EP1268422A1 - Indoles for treating diseases that can be treated using thyroid hormones - Google Patents

Abstract

The invention relates to novel indole derivatives, to methods for the production thereof and to their use in medicaments.

Description

 INDOLE FOR TREATING DISEASES

THOSE WITH THYROID HORMONES

CAN BE TREATED

The invention relates to new indole derivatives, processes for their preparation and their use in pharmaceuticals.

EP-A-580 550 describes oxamic acid derivatives which have cholesterol-lowering properties in mammals. The reduction in plasma cholesterol, in particular LDL cholesterol, is emphasized as a pharmacological property. Cholesterol-lowering effects are also described in EP-A-188 351 for certain diphenyl ethers with thyroid hormone-like effects which clearly differ in chemical structure from the compounds according to the invention.

Indoles which are connected in the 5-position via a bridge member to a substituted phenyl ring are known (WO 94/14770; EP-A-674 619 AI or WO 94/26737). No thyroid hormone-like properties have been described for these 5 -substituted indoles.

WO 99/50268 discloses substituted indolalkane carboxylic acids which are suitable for the treatment of chronic complications caused by diabetes mellitus.

WO 95/20588 discloses indole derivatives which act as 5-HT _r agonists.

WO 98/11895 discloses the use of 5-HT-agonists for the treatment of

Migraine; Indole derivatives are also indicated as suitable active ingredients. WO 98/06402 describes the use of the same structures for the treatment of the common cold or rhinitis. EP-A-639 573 discloses benzo-fused 5-ring heterocycles and their use in medicines and diagnostics. The compounds disclosed are inhibitors of the cellular sodium proton antiporter.

US-A-5 468 899 relates to bicyclic aryl compounds with selective properties as LTB4 antagonists.

EP-A 377 450 discloses substituted indole, benzofuran and benzothiophene derivatives which act as 5-lipoxygenase inhibitors.

JP-A 07145 147 discloses testosterone-5-alpha-reductase inhibitors derived from benzoic acid, which can be used to treat prostate cancer and certain hair loss disorders.

GB-A-2 253 848 describes di-ortho-substituted phenyl-indole in the phenyl part

Described ethers with herbicidal activity, which can be used as crop protection agents. Thyromimetic effects have so far not been known for these ortho-substituted indoles.

The object of the invention is to provide new compounds with improved, in particular pharmaceutical, effects.

It has now been found that compounds of the general formula (I)

in which

represents O, S, CH ₂ , CHF or CF ₂ , R ¹ and R ^{2 are the} same or different and represent hydrogen, halogen, (C _j -Cg) alkyl, CF ₃ , CHF ₂ , CH ₂ F, vinyl or (C ₃ -C ₇ ) cycloalkyl, at least one is not equal to hydrogen for both substituents and is in the ortho position to the bridge bond,

R ³ for a head group with optionally derivatized carboxyl radical, preferably of the formula

A- (CH ₂ ) _n - (CO) _m -R8 _. wherein

A represents CH ₂ , O, S, CO or NR ⁹ , in which R ^{9 is} hydrogen, (C _r C ₆ ) alkyl or (C ₃ -Cg) cycloalkyl or for the group - (CH) _n - ( CO) _{m is} -O- (C _r C ₄ ) -alkyl,

n stands for a number from 0 to 3,

m represents 1 or 2,

R ⁸ for hydrogen, hydroxy, OR ¹⁰ , NR ^π R ¹² , (C _r C ₈ ) alkyl, (C ₃ -C ₈ ) -

Cycloalkyl, (C6-Cιo) aryl, or for a saturated, unsaturated or aromatic 5- to 10-membered heterocycle with up to four identical or different heteroatoms from the series S, O and / or N, the abovementioned radicals optionally by one, two or three identical or different substituents from the

Group halogen, hydroxy, cyano, nitro, amino, CF3, (Ci-Cg) alkyl, optionally substituted by R ²³ (C _r C6) alkoxy, (C ₃ -C ₈ ) cycloalkyl, -OCO-R ¹³ , -CO-OR ^, -CO-NR ¹⁵ R ¹⁶ , -NHCOR ¹⁷ or -NHCOOR ^{17 are} substituted, where R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ^{23 are the} same or different and each is hydrogen, phenyl, benzyl, (C _r C ₆ ) alkyl. (C _r C ₆ ) - Alkoxy or (C ₃ -Cg) cycloalkyl, which in turn are optionally mono- or polysubstituted by halogen, hydroxy, amino, (C1-C4) alkoxy, -CO-O (C ₁ -C ₄ ) alkyl, -NH- CO-O (C _r C ₄ ) -alkyl, -O-CO- (C _r C4) -alkyl, a heterocycle or phenyl which is optionally substituted by halogen or hydroxy,

R ⁴ and R ^{5 are the} same or different and each represents hydrogen, hydroxy, halogen, cyano, nitro, (-C-C4) alkyl, or the rest of the formula NR ¹⁸ R ¹⁹ , where R ¹⁸ and R ^{19 are} those for R ¹⁰ have the meaning given and can be identical or different with this substituent,

R ^{6 represents} halogen or has the meaning given for R ⁸ and is identical or different with this substituent or for the rest

stands in what

R ²⁰ and R ²¹ together with the carbon atom to which they are attached form a carbonyl group or are each the same or different and are hydrogen, halogen, hydroxy, (C _r C ₆ ) alkyl, (C _r C ₆ ) -

Alkoxy or the radical -NR ¹⁵ R ¹⁶ and

R ^{22 has} the meaning of R ⁸ and is the same or different with it,

R ^{7 represents} hydrogen or an acyl group, the physiological

Conditions can be split off to form an NH function, preferably represents hydrogen or acetyl,

and their salts, preferably the compounds which are mono-, in particular di-substituted in the phenyl part, and preferably substituted in the 2-, 4- and 6-position, and have a substituent in the 3-position in the indole ring

show a pharmacological effect and can be used as pharmaceuticals or for the production of pharmaceutical formulations.

The following may preferably be mentioned as heterocycles in the definition of R ⁸ or R ⁶ :

A 5- to 8-membered saturated, partially unsaturated or aromatic optionally benzo-fused heterocycle with up to 4 heteroatoms from the series S, N and / or O, i.e. a heterocycle which can contain one or more double bonds and which is linked via a ring carbon atom or a ring nitrogen atom. Examples include: tetrahydrofur-2-yl, tetrahydrofur-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolin-1-yl, piperidin-1-yl, piperididine 3-yl, 1,2-dihydropyridin-l-yl, 1,4-dihydropyridin-l-yl, piperazin-1-yl, morpholine-l-yl, azepin-1-yl, 1,4-diazepine l-yl, furan-yl, pyrrol-yl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyrimidinonyl, pyridazinonyl.

From this list, preferred are: pyridyl, pyrimidyl, pyridazinyl, pyrimidinonyl, pyridazinonyl and thiophenyl.

Derivatized carboxyl radicals in the definition of the substituent R ³ preferably mean groups which can be broken down in the sense of a prodrug to give the carboxylic acid or its salts, for example and preferably halides, anhydrides, esters and / or amides.

In the context of the invention, alkyl represents a straight-chain or branched alkyl radical having preferably 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 3 carbon atoms. A straight-chain or branched alkyl radical is preferred with 1 to 3 to carbon atoms. The following may be mentioned by way of example and preferably: methyl, ethyl, n-propyl, isopropyl, n-, i-, s- or t-butyl, n-pentyl and n-hexyl.

In the context of the invention, aryl stands for an aromatic radical having preferably 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

Cycloalkyl in the context of the invention represents a cycloalkyl group with preferably 3 to 8, 3 to 7 or 3 to 6 carbon atoms. Examples and preferably mentioned are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

In the context of the invention, alkoxy preferably represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. A straight-chain or branched alkoxy radical having 1 to 3 carbon atoms is preferred. Examples and preferably mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy.

Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Fluorine, chlorine or bromine are preferred.

Depending on the substitution pattern, the compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image diastereomers). The invention relates both to the enantiomers or diastereomers and to their respective mixtures. The racemic fora, like the diastereomers, can be separated into the stereoisomerically uniform constituents in a known manner.

Furthermore, certain compounds can exist in tautomeric forms. This is known to those skilled in the art and such compounds are also within the scope of the invention. The compounds according to the invention can also be present as salts. Physiologically acceptable salts are preferred in the context of the invention.

Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids. Salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carbon or sulfonic acids such as acetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, benzenesulfon are preferred onic acid, toluenesulfonic acid or

Naphthalenedisulfonic acid.

Physiologically acceptable salts can also be salts of the compounds according to the invention with bases, such as, for example, metal or ammonium salts. Preferred examples are alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example magnesium or calcium salts), and also ammonium salts which are derived from ammonia or organic amines, such as, for example, ethylamine, di- or triethylamine, ethyldiisopropylamine, monoethanolamine, di- or Triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine, methylpiperidine, arginine, lysine,

Ethylenediamine or 2-phenylethylamine.

The compounds according to the invention can also be present in the form of their solvates, in particular in the form of their hydrates.

Compounds of the general formula (I) are preferred

in which

represents O, CH ₂ or CF ₂ , R ¹ and R ^{2 are the} same or different and represent hydrogen, fluorine, chlorine, bromine,

(C _r C ₄ ) alkyl, CF ₃ , CHF ₂ , CH ₂ F, vinyl or (C ₃ -C ₆ ) cycloalkyl, where at least one of the two substituents is not equal to hydrogen and is ortho to the bridge bond, in particular both substituents are not hydrogen and both are in the ortho position,

R ³ for a head group with optionally derivatized carboxyl radical, preferably for a group of the formula

A- (CH ₂ ) _n - (CO) _m -R ⁸ , is in the para position to the bridge bond,

embedded image in which

A represents CH ₂ ,

n represents 0 or 1,

m represents 1 or 2,

R ⁸ for hydrogen, hydroxy, OR ¹⁰ , NR ⁿ R ¹² , (C _r C ₆ ) - alkyl, (C ₃ -C ₈ ) -

Cycloalkyl, (C6-Cιo) aryl, or for a saturated, unsaturated or aromatic Cs-Cjo-membered heterocycle with up to four identical or different heteroatoms from the series S, O and / or N, the abovementioned hydrocarbon radicals and heterocycles optionally by one, two or three identical or different substituents from the group halogen, hydroxy, cyano, nitro, amino, CF ₃ , (C _r C ₄ ) - alkyl, (C _r C ₄ ) - alkoxy, (C ₃ - C ₈ ) - Cycloalkyl, O-CO-R ¹³ , -CO-OR ¹⁴ , -CO-NR ¹⁵ R ¹⁶ or -NHCOOR ^{17 are} substituted, where RIO, Rll, Rl, Rl, RI ^4th Rl5, Rl6 _and R17 are the same or different and each represents hydrogen, benzyl, (- C ₄ ) -alkyl or (C -C ₆ ) -cycloalkyl, which in turn are optionally substituted by amino or (C ₁ -C ₄ ) -alkoxy,

R ⁴ and R ^{5 are the} same or different and each represents hydrogen, halogen or (C _r C ₄ ) -alkyl,

R ^{6 has} the meaning given for R ⁸ and is the same or different with the above substituent or for the rest

stands, in which

R ²⁰ and R ²¹ together represent oxygen, or are each identical or different and represent hydrogen, halogen, hydroxy, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy or the radical -NR ¹⁵ R ¹⁶ stand and

R ^{22 has} the meaning of R ⁸ and is the same or different with it,

R ^{7 represents} hydrogen,

and their salts.

Compounds of the general formula (I) are preferred

in which

Z represents O, CH ₂ or CF ₂ ,

R ¹ and R ^{2 are the} same or different and represent hydrogen, fluorine, chlorine, bromine, (C _r C ₄ ) alkyl, CF ₃ , CHF ₂ , CH ₂ F, vinyl or (C ₃ -C ₆ ) cycloalkyl . where at least one of the two substituents is not hydrogen and is in the ortho position to the bridge bond, in particular both substituents are not hydrogen and both are in the ortho position,

for a head group with optionally derivatized carboxyl radical, preferably for a group of the formula

A- (CH ₂ ) _n - (CO) _m -R ⁸ , is in the para position to the bridge bond,

wherein

A stands for O,

n represents 0 or 1,

m represents 1 or 2,

R ⁸ for hydrogen, hydroxy, OR ¹⁰ , NR ^U R ¹² , (C _r C ₆ ) alkyl, (C ₃ -C ₈ cycloalkyl, (Cg-Cιo) aryl, or for a saturated, unsaturated or aromatic Cs- Cio-membered heterocycle having up to four identical or different heteroatoms from the series S, O and / or N, the abovementioned hydrocarbon radicals and heterocycles optionally being substituted by one, two or three identical or different substituents from the group halogen, hydroxy, cyano, Nitro, amino, CF ₃ , (C _r C ₄ ) alkyl, (C _r C ₄ ) alkoxy, (C ₃ -C ₈ ) -

Cycloalkyl, O-CO-R ¹³ , -CO-OR * ⁴ , -CO-NR ¹⁵ R ¹⁶ or -NHCOOR ^{17 are} substituted, where R ¹⁰ , RU, R * ² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ^{17 are the} same or different and each represents hydrogen, benzyl, (Cj-C) alkyl or (C ₃ -C ₆ ) cycloalkyl, which in turn may be by amino or (-C-C4) ~ Alko y are substituted, R ⁴ and R ^{5 are the} same or different and each represents hydrogen, halogen or (C _r C ₄ alkyl,

R ^{6 has} the meaning given for R ⁸ and is the same or different with the above substituent or for the rest

stands, in which

R ²⁰ and R ² 1 together represent oxygen, or are each the same or different and are hydrogen, halogen, hydroxy, (-C-C ₄ ) - alkyl, (C _r C ₄ ) - alkoxy or the radical -NR ¹⁵ Rl ⁶ stand and

R ^{22 has} the meaning of R ⁸ and is the same or different with it,

R ^{7 represents} hydrogen,

and their salts.

Compounds of the general formula (I) are preferred

in which

Z represents O, CH ₂ or CF ₂ ,

Rl and R ^{2 are the} same or different and represent hydrogen, fluorine, chlorine, bromine,

(C _r C ₄ ) alkyl, CF ₃ , CHF ₂ , CH ₂ F, vinyl or (C ₃ -C ₆ ) cycloalkyl, where at least one of the two substituents is not equal to hydrogen and is ortho to the bridge bond, in particular both substituents are not hydrogen and both are in the ortho position, R ³ for a head group with optionally derivatized carboxyl radical, preferably for a group of the formula

A- (CH ₂ ) _n - (CO) _m -R ⁸ , is in the para position to the bridge bond,

wherein

A represents NR ⁹ , in which R ^{9 is} hydrogen, (C _r C ₄ ) alkyl or (C ₃ -C ₇ cycloalkyl,

n represents 0 or 1,

m represents 1 or 2,

R ⁸ for hydrogen, hydroxy, OR ¹ °, NRüR ² , (C _r C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₆ -Cιo) aryl, or for a saturated, unsaturated or aromatic C ₅ -Cιo-membered heterocycle with up to four identical or different heteroatoms from the series S, O and / or N, the aforementioned hydrocarbon radicals and

Heterocycles optionally by one, two or three identical or different substituents from the group halogen, hydroxy, cyano, nitro, amino, CF ₃ , (C _r C ₄ ) - alkyl, (C _r C ₄ ) - alkoxy, (C ₃ - C ₈ > cycloalkyl, O-CO-R ¹³ , -CO-OR ¹⁴ , -CO-NR ¹⁵ R ¹⁶ or -NHCOOR ^{17 are} substituted, where R ¹ °, RU, R ⁿ , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ^l? Are the same or different and each represents hydrogen, benzyl, (C ^ - C ₄ ) alkyl or (C ₃ -C ₆ ) cycloalkyl, which in turn may optionally be replaced by amino or (-C-C ₄ ) Alkoxy are substituted,

R ⁴ and R ^{5 are the} same or different and each represents hydrogen, halogen or

(C 1 -C ₄ ) -alkyl, R ^{6 has} the meaning given for R ⁸ and is the same or different with the above substituent or for the rest

stands, in which

R ²⁰ and R ² together represent oxygen, or are in each case identical or different and represent hydrogen, halogen, hydroxy, (C 1 -C ₄ ) alkyl, (C _r C ₄ ) alkoxy or the radical -NR ¹⁵ Rl ⁶ and

R ^{22 has} the meaning of R ⁸ and is the same or different with it,

R ^{7 represents} hydrogen,

and their salts.

Compounds of the general formula (I) are preferred

in which

Z represents O, CH ₂ or CF ₂ ,

Rl and R ^{2 are the} same or different and represent hydrogen, fluorine, chlorine, bromine, (C _r C ₄ ) alkyl, CF ₃ , CHF ₂ , CH ₂ F, vinyl or (C ₃ -C ₆ ) cycloalkyl, where at least one of the two substituents is not hydrogen and is in the ortho position to the bridge bond, in particular both substituents are not hydrogen and both are in the ortho position, for a head group with optionally derivatized carboxyl radical, preferably of the formula

A- (CH ₂ ) _n - (CO) _m -R ⁸ which is preferably in the para position to the bridge bond,

embedded image in which

A represents CH ₂ , O or NR ⁹ , in which R ^{9 is} hydrogen, (C _r C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl or for the group - (CH ₂ ) _n -

(CO) _m -O- (C _r C ₄ ) -alkyl,

n represents the number 0 or 1,

m represents the number 1 or 2,

R ⁸ for hydrogen, hydroxy, OR ¹⁰ , NRURI ² , (C _r C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (Cg-C _j o ^ aryl, or for a saturated, unsaturated or aromatic 5 is a 10-membered heterocycle having up to four identical or different heteroatoms from the series S, O and / or N, the abovementioned hydrocarbon radicals and heterocycles optionally being substituted by one, two or three identical or different substituents from the group halogen, hydroxyl, Cyano, nitro, amino, CF ₃ , (C _r C ₄ ) alkyl, (C _r C ₄ ) alkoxy, (C _r C ₄ ) alkoxyphenyl, (C ₃ -C ₈ ) cycloalkyl, -O-CO -R ³ , -CO-OR ¹⁴ , -CO-

NR15R16 _? -NHCORl ⁷ or -NHCOOR ^{17 are} substituted, where Rl °, RU, R ^{! 2} , R, Rl ⁴ , R ⁵ , R16 and R ^{i7 are the} same or different and are each hydrogen, benzyl, (-Cg ^ alkyl or ( C ₃ -Cg) - cycloalkyl, which in turn are optionally mono- or polysubstituted by fluorine, chlorine, hydroxy, amino, -CO-O (C _r C ₄ ) -alkyl, -NH-CO- O (C 1 -C ₄ ) -alkyl, -O-CO- (C _r C ₄ ) -alkyl, imidazolyl, hydroxyphenyl or (Cj-C) - alkoxy are substituted,

R ⁴ and R ^{5 are the} same or different and each represents hydrogen, halogen or (C _r C ₄ ) -alkyl,

R ^{6 represents} chlorine, fluorine, bromine or has the meaning given for R ⁸ and is the same or different with the above substituent or for the rest

stands, in which

R ²⁰ and R ²ⁱ together with the carbon atom to which they are attached form a carbonyl group, or are each the same or different and are hydrogen, halogen, hydroxyl, (C _j -C) - alkoxy or the radical -NR ⁱ⁵ R ¹⁶ and

R ^{22 has} the meaning of R ⁸ and is the same or different with it,

R ^{7 represents} hydrogen,

and their salts.

Of particular importance are compounds of the general formula (I) in which

Z represents oxygen or CH ₂ , Rl and R ^{2 are the} same or different and represent methyl, ethyl, propyl, isopropyl, chlorine, bromine, CF ₃ , vinyl or cyclopropyl, where both substituents are in the ortho position to the bridge bond,

R ^{3 stands} for the group -ΝR ⁹ - (CO) _m -R ⁸ in the para position to the bridge bond, where

R ^{9 is} hydrogen, (C _r C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,

m represents 2,

R ^{8 stands} for (-C _f -alkyl, pyridyl, OR ° or NRl R,

where R 1 °, RU and R ^{12 are} hydrogen, benzyl, (C _r C ₄ ) -alkyl or (C ₃ -C 6) -cycloalkyl,

R ⁴ and R ^{5 represent} hydrogen, methyl, fluorine or chlorine,

R ⁶ for hydrogen, hydroxy, ORl °, NR ^Ü Rl ² , (C _r C ₄ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C6-Cιo) aryl, or for a saturated, unsaturated or aromatic C5-Cιo-membered heterocycle having up to three identical or different heteroatoms from the series S, O and / or N, the aforementioned hydrocarbon radicals and heterocycles optionally being substituted by one, two or three identical or different substituents from the group halogen, Hydroxy, cyano, nitro, amino, CF ₃ , (-CC ₄ ) - alkyl, (Ci

C ₄ ) -alkoxy, (C ₃ -C ₈ ) -cycloalkyl, O-CO-Rl ³ , -CO-O-Rl ⁴ , -CO-NR15R16 or -NHCOORI ⁷ , where Rio, RU, Rl ² , Rl, Rl ⁴ , Rl5. Rl6 and Rl ^{"7 are the} same or different and each represents hydrogen, benzyl, (C ₁ -C ₄ ) alkyl or (C ₃ -C 6) cycloalkyl, which in turn may be substituted by amino or (C 1 -C ₄ ) alkoxy are, or for the rest

in which

R ²⁰ and R 1 together represent oxygen, or are each identical or different and represent hydrogen, halogen, hydroxy, (C1-C4) alkyl, (C ₁ -C ₄ ) alkoxy or the radical -NRl ⁵ Rl ⁶ and

R ²² for hydrogen, hydroxy, OR ¹⁰ , N ^Ü R ² , (C _r C ₄ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C6-Cιo) aryl, or for a saturated, unsaturated or aromatic C5-Cιo-membered heterocycle with up to three identical or different heteroatoms from the series S, O and / or N, the aforementioned hydrocarbon radicals and

Heterocycles optionally by one, two or three identical or different substituents from the group halogen, hydroxy, cyano, nitro, amino, CF ₃ , (C _r C ₄ ) alkyl, (C _r C ₄ ) alkoxy, (C ₃ - C ₈ cycloalkyl, O-CO-Rl ³ , -CO-O-Rl ⁴ , -CO-NRl ⁵ Rl ⁶ or -NHCOORI ^{7 are} substituted, where Rio, Rll, Rl ² , Rl3 R14 _{} R} 15 _{5 R} 16 _{and R} 17 are the same or different and each represents hydrogen, benzyl, (-C ~ C4) alkyl or (C ₃ -C ₆ ) cycloalkyl, which in turn are optionally substituted by amino or (C1-C4) alkoxy,

R ^{7 represents} hydrogen,

and their salts.

