratagene) with the mineralocorticoid receptor (MR, amino acids 734 and 985), the progestogen receptor (PR, amino acids 680 and 933) and the androgen receptor (AR, amino acids 667 and 919) were cloned into vector pIRES2 (from Clontech). A reporter construct comprising five copies of the GAL4 binding site upstream of the thymidine kinase promoter such that luciferase (Photinus pyralis) is expressed following activation and binding of the GAL 4-steroid hormone receptor chimera by the respective specific agonists aldosterone (MR), dexamethasone (GR), Progestin (PR) and dihydrotestosterone (AR).

Test procedure:

one day prior to the assay, MR, PR and AR cells were plated (autoslattieren) in media (Optimem, 2.5% FCS, 2mM glutamine, 10mM HEPES) in 96- (or 384-or 1536-) well microtiter plates and maintained in a cell incubator (96% humidity, 5% v/v carbon dioxide, 37 ℃). On the day of the assay, the substance to be tested is contained in the above-mentioned medium and the cells are added. About 10-30 minutes after the addition of the test substance, the respective specific agonist of the steroid hormone receptor is added. After further incubation for a period of 5 to 6 hours, luciferase activity was measured by means of a camera. The measured relative light units yield a sigmoidal stimulation curve as a function of substance concentration. Computing IC with the aid of GraphPad PRISM computer program (version 3.02) ₅₀The value is obtained.

Table A shows the IC's of representative exemplary compounds₅₀Value (MR):

TABLE A

2. In vivo assays for detecting cardiovascular effects: diuresis study in awake rats in metabolic test cages

Wistar rats (weighing 250-. Approximately 72 hours before the start of the test, the animals no longer received the normal feed, but exclusively a feed with a salt reduction of 0.02% sodium chloride content (ssniff R/M-H, 10mm, 0.02% Na, S0602-E081, ssniff)GmbH, D-59494 Soest). During the test period, the animals were housed individually in metabolic test cages (from Techniplast, Germany GmbH, D-82383 Hohenpei. beta. enberg) suitable for this weight class of rats, with free access to the salt-reduced feed and drinking water for about 24 hours. At the start of the test, the substance to be tested is administered to the stomach of the animal by gavage in a volume of 0.5 ml/kg body weight of the appropriate solvent. Control animals received solvent only. The control and substance tests were performed in parallel on the same day. The control group and the substance-dose group each consisted of 6 to 8 animals. During the test, urine excreted by the animals was collected continuously in a receiving container on the bottom of the cage. Urine volume per unit time was determined for each animal individually, by means of a standard flame The concentration of sodium and potassium ions excreted in urine is measured photometrically. From this measurement, the sodium/potassium ratio was calculated as a measure of the effect of the substance. The measurement interval is typically up to 8 hours after the start of the test (day interval) and 8 to 24 hours after the start of the test (night interval). In a modified test design, urine was collected and measured at 2 hour intervals during the daytime interval. To obtain sufficient urine volume for this purpose, the animals received a defined amount of water by gavage at the beginning of the test and then at 2 hour intervals.

DOCA/salt model

Administration of deoxycorticosterone acetate (DOCA) with a high-salt diet and unilateral renal ablation in rats induced hypertension, characterized by relatively low renin levels. As a result of this endocrine hypertension (DOCA is the direct precursor of aldosterone), depending on the DOCA concentration chosen, there is cardiac hypertrophy and further end organ damage, e.g. of the kidney, which is characterized inter alia by proteinuria and glomerulosclerosis. The presence of anti-hypertrophy and end organ protection effects of the test substance in this rat model can thus be investigated.

Male Sprague-Dawley (SD) rats at approximately 8 weeks of age (body weight between 250-300 g) underwent left mononephrectomy. For this purpose, the rats used 66% N ₂O and 33% of O₂The mixture of (1.5-2%) was anesthetized with isoflurane and the kidneys were removed by lateral resection. So-called sham operated animals, in which the kidneys were not removed, were used as subsequent control animals.

SD rats after unilateral nephrectomy received 1% sodium chloride in drinking water and were injected subcutaneously with deoxycorticosterone acetate (dissolved in sesame oil; from Sigma) every other week between shoulder blades (bolus: 100 mg/kg/week s.c.; normal dose: 30 mg/kg/week s.c.).

The substances whose in vivo protective effect is to be investigated are administered by gavage or via feed (from Ssniff). The day before the test began, animals were randomized and assigned to groups with the same number of animals, typically n-10. Animals had access to drinking water and feed ad libitum throughout the test period. The substance is administered via feed or by gavage once a day for 4-8 weeks. Animals that served as placebo groups were treated in the same manner, but received only solvent or no test substance feed.

The effect of the test substance was determined as follows: measuring hemodynamic parameters [ blood pressure, heart rate, change in muscular contraction force (dp/dt), relaxation time (τ), maximum left ventricular pressure, left ventricular end-diastolic pressure (LVEDP) ], determining the weight of heart, kidney and lung, measuring protein excretion, and measuring gene expression of biomarkers (e.g., ANP, atrial natriuretic peptides, and BNP, brain natriuretic peptides) by RT/TaqMan-PCR after isolation of RNA from heart tissue.

Statistical analysis was performed after previously checking for differences in homogeneity using the Student's t-test.

4. In vivo assay for the detection of antimineralocorticoid activity in conscious dogs

The main objective of the experiment was to study the effect of test compounds with anti-mineralocorticoid receptor activity on aldosterone-induced sodium retention. The procedure for this is similar to the published method: rosenthale, m.e., Schneider f., Kassarich, J. & Datko, L. (1965): determination of antisense activity in normal logs, Proc. Soc. Exp. biol. Med. 118, 806-.

Male or female Beagle dogs (Beagle) weighing between 8-20 kg received a standard diet and had free access to drinking water. On the day of the experiment, dogs were fasted. With propofol (4-6 mg/kg intravenous; propofol 1%)Germany) to obtain an aliquot of urine (as initial value on day 1) through the bladder catheter.

On day 2, all dogs received 0.3 mg of Astonin, a metabolically stable aldosterone derivative (Astonin H, Merck, germany) at approximately 16 hours.

The next morning (day 3), the test substance was orally administered to the dogs in gelatin capsules. After 5 hours, blood was taken from the dog to determine the plasma concentration of the substance. Subsequently, the anaesthesia is again brief and urine is obtained through the bladder catheter.

Treatment with the test substance resulted in an increase in the sodium-potassium ratio in the urine after 5 hours (sodium and potassium determination by flame photometry). Spironolactone, which also dose-independently increases the sodium/potassium ratio in urine, serves as a positive control, and treatment with empty capsules serves as a negative control.

Evaluation was performed by comparing the sodium/potassium ratio in urine between days 1 and 3. Alternatively, the sodium/potassium ratio can also be compared between placebo and the substance on day 3.

5. Model of chronic myocardial infarction in conscious rats

Male Wistar rats (280-300 g body weight; Harlan-Winkelmann) were anesthetized with 5% isoflurane in an anesthesia cage, cannulated, connected to a ventilation pump (ugo basile 7025 rodent, 50 strokes/min, 7 ml) and treated with 2% isoflurane/N₂O/O₂And (6) ventilating. Body temperature was maintained at 37-38 ℃ by a heating pad. 0.05 mg/kg buprenorphine was administered subcutaneously as an analgesic. The chest cavity is opened laterally between the third and fourth ribs, exposing the heart. The left ventricular coronary artery (LAD) was permanently ligated with a line of occlusion (Prolene 1 metric5-0 Ethicon1H) passing slightly below its origin (below the left atrium). The occurrence of myocardial infarction was monitored by EKG measurements (Cardioline, Remco, italy). The chest was re-closed and the muscle layers were sutured with Ethibond excel 1m etric 5/06951H and the epidermis was sutured with Ethibond excel 3/06558H. Surgical sutures are wetted with a spray dressing (e.g. by Spray dressing, active ingredient: neomycin sulfate), and then the anesthesia is terminated.