Of particular importance are compounds of the general formula (I) in which Z represents oxygen or CH ₂ ,

Rl and R ^{2 are} identical or different and represent methyl, ethyl, propyl, isopropyl, chlorine, bromine, CF ₃ , ninyl or cyclopropyl, both substituents being in the ortho position to the bridge bond,

R ^{3 stands} for the group -O- (CH) _n -CO-R ⁸ in the para position to the bridge bond, where

R ^{9 is} hydrogen, (C _r C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,

n stands for 1,

R ^{8 represents} (dC ^ alkyl, pyridyl, ORl ° or ΝRl R ² ,

where Rio, RU and R ^{ϊ2 are} hydrogen, benzyl, (C _r C ₄ ) -alkyl or (C ₃ -C6) -cycloalkyl,

R ⁴ and R ^{5 represent} hydrogen, methyl, fluorine or chlorine,

R ⁶ for hydrogen, hydroxy, ORl °, N ^Ü R ² , (C ₁ -C ₄ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C6-Cι ₀ ) aryl, or for a saturated , unsaturated or aromatic C 5 -hedral heterocycle with up to three identical or different heteroatoms from the S, O and / or Ν series, the aforementioned hydrocarbon radicals and heterocycles optionally being distinguished by one, two or three identical or different substituents from the group halogen, hydroxy, cyano, Νitro, amino, CF ₃ , (C1-C4) - alkyl, (Cj- C ₄ ) alkoxy, (C ₃ -C ₈ ) cycloalkyl, O-CO-Rl ³ , - CO-O-Rl ⁴ , -CO-ΝR15R16 or -NHCOORl ^{7 are} substituted, where Rl °, Rl ¹ , Rl, R ⁱ³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and RI ^{7 are the} same or different and each represents hydrogen, benzyl, (-C-C ₄ ) alkyl or (C ₃ -C ₆ ) cycloalkyl, which in turn are optionally substituted by amino or (C- _[ -C ₄ ) - alkoxy,

or for the rest

in which

R ²⁰ and R ²¹ together represent oxygen, or are each the same or different and represent hydrogen, halogen, hydroxy, (-C-C ₄ ) alkyl, (C _r C ₄ ) alkoxy or the radical -NRl ⁵ Rl ⁶ and

R ²² for hydrogen, hydroxy, ORl °, NR ^Ü R ² , (C _r C ₄ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (Cg-Cio aryl, or for a saturated, unsaturated or aromatic C5- Cι stands _υ -gtiedrigen heterocycle having up to three identical or different hetero atoms from the series S, O and / or N, where the abovementioned hydrocarbon radicals and heterocycles optionally same by one, two or three or! various substituents from the group halogen, hydroxy,

Cyano, nitro, amino, CF ₃ , (C _r C ₄ ) alkyl, (C _r C ₄ ) alkoxy, (C ₃ -C ₈ cycloalkyl, O-CO-Rl ³ , -CO-O-Rl ⁴ , -CO-NR ¹⁵ R ¹⁶ or -NHCOORI ^{7 are} substituted, where Rl °, RU, R ^Ϊ2 , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and Rl ^{7 are the} same or different and each represents hydrogen, benzyl, (Cj C) -alkyl or (C ₃ -Cg) -cycloalkyl, which in turn are optionally substituted by amino or (CC ₄ ) -alkoxy,

R ^{7 represents} hydrogen,

and their salts. Of particular importance are compounds of the general formula (I) in which

Z represents CH ₂ or in particular oxygen,

Rl and R ^{2 are} identical or different and represent methyl, ethyl, propyl, isopropyl, chlorine, bromine, CF ₃ , ninyl or cyclopropyl, both substituents being in the ortho position to the bridge bond,

R ³ for the group -O- (CH ₂ ) _n -CO-R ⁸ or preferably for the group ΝR ⁹ - (CH) _n - (CO) _m -R ⁸ , each of which is in the para position to the bridge bond, where

R ⁹ -CH ₂ -CO-O- (C ₁ -C ₄ ) alkyl substituted (C _r C ₄ ) alkyl, (C ₃ -C ₇ ) -

Cycloalkyl, -CO-CO-O- (-C-C ₄ ) alkyl or in particular hydrogen, means

m represents the number 1 or in particular 2,

n represents the number 1 or 0,

R ⁸ for methyl, ethyl, n-propyl, isopropyl, n-, i-, s- or t-butyl, n-pentyl or n-hexyl, thiophenyl, pyridyl or for the groups -CH ₂ -O- benzyl, ORI ° or ΝR ¹ ! R ^{! 2}

where Rio stands for hydrogen, or straight-chain or branched alkyl with up to 7 carbon atoms optionally substituted by hydroxy, where R ⁿ and R ^{12 are} identical or different and represent hydrogen,

Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy, n-hexoxy or straight-chain or branched alkyl having up to 6 carbon atoms, where alkyl in turn may be one or more identical or different by hydroxy, -CO-O (-CC ₄ ) - alkyl, -NH-CO-O (C _r C ₄ ) alkyl, Lnidazolyl and / or hydroxyphenyl is substituted,

R ⁴ and R ^{5 represent} methyl, fluorine or chlorine or in particular hydrogen,

R ⁶ for hydrogen, hydroxy, ORl °, R ^Ü R ² , methyl ethyl, n-propyl, isopropyl, n-, i-, s- or t-butyl, n-pentyl, (C ₃ -C6) cycloalkyl, (Cg-Cιo) aryl, or for a saturated, unsaturated or aromatic 5- to 10-membered heterocycle with up to three identical or different heteroatoms from the series S, O and or N, the abovementioned hydrocarbon radicals and heterocycles optionally by one, two or three identical or different substituents from the group halogen, hydroxy, cyano, nitro, amino, CF ₃ , (C _r C ₄ ) alkyl, (C _r C ₄ ) alkoxy, (C ₃ -C ₈ ) -Cycloalkyl, O-CO-Rl ³ , -CO-O-Rl ⁴ , -CO-NRl ⁵ Rl6 or -NHCOORI ^{7 are} substituted, whereby Rio, RU, Rl ² , Rl ³ , Rl ⁴ , Rl5 , R16 _and R17 are the same or different and each represents hydrogen, benzyl, (C _j -C ₄ ) alkyl or (C ₃ - Cö) cycloalkyl, which in turn may optionally be amino or (Cj-C ₄ ) alkoxy are substituted,

or for the rest

stands, in which R ²⁰ and R ^2Ϊ together with the carbon atom to which they are attached form a carbonyl group, or are in each case identical or different and for hydrogen, halogen, hydroxy, (-C-C ₄ ) - alkyl, (C ^ -C ₄ ) - Alkoxy or the radical -NRl ⁵ Rl ⁶ and

R ²² for hydrogen, hydroxy, OR ¹⁰ , R.HR! ² , (C _r C ₄ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C6-C ₁ o) aryl, or for a saturated, unsaturated or aromatic 5- to 10-membered heterocycle with up to three the same or different heteroatoms from the series S, O and / or N, the aforementioned hydrocarbon radicals and

Heterocycles optionally by one, two or three identical or different substituents from the group halogen, hydroxy, cyano, nitro, amino, CF ₃ , (C _r C ₄ ) alkyl, (C _r C ₄ ) alkoxy, (C ₃ - C ₈ ) - Cycloalkyl, O-CO-R ³ , -CO-O-Rl ⁴ , -CO-NR ¹⁵ Rl ⁶ or -NHCOORl ^{7 are} substituted, where R ¹⁰ , RU, R ¹² , Rl ³ , R ⁱ⁴ , R ⁱ⁵ , R ⁶ and Rl ^{7 are the} same or different and each represents hydrogen, benzyl, (C - C) alkyl or (C ₃ -C6) cycloalkyl, which in turn may be substituted by amino or (Cj-C ₄ ) - A_koxy are substituted,

R ^{7 represents} hydrogen,

and their salts.

The general definitions given above or those specified in preferred ranges apply both to the end products of the formula (I) and correspondingly to the starting materials or intermediates required in each case for the preparation.

The radical definitions specified in detail in the respective combinations or preferred combinations of radicals are also replaced by radical definitions of other combinations, regardless of the respectively specified combinations of the radicals. Ner compounds of the formula (I) in which Z represents oxygen are particularly preferred.

Ner compounds of the formula (I) in which R ^{3 is} particularly preferred for the group

ΝH-CO-CO-R ^{8 is} in the para position to the bridge bond and R ^{8 has} the meanings given for a group which can be degraded in the sense of a prodrug to carboxylic acid or its salts.

Ner compounds of the formula (I) in which R ⁴ , R ⁵ and R ⁷ are particularly preferred

Stand hydrogen.

Particularly preferred are Nerbindungen of formula (I) in which Rl and R ^{2 are} both arranged in the meta position to each other and in particular both in the ortho position to Z and for chlorine, bromine, trifluoromethyl, cyclopropyl and in particular

Stand methyl.

The following individual compounds are mentioned by way of example and preferably:

Ner compounds of the formula 1 in which X ^{1 has} the meanings given in table 1 (* in the table means the point of attachment)

Sheetl

Individual compounds of the formula 2 in which X ¹ each has the meanings given in Table 1 and X ² instead of methyl from the formula 1 for each of the individual compounds 1 to 68 has the meanings given in Table 2 for X ² :

Table 2

Individual compounds of the formula 3 in which X ¹ and X ² each have the meanings given in Tables 1 and 2 and X ³ instead of methyl from the formula 2 for each of the individual compounds 1 to 2788 in each case the meanings given in Table 3 for X have

Table 3

Individual compounds of the formula 4 in which X ¹ , X ² and X ³ each have the meanings given in Tables 1, 2 and 3 and X ⁴ instead of methyl from the formula 3 for each of the individual compounds 1 - 114 308 in each case in of Table 4 have meanings for X ⁴

Table 4

The inventive compounds of the general formula (I) can be prepared by reacting reactive indole derivatives of the general formula (II) with reactive phenyl derivatives of the general formula (III)

(II) (III) (IN)

wherein the substituents Rl, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meanings given above and

R ³ 'has the meaning given for R ³ or represents ΝO ₂ , NH ₂ or NPG,

where PG stands for a protective group, X and Y each represent groups of opposite reactivity, where, for example, X can be an electrophilic radical which reacts with a nucleophilic Y substituent and vice versa,

Z 'has the meaning given for Z or represents CHOH,

if appropriate in the presence of inert solvents and catalysts and if appropriate with isolation of the intermediates of the general formula (IV), or directly to Nerbindungen of formula (I).

Coupling catalysts such as Pd and / or Cu compounds may be mentioned as examples of catalysts.

The following may be mentioned as examples of the reactive groups X and Y: halogen, hydroxy,

CH ₂ Br, Mercapto, CHO, Li, MgHal, Sn or boron derivatives.

The indoles of the general formula (II) which can be used according to the invention are known or can be prepared by known methods (compare, for example, Oza i et al., Heterocycles, 1999, 51, pp. 727-731, Harvey et al., J. Chem. Soc 1959, 473;

Quadbeck et al., Hoppe-Seyler's Z. Physiolog. Chem. 297 (1954) 229; Chen et al., J. Org. Chem. 59 (1994), 3738).

The phenyl derivatives of the general formula (III) are also known or can be prepared by known methods (compare, for example, EP 580 550 A).

The reaction of the starting compounds (II) with (HI) generally takes place under normal pressure. However, it can also be carried out under increased or reduced pressure. The reaction can be carried out in a temperature range from -100 ° C to 200 ° C, preferably between -78 ° C and 150 ° C in the presence of inert solvents. The following may be mentioned as inert solvents: dimethyl sulfoxide (DMSO), dimethylformnamide (DMF), tetrahydofuran (THF), diethyl ether etc.

Depending on the specific substituent pattern, intermediates of the formulas (IN) or (IN ') may also be formed in the reaction of (II) and (III), in which, for example, the substituent R ^{3 is} an Νitro group or Z is a CHOH group, which can then be reduced with or without isolation of these intermediates to the corresponding amino groups or methylene groups by customary methods and can then be reacted further using customary methods with carboxylic acids or carboxylic acid derivatives such as esters, anhydrides or halides to give amide compounds in the formula (I) ,

The method according to the invention can be illustrated by the following formula schemes:

Nerfahr Variant (A)

(IV ") (I)

Nerating variant (B)

Depending on the meaning of the substituents R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , it may be expedient or necessary to vary them at individual levels of the process within the stated scope. The nor stages or intermediates of the formula (IN) which occur in the reaction of (II) and (III) and which are identified in the above formula scheme with (TV) and (IN ") are new. This application therefore also relates to compounds of the general formula (IN)

in which

Rl, R ² , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meaning given above for formula (I),

Z 'has the meaning given for Z or represents CHOH, and

R ³ 'has the meaning given for R ³ or stands for ΝO ₂ , NH ₂ or NPG, where PG stands for a protective group (protective group),

with the proviso that when Z 'is CH ₂ , R ³ ' is not NO ₂ ,

and that if

Z 'represents CH ₂ ,

R ³ 'represents NH ₂ ,

Rl and R ^{2 represent} (Ci-C ^ alkyl,

R ⁴ and R ⁵ stand for H and R ^{6 stands} for C ₃ -C ⁶ cycloalkyl substituted with amino,

R ⁷ does not represent hydrogen. Protective groups (PG) in the present application are understood to mean groups in starting, intermediate and / or end products which protect functional groups present, such as carboxyl, amino or hydroxyl groups, and those in preparative organic chemistry are common. The groups protected in this way can then be converted into free functional groups in a simple manner under known conditions.

The compounds of the formula (I) according to the invention have a surprising and valuable spectrum of pharmacological activity and can therefore be used as versatile drugs. In particular, they can be used for all indications that can be treated with natural thyroid hormones, such as, for example and preferably, depression, goiter or thyroid cancer. Arteriosclerosis, hypercholesterolemia and dyslipidemia can preferably be treated with the compounds of formula (I) according to the invention. In addition, obesity and heart failure can be treated and a postprandial reduction in triglycerides can be achieved.

The compounds are also suitable for the treatment of certain respiratory diseases, in particular pulmonary emphysema and for the medicinal promotion of pulmonary maturation.

The compounds are also suitable for the treatment of Alzheimer's disease.

The Nerbindungen are also suitable for the treatment of osteoporosis, cardiac arrhythmias, hypothyroidisms and skin diseases.

The Nerbindungen are also suitable for the treatment of pain, in particular for the treatment of migraines. The Nerbindungen can also be used to promote and regenerate hair growth and to treat diabetes.

The active compounds according to the invention open up a further treatment alternative and represent an enrichment of the pharmaceutical industry. In comparison to the known and previously used thyroid hormone preparations, the inventive compounds show an improved spectrum of action. They are preferably characterized by great specificity, good tolerance and fewer side effects, especially in the cardiovascular area.

The activity of the compounds according to the invention can e.g. Check in vitro using the known T 3 promoter assay cell test described below:

The test is carried out with a stably transfected, human HepG2 hepatocarcinoma cell which expresses a luciferase gene under the control of a thyroid hormone-regulated promoter. The vector used for the transfection carries a minimal thymidine kinase promoter with a thyroid hormone responsive element (TRE) which consists of two inverted palindromes of 12 bp each and an 8 bp spacer in front of the luciferase gene.

For the test, the cell cultures are sown in 96-well plates in Eagle's Minimal Essential Medium with the following additives: glutamine, tricine, sodium pyruvate, non-essential amino acids, insulin, selenium and transfine. The cultures are grown for 48 hours at 37 ° C. and 10% CO ₂ atmosphere. Then serial dilutions of test substance or reference compound (T3, T4) and costimulator retinoic acid are added to the test cultures and these are incubated for a further 48 or 72 hours as before. Each substance concentration is tested in four replicates. To determine the luciferase induced by T3 or other substances, the cells are then lysed by adding a buffer containing triton and luciferin and immediately measured luminometrically. The EC50 values of each connection are calculated (see Table 1). Table 1

In the in vivo test described in the following, too, the inventive compounds show surprisingly advantageous properties:

Test description for the detection of pharmacologically active substances:

The substances that are to be tested for their serum cholesterol-lowering effect in vivo are administered orally to male mice with a body weight between 25 and 35 g. The animals are divided into groups with the same number of animals, usually n = 7-10, one day before the start of the test. During the entire experiment, drinking water and feed are available to the animals ad libitum. The substances are administered orally once a day for 7 days. For this purpose, the test substances are, for example, in a solution made from Solutol HS 15 +

Dissolved ethanol + saline (0.9%) in a 1 + 1 + 8 ratio or in a solution of Solutol HS 15 + saline (0.9%) in a 2 + 8 ratio. The dissolved substances are applied in a volume of 10 ml / kg body weight with a gavage. Animals that are treated in the same way but only receive the solvent (10 ml / kg body weight) without test substance serve as a control group. Before the first substance application, blood is taken from each mouse to determine the serum cholesterol by puncturing the retroorbital venous plexus (normal value). The animals are then given the test substance for the first time using a pharyngeal tube. 24 hours after the last substance application, (on the 8th day after the start of treatment), blood is again taken from each animal for the determination of the serum cholesterol by puncturing the retroorbital venous plexus. The blood samples are centrifuged and after the serum has been obtained, the cholesterol is determined photometrically using an EPOS Analyzer 5050 (Eppendorf-Gerätebau, Νetheler & Hinz GmbH, Hamburg). The determination is carried out using a commercially available enzyme test (Boehringer Mannheim, Mannheim).

The effect of the test substances on the serum cholesterol concentration is determined by subtracting the cholesterol value of the 1st blood sample (previous value) from the cholesterol value of the 2nd blood sample (after treatment). The differences of all cholesterol values in a group are averaged and compared with the mean value of the differences in the control group.

Statistical evaluation is carried out using Student's t-test after checking the variants for homogeneity.

Substances that reduce the serum cholesterol of the treated animals statistically significantly (p <0.05) by at least 10% compared to that of the control group are considered to be pharmacologically active.

At the end of the test, the animals are weighed and killed after the blood is drawn. To check for potential cardiovascular side effects under the influence of the substance, the hearts are removed and weighed. An effect on the cardiovascular system can be determined by a significant increase in heart weight. A change in body weight can be used as a further parameter for the substance effect. In an analogous manner, NMRI mice, for example, whether-ob mice, Wistar rats or fa, fa sugar rats can be used as test animals for this test.

Another in vivo test in which the inventive compounds show surprisingly advantageous properties is the animal model of the cholesterol-fed rat [A. Taylor et al., Molecular Pharmacology 52, 542-547 (1997); Z. Stephan et al., Atherosclerosis 126, 53-63 (1996)].

Furthermore, the cholesterol-lowering effect of the Nerbindungen invention can also be checked on normocholesterolemic dogs by oral administration of the test substances for 5-7 days.

For further investigation of potential cardiovascular side effects under the influence of substances, the determination of the expression of the mRNA of the

"HCN2" ion channels ("hyperpolarization-activated cyclic nucleotide-gated channel") are used in mouse or rat hearts [cf. also: Trost et al., Endocrinology 141 (9), 3057-3064 (2000); Gloss et al., Endocrinology 142 (2), 544-550 (2001); Pachuki et al., Circulation Research 85, 498-503 (1999)]:

HCN2 assay:

The mRNA of the "hyperpolarization-activated cyclic nucleotide-gated" cation channel (HCN2) in rat hearts was carried out by real-time PCR (TaqMan-PCR; Heid et al., Genome Res. 6 (10), 986-994) , This was done after

Preparation of the hearts, the total RNA was isolated using RNaesy columns (Qiagen), digested with DNase and then rewritten into cDNA (SUPERSCRIPT-II RT cDNA synthesis kit, Gibco). The HCN2 mRNA determination was carried out on an ABI Prism 7700 device (from Applied Biosystems). The sequence of the "forward" and "reverse" primers was: 5'-

GGGAATCGACTCCGAGGTC-3 'or 5'-GATCTTGGTGAAACGCACGA-3', that of the fluorescent sample 5'-6FAM-ACAAGACGGCCCGTGCACTACGC-TAMRA-3. During the polymerase chain reaction, the 5 ^c -exonuclease activity of the Taq polymerase cleaves off the fluorescent dye FAM and thereby the previously quenched fluorescence signal is obtained. The number of cycles at which the fluorescence intensity was 10th was recorded as the so-called "threshold cycle" (Ct value)

Standard deviations were above the background fluorescence. The relative expression of the HCN2 mRNA calculated in this way was then normalized to the expression of the ribosomal protein L32.

This assay can also be carried out in an analogous manner with mouse hearts.

The sequence of the "forward" and "reverse" primer in this case was 5'-CGAGGTGCTGGAGGAATACC-3 'and 5'-CTAGCCGGTCAATAGCCACAG-3', that of the fluorescent sample 5'-6FAM-CATGATGCGGCGTGCCTTTGAG-TAMRA-3.

For the application of the compounds of the general formula (I), all customary application forms come into consideration, i.e. i.e. orally, parenterally, inhalatively, nasally, sub-lingually, rectally or externally, e.g. transdermally, particularly preferably orally or parenterally. In parenteral administration, intravenous, intramuscular, subcutaneous administration should be mentioned in particular, e.g. as a subcutaneous depot. Oral application is very particularly preferred.

The active ingredients can be administered alone or in the form of preparations. Preparations suitable for oral administration include tablets, capsules, pellets, dragees, pills, granules, solid and liquid aerosols, syrups, emulsions, suspensions and solutions. The active ingredient must be present in such an amount that a therapeutic effect is achieved. In general, the active ingredient can be present in a concentration of 0.1 to 100% by weight, in particular 0.5 to 90% by weight, preferably 5 to 80% by weight. In particular, the concentration of the active ingredient should be 0.5-90% by weight, ie the active ingredient should be in Amounts are available which are sufficient to achieve the dosage range indicated.

For this purpose, the active ingredients can be converted into the customary preparations in a manner known per se. This is done using inert, non-toxic, pharmaceutically suitable carriers, auxiliaries, solvents, vehicles, emulsifiers and / or dispersants.

Examples of auxiliary substances are: water, non-toxic organic solvents such as e.g. Paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g.

Ethanol, glycerin), glycols (e.g. polyethylene glycol), solid carriers such as natural or synthetic rock flour (e.g. talc or silicates), sugar (e.g. milk sugar), emulsifiers, dispersants (e.g. polyvinylpyrrolidone) and lubricants (e.g. magnesium sulfate).

In the case of oral administration, tablets can of course also contain additives such as sodium citrate together with additives such as starch, gelatin and the like. Aqueous preparations for oral administration can also be mixed with flavor enhancers or colorants.

In the case of oral administration, doses of 0.001 to 5 mg kg, preferably 0.005 to 3 mg / kg body weight, are preferably administered per 24 hours.

The new active ingredients can be used alone and, if necessary, in combination with other active ingredients, preferably from the group CETP inhibitors, antidiabetic agents,

Antioxidants, cytostatics, calcium antagonists, antihypertensive agents, thyroid hormones, inhibitors of HMG-CoA reductase, inhibitors of HMG-CoA reductase gene expression, squalene synthesis inhibitors, ACAT inhibitors, anticoagulant agents, antiplatelet agents, anticoagulant antagonists, anti-platelet agents Receptor antagonists, cholesterol absorption inhibitors, MTP-Mii- bittern, fibrates, niacin, anorectics, lipase inhibitors and PPAR agonists can be administered.

The following exemplary embodiments are intended to illustrate the invention by way of example without restricting the scope of protection.

Exemplary embodiments (output connections)

Example I

5- [4-nitro-2,6-bis (trifluoromethyl) phenoxy] -lH-indole

3 g (22.5 mmol) of 5-hydroxyindole are mixed with 6.61 g (22.5 mmol) of 2,6-bistrifluoromethyl-4-nitrochlorobenzene and 3.43 g of potassium carbonate (24.8 mmol) in 250 ml of DMSO dissolved and stirred at 80 ° C for 3 hours. It is diluted with water and ethyl acetate, the organic phase is extracted 3 times with sodium chloride solution, dried over sodium sulfate and the solvent is removed in vacuo. Chromatographic purification (toluene / cyclohexane = 1: 1) gives 4.98 g (56%) of 5- [4-nitro-2,6-bis (trifluoromethyl) phenoxy] - 1 H-indole.

200 MHz iH NMR (DMSO-d6): 6.32, m, 1H; 6.80, dd, 1H; 6.88, m 1H; 7.36, m 2H; 8.86, s, 2H; 11.15, s, lH.

Example II

4- [1 H-indole-5-yloxy) -3, 5-bis (trifluoromethyl) aniline

2 g (5.1 mmol) of 5- [4-nitro-2,6-bis (trifluoromethyl) phenoxy] 1H-indole are dissolved in 250 ml of ethyl acetate and hydrogenated with 200 mg of Pd / carbon (10%) at 4 bar. you sucks off through diatomaceous earth, removes the solvent in vacuo and receives 1.84 g (99%) of 4- [lH-indol-5-yloxy) -3,5-bis (trifluoromethyl) aniline.

200 MHz iH-ΝMR (DMSO-d6): 6.00, s, 2H; 6.30, s, 1H; 6.66, m 2H; 7.22, s, 2H; 7.28, m, 2H; l 1.00, s, lH.

Example III

5- (2,6-dimethyl-4-nitrophenoxy) -lH-indole

2.3 g (17.27 mmol) of 5-hydroxyindole are mixed with 3.21 g (17.27 mmol) of 2,4-dimethyl-3-chloronitrobenzene and 11.26 g of cesium carbonate (34.55 mmol) in 200 ml of DMSO dissolved and stirred for 12 hours at room temperature. The mixture is diluted with water and ethyl acetate, the organic phase is extracted 3 times with sodium chloride solution, dried over sodium sulfate and the solvent is removed in vacuo. 2.63 g (54%) of 5- (2,6-dimethyl-4-nitrophenoxy) -lH-indole are obtained.

200 MHz iH-ΝMR (DMSO-d6): 6.30, m, 1H; 6.72, m, 2H; 7.32, m 2H; 8.12, s 2H; ll, 09, s, 1H.

Example IN

4- (1 H -indole-5-yloxy) -3,5-dimethyl laniline

2.61 g (9.25 mmol) of 5- (2,6-dimethyl-4-nitrophenoxy) lH-indole are hydrogenated in 100 ml of ethyl acetate with 261 mg of Pd on carbon (10%) for 2 hours at 3 bar. It is filtered through diatomaceous earth and the solvent is removed in vacuo. 2.33 g (99%) of 4- [1H-indol-5-yloxy) -3,5-dimethylaniline are obtained. Rf = 0.49 (toluene / ethyl acetate = 4: 1)

Example V

5- (2,6-dimethyl-4-nitrophenoxy) -3-methyl-lH-indole

440 mmg (3 mmol) of 3-methyl-1H-indol-5-ol, 567 mg (3 mmol) of 2,6-dimethyl-4-nitrochlorobenzene and 460 mg (3.3 mmol) of potassium carbonate are dissolved in 15 ml of DMSO 48 Stirred at 125 ° C for hours. It is diluted with water, extracted with dichloromethane and 3 times with ethyl acetate, the combined organic phases are dried over sodium sulfate and the solvent is removed in vacuo. Chromatographic purification gives 333 mg (37%) of 5- (2,6-dimethyl-4-nitrophenoxy) -3-methyl-1H-indole.

400 MHz! H-ΝMR (DMSO-d6): 2.12, s, 3H; 2.20, s, 6H; 6.68, m, 2H; 7.11, m, 1H; 7.29, d, 1H; 8.12, s 2H; 10.73, s, 1H. Example VI

3,5-dimethyl-4- [ ^" 3-methyl-1 H-indol-5-yl) oxy] aniline

510 mg (1.72 mmol), 5- (2,6-dimethyl-4-nitrophenoxy) -3-methyl-1H-indole are mixed with 510 mg Pd / C (10%) in 150 ml ethyl acetate for 2 hours at 3 bar Hydrogen hydrogenates. It is diluted with THF, filtered through diatomaceous earth and the solvent is removed in vacuo. 458 mg (99%) of 3,5-dimethyl-4 - [(3-methyl-1H-indol-5-yl) oxy] aniline are obtained.

200 MHz iH-ΝMR (DMSO-d6): 1.92, s, 6H; 2.10, s, 3H; 4.81, s, 2H; 6.32, s, 2H; 6.60, m, 2H; 7.05, s, 1H; 7.21, d, 1H; 10.59, s, 1H.

Example Nile

3-isopropyl-5- (4-nitro-2,6-bistrifluoro-methyl-phenoxy) -lH-indole

346.0 mg (1.97 mmol) of 5-hydroxy-3-isopropyl-indole are dissolved in 4 ml of dimethyl sulfoxide, 300.18 mg (2.17 mmol) of potassium carbonate are solidly added and then 579.63 mg (1.97 mmol ) 2,6-Bis-trifluoraιethyl-4-nitro-chlorobenzene slowly added within one hour. Immediately afterwards, the mixture is distributed in 20 ml of water and 30 ml of ethyl acetate; the ethyl acetate phase is separated off and extracted three more times with ethyl acetate. The combined ethyl acetate extracts are washed twice with Washed brine, dried with sodium sulfate and concentrated to an oil. The oily residue is dissolved in 4 ml of cyclohexane / ethyl acetate (9: 1), applied to 200 ml of dry SiO 2 and then eluted with cyclohexane in gradient mode with the addition of ethyl acetate.

Yield: 6.48 mg (75.8%)

Rf 0.23 (cyclohexane: ethyl acetate = 9: 1)

HPLC: rt (%) = 5.28 (98.9); 1% HClO acetonitrile

Example VIII

4- (3-isopropyl-lH-indol-5-yloxy) -3,5-bis-trifluoromethyl-phenylamine

648.0 mg (1.5 mmol) of 3-isoropropyl-5- (4-nitro-2,6-bistrifluoromethylphenoxy) -lH-indole are dissolved in 14 g of ethanol p.a. dissolved, mixed with 210 mg palladium on activated carbon (5%) and hydrogenated at hydrostatic hydrogen pressure for 42 hours. The palladium catalyst is suctioned off over SiO 2, washed with ethanol and concentrated to an oil. The crude product is dissolved in about 50 ml of toluene, applied to about 200 ml of dry silica gel and eluted first with 490 ml of toluene, 10 ml of ethyl acetate mixture and then with 480 ml of toluene and 20 ml of ethyl acetate mixture. The eluate is evaporated down, dissolved with a little dichloromethane and concentrated again, with crystallization sometimes starting.

Yield: 467 mg (76.9%)

Rf 0.43 (toluene-ethyl acetate = 9: 1)

HPLC: rt (%) = 4.86 (99.36);

1% HClO4 / acetonitrile Example IX

3- (4-fluorobenzyl) -5-r4-nitro-2,6-bis (trifluoromethyl) phenoxy1-lH-indole

100 mg (0.41 mmol) 3- (4-fluorobenzyl) -lΗ-indol-5-ol are dissolved in 5 ml DMSO, at room temperature with 63 mg (0.46 mmol) potassium carbonate and then with 121 mg (0.41 mmol) 2-chlorine -5-nitro-l, 3-bis (trifluoromethyl) benzene added. The mixture is stirred for 5 hours at room temperature. The approach is based on sat. Given ammonium chloride solution, extracted 3 times with ethyl acetate, the combined organic phases once with sat. Washed NaCl solution, dried over sodium sulfate and evaporated. The residue is purified by chromatography (cyclohexane / ethyl acetate = 10: 1). 140 mg (62%) of 3- (4-fluorobenzyl) -5- [4-nitro-2,6-bis (trifluoromethyl) phenoxy] -1 H-indole are obtained.

300MΗz 1H NMR (CDC1 ₃ ): 3.95, s, 2H; 6.46, d, 1H; 6.87, m, 5H; 7.10, m, 2H; 7.96, s, broad, 1H; 8.80, s, 2H.

Example X

4 - ([3- (4-fluorobenzyl) -lH-indol-5-ylloxyl-3,5-bis (trifluoromethvDanilin

331 mg (1.57 mmol) of tin dichloride dihydrate are concentrated to 5 ml. Given ΗC1 and heated to approx. 50 ° C. Then 122 mg (0.245 mmol) of 3- (4-fluorobenzyl) -5- [4-nitro-2,6-bis (trifluoromethyl) phenoxy] -IH-indole are added all at once. The suspension is heated to about 70 ° C. overnight. Then allowed to cool to room temperature. The mixture is poured into water, made alkaline with IN NaOΗ, extracted twice with ethyl acetate, the combined organic phases once with sat. Washed NaCl solution, dried, evaporated and dried in vacuo.

300MΗz 1H NMR (CDC1 ₃ ): 3.95, s, 2H; 4.00, s, broad, 2H; 6.45, d, IH; 6.84, m, 4H; 7.12, m, 6H; 7.88, s, broad, lH.

Example XI

5- (2,6-Dibromo-4-mtrophenoxy ^' ) -3-r4-fluorobenzv-1H-indole

100 mg (0.41 mmol) of 3- (4-fluorobenzyl) -IH-indol-5-ol are dissolved in 5 ml of DMSO, at room temperature with 63 mg (0.46 mmol) of potassium carbonate and then with 124 mg (0.41 mmol) of 2-fluorine -5-nitro-l, 3-dibromobenzene added. The mixture is stirred for 5 hours at room temperature. The approach is based on sat. Given ammonium chloride solution, extracted 3 times with ethyl acetate, the combined organic phases 1 time with sat.

Washed NaCl solution, dried over sodium sulfate and evaporated. The residue is purified by chromatography (cyclohexane / ethyl acetate = 10: 1). 142 mg (62%) of 5- (2,6-dibromo-4-nitrophenoxy) -3- (4-fluorobenzyl) -IH-indole are obtained.

300MΗz 1H NMR (CDC1 ₃ ): 4.02, s, 2H; 6.60, d, lH; 6.93, m, 4H; 7.18, m, 2H; 7.35, d, IH; 8.02, s, broad, IH; 8.53, s, 2H.

Example XII

3,5-dibromo-4--, 3- (4-fluorobenzyl) -lH-indol-5-yl] oxy} aniline

320 mg (1.42 mmol) of tin dichloride dihydrate are concentrated to 5 ml. Given ΗC1 and heated to approx. 50 ° C. Then 123 mg (0.245 mmol) of 5- (2,6-dibromo-4-nitro-phenoxy) -3- (4-fluorobenzyl) -IH-indole are added all at once. The suspension is heated to about 70 ° C. overnight. Then allowed to cool to room temperature. The mixture is poured into water, made alkaline with IN NaOΗ, extracted twice with ethyl acetate, the combined organic phases once with sat. Washed NaCl solution, dried, evaporated and dried in vacuo. 300MHz 1H NMR (CDC1 ₃ ): 3.71, s, broad, 2H; 3.92, s, 2H; 6.62, d, IH; 6.89, m, 6H; 7.18, m, 3H; 7.87, s, broad, IH.

Example XIII tert-butyl-4- [{1 - | ^" tert-butyl (dimethv silyl] -3-isopropyl-1H-indol-5-yll (hydroxy) methyl" -3,5-dimethyl-phenyl carbamate

0.87 ml of methyl lithium (1.6M in diethyl ether, 1.39 mmol) are placed in 1 ml of ether and 400 mg (1.33 mmol) of tert-butyl 4-bromo-3,5-dimethylphenylcarbamate (dissolved in 0.53 ml of ether) are added -78 ° C. The mixture is stirred for 20 min. 0.94 ml of tert-butyllithium (1.7M in pentane, 1.59 mmol) are slowly added and the reaction mixture is stirred at -78 ° C. for 30 min. Then a solution of 321 mg (1.07 mmol) of l- [tert-butyl (dimethyl) silyl] -3-isopropyl-lΗ-indole-5-carbaldehyde in 0.5 ml of ether is added dropwise and the mixture is stirred at -78 ° C. for 1.75 h , The cooling bath is removed and NH C1 solution is added. It is poured onto diethyl ether and washed with saturated NaCl solution. The organic phase is dried over sodium sulfate and evaporated. Chromatographic purification (cyclohexane ethyl acetate) gives 46 mg (13%) tert-butyl 4 - [{l- [tert-butyl (dimethyl) silyl] -3-isoropropyl-lH-indol-5-yl} (hydroxy) - methyl] -3,5-dimethylphenyl carbamate.

R = 0.38 (cyclohexane / ethyl acetate = 3: 1) Example XIV

4 - [(3-isopropyl-lH-indol-5-yDmethyl] -3-5-dimethylamlin

A solution of 41 mg (0.078 mmol) of tert-butyl-4 - [{l- [tert-butyl (dimethyl) silyl] -3-isopropyl-1H-indol-5-yl} (hydroxy) methyl] -3.5 dimethylphenyl carbamate in 1 ml dichloromethane is added dropwise at 0 ° C. over 30 minutes to a solution of 55 mg (0.47 mmol) triethylsilane and 1 mg trimethylsilyl triflate in 5 ml dichloromethane. The mixture is stirred at 0 ° C. for 30 min and at room temperature for 60 min. It is poured onto NaΗCO3 solution, extracted with dichloromethane, dried over sodium sulfate and rotated in. The crude product obtained is stirred overnight in 10 ml of 10% trifluoroacetic acid in dichloromethane. It is neutralized with NaHCO3 solution, the organic phase is dried and rotated in. 11 mg of 4 - [(3-isopropyl-1H-indol-5-yl) methyl] -3,5-dimethylaniline are obtained.

300MΗz 1H NMR (CDC1 ₃ ): 1.30, d, 6H; 2.26, s, 6H; 3.11, hept, IH; 4.12, s, 2H; 5.71, s, broad, 2H; 6.66, dd, IH; 6.92, s, IH; 7.02, s, 2H; 7.20, m, 2H; 7.78, s, broad, IH.

Example XV

3-Isoproρyl-5- (4-nitro-2,6-dibromo-phenoxy) -lH-indole

546.7 mg (3.12 mmol) of 5-hydroxy-3-isopropyl-indole are based on the procedure of Example VII in dimethyl sulfoxide with 932.5 mg (3.12 mmol) of 2,6- Dibromo-4-nitro-fluorobenzene and 474.3 mg (3.43 mmol) of potassium carbonate were reacted at room temperature within 3 hours. The crude product is purified chromatographically using cyclohexane / ethyl acetate (from 9.5: 0.5 to 9: 1).

Yield: 1056.6 mg (73.3%)

Rf: 0.47 (cyclohexane: ethyl acetate = 8: 2) MS (EI): 454 ([M + H] ⁺ , 44%)

NMR (300 MHz, CDd ₃ ): 5 = 1.3 (d, 6H); 3.09 (quin, IH); 6.77 (dd, IH); 6.95 (d, IH); 7.0 (d, IH); 7.28 (d, IH); 7.89 (broad s, IH); 8.51 (s, 2H) ppm.

Example XVI

4- (3-isopropyl-lH-indol-5-yloxy) -3,5-dibromo-phenylamine

To a solution of 0.51 g (1.13 mmol) of indole derivative from Example XV in 10 ml of dimethylformamide and 1.0 ml of water is added 1.32 g (5.67 mmol) of tin (IΙ) chloride and dihydrate stir for 3 hours at 50 ° C. After cooling to room temperature, the reaction solution is then mixed with 50 ml of saturated sodium hydrogen carbonate solution and 50 ml of ammonium chloride solution and extracted four times with ethyl acetate. The organic phases are combined, shaken once with brine, dried over sodium sulfate and the solvent i. Vak. away. The residue is purified on silica gel using toluene ethyl acetate (9: 1) by chromatography.

Yield: 0.346 g (69.6%)

Rf: 0.58 (toluene: ethyl acetate = 8: 2) MS (ESI): 425 ([M + H] ⁺ , 100%) NMR (300 MHz, d ₆ -DMSO): δ = 1.21 (d, 6H); 2.97 (quin, IH); 5.55 (broad s, 2H); 6.61 (dd, IH); 6.71 (d, IH); 6.9 (s, 2H); 7.04 (d, IH); 7.22 (d, IH); 10.68 (s, IH) ppm.

Example XVII

3-isopropyl-5- (4-nitro-2,6-divinyl-phenoxy) -lH-indole

500 mg (1.10 mmol) of the indole derivative from Example XV are dissolved in 33 ml of toluene, 1745.7 mg (5.51 mmol) of tributyl vinyl stannane and 508.9 mg (0.44 mmol) of tetrakis - ( triphenylphosphine) - palladium added. The solution is made under argon 20

Cooked under reflux for hours; the mixture is then cooled and the reaction solution is applied to 200 ml of dry silica gel. It is eluted with 1000 ml of toluene, 500 ml of toluene / ethyl acetate (9: 1) and the desired fractions i. Vak. concentrated.

Yield: 321.4 mg (80.9%)

Rf: 0.65 (toluene: ethyl acetate = 9: 1)

MS (EI): 348 ([M] ⁺ , 64%)

NMR (300 MHz, CDCI ₃ ): δ = 1.27 (d, 6H); 3.02 (quin, IH); 5.32 (d, 2H); 5.86 (d,

2H); 6.73 (dd, IH); 6.83-6.91 (m, 3H); 6.95 (d, IH); 7.24 (s, IH); 7.82 (broad s, IH); 8.41 (s, 2H) ppm. Example XVIII

4- (3-isopropyl-lH-indol-5-yloxy) -3,5-divinyl-phenylamine

Following the instructions of Example XVI, 100 mg (0.29 mmol)

Nitro compound from Example XVII in 2 ml DMF and 0.2 ml water with 323.8 mg (1.44 mmol) tin (IΙ) chloride dihydrate stirred overnight at room temperature.

The crude product is purified by chromatography on silica gel using toluene / ethyl acetate (9.5: 0.5).

Yield: 70.6 mg (77.2%)

Rf: 0.38 (toluene: ethyl acetate = 9: 1)

MS (ESI): 319 ([M + H] ⁺ , 100%)

NMR (200 MHz, CDCI ₃ ): δ = 1.27 (d, 6H); 3.04 (quin, IH); 3.67 (broad s, 2H); 5.11 (dd, 2H); 5.65 (dd, 2H); 6.72-6.91 (mm, 5H); 6.90 (s, 2H); 7.2 (d, IH); 7.75 (broad s, IH) ppm.

Example XIX

3-isopropyl-5- (4-nitro-2,6-dicyclopropyl-phenoxy) -lH-indole

102.2 mg (0.29 mmol) of divinyl derivative from Example XVII are mixed with 30 ml (30.0 mmol) of diazomethane-diethyl ether solution (prepared from diazald) at 0 ° C. under argon (not argon flow). After rising to room temperature, the mixture is left to stand for 2 days and then diazomethane is expelled in a stream of argon. The remaining residue is dissolved in 30 ml of xylene and refluxed for 2.5 hours

(Bath temperature: 160 ° C) cooked. After concentrating the xylene solution, the residue is dissolved in toluene and applied to 100 ml of dry silica gel. It is eluted with 500 ml of toluene and concentrated to dryness.

Yield: 70.8 mg (64.1%)

MS (DCI): 394 ([M + NH ₄ ] ⁺ , 100%) HPLC: rt (%) = 5.64 (93, 1%)

0.01 mol. H ₃ PO_ι / Aceto__itril Kromasil column C18 (60 x 2 mm) - flow 0.75 ml / min, 210 nm.

Example XX

4- (3-isopropyl-lH-indol-5-yloxy) -3,5-dicyclopropyl-phenylamine

The preparation is carried out in analogy to the procedure of Example XVI from 70.0 mg (0.19 mmol) of nitro compound of Example XIX with 0.21 g (0.93 mmol) of tin (II) chloride dihydrate at 40 ° C. for 2 hours and 1 hour at 55 ° C. The crude product (60.6 mg) is on a YMC polyamine II column with tert-butyl methyl ether / methanol (97.5: 2.5) at a flow of 20 ml / min. Chromatograph.

Yield: 45.0 mg (69.1%) MS (ESI): 347 ([M + H] ⁺ , 100%) HPLC: rt (%) = 4.76 (99.7%) tert-butyl methyl ether / methanol (95: 5)

YMC polyamine Il column 5μm (250 x 4 mm), 210 nm

Flow 1 ml / min.

Example XXI

3- (2-tert-Butoxycarbonylamino-ethyl) -5- (4-nitro-2,6-bis-trifluoromethyl-phenoxy) - 1H-indole

The preparation is carried out in analogy to the procedure of Example VII from 643.7 mg (1.7 mmol) l, 3-bis (2-tert-butoxycarbonyl) -3-aminoethyl-5-hydroxyindoline and 499.3 mg (1.7 mmol) of 2,6-bis-trifluoromethyl-4-nitro-chlorobenzene in 6 ml of dimethyl sulfoxide in the presence of 258.6 mg (1.87 mmol) of potassium carbonate, rearomatization of the indole with elimination of the tert .-Butoxycarbonyl protecting group takes place on the indole nitrogen.

Yield: 410.5 mg (44.6%) MS (DCI): 551 ([M + NH ₄ ] ⁺ , 100%)

Rf: 0.64 (Toluok ethyl acetate = 8: 2) HPLC: rt (%) = 5.17 (98.6%)

1% HCIO ₄ / acetonitrile Kromasil column C18 (60 x 2 mm) flow 0.75 ml min, 210 nm. Example XXII

3- (2-tert-Butoxycarbonylamino-ethyl) -5- (4-amino-2,6-bis-trifluoromethyl-phenoxy) - 1H-indole

Following the instructions of Example VIII, 396.2 mg (0.74 mmol)

Nitro compound of Example XXI hydrogenated with 80 mg of 10% palladium on activated carbon in 30 ml of ethanol for 2 days. Then the hydrogenation solution is suctioned off over 15 ml of silica gel, rinsed with ethanol and i. Vak. concentrated. After the concentrate has been dissolved in 20 ml of toluene, it is purified by chromatography on 250 ml of silica gel with toluene with the addition of ethyl acetate.

Yield: 371 mg (97.6%)

Rf: 0.28 (toluene: ethyl acetate = 8: 2)

MS (ESI): 387 ([M + H] ⁺ , 100%)

NMR (300 MHz, CDCI ₃ ): 5 = 1.43 (s, 9H); 2.82 (t, 2H); 3.38 (m. 2H); 4.0 (broad s, 2H); 4.56 (broad s, IH); 6.75 (dd, IH); 6.8 (d, IH); 7.0 (d, IH); 7.15 (s. 2H); 7.22 (d, 1H); 7.9 (s, 1H) ppm.

Example XXIII

3-isopropyl-5- (4-nitro-2,6-dimethyl-phenoxy) -lH-indole

11.44 g (58.76 mmol) 5-hydroxy-3-isopropyl-indole are dissolved in 350 ml DMSO,

8.93 g (64.63 mmol) of potassium carbonate are firmly added and then 9.94 g (58.76 mmol) of 3,5-dimethyl-4-fluoronitrobenzene are added. The reaction solution is stirred for 2 hours at 100 ° C. under argon. The mixture is then cooled to room temperature, 100 ml of ethyl acetate and 600 ml of H O are added; after phase separation, ethyl acetate is separated off and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed twice with brine, dried over sodium sulfate, filtered and evaporated to dryness.

The residue is purified by chromatography on silica gel using cyclohexane / ethyl acetate (10: 1).

Yield: 11.96 g (62.8%)

MS (DCI): 342 ([M + NH ₄ ] ⁺ , 100%)

R _f = 0.26 (cyclohexane: ethyl acetate = 8: 2)

300 MHz 1H NMR (CDC1 ₃ ): 1.28 (d, 6H); 2.24 (s, 6H); 3.05 (quin, IH), 6.72 (dd, IH); 6.84 (d, IH); 6.99 (d, IH), 7.27 (d, IH); 7.87 (s, IH), 8.03 (s, 2H).

The following compounds (Examples XXIV and XXV) are prepared in analogy to the procedure of Example XXIII: Example XXTV

3-sec-butyl-5- (4-nitro-2,6-dimethyl-phenoxy) -lH-indole

reactants:

5 g (26.42 mmol) 5-hydroxy-3-sec-butyl-indole

8.94 g (52.84 mmol) of 3,5-dimethyl-4-fluoronitrobenzene

4.02 g (29.06 mmol) potassium carbonate in 60 ml DMSO

Yield: 2.27 g (22.7%)

MS (LC method, ES ⁺ ): 339 ([M + H] ⁺ , 100%)

R _f = 0.43 (cyclohexane: ethyl acetate = 8: 2)

HPLC rt = 5.80 (89.2%)

0.01 mol HaPO acetonitrile Kromasil C18 (60x2 mm) flow: 0.75 ml / min, 210 nm

Example XXV

3-isobutyl-5- (4-nitro-2,6-dimethyl-phenoxy) -lH-indole

reactants:

5 g (22.84 mmol) 5-hydroxy-3-isobutyl-indole 3.86 g (22.84 mmol) of 3,5-dimethyl-4-fluoronitrobenzene 3.47 g (25.12 mmol) of potassium carbonate in 100 ml of DMSO

Yield: 4 g (51.7%)

R _f = 0.28 (toluene: ethyl acetate = 9: 1)

Example XXVI

3-isobutyl-5- (4-nitro-2,6-bis-trifluoromethyl-phenoxy) -lH-indole

2.0 g (10.57 mmol) of 5-hydroxy-3-isobutyl-indole are dissolved in 20 ml of DMSO, 1.61 g (11.62 mmol) of potassium carbonate are added and then 2.79 g (9.50 mmol ) 2,6-bis-trifluoromethyl-4-nitro-chlorobenzene added in portions. After stirring for 30 min at room temperature, the mixture is diluted with water and ethyl acetate, the ethyl acetate phase is separated off and the aqueous phase is extracted three more times with ethyl acetate. The combined organic phases are washed with brine, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The residue is purified by chromatography on silica gel using cyclohexane / ethyl acetate (9: 1).

Yield: 0.583 g (12.4%)

R _f = 0.76 (toluene: ethyl acetate = 4: 1)

The following compounds (Examples XXVII to XXXI) are used in analogy to

Example XXVI produced: Example XXVII

3-sec-butyl-5- (4-nitro-2,6-bis-trifluoromethyl-phenoxy) -lH-indole

Reactants: 2.09 g (8.9 mmol) 5-hydroxy-3-sec-butyl-indole

1.3 g (4.45 mmol) of 2,6-bis-trifluoromethyl-4-nitro-chlorobenzene 1.35 g (9.79 mmol) of potassium carbonate in 20 ml of DMSO

Yield: 1.38 g (80.2%)

R _f = 0.4 (cyclohexane: ethyl acetate = 4: 1) MS (EI): 446 (M ⁺ , 30%) HPLC: rt = 5.54 (80.2%)

0.01 mol H ₃ PO ₄ / acetonitrile Kromasil column C 18 (60x2 mm)

Flow: 0.75 ml; 210 nm

Example XXVIII

3- (4-fluorophenyl-5- (4-nitro-2,6-bis-trifluoromethyl-phenoxy) -lH-indole

reactants:

250 mg (1.10 mmol) 5-hydroxy-3- (4-fluorophenyl) indole 320 mg (1.20 mmol) 2,6-bis-trifluoromethyl-4-nitro-chlorobenzene 170 mg (1.21 mmol) Potassium carbonate in 6 ml DMSO

Yield: 135 mg (25.3%)

MS (EI): 484 ([M ⁺ ], 100%)

R _f = 0.27 (cyclohexane / ethyl acetate = 8: 2) HPLC rt = 5.24 (93.6%)

0.5% HCLO ₄ acetonitrile Kromasil column C18 (60x2 mm) flow: 0.75 ml / min .; 210 nm

Example XXIX

3-methyl-5- (4-nitro-2,6-bis-trifluoromethyl-phenoxy) -lH-indole

Reactants: 960 mg (6.51 mmol) 5-hydroxy-3-methyl-indole

1.91 g (6.51 mmol) of 2,6-bis-trifluoromethyl-4-nitro-chlorobenzene 990 mg (7.17 mmol) of potassium carbonate in 15 ml of DMSO

Yield: 554 mg (20.6%)

MS (LC method, ES ^" ): 403 fl -BT, 100%) HPLC rt = 4.99 (97.9%)

0.01 mol HsPO acetonitrile Kromasil column C18 (60x2 mm) flow: 0.75 ml / min .; 210 nm R _f = 0.25 (cyclohexane: ethyl acetate = 8: 2)

Example XXX

3- (methoxycarbonylmethyl) -5- (4-nitro-2,6-bis-trifluoromethyl-phenoxy) -lH-indole

reactants:

1.00 g (4.87 mmol) 5-hydroxy-3- (methoxycarbonylmethyl) indole

0.715 g (2.43 mmol) of 2,6-bis-trifluoromethyl-4-nitro-chlorobenzene

0.74 g (5.36 mmol) potassium carbonate in 10 ml DMSO

Yield: 1.18 g (50.7%)

MS (EI): 462 ([M] ⁺ , 49%)

HPLC rt = 4.87 (97.1%)

0.01 mol H ₃ PO ₄ / acetonitrile Kromasil column C 18 (60x2 mm)

Flow: 0.75 ml / min .; 210 nm Example XXXI

Methyl 2-acetylamino-3-f5- (4-nitro-2,6-bis-trifluoromethylphenoxy) -lH-indol-3-yl] - propionate (DL)

reactants:

0.5 g (1.81 mmol) DL-N-acetyl-5-hydroxy-tryptophan methyl ester

0.265 g (0.903 mmol) of 2,6-bis-trifluoromethyl-4-nitro-chlorobenzene

0.28 g (1.99 mmol) potassium carbonate in 9 ml DMSO

Yield: 0.25 g (22.7%) MS (ESI): 534 ([M + H] ⁺ , 35%) HPLC rt = 4.56 (87.4%)

0.5% HClO ₄ / acetonitrile

Kromasil column C18 (60x2 mm)

Flow: 0.75 ml / min., 210 nm

Example XXXII

2-acetylamino-3-f5- (4-nitro-2,6-dibromo-phenoxy) -lH-indol-3-yl] -propionic acid methyl ester (DL)

reactants:

1.00 g (3.60 mmol) DL-N-acetyl-5-hydroxy-tryptophan methyl ester

1.08 g (3.60 mmol) 2-fluoro-5-nitro-l, 3-dibromobenzene

0.55 g (3.96 mmol) potassium carbonate in 30 ml DMSO

Yield: 1.7 g (76%)

MS (LC method, ES): 556 ([M + H] ⁺ , 100%)

R = 0.63 (dichloromethane / methanol = 9: 1)

300 MHz 1H NMR (CDC1 ₃ ): 1.96 (s, 3H); 3.22 (d. 2H); 3.69 (s, 3H); 4.9 (sext, IH);

5.96 (d, IH); 6.74 (dd, IH); 6.88 (d, IH); 7.01 (d, IH); 7.29 (d, IH); 8.15 (broad s, IH); 8.53 (s, 2H).