One week after LAD occlusion, the size of the myocardial infarction was assessed by echocardiography (Sequoia 512, Acuson). Animals were randomized and divided into treatment groups alone and control groups without substance treatment. A "sham" group in which only surgical procedures were performed but no LAD occlusion was included as a further control.

Substance treatment was performed within 8 weeks by gavage or by adding test compounds to the feed or drinking water. Animals were weighed weekly and water and feed consumption was determined every 14 days.

After 8 weeks of treatment, the animals were again anesthetized (2% isoflurane/N)₂O/air), and a pressure catheter (milliar SPR-3202F) was inserted into the left ventricle via the carotid artery. There heart rate, Left Ventricular Pressure (LVP), left ventricular end-diastolic pressure (LVEDP), contractility (dp/dt and relaxation rate (τ) are measured and recorded and evaluated by means of Powerlab system (AD Instruments, ADI-PWLB-4SP) and Chart 5 software (SN 425-0586).

6. Rat model of stroke-prone spontaneous hypertension

Administration of sodium chloride to so-called stroke-prone spontaneously hypertensive rats (SP-SHR) resulted in the abrogation of the inhibition of physiological salt-induced renin and angiotensin release after several days in this model, in reverse. Thus, hypertension in SP-SHR animals is characterized by relatively high renin levels. Due to the progressive hypertension, there is significant end-organ damage to the heart and kidneys, characterized inter alia by proteinuria and glomerulosclerosis, and by general vascular changes. Thus, especially stroke can develop predominantly through cerebrovascular injury ("stroke-prone"), which results in high mortality in untreated animals. The blood pressure reduction and the protective effect of the terminal organ of the test substance in this rat model can thus be investigated.

One day before the start of the test, male SP-SH rats (weighing between 190 and 220 grams) aged about 10 weeks were randomized and assigned to groups with the same number of animals, typically n-12-14. Throughout the test period, animals had free access to drinking water and feed containing sodium chloride (2% NaCl). The substance is administered once a day for 6-8 weeks by gavage or with feed (Ssniff, Germany). Animals treated in the same manner, but receiving only solvent or no feed of the test substance served as placebo. In the context of the mortality study, the test was terminated when about 50% of the placebo-treated animals had died.

The effect of the test substance was tested by measuring systolic pressure (via the tail cuff) and protein excretion in the urine. Post-mortem determinations of heart, kidney and lung weights were performed, and histopathological analysis of the heart, kidney and brain was performed by semi-quantitative scoring of tissue changes. Various biomarkers (e.g., ANP, atrial natriuretic peptide, and BNP, brain natriuretic peptide, KIM-1, kidney-induced molecule 1, osteopontin-1) were determined by RT/TaqMan-PCR after RNA isolation from cardiac and renal tissue or serum or plasma.

CYP inhibition assay

The inhibitory properties of active ingredients on human cytochrome P450(CYP) may require extensive clinical efficacy (drug interactions) verification, as most prescribed drugs are degraded (metabolized) by these enzymes. Those involved here are in particular the CYP isozymes of the 1A and 2C families, CYP2D6 and CYP3a4 with a proportion of almost 50%. To exclude or minimize these potential Drug Interactions (DDI), the ability of substances capable of inhibiting CYP1a2, CYP2C8, CYP2C9, CYP2D6 and CYP3a4 in humans was investigated using human liver microsomes (a population consisting of various individuals). This is done by measuring CYP isoform-specific metabolites formed by standard substrates such as phenacetin, amonoquine, diclofenac, dextromethorphan, midazolam, and testosterone. Six different concentrations of test compound (1.5, 3.1, 6.3, 12.5, 25 and 50 μ M as maximum concentration or 0.6, 1.3, 2.5, 5, 10 and 20 μ M as maximum concentration) were investigated, compared to the degree of CYP isoform-specific metabolite formation of standard substrates in the absence of test compound, and the corresponding IC was calculated₅₀The value is obtained. CYP isoform-specific standard inhibitors, such as fluvoxamine, quercetin, sulfaphenazole, fluoxetine and ketoconazole serve as controls for the results obtained. To obtain an indication of CYP3a4 based on inhibitors of possible Mechanisms (MBI), human liver microsomes were incubated for 30 minutes in the presence of the inhibitor to be investigated, followed by the addition of midazolam or testosterone as standard substrates for CYP3a 4. IC obtained compared to batches without preculture₅₀Serves as an indicator of mechanism-based suppression. Mibefradil served as a positive control.

The procedure is as follows:

the incubation of standard substrates and human liver microsomes (23-233 μ g/ml) in the presence of test compounds (as potent inhibitors) was performed in 96-well plates at 37 ℃ in a workstation (Tecan, Genesis, Crailsheim, germany). The incubation time is 15-20 minutes. The test compounds are preferably dissolved in acetonitrile (1.0 or 2.5mM stock). The 96-well plate was produced by sequentially adding stock solutions of NADP +, EDTA, glucose-6-phosphate, and glucose-6-phosphate dehydrogenase in a phosphate buffer (pH7.4), a test compound, and a solution of a standard substrate and human liver microsomes in a phosphate buffer (pH 7.4). The total volume was 200. mu.l. Corresponding control cultures with and without standard inhibitors were also performed on 96-well plates. The incubation was stopped after the respective incubation time by adding 100 μ l of acetonitrile in which the appropriate internal standard was present. Precipitated proteins were removed by centrifugation (3000rpm, 10 min, 10 ℃). The resulting supernatants from each plate were combined on one plate and analyzed by LC-MS/MS. IC (integrated circuit) ₅₀Values were generated from the resulting measurements and used to evaluate the inhibitory potential of the test compounds.

TABLE B

8. Test for evaluating irreversible CYP3A4 inhibition

Cytochrom P450 enzyme inhibition, particularly irreversible enzyme inhibition, also known as mechanism-based inhibition (MBI), is an undesirable metabolic property of a substance that may result in significant drug interactions when other drugs are administered concurrently. Criteria for the presence of irreversible inhibition are time, concentration and cofactor (nicotinamide adenine dinucleotide phosphate, NADPH) -dependent inhibition. To this end, the compounds according to the invention were cultured in vitro and in human liver microsomes, the effect on CYP3A4 activity and the metabolic breakdown of the novel active ingredient were determined, and the prototype parameter k thus determined_inact、K_iAnd a distribution ratio r.

The procedure is as follows:

the compounds of the invention were cultured at a concentration of 2-20. mu.M. For this purpose, stock solutions of the active ingredient at concentrations of 0.2 to 2mM are prepared in acetonitrile and then diluted 1: 100 into the culture mixture with a pipette. Liver microsomes were cultured in 50mM potassium phosphate buffer (pH7.4) at 37 ℃ with and without an NADPH-producing system consisting of: 1mM NADP⁺5mM glucose-6-phosphate and 1 unit of glucose-6-phosphate dehydrogenase. After a defined pre-incubation time of 0-50 minutes, aliquots were removed from these batches, diluted 1: 25 in new medium, and incubated again for 20 minutes in the presence of testosterone and a new NADPH-producing system. These culture batches were terminated with acetonitrile (final concentration of about 30% v/v) and the protein was removed by centrifugation at about 15000 Xg. The samples thus terminated were either analyzed directly or stored at-20 ℃ until analyzed.

Analysis was performed by high performance liquid chromatography with mass spectrometry detection (LC-MS). The formation of 6 β -epididymidone was taken as a measure of CYP3a4 activity and the test substance still remaining was quantitatively measured. From this, the parameter k is determined_inact、K_iAnd assigning a ratio r to evaluate the novel active ingredient relative to MBIAnd (4) dividing.

Watch C

Example numbering	Distribution ratio r
		56-1	100
59-1	220
		73	＞500
107	＞400
		113	＞500
118-1	250
		147	90
Example numbering	Distribution ratio r
		169	＞500
172	120
		261-1	＞200
266-1	＞200
		271-1-1	＞200
273-1-2	＞200
		277-1-1	＞200

C. Working examples of pharmaceutical compositions

The compounds of the invention can be converted into pharmaceutical preparations in the following manner:

and (3) tablet preparation:

consists of the following components:

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

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

Production:

the compound of the invention, a mixture of lactose and starch, is granulated with a 5% strength solution (m/m) of PVP in water. After drying the granules were mixed with magnesium stearate for 5 minutes. The mixture is compressed using a conventional tablet press (see above for tablet forms). The guiding pressure for pressing was 15 kN.