Example XXXIII 4- (3-isobutyl-1 H-indole-5-yloxy) -3,5-dimethyl-phenylamine

4.0 g (11.82 mmol) of nitro compound from Example XXV are dissolved in 80 ml of methanol / ethanol (1: 1), mixed with 210 mg of palladium on activated carbon (10%) and hydrogenated at 3 bar with hydrogen overnight. The palladium catalyst is suctioned off over kieselguhr, washed with ethanol and concentrated in vacuo. The raw product is directly implemented further.

Yield: 0.151 g (78.4%) MS (DCI): 309 ([M + H] ⁺ , 100%) R _f = 0.32 (toluene: acetonitrile = 9: 1)

HPLC rt = 3.86 (95.9%)

0.01 mol HsPOJ acetonitrile

Kromasil column C18 (60x2 mm)

Flow: 0.75 ml / min .; 210 nm

The following compounds (Examples XXXIV to XL) are prepared in analogy to the procedure of Example XXXIII:

Example XXXIV 4- (3-isopropyl-1H-indol-5-yloxy) -3,5-dimethylphenylamine

reactants:

11.95 g (36.85 mmol) nitro compound from Example XXIII 550 mg palladium / activated carbon (10%)

500 ml methanol / ethanol mixture 3 bar, hydrogen Yield: 10.75 g (97.9%)

MS (DCI): 295 ([M + H] ⁺ , 100%)

R _f = 0.36 (toluene: ethyl acetate = 9: 1) HPLC rt = 4.15 (98.9%)

0.5% HClO ₄ / acetonitrile Kromasil column C18 (60x2 mm) flow: 0.75 ml / min .; 210 nm

Example XXXV

4- (3-sec-butyl-lH-indol-5-yloxy) -3,5-dimethyl-phenylamine

reactants:

1.67 g (4.935 mmol) of nitro compound from Example XXIV

167 mg palladium / activated carbon (10%) in 395 ml ethanol

3 bar, hydrogen

Yield: 1.522 (100%)

MS (ESI): 309 ([M + H] ⁺ , 47%)

HPLC rt = 4.26 (86.5%)

0.5% HClO ₄ / acetonitrile Kromasil column C 18 (60x2 mm)

Flow: 0.75 ml; 210 nm Example XXXVI

4- (3-isobutyl-lH-indol-5-yloxy) -3,5-bis-trifluoromethyl-phenylamine

reactants:

0.583 g (1.31 mmol) of nitro compound from Example XXVI

58 mg palladium / activated carbon (10%) in 100 ml methanol

3 bar, hydrogen

Yield: 543 mg (99.9%)

R _f = 0.58 (toluene: ethyl acetate = 4: 1)

Example XXXVII

4- (3-sec-butyl-lH-indol-5-yloxy) -3,5-bis-trifluoromethyl-phenylamine

Reactants: 1.08 g (2.42 mmol) nitro compound from Example XXVII

101 mg palladium / Aktivkohe (10%) in 36 ml ethanol pa 3 bar, hydrogen

Yield: 0.869 g (89.5%) MS (ESI): 417 ([M + H] ⁺ , 100%) HPLC rt = 5.08 (89.5%)

0.5% HClO ₄ / acetonitrile

Kromasil column C18 (60x2 mm)

Flow: 0.75 ml / min .; 210 nm

Example XXXVIII

4- - (4-fluorophenyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethyl-phenylamine

reactants:

100 mg (0.206 mmol) nitro compound from Example XXVIII

100 mg palladium / activated carbon (10%) in 10 ml ethanol

3 bar, hydrogen Yield: 38.8 mg (39.6%)

MS (ESI): 455 ([M + H] ⁺ , 100%)

200 MHz 1H NMR (CDC1 ₃ ): 4.07 (broad s, 2H); 6.78 (dd, IH); 7.04 - 7.16 (m, 5H);

7.25 - 7.31 (m, 2H); 7.45 - 7.51 (m, 2H); 8.12 (broad s, IH). Example XXXIX

4- (3-methyl-lH-indol-5-yloxy) -3,5-bis-trifluoromethyl-phenylamine

reactants:

0.55 g (1.37 mmol) of nitro compound from Example XXIX

350 mg palladium activated carbon (10%) in 100 ml methanol

3 bar, hydrogen

Yield: 0.341 g (66.4%)

MS (ES): 374 ([M] ⁺ , 100%)

R _f = 0.69 (toluene: ethyl acetate = 1: 1)

Example XL

4 - [(3-methoxycarbonylmethyl) -IH-indol-5-yloxy1-3,5-bis-trifluoromethylphenylamine

reactants:

0.55 g (1.05 mmol) nitro compound from Example XXX 50 mg palladium / activated carbon (10%) in 20 ml methanol 3 bar, hydrogen Yield: 0.436 g (94.8%) MS (ESI): 433 ([M + H] ⁺ , 15%)

300 MHz 1H NMR (CDC1 ₃ ): 3.62 (s, 3H); 3.67 (s, 2H); 4.0 (s, 2H); 6.79 (m. 2H); 7.13 (s. 3H); 7.22 (d, IH); 7.95 (broad s, IH).

Example XLI

2-Acetylamino-3- [5- (4-amino-2,6-bis-trifluoromethyl-phenoxy) -lH-indol-3-yll-propionic acid methyl ester (DL)

reactants:

250 mg (0.41 mmol) of nitro compound from Example XXXI

120 mg palladium / activated carbon (10%) in 100 ml methanol

3 bar, hydrogen

Yield: 228.6 mg (94.4%)

MS (DCI): 521 ([M + NH ₄ f, 100%)

R _f = 0.1 (toluene: ethyl acetate = 1: 2)

HPLC rt = 4.18 (84.7%)

0.5% HClO acetonitrile Kromasil column C18 (60x2 mm) flow: 0.75 ml / min .; 210 nm Example XLII

2-Acetylamino-3- [5- (4-amino-2,6-dibromo-phenoxy) -lH-indol-3-yll-propionic acid methyl ester (DL)

To a solution of 0.868 g (1.563 mmol) of nitro compound from Example XXXII in 16 ml of dimethylformamide and 1.6 ml of water is added 1.764 g (7.817 mmol) of tin (II) chloride dihydrate and stirred for 2 hours at 50 ° C. The reaction solution is then mixed with 50 ml of saturated sodium bicarbonate solution and 50 ml of ammonium chloride solution and extracted four times with ethyl acetate. The organic phases are combined, filtered and concentrated in vacuo. The residue is purified on silica gel using toluene / ethyl acetate (20: 1) by chromatography.

Yield: 0.697 g (84.9%)

MS (LC method, ES ⁺ ): 526 ([M + H] ⁺ , 100%)

R _f = 0.81 (toluene: ethyl acetate = 9: 1)

Example XLIII

3-Cyclobutanecarbonyl-5 - (4-nitro-2,6-bis-trifluoromethyl-phenoxy) - 1 H-indole

380 mg (2.8 mmol) of zinc chloride and 0.47 ml (1.43 mmol) of ethyl magnesium bromide (3 molar in ether) are added to 550 mg (1.4 mmol) of the compound from Example I dissolved in 7 ml of dichloromethane under argon. added. After stirring for 1 hour at room temperature, 0.2 ml (1.77 mmol) of cyclobutane carbonyl chloride is added and the mixture is stirred

1 hour at room temperature after. After addition of 80 mg (0.61 mmol) of aluminum chloride, the reaction solution is left to stir at room temperature overnight. The mixture is then diluted with dichloromethane and 1 ml of saturated ammonium chloride solution and 10 ml of water are added. The organic phase is separated off, washed with sodium hydrogen carbonate solution and sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified chromatographically on silica gel using toluene / ethyl acetate (9: 1).

Yield: 283.8 mg (32.2%)

MS (ESI)): 473 ([M + H] ⁺ , 100%) R _f = 0.24 (toluene: ethyl acetate = 2: 1)

Example XLIV 4- (3-cyclobutylmethyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethyl-phenylamine

150 mg (0.24 mmol) of nitro compound from Example XLIII are based on the instructions of Example XXXIII with 150 mg of palladium / activated carbon (10%) in

Hydrogen atmosphere hydrogenated at 3 bar for 8 days. Yield: 69.2 mg (63%)

MS (ESI): 429 ([M + H] ⁺ , 100%)

HPLC rt = 5.04 (93.1%) 0.5% HClO acetonitrile

Kromasil column C18 (60x2 mm) flow: 0.75 ml / min .; 210 nm

Example XLV 5 - (2, 6-dibromo-4-nitror-henoxy - 1 H-indole

8.00 g (26.77 mmol) l, 3-dibromo-2-fluoro-5-nitrobenzene are dissolved in 100 ml DMSO. At room temperature, 4.069 g (29.44 mmol) of potassium carbonate and 3.674 g

(26.77 mmol) 5-hydroxyindole added. The mixture is stirred for 3 h at room temperature, 50 ml of sat. Ammonium chloride solution and the organic phase extracted twice with ethyl acetate. The combined organic extracts are washed once with sat. Sodium chloride soln. Washed and dried over sodium sulfate and freed from solvent in vacuo. Mix the residue

(Cyclohexane / diethyl ether / dichloromethane 3: 3: 1) gives 7.9 g (72%) of 5- (2,6-dibromo-4-nitrophenoxy) -IH-indole as a yellow solid.

300 MΗz 1H NMR (DMSO): 6.31, m, 1Η; 6.79, .2Η; 7.37, m, IH; 7.39, d, IH; 8.63, s, 2H; 11.12, s, broad, IH. Example XLVI

3-cyclohexylcarbonyl-5- (2,6-dibromo-4-nitrophenoxyVlH-indole

A solution of 178 mg (1.21 mmol) of cyclohexanoic acid chloride in 5 ml of dichloromethane is added dropwise at 0 ° C. to a suspension of 324 mg (2.43 mmol) of aluminum trichloride in 10 ml of dichloromethane. The mixture is stirred for 1 h at room temperature, then a solution of 500 mg (1.21 mmol) of 5- (2,6-dibromo-4-nitrophenoxy) -IH-indole in 8 ml of dichloromethane is added dropwise at 0.degree. The reaction mixture is stirred at room temperature overnight, then heated to 50 ° C. for 8 hours and heated to 50 ° C. overnight with the further addition of 178 mg (1.21 mmol) of cyclohexanoic acid chloride. The mixture is then poured onto ice / 2N hydrochloric acid, the aqueous phase is extracted twice with dichloromethane and the combined organic extracts are dried over sodium sulfate. After removing the

Solvent in vacuo is obtained by stirring the residue in diethyl ether 441 mg (70%) of 3-cyclohexylcarbonyl-5- (2,6-dibromo-4-nitrophenoxy) - 1H-indoles.

200 MΗz 1H NMR (DMSO): 1.37, m, 5Η; 1.71, m, 5H; 3.12, m, IH; 6.95, dd, IH;

7.44, dd, IH; 7.47, d, IH; 8.38, d, IH; 8.67, s, 2H; 12.00, d, broad, IH. Example XLVII

5 - (2,6-dibromo-4-nitrophenoxy) -3-isopropylcarbonyl-1 H-indole

In an analogous manner, 5- (2,6-dibromo-4-nitro-phenoxy) -IH-indole, 129 mg (1.21 mmol) of isobutyric acid chloride and 324 mg (2.43 mmol) aluminum trichloride after stirring the crude product in diisopropyl ether / dichloromethane 5: 1 276 mg (47%) of 3-isopropylcarbonyl-5- (2,6-dibromo-4-nitrophenoxy) - 1 H-indole.

300 MΗz 1H NMR (DMSO): 1.07, d, 6Η; 3.40, sept, IH; 6.97, dd, IH; 7.46, dd, IH; 7.49, d, IH; 8.39, d, IH; 8.67, s, 2H; 12.01, d, broad, IH.

Example XLVIII

3-RN-benzyl-N-isopropylaminomethyl -5- (2,6-dibromo-4-nitrophenoxy) -IH-indole

To a solution of 300 mg (0.73 mmol) of 5- (2,6-dibromo-4-nitrophenoxy) -IH-indole and 119.5 mg (0.80 mmol) of N-benzyl-N-isopropylamine in 2 ml 1,4-dioxane and 0.4 ml of acetic acid at room temperature 63 ul (0.80 mmol) of a 35% formaldehyde solution. given. The mixture is stirred for 45 min, then water is added and the pH is adjusted to 11 using potassium carbonate. The aqueous phase is extracted twice with dichloromethane, the combined organic extracts are dried over sodium sulfate and the solvent is removed in vacuo. Purification of the residue on silica gel 60 (cyclohexane / ethyl acetate 10: 1 - 2: 1) gives 286 mg (69%) of 3- (N-benzyl-N-isopropylaminomethyl) -5- (2,6-dibromo - 4-nitrophenoxy) l-1H-indols.

200 MΗz 1H-ΝMR (DMSO): 0.88, d, 6Η; 2.74, sept, IH; 3.40, s, 2H; 3.50, s, 2H;

6.88, s, IH; 6.91, dd, IH; 7.16, m, 6H; 7.34, d, IH; 8.72, s, 2H; 10.85, d, broad, IH.

Example IL

3- (N-Benzyl-N-ethylaminomethyl ^' ) -5- (2.6-dibromo-4-nitrophenoxy) -lH-indole

In an analogous manner, the reaction of 350 mg (0.85 mmol) of 5- (2,6-dibromo-4-nitrophenoxy) -IH-indole with 126.3 mg (0.93 mmol) of N-benzyl -N-ethylamine and 74 μl (0.93 mmol) 35% formaldehyde solution. in 2 ml of 1,4-dioxane and 0.4 ml

Acetic acid 272 mg (57%) 3- (N-benzyl-N-ethylaminomethyl) -5- (2,6-dibromo-4-nitrophenoxy)! - 1 H-indole.

200 MΗz 1H-ΝMR (DMSO): 0.88, t, 3Η; 2.30, q, 2H; 3.40, s, 2H; 3.52, s, 2H; 6.86, dd, IH; 6.89, s, IH; 7.20, m, 6H; 7.33, d, IH; 8.71, s, 2H; 10.92, d, broad, IH. Example L

5- (4-amino-2,6-dibromphenoxyVlH-indole

3.25 g (7.89 mmol) of 5- (2,6-dibromo-4-nitrophenoxy) -IH-indole are dissolved in 35 ml of DMF and 8 ml of water. A solution of 8.90 g (39.44 mmol) of tin (II) chloride dihydrate in 8 ml of conc. ΗC1 added dropwise, the reaction solution heating to 50 ° C. After the addition, the mixture becomes more

Stirred for 4 h, then adjusted to pH 12 with 45% sodium hydroxide solution, mixed with 10 ml of water and the aqueous phase is extracted three times with ethyl acetate. The combined organic extracts are dried over sodium sulfate and freed from the solvent in vacuo. The residue obtained is crystallized from diethyl ether and the mother liquor is purified again by chromatography (silica gel

60, cyclohexane / ethyl acetate 3: 1). A total of 2.53 g (84%) of 5- (4-amino-2,6-dibromophenoxy) -IH-indole is obtained as a white solid.

300 MΗz 1H NMR (DMSO): 5.57, s, broad, 2Η; 6.30, m, IH; 6.68, m, IH; 6.70, dd, IH; 6.90, s, 2H; 7.30, m, 2H; 10.98, s, broad, IH.

Example LI

5- (4-Amino-2,6-dibromophenoxy -3-cyclohexylcarbonyl-1H-indole

A solution of 600 mg (3.447 mmol) of sodium dithionite is added to a solution of 300 mg (0.575 mmol) of 3-cyclohexylcarbonyl-5- (2,6-dibromo-4-nitrophenoxy) -IH-indole in 25 ml of ethanol at 50 ° C. added dropwise in 15 ml of water. When the addition is complete, the mixture is heated under reflux for 3 h, again with 200 mg (1.15 mmol)

Sodium dithionite in 5 ml of water and heated under reflux overnight. After cooling, the solid residues are filtered off, the filtrate is concentrated in vacuo and taken up in dichloromethane and a little methanol. The organic phase is washed with sat. NaΗCO ₃ solution. washed, the aqueous phase is extracted twice with dichloromethane, the combined organic extracts are dried over sodium sulfate and concentrated in vacuo. Purification of the crude product on silica gel 60 (cyclohexane / ethyl acetate 5: 2) gives 70 mg (25%) of 5- (4-amino-2,6-dibromophenoxy) -3-cyclohexylcarbonyl-1H-indole.

200 MΗz 1H NMR (DMSO): 1.35, m, 5Η; 1.72, m, 5H; 3.13, m, IH; 5.10, s, wide,

2H; 6.87, dd, IH; 6.90, s, 2H; 7.36, d, IH; 7.39, d, IH; 8.31, s, IH; 11.89, s, broad, IH.

Example LII 5- (4-Amino-2,6-dibromophenoxy -3-isopropylcarbonyl-1H-indole

To a solution of 276 mg (0.572 mmol) of 5- (2,6-dibromo-4-nitrophenoxy) -3-isopropylcarbonyl-lH-indole in 30 ml of DMF / water (5: 1) are added 646 mg (2, 86 mmol) of tin (II) chloride dihydrate are added and the reaction mixture is stirred at 50 ° C. for 2 h.

Then the mixture is sat. NaΗCO ₃ solution. given, the aqueous phase extracted 3 times with ethyl acetate and the combined organic extracts dried over sodium sulfate. After removing the solvent in vacuo, Purification of the residue on silica gel 60 (cyclohexane / ethyl acetate 5: 2) 142 mg (55%) of 5- (4-amino-2,6-dibromophenoxy) -3-isopropylcarbonyl-1H-indole.

400 MΗz 1H NMR (DMSO): 1.08, d, 6Η; 3.39, sept., IH; 5.58, s, broad, 2H; 6.87, dd, IH; 6.92, s, 2H; 7.40, m, 2H; 8.30, d, IH; 11.87, d, broad, IH.

Example LHI

5- (4-Amino-2,6-dibromophenoxy -3- (N-benzyl-N-isopropyl-aminomethyl) -IH-indole

Analogously, reaction of 285 mg (0.497 mmol) of 3- (N-benzyl-N-isopropylaminomethyl) -5- (2,6-dibromo-4-nitrophenoxy) -IH-indole with 561 mg

(2.49 mmol) tin (II) chloride dihydrate in 1.8 ml DMF and 0.2 ml water after 3 h at 50 ° C and working up with sat. ΝaΗCO ₃ solution. 148 mg (55%) of 5- (4-amino-2,6-dibromophenoxy) -3- (N-benzyl-N-isopropyl-aminomethyl) -IH-indole.

300 MΗz 1H-ΝMR (DMSO): 0.91, d, 6Η; 2.77, sept., IH; 3.42, s, 2H; 3.48, s, 2H; 5.54, s, broad, 2H; 6.80, dd, IH; 6.96, d, IH; 6.97, s, 2H; 7.20, m, 7H; 10.69, d, broad, IH. Example LIV

5- ( ^, 4-Amino-2,6-dibromophenoxy) -3- (N-benzyl-N-ethyl-aminomethyl) -IH-indole

Analogously, reaction of 250 mg (0.447 mmol) of 3- (N-benzyl-N-ethylaminomethyl) -5- (2,6-dibromo-4-nitrophenoxy) -IH-indole with 504 mg (2.24 mmol) of tin (II) chloride dihydrate in 1.8 ml DMF and 0.2 ml of water after 2 _^1/2 hours at 50 ° C and workup with sat. ΝaΗCO ₃ solution. 205 mg (86%) of the 5- (4-amino-2,6-dibromophenoxy) -3 - (N-benzyl-N-ethyl-aminomethy 1) - 1 H-indole.

200 MΗz 1H-ΝMR (DMSO): 0.92, t, 3Η; 2.29, q, 2H; 3.40, s, 2H; 3.49, s, 2H; 5.57, s, broad, 2H; 6.78, dd, IH; 6.94, d, IH; 6.97, s, 2H; 7.22, m, 7H; 10.78, d, broad, IH.

Example LV

4-benzyloxyphenylhydrazine hydrochloride

40 g (0.2 mol) of 4-benzyloxyaniline are suspended in 400 ml of water and concentrated at 0 ° C. with 1600 ml. HCl added. 16.6 g (0.24 mol) of sodium nitrite, dissolved in 100 ml of water, are added dropwise. The mixture is stirred vigorously at 0-5 ° C. for 3 hours. The dark solution is cooled to -10 ° C. and carefully concentrated with 113 g (0.5 mol) of tin chloride dihydrate in 50 ml. HCl added dropwise. The mixture is stirred for one hour at this temperature, the suction violet solid, washed with ether and dried in vacuo. The product (51.6 g) is used without further purification.

Example INI 5-benzyloxy-3-isoproρylindol

51.6 g (0.2 mol) of 4-benzyloxyphenylhydrazine hydrochloride are concentrated in 800 ml of methanol with 2 drops. Sulfuric acid and 17.7 g (0.2 mol) of 3-methylbutyraldehyde heated under reflux for 3 hours. The solvent is removed in vacuo and the residue is digested with ethyl acetate. The organic solution is saturated with sat. ΝaHCO ₃ solution and sat. Washed NaCl solution, dried and the solvent removed in vacuo. Chromatography (cyclohexane / ethyl acetate = 20: to 10: 1) gives 38.5 g (57%, 81% purity) of 5-benzyloxy-3-isoρropylindol.

300 MHz 1H NMR (CDC1 ₃ ): 1.32, d, 6H; 3.13, hept, IH; 5.11, s, 2H; 6.91, m, 2H;

7.35, m, 7H; 7.76, s, broad, IH.

Example LVII

5 -B enzyloxy-3 -hexylindole

Analogously, 1.21 g (81%, 82% purity) of 5-benzyloxy-3-hexylindole are obtained starting from 1 g (4 mmol) of 4-benzyloxyphenylhydrazine hydrochloride and 511 mg (4 mmol) of octanal. The product is used without further cleaning.

Example LVIII

5-Benzyloxy-3-cyclohexylmethylindol

In an analogous manner, 1.45 g (76%) of 5-benzyloxy-3-hexylindole are obtained from 1.5 g (6 mmol) of 4-benzyloxyphenylhydrazine hydrochloride and 839 mg (6 mmol) of 3-cyclohexylpropionaldehyde.

300 MHz 1H NMR (CDC1 ₃ ): 1.29, m, 6H; 1.65, m, 5H; 2.56, d, 2H; 5.11, s, 2H;

6.93, m, 2H; 7.37, m, 7H; 7.81, s, broad, IH.

Example LIX

5 -B enzyloxy-3-pentylindole

Analogously, 1.58 g (6 mmol) of 4-benzyloxyphenylhydrazine hydrochloride and 683 mg (6 mmol) of heptanal give 1.58 g (crude yield) of 5-benzyloxy-3-pentylindole.

300 MHz 1H NMR (CDC1 ₃ ): 0.95, m, 3H; 1.30, m, 2H; 1.55, .4H; 2.69, t, 2H; 5.11, s, 2H; 6.93, m, 2H; 7.38, m, 7H; 7.79, s, broad, IH.

Example LX

5-Benzyloxy-3-butylindole

In an analogous manner, starting from 1.5 g (6 mmol) of 4-benzyloxyphenylhydrazine hydrochloride and 599 mg (6 mmol) of hexanal, 1.36 g (crude yield) of 5-benzyloxy-3-butylindole are obtained. The product is used without further cleaning.

Example LXI

5 -B enzy loxy-3-propylindol

In an analogous manner, starting from 5 g (19.9 mmol) of 4-benzyloxyphenylhydrazine hydrochloride and 1.72 g (19.9 mmol) of pentanal, 1.1 g (20%) of 5-benzyloxy-3-propylindole are obtained.

300 MHz 1H NMR (CDC1 ₃ ): 1.00, t, 3H; 1.71, m, 2H; 2.69, t, 2H; 5.12, s, 2H; 6.95, m, 2H; 7.35, m, 7H; 7.80, s, broad, IH. Example LXII

5 -Hydroxy-3 -hexylindole

1.39 g (3.63 mmol) of 5-benzyloxy-3-hexylindole are dissolved in 50 ml of methanol and hydrogenated with 140 mg of Pd on carbon (10%) overnight at atmospheric pressure. The reaction mixture is filtered through Celite, the solvent is removed in vacuo and the residue is purified by chromatography (cyclohexane / ethyl acetate = 10: 1). 223 mg (27%) of 5-hydroxy-3-hexylindole are obtained.

300 MHz 1H NMR (CDC1 ₃ ): 0.89, m, 5H; 1.29, m, 4H; 1.68, m, 2H; 2.67, t, 2H; 4.42, s, IH; 6.75, dd, IH; 6.95, m, 2H; 7.20, d, IH; 7.77, s, broad, IH.

Example LXIII

5-hydroxy-3-cyclohexylmethylindol

In an analogous manner, starting from 1.45 g (4.54 mmol) of 5-benzyloxy-3-cyclohexylmethylindole, 344 mg (32%) of 5-hydroxy-3-cyclohexylmethylindole are obtained.

300 MHz 1H NMR (CDC1 ₃ ): 0.96, m, 5H; 1.19, m, 4H; 1.71, m, H; 2.56, d, 2H; 4.40, s, IH; 6.72, dd, IH; 6.96, dd, IH; 7.21, d, IH; 7.77, s, broad, IH.

Example LXIV

5-hydroxy-3-pentylindol

Analogously, starting from 1.57 g (5.35 mmol) of 5-benzyloxy-3-pentylindole in a mixture of 20 ml of methanol and 10 ml of ether, 241 mg (19%)

5-hydroxy-3-pentylindol

300 MHz 1H NMR (CDCI ₃ ): 0.90, m, 5H; 1.36, m, 2H; 1.68, m, 2H; 2.68, t, 2H;

4.48, s, IH; 6.75, dd, IH; 6.98, dd, IH; 7.20, d, IH; 7.75, s, broad, IH.

Example LXV

5-hydroxy-3-butylindole

In an analogous manner, starting from 1.35 g (4.83 mmol) of 5-benzyloxy-3-butylindole in a mixture of 20 ml of methanol and 20 ml of ether, 273 mg (19%) of 5-hydroxy-3-butylol are obtained.

300 MHz 1H NMR (CDC1 ₃ ): 0.93, t, 3H; 1.41, m, 2H; 1.68, .2H; 2.68, t, 2H; 4.43, s, IH; 6.75, dd, IH; 6.97, dd, IH; 7.20, d, IH; 7.75, s, broad, IH.

Example LXVI

5-hydroxy-3-propylindole

In an analogous manner, starting from 1.08 g (4.07 mmol) of 5-benzyloxy-3-propylindole, 565 mg (79%) of 5-hydroxy-3-propylindole are obtained.

300 MHz 1H NMR (CDCI ₃ ): 0.99, t, 3H; 1.70, sext., 2H; 2.65, t, 2H; 4.42, s, IH; 6.75, dd, IH; 6.99, dd, IH; 7.20, d, IH; 7.77, s, broad, IH.

Example LXVII

5- (2,6-dimethyl-4-mtrophenoxy) -3-propyl-lH-indole

116 mg (0.66 mmol) of 5-hydroxy-3-propylindol are dissolved in 4 ml of DMSO. at

100 mg (0.73 mmol) of potassium carbonate and 112 mg (0.66 mmol) of 2-fluoro-1,3-dimethyl-5-nitrobenzene are added at room temperature. You stir 3h at room temperature and 2h at 110 ° C. The reaction mixture is saturated with ammonium chloride solution. given, extracted 3 times with EA, the combined organic phases are washed 3 times with saturated NaCl solution. washed, dried and evaporated. The residue is purified by chromatography (cyclohexane / ethyl acetate = 10: 1). 173 mg (78%) of 5- (2,6-dimethyl-4-nitrophenoxy) -3-propyl-1H-indole are obtained.

300 MHz 1H NMR (CDC1 ₃ ): 0.91, t, 3H; 1.70, sext., 2H; 2.27, s, 6H; 2.58, t, 2H; 6.77, m, 2H; 6.90, m, IH; 7.26, dd, IH; 7.87, s, broad, IH; 8.02, s, 2H.

Example LXVIII

5 - [4-Nitro-2,6-bis (trifluoromethyl) phenoxy1 -3-propyl-1 H-indole

Analogously, starting from 120 mg (0.68 mmol) of 5-hydroxy-3-propylindole, 104 mg (0.75 mmol) of potassium carbonate and 201 mg of 2-chloro-5-nitro-l, 3- bis (trifluoromethyl ) benzene at room temperature 301 mg (98%) 5- [4-nitro-2,6-bis (trifluoromethyl) phenoxy] -3-propyl-1H-indole.

300 MHz 1H NMR (CDC1 ₃ ): 0.95, t, 3H; 1.64, sext, 2H; 2.59, t, 2H; 6.72, dd, IH;

6.83, d, IH; 7.00, d, IH; 7.27, d, IH; 7.90, s, broad, IH; 8.82, s, 2H. Example LXIX

5 - (2,6-dibromo-4-nitrophenoxy) -3-propyl-1H-indole

Analogously, starting from 100 mg (0.57 mmol) of 5-hydroxy-3-propylindole, 87 mg (0.63 mmol) of potassium carbonate and 171 mg (0.57 mmol) of 2-fluoro-5-nitro-l , 3-dibromobenzene 247 g (71%) 5- (2,6-dibromo-4-nitrophenoxy) -3-propyl-1H-indole.

300 MHz 1H NMR (CDC1 ₃ ): 0.98, t, 3H; 1.68, sext., 2H; 2.62, t, 2H; 6.78, dd, IH; 6.89, d, IH; 7.01, m, IH; 7.29, dd, IH; 7.92, s, broad, IH; 8.52, s, 2H.

Example LXX

5- (2,6-dibromo-4-nitrophenoxy) -3-methyl-lH-indole

Analogously, starting from 1.26 g (8.56 mmol) of 5-hydroxy-3-methylindole, 1.3 g (9.4 mmol) of potassium carbonate and 2.56 g (8.56 mmol) of 2-fluorine -5-nitro-l, 3-dibromobenzene 2.81 g (75%) 5- (2,6-dibromo-4-nitrophenoxy) -3-methyl-lH-indole.

300 MHz 1H NMR (CDC1 ₃ ): 2.23, s, 3H; 6.82, m, 2H; 7.00, m, IH; 7.28, dd, IH; 7.88, s, broad, IH; 8.53, s, 2H. Example LXXI

3-butyl-5 - (2, 6-dibromo-4-nitrophenoxy) - 1 H-indole

Analogously, 130 mg (0.44 mmol) of 5-hydroxy-3-butylindole, 66 mg (0.48 mmol) of potassium carbonate and 131 mg (0.44 mmol) of 2-fluoro-5-nitro-l are obtained , 3-dibromobenzene 141 mg (66%) 3-butyl-5- (2,6-dibromo-4-nitrophenoxy) -lH-indole.

300 MHz 1H NMR (CDC1 ₃ ): 0.93, t, 3H; 1.38, m, 2H; 1.63, m, 2H; 2.63, t, 2H; 6.77, dd, IH; 6.90, d, IH; 7.02, m, IH; 7.28, d, IH; 7.89, s, broad, IH; 8.51, s, 2H.

Example LXXII

3-butyl-5- [4-nitro-2,6-bis (trifluoromethyl) phenoxy] -1 H-indole

In an analogous manner, starting from 130 mg (0.44 mmol, purity 64%), 5-hydroxy-3-butylindole, 67 mg (0.48 mmol) potassium carbonate and 129 mg (0.44 mmol) 2-chloro-5 are obtained -nitro-1,3-bis (trifluoromethyl) benzene at room temperature 126 mg (57%) 3-butyl-5- [4-nitro-2,6-bis (trifluoromethyl) phenoxy] -lH-indole. 300 MHz 1H NMR (CDC1 ₃ ): 0.90, t, 3H; 1.35, m, 2H; 1.60, m, 2H; 2.62, t, 2H; 6.71, dd, IH; 6.83, d, IH; 7.00, m, IH; 7.24, d, IH; 7.89, s, broad, IH; 8.82, s, 2H.

Example LXXIII

5- [4-nitro-2,6-bis (trifluoromethyl) phenoxyl-3-pentyl-lH-indole

Analogously, starting from 110 mg (0.54 mmol, purity 64%), 5-hydroxy-3-pentylindole, 82 mg (0.59 mmol) potassium carbonate and 159 mg (0.54 mmol) 2-chloro-5 are obtained -nitro-l, 3-bis (trifluoromethyl) benzene at room temperature 91 mg (34%) 3-butyl-5- [4-nitro-2,6-bis (trifluoromethyl) phenoxy] -lH-indole.

300 MHz 1H NMR (CDCI ₃ ): 0.87, t, 3H; 1.31, m, 4H; 1.62, m, 2H; 2.61, t, 2H; 6.73, dd, IH; 6.82, d, IH; 7.00, m, IH; 7.25, d, IH; 7.91, s, broad, IH; 8.82, s, 2H.

Example LXXIV

5- (2,6-dibromo-4-nitrophenoxy) -3-pentyl-lH-indole

In an analogous manner, starting from 110 mg (0.54 mmol) of 5-hydroxy-3-pentylindole, 82 mg (0.59 mmol) of potassium carbonate and 162 mg (0.54 mmol) of 2-fluoro-5-nitro-l , 3-dibromobenzene 72 mg (22%) 5- (2,6-dibromo-4-nitrophenoxy) -3-pentyl-1H-indole.

300 MHz 1H NMR (CDC1 ₃ ): 0.88, t, 3H; 1.30, m, 4H; 1.65, m, 2H; 2.62, t, 2H; 6.77, dd, IH; 6.88, d, IH; 7.01, m, IH; 7.29, d, IH; 7.89, s, broad, IH; 8.52, s, 2H.

Example LXXV

3- (cyclohexylmethyl) -5-r4-nitro-2,6-bis (trifluonnethyl) phenoxy] -lH-indole

Analogously, starting from 170 mg (0.74 mmol) of 5-hydroxy-3-cyclohexylmethylindole, 113 mg (0.82 mmol) of potassium carbonate and 217 mg (0.74 mmol) of 2-chloro-5-nitro-l , 3-bis (trifluoromethyl) benzene at room temperature 319 mg (84%) 3- (cyclohexylmethyl) -5- [4-nitro-2,6-bis (trifluoromethyl) phenoxy] - 1H-indole.

300 MHz 1H NMR (CDC1 ₃ ): 0.89, m, 2H; 1.19, m, 4H; 1.65, m, 5H; 2.50, d, 2H; 6.71, dd, IH; 6.83, d, IH; 6.98, m, IH; 7.23, d, IH; 7.92, s, broad, IH; 8.82, s, 2H.

Example LXXVI

3- (cyclohexylmethyl) -5- (2,6-dibromo-4-nitrophenoxy) -lH-indole

Analogously, starting from 165 mg (0.72 mmol) of 5-hydroxy-3-cyclohexylmethylindole, 109 mg (0.79 mmol) of potassium carbonate and 215 mg (0.72 mmol) of 2-fluoro-5-nitro-l , 3-dibromobenzene 281 mg (69%) 3- (cyclohexylmethyl) -5- (2,6-dibromo-4-nitrophenoxy) -lH-indole.

300 MHz 1H NMR (CDC1 ₃ ): 0.92, m, 2H; 1.18, m, 4H; 1.65, m, 5H; 2.52, d, 2H; 6.75, dd, IH; 6.91, d, IH; 7.25, d, IH; 7.91, s, broad, IH; 8.51, s, 2H.

Example LXXVII

3-hexyl-5 | ^" 4-nitro-2,6-bis (trifluoromethyl) phenoxy] -lH-indole

Analogously, starting from 97 mg (0.4 5 mmol) of 5-hydroxy-3-hexylindole, 68 mg (0.49 mmol) of potassium carbonate and 131 mg (0.45 mmol) of 2-chloro-5-nitro-l , 3-bis (trifluoromethyl) benzene at room temperature 121 mg (57%) 3-hexyl-5- [4-nitro-2,6-bis (trifluoromethyl) ρhenoxy] -IH-indole.

300 MHz 1H NMR (CDC1 ₃ ): 0.89, m, 5H; 1.25, m, 4H; 1.62, m, 2H; 2.60, t, 2H; 6.73, dd, IH; 6.84, d, IH; 7.00, m, IH; 7.25, d, IH; 7.90, s, broad, IH; 8.82, s, 2H.

Example LXXVIII 5 - (2, 6-dibromo-4-nitrophenoxy) -3 -hexyl-1H-indole

Analogously, starting from 97 mg (0.45 mmol) of 5-hydroxy-3-hexylindole, 68 mg (0.49 mmol) of potassium carbonate and 133 mg (0.45 mmol) of 2-fluoro-5-nitro-l , 3-dibromobenzene 108 mg (49%) 5- (2,6-dibromo-4-nitrophenoxy) -3-hexyl-lH-indole.

300 MHz 1H NMR (CDC1 ₃ ): 0.88, m, 5H; 1.29, m, 4H; 1.65, m, 2H; 2.62, t, 2H; 6.79, d "IH; 6.89, d, IH; 7.00, IH; 7.28, d, IH; 7.90, s, broad, IH; 8.52, s, 2H.

Example LXXIX {5- [4-nitro-2,6-bis (trifluoromethyl) phenoxyl-1H-indol-3-yl) (phenyl) methanone

200 mg (0.4 mmol) 3-benzyl-5- [4-nitro-2,6-bis (trifluoromethyl) phenoxy] -lH-indole are dissolved in 3 ml of a mixture THF / water (10: 1) and at A solution of 182 mg (0.8 mmol) of 2,3-dichloro-5,6-dicyano-l, 4-benzoquinone in 2 ml of THF was added dropwise to room temperature. The mixture is stirred at room temperature for 1 h, the solvent is removed in vacuo and the residue is stirred with dichloromethane. It is suctioned off and the solid is dried. 165 mg (80%) of {5- [4-nitro-2,6-bis (trifluoromethyl) phenoxy] -lH-indol-3-yl} (phenyl) methanone are obtained.

300 MHz 1H NMR (CDCI ₃ ): 7.03,, IH; 7.13, m, 2H; 7.42, d, IH; 7.52, d, IH; 7.69, d, IH; 7.80, dd, 2H; 8.68, s, broad, IH; 8.83, s, 2H. Example LXXX

3,5-dibromo-4-r (3-hexyl-lH-indol-5-yl) oxy] aniline

102 mg (0.21 mmol) of 5- (2,6-dibromo-4-nitrophenoxy) -3-hexyl-lH-indole are combined in a solution of 278 mg (1.2 mmol) of tin chloride dihydrate in 2 ml. HCl dissolved and the solution is heated to 70 ° C for 60min. After cooling, the mixture is poured onto water, made alkaline with IN NaOH and extracted 3 times with ether. The combined organic phases are dried and the solvent is removed in vacuo. 68 mg (51%; 72% purity) of 3,5-dibromo-4 - [(3-hexyl-1H-indol-5-yl) - oxy] aniline are obtained, which is used without further purification.

300 MHz 1H NMR (CDC1 ₃ ): 0.98, m, 5H; 1.29, m, 4H; 1.65, m, 2H; 2.62, t, 2H; 3.71, s, broad, 2H; 6.80, m, IH; 6.92, m, 3H; 7.23, d, IH; 7.80, s, broad, IH.

Example LXXXI

3,5-dibromo-4- {3- (cyclohexylmethyl) -IH-indol-5-yl] oxy} aniline

Analogously, starting from 265 mg (0.52 mmol) of 3- (cyclohexylmethyl) -5- (2,6-dibromo-4-nitrophenoxy) -l H-indole and 706 mg (3.13 mmol) Tin chloride dihydrate with the addition of ethanol 193 mg (53%) 3,5-dibromo-4 - {[3- (cyclohexylmethyl) -lH-mdol-5-yl] oxy} aniline.

300 MHz 1H NMR (CDC1 ₃ ): 0.90, m; 1.88, m; 1.68, m; 2.52, d, 2H; 3.71, s, wide,

2H; 6.78, dd, IH; 6.92, m, 3H; 7.22, d, IH; 7.80, s, broad, IH.

Example LXXXII

4 - {[ ^" 3- (Cyclohexylmethyl) -IH-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) aniline

300 mg (0.62 mmol) of 3- (cyclohexylmethyl) -5- [4-nitro-2,6-bis (trifluoromethyl) phenoxy] -1 H-indole are dissolved in 30 ml of methanol at atmospheric pressure with 30 mg of palladium on carbon (10%) hydrogenated overnight. It is filtered through diatomaceous earth and the solvent is removed in vacuo. 258 mg (66%) of 4 - {[3- (cyclohexylmethyl) -1H-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) aniline are obtained. 300 MHz 1H NMR (CDC1 ₃ ): 0.92, m; 1.13, m; 1.67, M; 2.50, d, 2H; 3.99, s, broad, 2H; 6.71, dd, IH; 6.90, m, IH; 7.16, s, 2H; 7.70, d, IH; 7.80, s, broad, IH.

Example LXXXIII 3,5-dibromo-4- (3-pentyl-1H-indol-5-yl) oxy] aniline

65 mg (0.11 mmol) of 5- (2,6-dibromo-4-nitrophenoxy) -3-pentyl-1 H-indole are concentrated in a solution of 146 mg (0.65 mmol) of tin chloride dihydrate in 2 ml. HCl and 2 ml ethanol dissolved and the solution is heated to 70 ° C for 60min. After cooling, the mixture is poured onto water, made alkaline with IN NaOH and extracted 3 times with ether. The combined organic phases are dried and the solvent is removed in vacuo. Chromatographic purification (cyclohexane / ethyl acetate = 5: 1) gives 35 mg (69%) 3,5-dibromo-4 - [(3-pentyl-1H-indol-5-yl) oxy] aniline.

300 MHz 1H-NMR (CDCI3): 0.89, m; 1.32, m; 1.68, M; 2.63, t, 2H; 3.70, s, wide,

2H; 6.80, dd, IH; 6.93, m, 3H; 7.23, d, IH; 7.80, s, broad, IH.

Example LXXXIV

4 - [(3-pentyl-lH-indol-5-yl) oxy-3,5-bis (trifluoromethyl) aniline,

72 mg (0.16 mmol) of 5- [4-nitro-2,6-bis (trifluoromethyl) phenoxy] -3-pentyl-1H-indole are dissolved in 10 ml of methanol at atmospheric pressure with 7 mg of palladium on carbon (10%) hydrated overnight. It is filtered through diatomaceous earth and the solvent is removed in vacuo. Chromatography (cyclohexane / ethyl acetate = 5: 1) gives 46 mg (66%) of 4 - [(3-pentyl-lH-indol-5-yl) oxy] -3,5-bis (trifluoromethyl) aniline.

300 MHz 1H NMR (CDC1 ₃ ): 0.88, m, 5H; 1.29, m; 1.69, m; 2.60, t, 2H; 4.00, s, broad, 2H; 6.71, dd, IH; 6.80, m, IH; 6.92, m, IH; 7.16, s, 2H; 7.20, d, IH; 7.77, s, broad, IH.

Example LXXXV

3,5-dibromo-4 - [(3-butyl-lH-indol-5-yl) oxy1anilin

119 mg (0.25 mmol) 3-butyl-5- (2,6-dibromo-4-nitrophenoxy) -lH-indole are concentrated in 4 ml. HCl, 2 ml ethanol and 2 ml THF with 343 mg (1.52 mmol) tin chloride dihydrate heated to 70 ° C for 60 min. After cooling, the mixture is poured onto water, made alkaline with IN NaOH and extracted 3 times with ether. The combined organic phases are dried and the solvent is removed in vacuo.

Chromatographic purification (cyclohexane / ethyl acetate = 10: 1) gives 78 mg (61%, 86% purity) 3,5-dibromo-4 - [(3-butyl-lH-indol-5-yl) oxy] anüin.

300 MHz 1H NMR (CDC1 ₃ ): 0.92, m; 1.38, m; 1.70,; 2.63, t, 2H; 6.80, dd, IH; 6.92, m, 4H; 7.22, d, IH; 7.80, s, broad, IH. Example LXXXVI

4 - [(3-butyl-lH-indol-5-yl) oxy-3,5-bis (trifluoromethyl) aniline

104 mg (0.23 mmol) of 3-butyl-5- [4-nitro-2,6-bis (trifluoromethyl) phenoxy] -IH-indole are dissolved in 10 ml of methanol at atmospheric pressure with 10 mg of palladium on carbon

(10%) hydrogenated overnight. It is filtered through diatomaceous earth and the solvent is removed in vacuo. Chromatography (cyclohexane ethyl acetate = 10: 1) gives 50 mg (49%) 4 - [(3-butyl-lH-indol-5-yl) oxy] -3,5-bis (trifluoromethyl) aniline.

300 MHz 1H NMR (CDC1 ₃ ): 0.91, t, 3H; 1.37, m, 2H; 1.62, m, 2H; 2.62, t, 2H; 3.98, s, broad, 2H; 6.71, dd, IH; 6.81, d, IH; 6.95, m, IH; 7.28, s, 2H; 7.21, d, IH; 7.79, s, broad, IH.

Example LXXXVII

4 - [(3-propyl-lH-indol-5-yl) oxy] -3,5-bis (trifluoromethyl) aniline

290 mg (0.67 mmol) of 5- [4-nitro-2,6-bis (trifluoromethyl) phenoxy] -3-propyl-1H-indole are dissolved in 30 ml of methanol at atmospheric pressure with 30 mg of palladium on carbon (10%) hydrated overnight. It is filtered through diatomaceous earth and the solvent is removed in vacuo. Chromatography (cyclohexane / ethyl acetate = 5: 1) gives 77 mg (28%) of 4 - [(3-propyl-lH-indol-5-yl) oxy] -3,5-bis (trifluoromethyl) aniline. 300 MHz 1H NMR (CDC1 ₃ ): 0.95, t, 3H; 1.66, sext., 2H; 2.61, t, 2H; 6.76, dd, IH; 6.86, m, IH; 6.98, m, IH; 7.28, m; 7.86, s, broad, IH.

Example LXXXVIII

3,5-dibromo-4 - [(3-propyl-lH-indol-5-yl) oxylanilin

240 mg (0.53 mmol) of 5- (2,6-dibromo-4-nitrophenoxy) -3-propyl-1H-indole are dissolved with 716 mg (3.17 mmol) of tin chloride dihydrate in 8 ml of conc. HCl added. Ethanol is added until a clear solution is reached and the mixture is heated at 70 ° C. for 60 min. After cooling, the mixture is poured onto water, made alkaline with IN NaOH and extracted 3 times with ether. The combined organic phases are dried and the solvent is removed in vacuo. Chromatographic purification (cyclohexane / ethyl acetate = 10: 1) gives 215 mg (96%) 3,5-dibromo-4 - [(3-propyl-1H-indol-5-yl) oxy] aniline.

300 MHz 1H NMR (CDC1 ₃ ): 0.97, t, 3H; 1.67, sext., 2H; 2.62, t, 2H; 3.71, s, broad, 2H; 6.79, dd, IH; 6.92, m, 4H; 7.23, d, IH; 7.81, s, broad, IH.

embodiments

example 1

Ethyl 2- [4- (1H-indol-5-yloxy) -3,5-bis (trifluoromethyl) anilino] -2-oxoacetate

200 mg (0.56 mmol) of 4- (1H-indol-5-yloxy) -3,5-bis (trifluoromethyl) aniline are refluxed with 1.05 g (7.22 mmol) of diethyl oxalate in 10 ml of toluene overnight heated. The reaction mixture is diluted with water, the organic phase over

Dried sodium sulfate and the solvent removed in vacuo. After chromatographic purification, 158 mg (62%) of ethyl 2- [4- (1H-indol-5-yloxy) -3,5-bis (trifluoromethyl) anilino] -2-oxoacetate are obtained.

200 MHz iH NMR (DMSO-d6): 1, 3r, t, 3H: 4.36, quart, 2H; 6.30 s, IH: 6.71, m,

2H; 7.30, m, 2H; 8.61, s, 2H; 11.05, s, IH; 11.42, s, IH.

Example 2

Ethyl 2- \ 4- (1 H -indole-5-yloxy) -3,5-dimethylanilinol-2-oxoacetate

840 mg (3.33 mmol) of 4- (1H-indol-5-yloxy) -3,5-dimethylaniline are refluxed overnight with 6.32 g (43.3 mmol) of diethyl oxalate in 60 ml of toluene. The The reaction mixture is subjected to chromatographic purification (toluene / ethyl acetate = 4: 1). 890 mg (76%) of ethyl 2- [4- (1H-indol-5-yloxy) -3,5-bis-dimethylanilino] -2-oxoacetate are obtained.

400 MHz Η NMR (DMSO-d6): 1.33, t, 3H: 2.08, s, 6H; 4.31, quart, 2H; 6.26, m, IH; 6.63, m, IH; 6.71, dd, IH; 7.30, m, 2H; 7.51, s, 2H; 10.62, s, IH; 10.95, s, IH.

Example 3

Ethyl 2- {3.5 -dimethyl-4- [3 -methyl-1H-indole-5-vDoxy] anilino) -2-oxoacetate

72 mg (0.72 mmol) of 3,5-dimethyl-4 - [(3-methyl-lΗ-indol-5-yl) oxy] aniline are mixed with 513 mg (3.5 mmol) of oxalic acid ethyl chloride in 5 ml of toluene overnight stirred at room temperature. Chromatographic purification (toluene / ethyl acetate = 9: 1 ethyl acetate) gives 97 mg (99%) ethyl-2- {3,5-dimethyl-4 - [(3-methyl-lH-indol-5-yl) oxy] - anilino} -2-oxoacetate.

200 MΗz Η NMR (DMSO-d6): 1.33, t, 3Η: 2.08, s, 6H; 2.11 s, 3H: 4.31, quart, 2H; 6.62, s, 2H; 7.08, m, IH; 7.25, dd, IH; 7.52, s, 2H; 10.66, s, IH; 10.70, s, IH.

Example 4

N- [4- (3-Isopropyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethylphenyl1oxamic acid ethyl ester

457 mg (1.14 mmol) of 4- (3-isopropyl-lH-indol-5-yloxy) -3,5-bis-trifluoromethylphenylamine are dissolved in 100 ml of dichloromethane, with 0.2 ml (1.43 mmol ) Added triethylamine and reacted dropwise under argon with 210 mg (1.53 mmol) ethyl oxalate chloride - dissolved in 50 ml dichloromethane - within 1 hour at room temperature. After 3 hours, the reaction solution is stopped by adding 100 ml of buffer solution (pH = 7.0), the dichloromethane layer is separated off and the aqueous layer is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate and concentrated, leaving a gray powder. The crude product is purified by chromatography on 200 ml of cheese gel, with toluene with the addition of ethyl acetate using the gradient method (490 ml of toluene / 10 ml of ethyl acetate to 400 ml of toluene / 100 ml of ethyl acetate mixture).