Suspensions that can be administered orally:

consists of the following components:

1000 mg of a compound of the invention, 1000 mg of ethanol (96%), 400 mg of (Xanthan gum, from FMC, Pennsylvania, USA) and 99 grams of water.

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

Production:

rhodigel was suspended in ethanol and the compounds of the invention were added to the suspension. Water was added while stirring. The mixture was stirred for about 6 hours until swelling of the Rhodigel was complete.

Solutions that can be administered orally:

consists of the following components:

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

Production:

the compounds of the invention are suspended in a mixture of polyethylene glycol and polysorbate under stirring. The stirring process is continued until the compound according to the invention has completely dissolved.

Intravenous solution:

the compounds of the invention are dissolved at concentrations below the saturation solubility of physiologically tolerable solvents (e.g. isotonic saline solution, 5% glucose solution and/or 30% PEG 400 solution). The solution was sterile filtered and used to fill sterile and pyrogen-free injection containers.

Claims

1. A compound of formula (I)

Wherein

A is-S-, -S (═ O) -or-S (═ O)₂-，

R¹Is (C)₁-C₄) -an alkyl group or a cyclopropyl group,

R²is hydrogen, fluorine or chlorine,

R³is hydrogen, fluorine, chlorine or methyl,

R⁴is hydrogen or fluorine, and is selected from the group consisting of,

R⁵is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

d is-CH₂-、-O-、-CH₂-CH₂-or-CH₂-O-，

R⁶Is (C)₁-C₄) -alkyl or (C)₃-C₆) -a cycloalkyl group,

and

R⁸is hydrogen, halogen, methyl or trifluoromethyl,

R⁹is phenyl, naphthyl or 5-to 10-membered heteroaryl,

wherein phenyl, naphthyl and 5-to 10-membered heteroaryl can be substituted with 1 to 3 substituents independently from each other selected from the group consisting of: halogen, cyano, (C)₁-C₄) -alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, (C)₁-C₄) -alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy and trifluoromethylthio,

or

Wherein two substituents bound to adjacent carbon atoms of the phenyl ring together form a group of the formula: -O-CH ₂-O-、-O-CHF-O-、-O-CF₂-O-、-O-CH₂-CH₂-O-or-O-CF₂-CF₂-O-，

and

R¹¹is hydrogen, methyl, ethyl, trifluoromethyl or cyclopropyl,

and salts, solvates and solvates of salts thereof.

2. A compound of formula (I) as claimed in claim 1 wherein

A is-S (═ O) -or-S (═ O)₂-，

R¹Is a methyl group or an ethyl group,

R²is hydrogen or fluorine, and is selected from the group consisting of,

R³is hydrogen or fluorine, and is selected from the group consisting of,

R⁴is a hydrogen atom, and is,

R⁵is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

R⁹is phenyl, naphthyl or benzothienyl,

Or

And

R¹¹is a hydrogen atom, and is,

and salts, solvates and solvates of salts thereof.

3. A compound of formula (I) as claimed in claim 1 wherein

A is-S (═ O) -or-S (═ O)₂-，

R¹Is a methyl group or an ethyl group,

R²is hydrogen or fluorine, and is selected from the group consisting of,

R³is hydrogen or fluorine, and is selected from the group consisting of,

R⁴is a hydrogen atom, and is,

R⁵is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

d is-CH₂-or-CH₂-O，

R⁶Is (C)₁-C₄) -alkyl or (C)₃-C₆) -a cycloalkyl group,

and

R⁷is hydrogen, fluorine, chlorine, methyl or trifluoromethyl,

R⁸is hydrogen, fluorine, chlorine, methyl or trifluoromethyl,

R⁹is phenyl, naphthyl or benzothienyl,

or

and

R¹¹is a methyl group or an ethyl group,

and salts, solvates and solvates of salts thereof.

4. A compound of formula (I) as claimed in claim 1 or 3 wherein

A is-S (═ O)₂-，

R¹Is a methyl group, and the compound is,

R²is hydrogen or fluorine, and is selected from the group consisting of,

R³is hydrogen or fluorine, and is selected from the group consisting of,

R⁴is a hydrogen atom, and is,

R⁵is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

R⁹is a radical of the formula

Wherein

Is connected to-CR¹⁰R¹¹The point (c) of (a) is,

R¹²are fluorine, chlorine, methyl and trifluoromethyl,

R¹³is hydrogen, fluorine or chlorine,

R¹⁴is hydrogen, fluorine or chlorine,

R¹⁵is hydrogen, fluorine or chlorine,

R¹⁰is a cyclopropyl group, and the compound is a cyclopropyl group,

and

wherein the cyclopropyl group can be substituted with a cyano substituent,

R¹¹is a methyl group, and the compound is,

and salts, solvates and solvates of salts thereof.

5. A compound of formula (I) as claimed in claim 1 or 3 wherein

A is-S (═ O)₂-，

R¹Is a methyl group or an ethyl group,

R²is hydrogen or fluorine, and is selected from the group consisting of,

R³is hydrogen or fluorine, and is selected from the group consisting of,

R⁴is a hydrogen atom, and is,

R⁵Is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

d is-CH₂-，

R⁶Is a methyl group, an ethyl group or a cyclopropyl group,

R⁷is hydrogen, fluorine, chlorine or methyl,

R⁸is hydrogen, fluorine or chlorine,

and salts, solvates and solvates of salts thereof.

6. A compound of formula (I) as claimed in claim 1 or 3 wherein

A is-S (═ O)₂-，

R¹Is a methyl group, and the compound is,

R²is hydrogen or fluorine, and is selected from the group consisting of,

R³is hydrogen or fluorine, and is selected from the group consisting of,

R⁴is a hydrogen atom, and is,

R⁵is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

R⁹is a radical of the formula

Wherein

Is connected to-CR¹⁰R¹¹The point (c) of (a) is,

R¹²are fluorine, chlorine, methyl and trifluoromethyl,

R¹³is hydrogen, fluorine or chlorine,

R¹⁴is hydrogen, fluorine or chlorine,

R¹⁵is hydrogen, fluorine or chlorine,

R¹⁰is 1-cyanoeth-2-yl, 1-cyano-2-methylethyl-2-yl or 1-cyanoprop-3-yl,

R¹¹is a methyl group or an ethyl group,

and salts, solvates and solvates of salts thereof.

7. A compound of formula (I) as claimed in claim 1 or 2 wherein

A is-S (═ O)₂-，

R¹Is a methyl group, and the compound is,

R²is hydrogen or fluorine, and is selected from the group consisting of,

R³is hydrogen or fluorine, and is selected from the group consisting of,

R⁴is a hydrogen atom, and is,

R⁵is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

R⁹is a radical of the formula

Wherein

Is connected to-CR¹⁰R¹¹The point (c) of (a) is,

R¹²are fluorine, chlorine, methyl and trifluoromethyl,

R¹³Is hydrogen, fluorine or chlorine,

R¹⁴is hydrogen, fluorine or chlorine,

R¹⁵is hydrogen, fluorine or chlorine,

R¹⁰is a radical of the formula

Wherein

Is linked to-CR⁹R¹¹The point (c) of (a) is,

R¹⁶is a fluorine or chlorine compound, and is,

R¹¹is a hydrogen atom, and is,

and salts, solvates and solvates of salts thereof.

8. A compound of formula (I) as claimed in claim 1 or 2 wherein

A is-S (═ O)₂-，

R¹Is a methyl group, and the compound is,

R²is hydrogen or fluorine, and is selected from the group consisting of,

R³is hydrogen or fluorine, and is selected from the group consisting of,

R⁴is a hydrogen atom, and is,

R⁵is of the formulaRadical (I)

Wherein

# is the point of attachment to the indole,

and

R⁹is a phenyl group or a benzothienyl group,

R¹⁰is 1-cyanoeth-2-yl, 1-cyano-2-methylethyl-2-yl or 1-cyanoprop-3-yl,

R¹¹is a hydrogen atom, and is,

and salts, solvates and solvates of salts thereof.