Yield: 492.5 mg (81.4%)

Rf. 0.36 (ToluohEssigester = 9: 1)

HPLC: rt (%) = 5.16 (94.28) Example 5

N-r4- (3-ethyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethyl-phenyl] oamide acid ethyl ester

Following the procedure of Example 4, 326.7 mg (0.84 mmol) of 4- (3-ethyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethylphenylamine with 235.0 mg

(1.72 mmol) ethyl oxalate chloride in the presence of 0.13 ml (0.93 mmol) triethylamine and 40 ml dichloromethane. After stirring for 3 hours

A further 80 mg (0.59 mmol) of ethyl oxalate chloride - dissolved in 50 ml of dichloromethane - are added dropwise at room temperature within 15 minutes.

After addition of the acid chloride, the isolation and chromography of the product is carried out in accordance with the instructions from Example 4.

Yield: 345.6 mg (94.2%)

Rf 0.38 (Toluok ethyl acetate = 9: 1)

HPLC: rt (%) = 4.98 (94.2) 1% HClOyacetonitrile

Example 6

Ethyl {F4-1 [3 - (4-fluorobenzyl-1H-indole-5-yl] oxy) -3,5-bisfirifluoromethyphenyl] amino} (oxo) acetate

106 mg (0.12 mmol) of 4 - {[3- (4-fluorobenzyl) -lH-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) aniline and 13 mg (0.13 mmol) of triethylamine are combined submitted in 1.3 ml dichloromethane. 22 mg (0.16 mmol) of oxalic acid ester chloride are added dropwise and the mixture is stirred at room temperature for 3 h. The reaction mixture is saturated with. NaΗCθ ₃ solution. added, the phases separated, the organic phase washed once more with saturated NaCl solution, dried and evaporated. Chromatographic purification (toluene / acetonitrile) gives 33 mg (40%) of ethyl - {[4 - {[3- (4-fluorobenzyl) -lH-indol-5-yl] oxy} -3,5-bis (trifluoromethyl ) phenyl] amino} (oxo) acetate.

300MHz 1H NMR (CDC1 ₃ ): 1.48, t, 3H; 3.95, s, 2H; 4.48, quart, 2H; 6.42, d, IH;

6.88, m, 4H; 7.12, m, 2H; 7.23, m, IH; 7.90, s, broad, IH; 8.21, s, 2H; 9.10, s, broad, IH.

Example 7

ethyl | ^" (3,5-dibromo-4 - {[3- (4-fluorobenzyl-1H-indol-5-yl1oxy> phenylamino] - (oxo) acetate

50 mg (0.10 mmol) 3,5-dibromo-4 - {[3- (4-fluorobenzyl) -lΗ-indol-5-yl] oxy} aniline and 11 mg (0.11 mmol) triethylamine are combined in 1.3 ml Submitted dichloromethane. 19 mg (0.14 mmol) of ethyl oxalate chloride are added dropwise and the mixture is stirred at room temperature for 3 h. The reaction mixture is saturated with. NaHCO ₃ solution. added, the phases separated, the organic phase washed once more with saturated NaCl solution, dried and evaporated. Chromatographic purification (toluene / acetonitrile) gives 34 mg (57%).

300MHz 1H NMR (CDC1 ₃ ): 1.45, t, 3H; 3.96, s, 2H; 4.45, quart, 2H; 6.57, d, IH; 6.88, m, 4H; 7.17, m, 2H; 7.28, m, IH; 7.90, s, broad, IH; 7.95, s, 2H; 8.87, s, IH.

Example 8

Ethyl - ({4 - [(3-isopropyl-1H-indol-5-yl) methyl] -3,5-dimethyl-phenyl-} amino) - (oxo) acetate

8 mg of 4 - [(3-isopropyl-lH-indol-5-yl) methyl] -3,5-dimethylaniline (0.026 mmol) and 5 mg (0.035 mmol) of ethyl oxalate chloride are initially introduced into 1 ml of dichloromethane. 3 mg (0.029 mmol) of triethylamine, dissolved in 1 ml of dichloromethane, are added dropwise at 0 ° C. in the course of about 20 min. The mixture is stirred at 0 ° C. for 4 h. It is diluted with dichloromethane, extracted with NaΗCθ ₃ - and NaCl solution, the organic phase is dried and rotated in. Chromatography (cyclohexane / ethyl acetate = 7: 1) gives 10 mg of ethyl - ({4 - [(3-isopropyl-1H-indol-5-yl) methyl] -3,5-dimethylphenyl -) - amino) - ( oxo) acetate. R _f (cyclohexane / ethyl acetate 3: 1) = 0.35

Example 9

N-F4- (3-isopropyl-lH-indol-5-yloxy) -3,5-dibromophenyl-oxamic acid, ethyl ester

The preparation is carried out in analogy to the procedure of Example 4 from 128.7 mg (0.3 mmol) of 4- (3-isopropyl-1H-indol-5-yloxy) -3,5-dibromo-ρhenylamine and 55.9 mg ( 0.41 mmol) ethyl oxalate chloride in the presence of 0.05 ml (0.36 mmol) triethylamine. The crude product is reprecipitated from 20 ml of toluene by adding cyclohexane, stirred in an ultrasound bath, suction filtered, washed on the suction filter with cyclohexane and dried in a high vacuum.

Yield: 156.1 mg (97.6%) Rf: 0.53 (toluene: ethyl acetate = 8: 2)

MS (DCI): 525 ([M + H] ⁺ , 40%)

NMR (300 MHz, CDCI ₃ ): 5 = 1.29 (d, 6H); 1.45 (t, 3H); 3.09 (quin, IH); 4.44 (quart, 2H); 6.78 (dd, IH); 6.96 (dd, 2H); 7.26 (d, IH); 7.83 (s, IH); 7.97 (s, 2H); 8.88 (s, IH) ppm. Example 10

N-F4- (3-isopropyl-lH-indol-5-yloxy) -3,5-dibromo-phenyll-oxamic acid

35 mg (0.067 mmol) of ethyl oxamic acid from Example 9 are dissolved in 2 ml of dioxane under argon and 0.9 ml of 1 molar sodium hydroxide solution is added dropwise. After 6 hours of stirring at room temperature, the reaction solution is mixed with 1 ml of 1 molar hydrochloric acid and 3 ml of NH C1 solution with the addition of 40 ml of ethyl acetate, the ethyl acetate layer is separated off and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. The crude product is purified by chromatography on silica gel using toluene / ethyl acetate (1: 1) and ethyl acetate / methanol (1: 1).

Yield: 21.3 mg (64.5%)

MS (ES): 497 ([M + H] ⁺ , 100%) HPLC: rt (%) = 4.43 (100%)

0.01 mol. H ₃ PO ₄ / acetonitrile Kromasil column C18 (60 x 2 mm) flow 0.75 ml / min, 210 nm. Example 11

Pyridin-2-carbonsäurer3,5-dibromo-4- (3-isopropyl-lH-indol-5-yloxy) -phenyl] -amide

To a solution of 110 mg (0.26 mmol) of phenylamine derivative from Example XVI in 10 ml of dichormethane, 0.11 ml (0.79 mmol) of triethylamine and 60 mg (0.40 mmol) of picolinoyl chloride hydrochloride are added in succession while cooling with ice. The mixture is then stirred for 3 hours at room temperature without cooling, the reaction solution is diluted with 60 ml of dichloromethane and washed with saturated NH C1 solution. After drying over sodium sulfate and removal of the solvent, the residue is purified by column chromatography on silica gel with toluene and toluene / acetonitrile (25: 1).

Yield: 115.2 mg (82.4%)

Rf: 0.67 (toluene: acetonitrile = 4: 1)

MS (DCI): 545 ([M + NH ₄ ] ⁺ , 52%)

NMR (200 MHz, CDCI ₃ ): 5 = 1.3 (d, 6H); 3.19 (quin, IH); 6.79 (d, IH); 6.84 (d, IH); 6.95 - 6.99 (dd, 2H); 7.27 (d, IH); 7.48-7.55 (m, IH); 7.81 (broad s, IH); 7.93 (m, IH); 8.13 (s. 2H); 8.3 (d, IH); 8.51 (m, IH); 10.1 (s, IH) ppm. Example 12

Hexanoic acid [3,5-dibromo-4- (3-isopropyl-lH-indol-5-yloxy) -phenyl] -amide

The preparation is carried out in analogy to the procedure of Example 11 from 80 mg (0.19 mmol) phenylamine derivative from Example XVI, 30 mg (0.25 mmol) n-hexanoyl chloride and 0.03 ml (0.21 mmol) triethylamine in 10 ml dichloromethane. The reaction solution is poured into saturated NH ₄ C1 and NaHCO ₃ solution, extracted three times with ethyl acetate, the organic phases are dried over sodium sulfate and the solvent is evaporated down i. Vak. distilled off.

Yield: 80.9 mg (80.3%) Rf: 0.35 (toluene: ethyl acetate = 9: 1) MS (DCI): 538 ([M + NH ₄ ] ⁺ , 68%)

NMR (400 MHz, CDCI ₃ ): 5 = 0.91 (t, 3H); 1.29 (d, 6H); 1.37 (m, 4H); 1.73 (m, 2H); 2.37 (t, 2H); 3.08 (quin, IH); 6.78 (dd, IH); 6.95 (dd, 2H); 7.08 (s, IH); 7.23 (d, IH); 7.8 (s, IH); 7.85 (s, 2H) ppm.

Example 13

N-r4- (3-isopropyl-lH-indol-5-yloxy) -3,5-divinyl-phenyl] oxamic acid-ethlyester

The preparation is carried out in analogy to the procedure of Example 4 from 62.2 mg (0.2 mmol) indole derivative from Example XVIII and 36.0 mg (0.26 mmol) ethyl oxalate chloride in the presence of 0.03 ml (0.21 mmol) triethylamine. The product is crystallized with diisopropyl ether.

Yield: 57.1 mg (68.2%)

Rf: 0.29 (toluene: ethyl acetate = 9: 1)

MS (ESI): 441 ([M + Na, 100%)

NMR (200 MHz, CDCI ₃ ): 5 = 1.27 (d, 6H); 1.46 (t, 3H); 3.03 (quin, IH); 4.45 (fourth,

2H); 5.21 (d, 2H); 5.77 (d. 2H); 6.72 (dd, IH); 6.81 (d, IH); 6.9 (dd, 2H); 7.21 (d, IH); 7.79 (broad s, IH); 7.85 (s. 2H); 8.9 (s, IH) ppm.

Example 14

N-r4- (3-isopropyl-lH-indol-5-yloxy) -3,5-dicyclopropyl-phenyl1-oxamic acid, ethyl ester

Following the instructions of Example 4, 40 mg (0.13 mmol) of indole derivative of Example XV with 30 mg (0.19 mmol) of oxalic acid ethyl ester chloride in the presence of 0.02 ml (0.15 mmol) of triethylamine implemented in 8 ml dichloromethane. After isolation and chromatography of the crude product, 8.1 mg are obtained

(15.7%).

MS (ESI): 496 ([M + Na, 96.8%) Rf: 0.58 (toluene-.acetonitrile = 8: 2) HPLC: rt (%) = 5.24 (96.8%)

0.01 mol. H ₃ PO ₄ / acetonitrile Kromasil column C18 (60 x 2 mm) flow 0.75 ml min, 210 nm.

Example 15

N- {3- (2-tert-Butoxycarbonylamino-ethyl) -IH-indol-5-yloxy] -3,5-bis-trifluoromethyl-phenylj-oxamic acid, ethyl ester

Following the instructions of Example 4, 254.3 mg (0.51 mmol) of indole derivative of Example XXII are mixed with 93.1 mg (0.68 mmol) of oxalic acid ethyl ester chloride in the presence of 0.08 ml (0.56 mmol) of trieethylamine in 35 ml of dichloromethane in 2.5 hours. The crude product was purified on about 80 ml of silica gel using toluene / acetonitrile (isocratic, 9: 1).

Yield: 331.7 mg (100%) MS (ESI): 604 ([M + H] ⁺ , 15%) Rf: 0.38 (toluene: acetonitrile = 8: 2) HPLC: rt (%) = 4, 80 (94.3%)

1% HCIO acetonitrile

Kromasil column C18 (60 x 2 mm)

Flow 0.75 ml / min, 210 nm. The following examples are prepared in analogy to the examples above:

Example 26

N- [4- (sec-butyl-1H-indole-5-yloxy) -3,5-dimethyl-phenyl] -oxamic acid ethyl ester

1.52 g (4.93 mmol) of 4- (3-sec-butyl-lH-indol-5-yloxy) -3,5-dimethylphenylamine are dissolved in 200 m dichloromethane, while stirring at room temperature 0.44 ml (5th , 43 mmol) pyridine and then 0.75 ml (6.66 mmol) ethyl oxalate chloride added dropwise under argon.

After stirring for one hour at room temperature, buffer of pH = 7 is added to the reaction solution, the organic phase is separated off and the aqueous phase is extracted twice more with dichloromethane. The combined organic phases are with saline, 1 N hydrochloric acid, NaHCO ₃ solution and finally with

Washed saline. After drying over sodium sulfate, the solvent is distilled off and the residue is dissolved in a little toluene and chromatographed over silica gel using toluene / ethyl acetate (20: 1).

Yield: 1.82 g (90.4%)

HPLC rt = 5.11 (96.0%)

0.01 mol H ₃ PO ₄ / acetonitrile Kromasil column C18 (60x2 mm) flow: 0.75 ml / min .; 210 nm MS (ESI): 409 ([M + H] ⁺ , 100%)

R _f = 0.31 (toluene: ethyl acetate = 9: 1)

200 MHz 1H NMR (CDC1 ₃ ): 1.85 (t, 3H); 1.24 (d, 3H); 1.43 (t, 3H); 1.53 - 1.78 (m, 2H); 2.15 (s, 6H); 2.81 (quart., IH); 4.43 (quart., 2H); 6.72 (dd, IH); 6.86 (d, IH); 6.93 (d, IH); 7.21 (d, IH); 7.4 (s. 2H); 7.81 (s, IH); 8.8 (s, IH).

The following compounds (Examples 27 to 40) are prepared in analogy to the procedure of Example 26: Example 27

N- [4- (3-isopropyl-lH-indol-5-yloxy) -3,5-dimethyl-phenyl] -oxamic acid ethyl ester

reactants:

12.78 g (43.41 mmol) of 4- (3-isopropyl-1H-indol-5-yloxy) -3,5-dimethyl-phenylamine

8.0 g (58.6 mmol) of ethyl oxalate chloride

3.86 ml (47.75 mmol) pyridine in 350 ml dichloromethane

Yield: 17.16 g (97.6%) MS (ESI): 315 ([M + H] ⁺ , 100%) R _f = 0.29 (toluene: ethyl acetate = 9: 1)

300 MHz, 1H NMR (CDC1 ₃ ): 1.26 (d, 6H); 1.43 (t, 3H); 2.17 (s, 6H); 3.06 (quin., IH); 4.42 (quart., 2H); 6.73 (dd, IH); 6.87 (d, IH); 6.94 (d, IH); 7.21 (d, IH); 7.39 (s. 2H); 7.78 (s, IH); 8.78 (s, IH).

Example 28

N- [4- (3-isobutyl-lH-indol-5-yloxy) -3,5-dimethyl-phenyl] -oxamic acid ethyl ester

reactants:

0.13 g (0.41 mmol) 4- (3-isobutyl-lH-indol-5-yloxy) -3,5-dimethylphenylamine 0.08 g (0.55 mmol) ethyl oxalate chloride 0.04 ml (0.49 mmol) pyridine in 10 ml dichloromethane

Yield: 32.2 mg (19.5%) MS (ESI): 409 ([M + H] ⁺ , 12%) HPLC rt = 5.23 (77.6%) 0.5% HClO ₄ / acetonitrile

Kromasil column C18 (60x2 mm)

Flow: 0.75 ml min .; 210 nm

Example 29

N- [4- (3-isobutyl-1H-indole-5-yloxy) -3,5-dimethylphenyl] -N'-methoxy-N '-methyl oxalamide

reactants:

80 mg (0.259 mmol) 4- (3-isobutyl-1H-indol-5-yloxy) -3,5-dimethyl-phenylamine

0.025 ml (0.311 mmol) pyridine

59 mg (0.389 mmol) (methoxy-methylamino) -oxo-acetyl chloride in 6 ml of dichloromethane

Yield: 85.2 mg (77.6%)

MS (ESI): 424 ([M + H] ⁺ , 100%)

HPLC: rt = 4.81 (94.6%)

0.5% HClO ₄ / acetonitrile Kromasil column C18 (60x2 mm) flow: 0.75 ml / min .; 210 nm

R _f : 0.44 (toluene: ethyl acetate = 8: 2)

Example 30

N- [4- (3-isobutyl-1H-indol-5-y loxy) -3,5-bis-trifluoromethyl-phenyl] -oxamic acid ethyl ester

reactants:

0.54 g (1.31 mmol) of 4- (3-isobutyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethyl-phenylamine

0.24 g (1.76 mmol) ethyl oxalate chloride

0.12 ml (1.44 mmol) pyridine in 10 ml dichloromethane

Yield: 354 mg (52.5%) MS (ESI): 517 ([M + H] ⁺ , 100%)

R _f = 0.34 (toluene: acetonitrile = 9: 1)

Example 31

N- [4- (3-sec-Butyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethyl-phenyl] -oxamic acid ethyl ester

reactants:

170 mg (0.4 mmol) of 4- (3-sec-butyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethyl-phenylamine 0.062 ml (0.44 mmol) of triethylamine

0.062 ml (0.54 mmol) ethyl oxalate chloride in 30 ml dichloromethane

Yield: 197.4 mg (93.8%) R _f = 0.44 (dichloromethane)

200 MHz 1H NMR (CDC1 ₃ ): 0.84 (t, 3H), 1.24 (d, 3H); 1.47 (t, 3H); 1.42 - 1.77 (m, 2H); 2.81 (quart, IH); 4.47 (quart, 2H); 6.72 (dd, IH); 6.83 (d, IH); 6.94 (d, IH); 7.22 (d, IH); 7.83 (s, IH); 8.24 (s, 2H); 9.09 (s, IH).

Example 32

N- [4- {3- (4-fluorophenyl) -IH-indol-5-yloxy} -3,5-bis-trifluoromethyl-phenyl] -oxamic acid ethyl ester

reactants:

30 mg (0.066 mmol) of 4- [3- (4-fluorophenyl) -IH-indol-5-yloxy] -3,5-bis-trifluoromethylphenylamine

0.01 ml (0.073 mmol) pyridine

0.01 ml (0.09 mmol) ethyl oxalate chloride in 10 ml dichloromethane

Yield: 23.6 mg (62.8%)

MS (LC method, ES ⁴ ): 572 ([M + NE, 100%) HPLC: rt = 5.00 (97.4%)

0.5% HClO ₄ / acetonitrile Kromasil column C18 (60x2 mm) flow: 0.75 ml / min .; 210 nm Example 33

N- [4- (3-Methyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethylphenyl) oxamic acid ethyl ether

reactants:

270 mg (0.673 mmol) of 4- (3-methyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethyl-phenylamine

0.06 ml (0.74 mmol) pyridine

0.101 ml (0.91 mmol) ethyl oxalate chloride in 35 ml dichloromethane

Yield: 307.7 mg (93.3%) MS (DCI): 492 ([M + NH ₄ ] ⁺ , 100%)

R _f = 0.17 (toluene: ethyl acetate = 9: 1) HPLC rt = 4.88 (96.7%)

0.01 mol H ₃ PO ₄ / acetonitrile Kromasil column C18 (60x2 mm) flow: 0.75 m / min .; 210 nm

Example 34

4- [N- (3-Cyclobutylmethyl-1H-mdol-5-yloxy) -3,5-bis-trifluoromethyl-phenyl] -oxamide acid ethyl ester

reactants:

64 mg (0.15 mmol) of 4- (3-cyclobutylmethyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethyl-phenylamine

0.013 ml (0.16 mmol) pyridine

0.023 ml (0.202 mol) ethyl oxalate chloride in 16 ml dichloromethane

Yield: 68 mg (77.9%)

MS (ESI): 529 ([M + H] ⁺ , 42%)

HPLC rt = 5.20 (90.4%)

0.5% HClO ₄ / acetonitrile

Kromasil column C18 (60x2 mm)

Flow: 0.75 ml / min .; 210 nm R _f = 0.16 (toluene: ethyl acetate = 9: 1)

Example 35

N- [4- (3-isopropyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethylphenyl] -N'-methoxy-N 'methoxy-oxalamide

reactants:

100 mg (0.249 mmol) of 4- (3-isopropyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethylphenylamine

0.022 ml (0.273 mmol) pyridine

51 mg (0.336 mmol) (methoxy-methylamino) -oxo-acetyl chloride in 10 ml of dichloromethane

Yield: 77.5 mg (60.3%) MS (ESI): 518 ([M + H] ⁺ , 100%)

300 MHz 1H NMR (CDC1 ₃ ): 1.27 (d, 6H); 1.5 (s, 3H); 3.05 (quin., IH); 3.84 (s, 3H); 6.73 (dd, IH); 6.84 (d, IH); 6.95 (d, IH); 7.21 (d, IH); 7.8 (s, IH); 8.21 (s, 2H); 9.65 (s, IH).

Example 36

N- [4- (3-sec-Butyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethyl-phenyl] -C-oxo-C-thiophene-2-yl-acetamide

reactants:

100 mg (0.24 mmol) of 4- (3-sec-butyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethylphenylamine

21 µl (0.264 mmol) pyridine

62.8 mg (0.36 mmol) 2-thiophene glyoxyloyl chloride in 8 ml dichloromethane

Yield: 68 mg (51.1%)

MS (LC method, ES ^" "): 555 ([M + H] ⁺ , 100%)

300 MHz 1H NMR (CDC1 ₃ ): 0.85 (t, 3H); 1.25 (d. 3H); 1.51 - 1.75 (m, 2H); 2.81 (quin., IH); 6.72 (dd, IH); 6.85 (d, IH); 6.93 (d, IH); 7.15 - 7.39 (m, IH); 7.23 (d, IH); 7.81 (s, IH); 7.92 (dd, IH); 8.32 (s, 2H); 8.53 (dd, IH); 9.37 (s, IH). Example 37

N- [4- (3-Isoρropyl-lH-indol-5-yloxy) -3,5-bis-trifluoromethyl-phenyl] -C-oxo-C-thiophene-2-yl-acetamide

reactants:

100 mg (0.248 mmol) of 4- (3-isopropyl) -IH-indol-5-yloxy) -3,5-bis-trifluoromethyl) phenylamine

0.1 ml (1.236 mmol) pyridine

86.8 mg (0.497 mmol) 2-thiophenylglyoxyloyl chloride in 5 ml dichloromethane

Yield: 69 mg (51.4%) MS (ESI): 541 ([M + H] ⁺ , 100%)

300 MHz 1H NMR (CDC1 ₃ ): 1.27 (d, 6H); 3.04 (quin., IH); 6.73 (dd, IH); 6.84 (d, IH); 6.93 (d, IH); 7.13 - 7.28 (m, 2H); 7.79 (s, IH); 7.92 (dd, IH); 8.3 (s. 2H); 8.53 (dd, IH); 9.35 (s, IH).

Example 38

N- [4- (3-methoxycarbonylmethyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethyl-phenyl] -oxamic acid ethyl ester

reactants:

150 mg (0.347 mmol) of 4- (3-methoxycarbonyl-methyl-1H-indol-5-yloxy) -3,5-trifluoromethyl-phenylamine

0.031 ml (0.382 mol) pyridine

0.052 ml (0.468 mmol) ethyl oxalate chloride in 10 ml dichloromethane

Yield: 118 mg (63.9%)

MS (ESI): 532 ([M + H] ⁺ , 53%)

HPLC rt = 4.75 (87.4%)

0.5% HClO ₄ / acetonitrile Kromasil column C18 (60x2 mm) flow: 0.75 ml / min .; 210 nm

Example 39

2-Acetylamino-3- (5- {2,6-bis-trifluoromethyl-4 - [(l-ethoxycarbonyl-methanoyl) - amino] -phenoxy} -lH-indol-3-yl) -propionic acid methyl ester (DL)

reactants:

218 mg (0.368 mmol) of methyl 2-acetylamino-3- [5- (4-amino-2,6-bis-trifluoromethylphenoxy) - 1H-indol-3-yl] propionate (DL) 0.033 ml (0.405 mmol) pyridine

0.056 ml (0.497 mmol) oxalic acid ethyl chloride in 15 ml dichloromethane Yield: 171.9 mg (90.4%) MS (ESI): 604 ([M + H] ⁺ , 30%) R _f = 0.23 (toluene: ethyl acetate = 1: 2)

HPLC rt = 4.42

0.5% HClO ₄ / acetonitrile Kromasil column C18 (60x2 mm) flow: 0.75 ml / min .; 210 nm Example 40

2-Acetylamino-3- (5- {2,6-dibromo-4 - [(l-ethoxycarbonyl-methanoyl) -amino] - ρhenoxy} -lH-indol-3-yl) -propionic acid methyl ester (DL)

reactants:

219 mg (0.22 mmol) of 2-acetylamino-3- [5- (4-amino-2,6-dibromophenoxy) -lH-indol-3-yl] -propionic acid methyl ester (DL)

0.02 ml (0.242 mmol) pyridine 0.034 ml (0.297 mmol) ethyl oxalate chloride in 10 ml dichloromethane

Yield: 100 mg (72.6%)

MS (ESI): 646 ([M + Na, 72%) HPLC rt = 4.31 (92.4%)

0.5% HClO ₄ / acetonitrile Kromasil column C18 (60x2 mm) flow: 0.75 ml / min .; 210 nm

200 MHz 1H NMR (CDC1 ₃ ): 1.44 (t, 3H); 1.93 (s, 3H); 3.21 (d. 2H); 3.68 (s, 3H); 4.45 (quart., 2H); 4.86 - 4.95 (m, IH); 5.93 (d, IH); 6.81 (dd, 2H); 6.99 (d, IH); 7.3 (s and d, 3H); 8.04 (s, IH); 8.9 (s, IH). Example 41

N- [4- (3-isopropyl-lH-indol-5-yloxy) -3,5-dimethyl-phenyl] oxamic acid

12.4 g (31.43 mmol) of oxamic acid ethyl ester from Example 27 are dissolved in 1300 ml of dioxane under argon, 330 ml of 1 molar sodium hydroxide solution are added and the mixture is stirred for about 10 minutes at room temperature (TLC control on starting material). The reaction solution is then acidified to pH 4 with concentrated hydrochloric acid, saturated with sodium chloride (test) and extracted four times with ethyl acetate. The combined organic phases are washed with sodium chloride solution, dried over sodium sulfate, filtered, concentrated and dried overnight under high vacuum. The substance is then dissolved in dichloromethane at 40 ° C and precipitated again by adding 10 times the amount of cyclohexane, suction filtered, washed with cyclohexane and dried overnight at 70 ° C in a vacuum drying cabinet.