9. A compound of formula (I) as claimed in claim 1 or 2 wherein

A is-S (═ O)₂-，

R¹Is a methyl group, and the compound is,

R²is hydrogen or fluorine, and is selected from the group consisting of,

R³is hydrogen or fluorine, and is selected from the group consisting of,

R⁴is a hydrogen atom, and is,

R⁵is a radical of the formula

Wherein

# is the point of attachment to the indole,

and

R⁹is a radical of the formula

Wherein

Is connected to-CR¹⁰R¹¹The point (c) of (a) is,

R¹²are fluorine, chlorine, methyl and trifluoromethyl,

R¹³is hydrogen, fluorine or chlorine,

R¹⁴Is hydrogen, fluorine or chlorine,

R¹⁵is hydrogen, fluorine or chlorine,

R¹⁰is a cyclopropyl group, and the compound is a cyclopropyl group,

wherein the cyclopropyl group can be substituted with a cyano substituent,

or

R¹¹is a hydrogen atom, and is,

and salts, solvates and solvates of salts thereof.

10. Process for the preparation of a compound of formula (I), characterized in that

[A] Indole derivatives of formula (I-1)

Wherein R is¹、R²、R³、R⁴And R⁵In each case having the meaning indicated in claims 1 to 9,

or

[B] Indole derivatives of formula (I-1)

or

[C] Indole derivatives of formula (II)

Wherein R is¹、R²、R³And R⁴In each case having the meaning indicated in claims 1 to 9,

Oxidation with a suitable oxidizing agent, preferably m-chloroperbenzoic acid, in an inert solvent to a compound of formula (II-2)

Wherein R is⁵Having the meaning indicated in claims 1 to 9,

to obtain a compound of formula (I-2),

or

[D] Indole derivatives of formula (II)

Wherein R is⁵Having the meaning indicated in claims 1 to 9,

to obtain a compound of formula (I-3),

and optionally separating the resulting compound of formula (I-2) or (I-3) into its enantiomers and/or diastereomers by methods known to those skilled in the art, and/or converting into a solvate of its solvate, salt and/or salt with a suitable (I) solvent and/or (ii) base or acid.

11. A compound as defined in any one of claims 1 to 9 for use in the treatment and/or prevention of a disease.

12. A compound of formula (I) as defined in any one of claims 1 to 9 for use in a method for the treatment and/or prevention of hyperaldosteronism, hypertension, acute and chronic heart failure, sequelae of myocardial infarction, cirrhosis of the liver, renal failure and stroke.

13. The use of a compound as defined in any one of claims 1 to 9 for the preparation of medicaments for the treatment and/or prophylaxis of aldosteronism, hypertension, acute and chronic heart failure, sequelae of myocardial infarction, cirrhosis of the liver, renal failure and stroke.

14. A medicament comprising a compound as defined in any one of claims 1 to 9, together with inert, non-toxic auxiliary agents suitable for pharmaceutical use.

15. Medicament comprising a compound as defined in any one of claims 1 to 9 and one or more further active ingredients selected from ACE inhibitors, renin inhibitors, angiotensin II receptor antagonists, β -blockers, acetylsalicylic acid, diuretics, calcium antagonists, statins, digitalis (digoxin) derivatives, vasopressin antagonists, adenosine a1 antagonists, calcium sensitizers, nitrates and antithrombotic agents.

16. The medicament according to claim 14 or 15 for the treatment and/or prophylaxis of aldosteronism, hypertension, acute and chronic heart failure, sequelae of myocardial infarction, cirrhosis of the liver, renal failure and stroke.

17. Method for the treatment and/or prophylaxis of aldosteronism, hypertension, acute and chronic heart failure, post-myocardial infarction, cirrhosis, renal failure and stroke in humans and animals, using an effective amount of at least one compound as defined in any of claims 1 to 9 or a medicament as defined in any of claims 14 to 16.