Yield: 11.49 g (99.7%) MS (ESI): 367 ([M + H] ⁺ , 100%)

300 MHz 1H NMR (d ₆ -DMSO): 1.2 (d, 6H); 2.06 (s, 6H); 6.61 (dd, IH); 6.71 (d,

IH); 7.03 (d, IH); 7.22 (d, IH); 7.53 (s. 2H); 10.43 (s, IH); 10.61 (s, IH). R _f = 0.18 (dichloromethane / methanol = 9: 1)

The following compounds (Examples 42 and 43) are prepared in analogy to the procedure of Example 41: Example 42

N- [4- (3-sec-butyl-1 H -indol-5-yloxy) -3, 5-bis-trifluoromethyl-phenyl] -oxamic acid

reactants:

90 mg (0.174 mmol) ethyl oxamic acid from Example 31

2.15 mg 1 molar sodium hydroxide solution and 4.5 ml dioxane

Yield: 75.8 mg (87.3%)

MS (LC method, ES ⁺ ): 489 ([M + H] ⁺ , 15%) HPLC rt = 4.76 (98.0%)

0.5% HClO ₄ / acetonitrile Kromasil column C18 (60x2 mm) flow: 0.75 ml min .; 210 nm

R _f = 0.16 (ethyl acetate: methanol = 9: 1)

Example 43

N- [4- (3-sec-butyl-lH-indol-5-yloxy) -3,5-dimethyl-phenyl] oxamic acid

reactants:

17 mg (0.042 mmol) of ethyl oxaidate from Example 26

0.45 ml 1 molar sodium hydroxide solution and 1.2 ml dioxane

Yield: 15.8 mg (100%)

MS (ES): 403 ([M + Na] ⁺ , 84%)

300 MHz 1H NMR (d ₆ -DMSO): 0.79 (t, 3H); 1.18 (d, 3H); 1.45 - 1.65 (m, 2H); 2.03 (s, 6H); 2.7 (quart., IH); 6.6 (dd, IH); 6.7 (d, IH); 7.05 (d, IH); 7.23 (d, IH); 7.55 (s. 2H); 10.37 (s, IH); 10.68 (s, IH).

Example 44

N- [4- (3-Isopropyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethyl-phenyl] -oxamic acid methyl ester

10 mg of N- [4- (3-isopropyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethyl-phenyl] -oxamide acid ethyl ester (Example 4) are dissolved in 10 ml of methanol at 40C and Let stand overnight at room temperature. After distilling off the solvent, the methyl ester is obtained quantitatively. MS (DCI): 506 ([M + NH ₄ ] ⁺ , 100%) R _f = 0.27 (toluene: ethyl acetate = 9: 1) Example 45

N- [4- (3-isopropyl-lH-indol-5-yloxy) -3,5-bis-trifluoπnethyl-ρhenyl] -oxalamide

200 mg (0.4 mmol) of N- [4- (3-isopropyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethyl-phenyl] -oxamic acid ethyl ester (Example 4) in 4 ml of methanol pa dissolved and initiated at -10 ° C ammonia until saturation. After 4 days at room temperature, the solution is concentrated in vacuo and the residue is dried in a high vacuum.

Yield: 185.5 mg (98.4%) MS (ESI): 474 ([M + H] ⁺ , 100%)

200 MHz 1H NMR (d ₆ -DMSO): 1.17 (d, 6H); 2.94 (quin., IH); 6.61 (dd, IH); 6.7 (d,

IH); 7.07 (d, IH); 7.23 (d, IH); 8.1 (s, IH); 8.42 (s, IH); 8.7 (s. 2H); 10.72 (d, IH).

Example 46

N-Isoρroρyl-N '- [4- (3-isopropyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethyl-phenyl] oxalamide

100 mg (0.2 mmol) of N- [4- (3-isopropyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethyl-phenyl] -oxamic acid ethyl ester (Example 4) in 3 ml of ethanol dissolved pa, cooled to 0 ° C and 0.136 ml (1.59 mmol) of isopropylamine added with argon and stirring. The mixture is stirred overnight at room temperature and then the solution is evaporated to dryness. The residue is stirred in cyclohexane, suction filtered and dried in vacuo.

Yield: 85.7 mg (83.5%)

MS (DCI): 533 ([M + NH ₄ ] ⁺ , 60%)

200 MHz 1H NMR (CDC1 ₃ ): 1.28 (dd, 12H); 3.05 (quin., IH); 4.12 (m, IH); 6.72 (dd, IH); 6.84 (d, IH); 6.94 (d, IH); 7.21 (d, IH); 7.36 (d, IH); 7.8 (s, IH); 8.28 (s. 2H); 9.67 (s, IH).

The following compounds (Examples 47 to 48) are prepared in analogy to the procedure of Example 46:

Example 47

N-Cyclopropyl-N '- [4- (3-isopropyl-lH-indol-5-yloxy) -3,5-bis-trifluoromethylphenylj-oxalamide

Reactants: 100 mg (0.199 mmol) of N- [4- (3-isopropyl-1H-indol-5-yloxy] -3,5-bis-trifluoromethylphenyl] oxamic acid ethyl ester (Example 4) 0.11 ml (1 , 59 mmol) cyclopropylamine in 4 ml ethanol pa Yield: 84.6 mg (82.8%)

MS (DCI): 531 ([M + NH ₄ ] ⁺ , 100%)

300 MHz 1H NMR (CDC1 ₃ ): 0.7 (, 2H); 0.91 (m, 2H); 1.27 (d. 6H); 2.88 (, IH); 3.04 (quin., IH); 6.71 (dd, IH); 6.84 (d, IH); 6.93 (d, IH); 7.21 (d, IH); 7.5 (s, IH); 7.79 (s, IH); 8.24 (s, 2H); 9.55 (s, IH).

Example 48

N- [4- (3-isopropyl-1 H-indole-5-yloxy] -3,5-bis-trifluoromethyl-phenyl] -N ^c , N '-dimethyl-oxalamide

Reactants: 100 mg (0.199 mmol) of ethyl N- [4- (3-isopropyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethylphenylj-oxamic acid (Example 4)

1.592 ml (1.592 mmol) dimethylamine as a 2.0 molar solution in tetrahydrofuran in 3 ml ethanol p.a.

Yield: 90.7 mg (90.9%)

MS (DCI): 519 ([M + NH ₄ ] ⁺ , 100%)

300 MHz 1H NMR (CDC1 ₃ ): 1.27 (d, 6H); 3.04 (quart., IH); 3.11 (s, 3H); 3.55 (s,

3H); 6.71 (dd, IH); 6.85 (d, IH); 6.93 (d, IH); 7.20 (d, IH); 7.79 (s, IH); 8.21 (s,

2H); 9.65 (s, IH). Example 49

N- (2-Hydroxyethyl) -N '- [4- (3-isopropyl-lH-indol-5-yloxy) -3,5-bis-trifluoromethylphenyl] oxalamide

reactants:

100 mg (0.199 mmol) of N- [4- (3-isopropyl-lH-indol-5-yloxy) -3,5-bis-trifluoromethyl-phenyl] -oxamic acid ethyl ester (Example 4) 0.12 ml (1, 99 mmol) 2-aminoethanol in 4 ml ethanol pa

Yield: 60 mg (51.6%)

MS (ESI): 518 ([M + H] ⁺ , 100%)

300 MHz 1H NMR (d ₆ -DMSO): 1.19 (d, 6H); 2.95 (quin., IH); 3.17-3.34 (m, 2H);

3.41 - 3.55 (m, 2H); 4.73 (sext, IH); 6.61 (dd, IH); 6.71 (d, IH); 7.06 (d, IH); 7.23 (d, IH); 8.52 (m, IH); 8.7 (s. 2H); 8.88 (t, IH); 10.7 (d, IH). R _f = 0.12 (toluene: ethyl acetate = 8: 2)

Example 50

N- [N- (3-Isopropyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethyl-phenyl] -N'-methyl-oxalamide

reactants:

100 mg (0.199 mmol) of ethyl N- [4- (3-isopropyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethyl-phenyl] -oxamic acid (Example 4)

0.498 ml (0.995 mmol) methylamine as a 2 molar solution in tetrahydrofuran in 3 ml ethanol p.a.

Yield: 79.3 mg (81.7%)

MS (LC method, ES ⁺ ): 488 ([M + H] ⁺ , 100%)

R _f = 0.33 (toluene: ethyl acetate = 8: 2)

300 MHz 1H NMR (d ₆ -DMSO): 1.18 (d, 6H); 2.75 (d. 3H); 2.97 (quin., IH); 6.61 (dd, IH); 6.71 (d, IH); 7.05 (d, IH); 7.23 (d, IH); 8.7 (s, 2H), 9.0 (s, IH); 10.69 (s, IH); 11.31 (s, IH).

Example 51

N- (2-Hydroxy-1,1-bis-hydroxymethyl-ethyl) -N '- [4- (3-isopropyl-1H-indol-5-yloxy) -3,5-bis-trifluoromethylphenyl] oxalamide

100 mg (0.199 mmol) of ethyl N- [4- (3-isopropyl-1H-indol-5-yloxy] -3,5-bis-trifluoromethylphenyl] oxamate (Example 4)

241 mg (1.99 mmol) tris (hydroxymethyl) methylamine in 4 ml ethanol and 0.3 ml water

Yield: 30.8 mg (26.8%)

MS (DCI): 594 ([M + NH ₄ f, 64%)

R _f = 0.5 (toluene: ethyl acetate = 1: 9) Example 52

N- (2-Hydroxypropyl) -N '- [4- (3-isopropyl-1H-indol-5-yloxy) bis-trifluoromethylphenyl] oxalamide

reactants:

80 mg (0.159 mmol) of N- [4- (3-isopropyl-lH-indol-5-yloxy] -3,5-bis-trifluoromethylphenylj-oxamic acid ethyl ester (Example 4)

0.123 ml (1.59 mmol) l-amino-2-propanol in 4 ml ethanol p.a.

Yield: 36.8 mg (43.5%)

MS (ESI): 532 ([M + Hf, 100%)

HPLC rt = 4.78 (100%)

0.5% HClO ₄ / acetonitrile Kromasil column C18 (60x2 mm) flow: 0.75 ml / min .; 210 nm

Example 53

N- [4- (3-isopropyl-lH-indol-5-yloxy) -3,5-dimethyl-phenyl] oxalamide

reactants:

100 mg (0.240 mmol) ethyl oxamic acid from Example 27

Add ammonia to saturation in 10 ml ethanol p.a.

Yield: 87.7 mg (100%) MS (ESI): 366 ([M + H] ⁺ , 100%) HPLC rt = 4.58 (100%)

0.5% HClO ₄ / acetonitrile Kromasil column C18 (60x2 mm)

Flow: 0.75 ml / min., 210 nm

Example 54

[(3,5-Dibromo-4 - {[lH-indol-5-yl] oχy} ρhenyl amino] (oxo) ethyl acetate

A solution is added to a suspension of 1.67 g (4.37 mmol) of 5- (4-amino-2,6-dibromophenoxy) -lH-indole and 531 mg (5.25 mmol) of triethylamine in 20 ml of dichloromethane while cooling with ice of 656 mg (4.81 mmol) ethyl oxalate chloride in 5 ml Added dropwise dichloromethane. The mixture is stirred for 30 min at room temperature, then the organic phase is washed once with water and dried over sodium sulfate. After removal of the solvent in vacuo, 2.13 g (87%) of the [(3,5-dibromo-4- {[lH-indol-5-yl] oxy} phenyl) amino] (oxo) acetic acid ethyl ester are obtained in good purity ,

300 MΗz 1H NMR (DMSO): 1.33, t, 3Η; 4.33, q, 2H; 6.32, m, IH; 6.71, m, 2H; 6.74, dd, IH; 7.33, m, IH; 7.35, d, IH; 8.22, s, 2H; 11.05, s, broad, IH; 11.10, s, broad, IH.

Example 55 (3,5-Dibromo-4 - {[3-cyclohexylcarbonyl-1H-indol-5-yl] oxy) phenyl) amino] (oxo) ethyl acetate

A solution of 35 mg (0.071 mmol) of 5- (4-amino-2,6-dibromophenoxy) -3-cyclohexylcarbonyl-1 H-indole and 6.5 mg (0.064 mmol) of triethylamine 4n in 2 ml of dichloromethane are 9 , 9 mg (0.071 mmol) of ethyl oxalate chloride are added and the mixture is stirred at room temperature overnight. A further 4.9 mg (0.035 mmol) of oxalic acid ester chloride and 1 mg of 4-dimethylammopyridine are then added and the mixture is stirred at room temperature for a further 12 h. The crude product is then purified over silica gel 60 (cyclohexane / ethyl acetate 3: 1 - 1: 1), 25 mg (59%) of [(3,5-dibromo-4 - {[3- (4-cyclohexylcarbonyl) - 1H-indol-5-yl] oxy} phenyl) amino] (oxo) ethyl acetate.

200 MΗz 1H NMR (DMSO): 1.33, t, 3Η; 1.35, m, 5H; 1.70, m, 5H; 3.10, m, IH;

4.34, q, 2H; 6.92, dd, IH; 7.37, d, IH; 7.46, d, IH; 7.95, s, IH; 8.25, s, IH; 8.35, s, IH; 11.14, s, broad, IH; 11.95, s, broad, IH. Example 56

[(3,5-Dibromo-4 - {[3-isopropylcarbonyl-lH-indol-5-yl] oxy} phenyl) amino] (oxo) ethyl acetate

Analogously, 40 mg (0.088 mmol) of 5- (4-amino-2,6-dibromophenoxy) -3-isopropylcarbonyl-lH-indole, 8.0 mg (0.080 mmol) of triethylamine, 17.8 mg (0.130 mmol) Oxalic acid ethyl ester chloride and 1 mg 4-dimethylaminopyridine in 2 ml dichloromethane and

3 drops of DMF to 47 mg (96%) [(3,5-dibromo-4 - {[3- (4-isopropylcarbonyl) -lH-indol-5-yl] oxy} phenyl) amino] (oxo) ethyl acetate.

200 MΗz 1H NMR (DMSO): 1.08, d, 6Η; 1.35, t, 3H; 3.39, sept., IH; 4.33, q, 2H; 6.92, dd, IH; 7.38, d, IH; 7.45, d, IH; 7.96, s, IH; 8.25, s, IH; 8.35, d, IH; 11.15, s, broad, IH; 11.96, s, broad, IH.

Example 57

[(3,5-Dibromo-4- {[3- (N-benzyl-N-isopropylamino) methyl-1H-indol-5-yl] oxy} phenyl) -amino] (oxo) ethyl acetate

To a solution of 119 mg (0.22 mmol) of 5- (4-amino-2,6-dibrornphenoxy) -3- (N-benzyl-N-isopropyl-aminomethyl) -IH-indole and 19.9 mg (0 , 20 mmol) triethylamine in 2 ml dichloromethane, 31.4 mg (0.23 mmol) ethyl oxalate chloride are added and the mixture is stirred for 15 min at room temperature. Then 1 ml is sat. ΝaΗCO ₃ solution. added, the aqueous phase is extracted twice with dichloromethane, the combined organic extracts are dried over sodium sulfate and freed from the solvent in vacuo. Purification of the residue on silica gel 60 (cyclohexane ethyl acetate 10: 1 - 1: 1) gives 84.4 mg (60%) of [(3,5-dibromo-4 - {[3- (N-benzyl-N- isoproρylamino) methyl-1H-indol-5-yl] - oxy} ρhenyl) amino] (oxo) ethyl acetate.

200 MΗz 1H-ΝMR (DMSO): 0.88, d, 6Η; 1.31, t, 2.75, sept., IH; 3.40, s, 2H; 3.49, s, 2H; 4.30, q, 2H; 6.87, dd, IH; 6.91, d, IH; 7.15, .6H; 7.30, d, IH; 7.96, s, IH; 8.30, s, 2H; 10.74, s, broad, IH; 11.10, s, broad, IH.

Example 58

[(3,5-Dibromo-4 - {[3- (N-benzyl-N-ethylamino) methyl-1H-indol-5-yl] oxy} phenyl) - amino] (oxo) ethyl acetate

Analogously, from 183 mg (0.346 mmol) of 5- (4-amino-2,6-dibromophenoxy) -3- (N-benzyl-N-ethyl-aminomethyl) -IH-indole, 31.5 mg (0.311 mmol) of triethylamine and 51.9 mg (0.380 mmol) oxalic acid ethyl ester chloride in 2 ml dichloromethane after cleaning the crude product twice over silica gel 60 (dichloromethane - dichloro- methane methanol 10: 1) 40 mg (16%) of [(3,5-dibromo-4 - {[3- (N-benzyl-N-ethylamino) methyl-1H-indol-5-yl] oxy} phenyl) amino] (oxo) acetic acid ethyl ester.

300 MΗz 1H-ΝMR (DMSO): 0.88, t, 3Η; 1.32, t, 3H; 2.28, q, 2H; 3.41, s, 2H; 3.50, s, 2H; 4.32, q, 2H; 6.83, dd, IH; 6.90, d, IH; 7.18, m, 7H; 7.30, d, IH; 8.30, s, 2H; 10.83, d, broad, IH; 11.12, s, broad, IH.

Example 59 [(3,5-Dibromo-4 - {[3- (N-4-fluorobenzyl-N-cyclopentylamino) methyl-1H-indol-5-yl] oxy} phenyl) amino] (oxo) acetic acid ethyl ester

To a solution of 20 mg (0.041 mmol) [(3,5-dibromo-4 - {[lH-indol-5-yl] oxy} - phenyl) amino] (oxo) ethyl acetate and 8.8 mg (0.046 mmol) 4-fluorobenzyl-cyclopentylamine in 0.5 ml of dioxane and 0.1 ml of acetic acid, 6 ul (0.069 mmol) of 35% formaldehyde solution. given. The solution is stirred for 1 h at room temperature, with ΝaΗC0 ₃ solution. are added, the aqueous phase is extracted with ethyl acetate and the combined organic extracts are freed from the solvent in vacuo. Purification on silica gel 60 (dichloromethane - dichloromethane / methanol 10: 1) gives 10 mg (35%) of [(3,5-dibromo-4 - {[3- (N-4-fluorobenzyl-N-cyclopentylamino) methyl-lH-indol-5-yl] oxy} phenyl) amino] (oxo) the ethyl acetate. 300 MHz 1H NMR (DMSO): 1.32, t, 3H; 1.33, m, 4H; 1.48, m, 4H; 2.95, m, IH; 3.43, s, 2H; 3.51, s, 2H; 4.32, q, 2H; 6.82, d, IH; 6.87, dd, IH; 6.99, dd, 2H; 7.11, dd, 2H; 7.21, d, IH; 7.30, d, IH; 8.31, s, 2H; 10.80, d, broad, IH; 11.15, s, broad, IH.

Example 60

[(3,5-Dibromo-4 - ([3- (4-morpholinyl) methyl-1H-indol-5-yl] oxy> phenyl ^ amino] (oxo-ethyl acetate

Analogously, 20 mg (0.041 mmol) of [(3,5-dibromo-4 - {[lH-indol-5-yl] oxy} phenyl) amino] (oxo) ethyl acetate, 4.3 mg (0.050 mmol) Morpholine and 3.6 μl (0.046 mmol) 35% formaldehyde solution. in 0.5 ml dioxane and 0.1 ml acetic acid after chromatographic purification (silica gel 60, ethyl acetate - dichloromethane / methanol 5: 1) 18 mg (67%) [(3,5-dibromo-4 - {[3- (4th -morpholinyl) - methyl-1H-indol-5-yl] oxy} phenyl) amino] (oxo) ethyl acetate.

300 MΗz 1H NMR (DMSO): 1.32, t, 3Η; 2.28, m, 4H; 3.47, m, 4H; 3.50, s, 2H; 4.33, q, 2H; 6.70, dd, IH; 6.95, d, IH; 7.21, d, IH; 7.29, d, IH; 8.23, s, 2H; 10.88, d, broad, IH; 11.10, s, broad, IH. Example 61 r (3.5-Dibromo-4 - ([ ^" 3- (1-piperidylmethyl-1H-indol-5-yl] oxy} phenylamino] (oxoV ethyl acetate

Analogously, 20 mg (0.041 mmol) of [(3,5-dibromo-4 - {[lH-indol-5-yl] oxy} phenyl) amino] (oxo) ethyl acetate, 4.2 mg (0.050 mmol) Piperidine and 3.6 μl (0.046 mmol) 35% formaldehyde solution. in 0.5 ml dioxane and 0.1 ml acetic acid after chromatographic purification (silica gel 60, ethyl acetate / triethylamine 20: 1) 10 mg (42%) [(3,5-dibromo-4 - {[(l-piperidyl ) methyl-1H-indol-5-yl] - oxy} phenyl) amino] (oxo) ethyl acetate.

300 MΗz 1H NMR (DMSO): 1.32, t, 3Η; 1.35, m, 6H; 2.25, m, 4H; 3.46, s, 2H; 4.33, q, 2H; 6.70, dd, IH; 6.95, d, IH; 7.18, d, IH; 7.27, d, IH; 8.23, s, 2H; 10.83, d, broad, IH; 11.10, s, broad, IH.

Example 62

[(3, 5 -Dibromo-4- {[3 - (1 -pyrrolidinvDmethy 1- 1 H-indol-5- yl] oxy> phenvDamino] (oxo - acetic acid)

Analogously, 20 mg (0.041 mmol) of [(3,5-dibromo-4 - {[lH-indol-5-yl] oxy} phenyl) amino] (oxo) ethyl acetate, 3.5 mg (0.050 mmol) Pyrrolidine and 3.6 μl (0.046 mmol) 35% formaldehyde solution. in 0.5 ml dioxane and 0.1 ml acetic acid after chromatographic purification (silica gel 60, dichloromethane / methanol 20: 1 + 5% triethylamine) and recrystallization from dichloromethane 5.9 mg (26%)

[(3, 5-Dibromo-4- {[(1-pyrrolidinyl) methy 1- 1 H -indol-5-yl] oxy} phenyl) amino] (oxo) acetic acid.

300 MΗz 1H NMR (DMSO): 1.86, m, 4Η; 3.10, m, 4H; 4.38, m, 2H; 6.71, dd, IH; 7.12, d, IH; 7.37, d, IH; 7.57, d, IH; 8.26, s, 2H; 10.28, s, broad, IH; 10.46, s, wide,

IH; 11.40, s, broad, IH.

Example 63

[ ^" (3,5-dibromo-4- {[3 - (diethylamino) methyl-1 H -indol-5-yl] oxy) phenyDamino] (oxo) acetic acid

Analogously, 20 mg (0.041 mmol) of [(3,5-dibromo-4 - {[lH-indol-5-yl] oxy} phenyl) amino] (oxo) ethyl acetate, 3.6 mg (0.050 mmol) Diethylamine and 3.6 μl (0.046 mmol) 35% formaldehyde solution. in 0.5 ml dioxane and 0.1 ml acetic acid after purification via überPLC 9.3 mg (42%) [(3,5-dibromo-4- {[(diethylamino) methyl-lH-indol-5-yl] oxy } phenyl) amino] (oxo) acetic acid.

300 MΗz 1H NMR (DMSO): 1.20, m, 6Η; 3.00, m, 4H; 4.37, m, 2H; 6.79, dd, IH; 6.96, d, IH; 7.40, d, IH; 7.60, m, IH; 8.28, s, 2H; 9.37, s, broad, IH; 10.46, s, wide,

IH; 11.50, s, broad, IH. Example 64 f (3,5-dibromo-4- {3- (diethylamino ^' ) methyl-1H-indol-5-ylloxy) phenvDamino1 (oxoV acetic acid

Analogously, 20 mg (0.041 mmol) of [(3,5-dibromo-4 - {[lH-indol-5-yl] oxy} phenyl) amino] (oxo) ethyl acetate, 5.6 mg (0.050 mmol) 40% dimethylamine solution. and 3.6 ul (0.046 mmol) of 35% formaldehyde solution. in 0.5 ml dioxane and 0.1 ml acetic acid after purification via überPLC 5.7 mg (27%) [(3,5-dibromo-4 - {[(dimethylamino) methyl-lH-indol-5-yl] oxy } phenyl) amino] (oxo) acetic acid.

300 MΗz 1H NMR (DMSO): 2.65, m, 6Η; 4.30, m, 2H; 6.72, dd, IH; 7.10, d, IH; 7.39, d, IH; 7.55, d, IH; 8.27, s, 2H; 9.92, s, broad, IH; 10.47, s, broad, IH; 11.42, s, broad, IH.

Example 65

[ ^" (3,5-Dibromo-4 - {[3- ( ^" N-benzyl-N-isopropylamino methyl-1H-indol-5-ylloxy} phenyl) amino] (oxo) acetic acid hydrochloride

A solution of 20 mg (0.031 mmol) [(3,5-dibromo-4 - {[3- (N-benzyl-N-isopropylamino) methyl-1H-indol-5-yl] oxy} phenyl) amino] (Oxo) acetic acid ethyl ester in 1 ml dioxane is mixed with 0.31 ml IN sodium hydroxide solution (0.31 mmol) and stirred for 1 h at room temperature. The mixture is then brought to pΗ2 with 1N hydrochloric acid, the aqueous phase is extracted 3 times with ethyl acetate, the combined organic extracts are dried over Na ₂ SO ₄ and the solvent is removed in vacuo. 20.2 mg (100%) of [(3,5-dibromo-4 - {[3- (N-benzyl-N-isopropylamino) methyl-1H-indol-5-yl] oxy} phenyl) amino are obtained ] (oxo) acetic acid hydrochloride.

200 MHz 1H-ΝMR (DMSO): 1.36, d, 6H; 1.31, t, 3.45, m, IH; 4.18, m, 2H; 4.46, m,

2H; 6.74, d, IH; 6.80, m, IH; 7.50, m, 7H; 8.28, s, 2H; 9.26, s, broad, IH; 10.98, s, broad, IH; 11.52, s, broad, IH.

Example 66 | ^" (3,5-dibromo-4- {| ^' lH-indol-5-yl] oxy | phenyl) amino] (oxo -N- (2-hydroxyethyl-acetamide

A solution of 50 mg (0.104 mmol) of [(3,5-dibromo-4 - {[1H-indol-5-yl] oxy} - phenyl) amino] (oxo) ethyl acetate and 9.5 mg (0.156 mmol) of aminoethanol in 1 ml TΗF is stirred for 2 h at room temperature. The solvent is then removed in vacuo and the remaining residue is purified on silica gel 60 (ethyl acetate). 44.5 mg (86%) of the [(3,5-dibromo-4 - {[lH-indol-5-yl] oxy} - phenyl) amino] (oxo) -N- (2-hydroxyethyl) acetamide are obtained , 300 MHz 1H NMR (DMSO): 3.29, q, 2H; 3.51, q, 2H; 4.76, t, IH; 6.31, t, IH; 6.72, s, IH; 6.73, dd, IH; 7.30, d, IH; 7.33, d, IH; 8.29, s, 2H; 8.85, t, IH; 11.01, m, wide, 2H.

Example 67

Methyl-No (3,5-dibromo-4 - ([ ^" 1H-indol-5-yl] oxy} phenyl amino] (oxo acetylglycinate

A solution of 50 mg (0.104 mmol) of [(3,5-dibromo-4 - {[lH-indol-5-yl] oxy} - phenyl) amino] (oxo) ethyl acetate, 19.5 mg (0.156 mmol) of glycine methyl ester Hydrochloride and 31.5 mg (0.311 mmol) triethylamine in 1.5 ml TΗF is heated under reflux for 24 h. The solvent is then removed in vacuo and the remaining residue is purified on silica gel 60 (dichloromethane). 35.5 mg (65%) of the methyl N - [(3,5-dibromo-4 - {[lH-indol-5-yl] oxy} phenyl) amino] (oxo) acetyl glycinate are obtained.

300 MΗz 1H-ΝMR (DMSO): 3.69, s, 3Η; 4.00, d, 2H; 6.31, t, IH; 6.72, s, IH; 6.73, dd, IH; 7.30, d, IH; 7.33, d, IH; 8.30, s, 2H; 9.34, t, IH; 11.01, s, broad, IH; 11.06, s, broad, IH.

Example 68 tert-Butyl-N- | ^" (3,5-dibromo-4 - f [lH-indol-5-yl] oxy) ρhenyl) amino] (oxo ^ acetyl glvcinate

A solution of 50 mg (0.104 mmol) [(3,5-Dibronι-4 - {[1H-indol-5-yl] oxy} phenyl) - amino] (oxo) ethyl acetate, 26.1 mg (0.156 mmol) glycine tert-butyl ester hydrochloride and 31.5 mg (0.311 mmol) triethylamine in 1.5 ml TΗF is heated under reflux for 24 h. The solvent is then removed in vacuo and the remaining residue is purified on silica gel 60 (dichloromethane). 45.6 mg are obtained

(78%) of the tert-butyl-N - [(3,5-dibromo-4 - {[lH-indol-5-yl] oxy} ρhenyl) amino] (oxo) acetylglycinate.

300 MΗz 1H-ΝMR (DMSO): 1.43, s, 9Η; 3.87, d, 2H; 6.31, t, IH; 6.72, s, IH; 6.73, dd, IH; 7.30, d, IH; 7.34, d, IH; 8.30, s, 2H; 9.23, t, IH; 11.02, s, broad, IH; 11.07, s, broad, IH.

Example 69

Methyl-Nl ( ^" 4- (r3- (isopropyl) -IH-indol-5-yl] oxy) -3,5-bistrifluoromethyl) phenyl] amino) (oxo) acetylglycinate

A solution of 35 mg (0.070 mmol) of ethyl - {[4 - {[3- (isopropyl) -1H-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) phenyl] amino} (oxo ) acetate, 17.5 mg (0.139 mmol) Glycine methyl ester hydrochloride and 21.1 mg (0.209 mmol) triethylamine in 1.5 ml THF is heated under reflux for 48 h. The solvent is then removed in vacuo and the remaining residue is purified on silica gel 60 (dichloromethane). 36.2 mg (95%) of the methyl N - {[4 - {[3- (isopropyl) -1H-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) phenyl] are obtained. amino) (oxo) acetylglycinate.

300 MΗz 1H-ΝMR (DMSO): 1.19, d, 6Η; 2.97, sept., IH; 3.68, s, 3H; 4.01, d, 2H; 6.62, dd, IH; 6.73, d, IH; 7.08, d, IH; 7.24, d, IH; 8.70, s, 2H; 9.38, t, IH; 10.70, s, broad, IH; 11.40, s, broad, IH.

Example 70

N-IT4-IT3- (isopropyD-1H-indol-5-yl] oxy) -3,5-bis (trifluoromethyl) phenyl] amino) - (oxo) acetylserine methyl ester

Analogously, 35 mg (0.070 mmol) of ethyl - {[4 - {[3- (isopropyl) -1H-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) phenyl] amino} (oxo ) acetate, 21.7 mg (0.139 mmol) serine methyl ester hydrochloride and 21.1 mg (0.209 mmol) triethylamine in 1.5 ml THF 35.7 mg (89%) of the N- {t4 - {[3- (isopropyl ) -lH-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) phenyl] amino} (oxo) acetylserine methyl ester.

300 MΗz 1H-ΝMR (DMSO): 1.19, d, 6Η; 2.97, sept., IH; 3.69, s, 3H; 3.84, .2H; 4.50, German, IH; 5.19, t, IH; 6.62, dd, IH; 6.73, d, IH; 7.08, d, IH; 7.24, d, IH; 8.70, s, 2H; 8.95, d, IH; 10.70, d, broad, IH; 11.43, s, broad, IH. Example 71 tert-Butyl-N- (r4- (3- (isopropyD-1H-indol-5-yl) oxy) -3,5-bistrifluoromethyl) phenyl] amino) (oxo) acetylglycinate

A solution of 100 mg (0.199 mmol) of ethyl- {[4- {[3 - (isopropyl) - lH-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) ρhenyl] amino} (oxo ) acetate, 66.7 mg (0.398 mmol) glycine tert-butyl ester hydrochloride, 60.3 mg (0.597 mmol) triethylamine and 0.2 mg (0.002 mmol) DMAP in 2 ml THF is heated under reflux for 24 h. The solvent is then removed in vacuo and the remaining residue is purified on silica gel 60 (dichloromethane). 115 mg (98%) of the tert-butyl-N - {[4 - {[3- (isopropyl) -1H-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) phenyl] are obtained. amino) (oxo) acetyl glycinate.

400 MΗz 1H-ΝMR (CDC1 ₃ ): 1.27, d, 6Η; 1.51, s, 9H; 3.06, sept., IH; 4.07, d. 2H;

6.73, dd, IH; 6.85, d, IH; 6.95, d, IH; 7.22, d, IH; 7.81, s, broad, IH; 7.91, t, IH; 8.26, s, 2H; 9.45, s, broad, IH.

Example 72 N- {[ ^" 4- {f 3 - (isopropyl) -1 H -indol-5-yl] oxy) -3,5-bis (trifluoromethyl) phenyl] amino) -

(Oxo) acetylthreoninmethyl ester

Analogously, 100 mg (0.199 mmol) of ethyl - {[4 - {[3- (isopropyl) -1H-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) ρhenyl] amino} (oxo ) acetate, 67.5 mg (0.398 mmol) threonine methyl ester hydrochloride, 60.3 mg (0.597 mmol) triethylamine and 0.2 mg (0.002 mmol) DMAP in 2 ml THF 85 mg (72%) of the N - {[4- {[3- (isopropyl) -1H-mdol-5-yl] oxy} -3,5-bis (trifluoromethyl) phenyl] amino} (oxo) acetylthreonine methyl ester.

400 MΗz 1H-ΝMR (CDC1 ₃ ): 1.27, d, 6Η; 1.29, t, 3H; 1.99, d, IH; 3.07, sept., IH; 3.82, s, 3H; 4.50, dq, IH; 4.60, dd, IH; 6.72, dd, IH; 6.83, d, IH; 6.95, d, IH; 7.22, d, IH; 7.80, s, broad, IH; 8.13, d, broad, IH; 8.28, s, 2H; 9.43, s, broad, IH.

Example 73

N - {[4 - {[3- (isopropyl) -IH-indol-5-yl] oxy) -3,5-bis (trifluoromethyl) phenyl] - amino) (oxo) acetyltyrosine methyl ester

Analogously, 100 mg (0.199 mmol) of ethyl - {[4 - {[3- (isopropyl) -1H-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) phenyl] amino} (oxo ) acetate, 92.2 mg (0.398 mmol) tyrosine methyl ester hydrochloride, 60.3 mg (0.597 mmol) triethylamine and 0.2 mg (0.002 mmol) DMAP in 2 ml THF 122 mg (94%) of the N - {[4- {[3- (isopropyl) -IH-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) phenyl] amino} (oxo) acetyltyrosine methyl ester. 200 MHz 1H NMR (CDC1 ₃ ): 1.27, d, 6H; 3.05, sept, IH; 3.13, t, 2H; 3.72, s, IH; 3.78, s, 3H; 4.84, German, IH; 6.72, dd, IH; 6.78, d, 2H; 6.83, d, IH; 6.95, d, IH; 7.02, d, 2H; 7.21, d, IH; 7.81, s, broad, IH; 7.88, d, broad, IH; 8.24, s, 2H; 9.39, s, broad, IH.

Example 74

N - {[4 - {[3- (isopropyl-1H-indol-5-yl] oxy) -3,5-bis (trifluoromethylphenyl] amino) - (oxo) acetylalanine methyl ester

Analogously, 100 mg (0.199 mmol) of ethyl - {[4 - {[3- (isopropyl) -1H-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) phenyl] amino} (oxo ) acetate, 55.6 mg (0.398 mmol) tyrosine methyl ester hydrochloride, 60.3 mg (0.597 mmol) triethylamine and 0.2 mg (0.002 mmol) DMAP in 2 ml THF 93 mg (84%) of the N - {[4- {[3- (isopropyl) -IH-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) phenyl] amino} (oxo) acetylalanine methyl ester.

300 MΗz 1H-ΝMR (CDC1 ₃ ): 1.27, d, 6Η; 1.55, d, 3H; 3.05, sept, IH; 3.80, s, 3H; 4.64, dq, IH; 6.72, dd, IH; 6.84, d, IH; 6.94, d, IH; 7.21, d, IH; 7.79, s, broad, IH; 7.97, d, broad, IH; 8.26, s, 2H; 9.43, s, broad, IH. Example 75

N- {r4- {f3- (isopronyl-1H-indol-5-yl1oxy) -3,5-bis (trifluoromethylphenvnamino) - (oxo) acetylleucine methyl ester

Analogously, 100 mg (0.199 mmol) of ethyl - {[4 - {[3- (isopropyl) -1H-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) phenyl] amino} (oxo ) acetate, 72.3 mg (0.398 mmol) leucine methyl ester hydrochloride, 60.3 mg (0.597 mmol triethylamine and 0.2 mg (0.002 mmol) DMAP in 2 ml THF 84 mg (70%) of the N - {[4- { [3- (isopropyl) -IH-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) phenyl] amino} (oxo) acetylleucine methyl ester.

200 Mz 1H-ΝMR (DMSO): 0.90, t, 6Η; 1.19, d, 6H; 1.62, m, 2H; 1.89, m, IH; 2.95, sept, IH; 3.67, s, 3H; 4.46, m, IH; 6.64, dd, IH; 6.71, d, IH; 7.08, d, IH; 7.25, d, IH; 8.70, s, 2H; 9.42, d, broad, IH; 10.74, d, broad, IH; 11.42, s, broad, IH.

Example 76

2 - ({r4 - {[3- (isopropyl) -IH-indol-5-yl] oxy) -3,5-bis (trifluoromethyl) ρhenyl] - amino) (oxo acetylamino) -6-tgrt-butoxycarbonylamino-hexanoic acid methyl ester

Analogously, 100 mg (0.199 mmol) of ethyl - {[4 - {[3- (isopropyl) -1H-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) phenyl] amino} (oxo ) acetate, 118.1 mg (0.398 mmol) 6-Boc-lysine methyl ester hydrochloride, 60.3 mg (0.597 mmol) triethylamine and 0.2 mg (0.002 mmol) DMAP in 2 ml THF 106 mg (74%) of the 2- ({[4 - {[3- (isopropyl) - lH-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) phenyl] amino} (oxo) acetylamino) -6-tert-butoxycarbonylamino-hexanoic acid methyl ester ,

300 MΗz 1H NMR (CDC1 ₃ ): 1.27, d, 6Η; 1.40, m, 2H; 1.44, p. 9H; 1.54, m, 2H; 1.85, m, IH; 2.00, m, IH; 3.05, quint, IH; 3.10, q, 2H; 3.79, s, 3H; 4.53, m, IH; 4.63, m, IH; 6.73, dd, IH; 6.85, d, IH; 9.94, d, IH; 7.22, d, IH; 7.81, s, broad, IH; 7.94, d, broad, IH; 8.26, s, 2H; 9.43, s, broad, IH.

Example 77

2- {[4- {[3 - (isopropyl) - lH-indol-5-yl] oxy) -3, 5 -bis ( ^" trifluoromethylphenyl] amino) - (oxo) acetylamino-3- (4- imidazolyl) -methylpropionate

Analogously, 100 mg (0.199 mmol) of ethyl - {[4 - {[3- (isopropyl) -1H-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) phenyl] amino} (oxo ) acetate, 81.9 mg (0.398 mmol) histidine methyl ester hydrochloride, 60.3 mg (0.597 mmol) triethylamine and 0.2 mg (0.002 mmol) DMAP in 2 ml THF 18 mg (14%) of 2- {[4- {[3 - (Isopropyl) - 1H-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) phenyl] amino} (oxo) acetylamino-3- (4-imidazolyl) methyl propionate. 300 MHz 1H NMR (CDC1 ₃ ): 1.27, d, 6H; 3.05, sept., IH; 3.16, dd, IH; 3.30, dd, IH; 3.74, s, 3H; 4.89, ddd, IH; 6.72, dd, IH; 6.84, d, IH; 6.87, s, IH; 6.94, d, IH; 7.22, d, IH; 7.67, s, IH; 7.80, s, broad, IH; 8.27, s, 2H; 9.12, s, broad, IH; 9.43, s, broad, IH.

Example 78

2 - ({[ ^" 4 - {[ ^' 3- (isopropyl) -IH-indol-5-yl] oxy) -3.5-bistrifluoromethylphenyl] - amino) (oxo) acetylamino) dimethylsuccinate

Analogously, 100 mg (0.199 mmol) of ethyl - {[4 - {[3- (isopropyl) -1H-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) phenyl] amino} (oxo ) acetate, 78.6 mg (0.398 mmol) dimethyl aspartic acid hydrochloride, 60.3 mg (0.597 mmol) triethylamine and 0.2 mg (0.002 mmol) DMAP in 2 ml THF 37 mg (30%) of the 2-2 - ({ [4 - {[3- (isopropyl) -IH-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) phenyl] amino} (oxo) acetylamino) dimethyl succinates.

200 MΗz 1H NMR (DMSO): 1.19, d, 6Η; 2.96, m, 2H; 3.20, m, IH; 3.62, s, 3H; 3.68, s, 3H; 4.85, q, IH; 6.63, dd, IH; 6.72, d, IH; 7.08, d, IH; 7.23, d, IH; 8.70, s, 2H; 9.48, d, broad, IH; 10.73, d, broad, IH; 11.48, s, IH. Example 79 tert-Butyl- {r4 - {[3- (isopropylVlH-indol-5-yl] oxy) -3.5-bis (trifluoromethydphenyl] amino) (oxo) acetate

To a solution of 100 mg (0.224 mmol) of 5- [4-amino-2,6-bis (trifluoromethyl) phenoxy] -3-isopropyl-1H-indole and 45.3 mg (0.447 mmol) of triethylamine in 2 ml of dichloromethane a solution of 38.7 mg (0.235 mmol) of oxalic acid tert-butyl ester chloride in 1 ml of dichloromethane is added at room temperature and the mixture

Stirred for 5 h. Purification of the crude product obtained on silica gel (cyclohexane / ethyl acetate 5: 1) gives 104 mg (88%) of the tert-butyl- {[4- {[3 - (isopropyl) - 1H-indol-5-yl] oxy} -3,5-bis (trifluoro-methyl) phenyl] amino} (oxo) acetate.

400 MΗz 1H NMR (CDC1 ₃ ): 1.27, d, 6Η; 1.63, s, 9H; 3.05, sept., IH; 6.73, dd, IH;

6.84, d, IH; 6.94, d, IH; 7.22, d, IH; 7.80, s, broad, IH; 8.24, s, 2H; 9.08, s, broad, IH.

Example 80

3- (2,5-Dimethvnpentyl- {r4 - {[3- ( ^, isopropyn-1H-indole-5-vnoxy) -3,5-bistrifluoromethyl) phenyl] amino) (oxo) acetate

In an analogous manner, 100 mg (0.249 mmol) of 5- [4-ammo-2,6-bis (trifluoromethyl) phenoxy] -3-isopropyl-1H-indole, 45.3 mg (0.497 mmol) of triethylamine and 50 , 3 mg (0.261 mmol) 3 - [(2,5-dimethyl) pentyl] chloro oxalate in 2 ml dichloromethane by purification on silica gel (cyclohexane / methylene chloride 1: 1) 120 mg (84%) of the 3- (2,5- Dimethyl) pentyl - {[4 - {[3- (isopropyl) -IH-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) phenyl] amino) (oxo) acetate.

200 MΗz 1H NMR (CDC1 ₃ ): 0.96, dd, 12Η; 1.27, d, 6H; 2.10, oct, 2H; 3.05, sept., 4.79, t, IH; 6.73, dd, IH; 6.82, d, IH; 6.94, d, IH; 7.23, d, IH; 7.81, s, broad, IH;

8.29, s, 2H; 9.14, s, broad, IH.

Example 81

2-Propyl- ([4- {f 3 - (isopropyl) - 1H-indol-5-yl] oxy) -3,5-bis (trifluoromethyl) phenyl] amino (oxo) acetate

In an analogous manner, 100 mg (0.224 mmol) of 5- [4-amino-2,6-bis (trifluoromethyl) phenoxy] -3-isopropyl-1H-indole, 45.3 mg (0.447 mmol) of triethylamine and 35 , 4 mg (0.235 mmol) oxalic acid isopropyl ester chloride in 2 ml dichloromethane by purification on silica gel (cyclohexane ethyl acetate 5: 1) 10 mg (9%) of 2-propyl - {[4- {[3 - (isopropyl) - 1 H -indole -5-yl] oxy) -3,5-bis (trifluoromethyl) phenyl] amino) (oxo) - acetate.

200 MΗz 1H NMR (DMSO): 1.18, d, 12Η; 1.34, d, 6H; 2.97, sept, IH; 3.05, sept, 5.12, sept, IH; 6.63, dd, IH; 6.72, d, IH; 6.94, d, IH; 7.08, d, IH; 7.26, d, IH; 8.61, s, 2H; 10.74, d, broad, IH; 11.38, s, broad, IH.

Example 82

2-Benzyloxy-N- {4 - {[ ^' 3- (isopropyl) -IH-indol-5-yl1oxy) -3,5-bis (trifluoromethyl) phenyl] acetamide

In an analogous manner, 200 mg (0.497 mmol) of 5- [4-amino-2,6-bis (trifluoromethyl) phenoxy] -3-isopropyl-1H-indole, 75.4 mg (0.746 mmol) of triethylamine and 96 , 4 mg (0.522 mmol) benzyloxyacetic acid chloride in 4 ml dichloromethane by purification on silica gel (cyclohexane / methylene chloride 1: 1) 200 mg (73%) of the 2-benzyloxy-N - {[4 - {[3- (isopropyl) -lH -indol-5-yl] oxy} -3,5-bis (trifluoromethyl) phenyl] acetamides.

300 MΗz 1H-ΝMR (CDC1 ₃ ): 1.27, d, 6Η; 3.05, sept., IH; 4.15, s, 2H; 4.70, s, 2H; 6.72, dd, IH; 6.83, d, IH; 6.93, d, IH; 7.21, d, IH; 7.40, m, 5H; 7.79, s, broad, IH;

8.14, s, 2H; 8.50, s, broad, IH. Example 83

2-Hvdroxy-N- {r4 - {[3- (isopropyl) -IH-indol-5-yl] oxy) -3,5-bis (trifluoromethyl) phenyl] acetamide

A solution of 166 mg (0.302 mmol) of 2-benzyloxy-N - {[4 - {[3- (isopropyl) -lH-indol-5-yl] oxy) -3,5-bis (trifluoromethyl) phenyl] Pd / C (10%) is added to acetamide in 10 ml of ethanol and hydrogenated overnight with hydrogen. By filtering off the catalyst over diatomaceous earth and removing the solvent in vacuo, 130 mg (94%) of the 2-hydroxy-N - {[4 - {[3- (isopropyl) -lH-indol-5-yl] oxy) - 3,5- bis (trifluoromethyl) phenyl] acetamids.

200 MΗz 1H-ΝMR (DMSO): 1.18, d, 6Η; 2.96, sept., IH; 4.08, d, 2H; 5.89, t, IH; 6.62, dd, IH; 6.68, d, IH; 7.06, d, IH; 7.23, d, IH; 8.62, s, 2H; 10.45, s, broad, IH; 10.73, s, broad, IH.

Example 84

[(3,5-Dibromo-4 - {[3- (4-fluorobenzyl) -1H-indol-5-yl] oxy) phenyl) amino] (oxo) acetic acid

20 mg (0.03 mmol) of ethyl - [(3,5-dibromo-4 - {[3- (4-fluorobenzyl) -IH-indol-5-yl] oxy} - phenyl) amino] (oxo) acetate stirred in 0.4 ml IN NaOH and 1 ml dioxane for 3.5 h at room temperature. The mixture is acidified to pH 4, extracted with ethyl acetate, dried over sodium sulfate and the solvent is removed in vacuo. 18 mg (93%) of [(3,5-dibromo-4- {[3- (4-fluorobenzyl) -1H-indol-5-yl] oxy) phenyl) amino] (oxo) acetic acid are obtained.

Example 85

Ethyl - ({3,5-dibromo-4 - [(3-hexyl-lH-indol-5-yl) oxy] phenyl) amino) (oxo) acetate

62 mg (0.13 mmol) 3,5-dibromo-4 - [(3-hexyl-lH-indol-5-yl) oxy] aniline and 15 mg triethylamine are dissolved in 2 ml dichloromethane and added dropwise with 25 mg (0.18 mmol) ethyl oxalate chloride added. The reaction mixture is saturated with sat. AHCO solution. shaken, the aqueous phase is extracted lx with ethyl acetate, the combined organic phases are lx with gesNaCl solution. washed, dried and evaporated. Chromatography (cyclohexane / ethyl acetate = 20: 1) gives 37 mg (50%) of ethyl - ({3,5-dibromo-4 - [(3-hexyl-lH-indol-5-yl) oxy] phenyl) amino) (oxo )acetate.

300 MHz 1H NMR (CDC1 ₃ ): 0.88, m, 5H; 1.30, m, 4H; 1.46, t, 3H; 1.65, m, 2H;

2.63, t, 2H; 4.46, quart., 2H; 6.80, dd, IH; 6.90, d, IH; 6.98, m, IH; 7.26, d, IH; 7.83, s, broad, IH; 7.97, s, 2H; 8.87, s, broad, IH. Example 86

Ethyl - [(3,5-dibromo-4- {3- (cyclohexylmethyl) -IH-indol-5-yl] oxy) phenyl) amino] (oxo) acetate

Analogously, starting from 122 mg (0.255 mmol) of 3,5-dibromo-4-

{[3- (cyclohexylmethyl) -IH-indol-5-yl] oxy) aniline 51 mg (35%) ethyl - [(3,5-dibromo-4 - {[3- (cyclohexylmethyl) -IH-indole-5 -yl] oxy) phenyl) amino] (oxo) acetate

300 MHz 1H NMR (CDC1 ₃ ): 0.95, m, 2H; 1.18, m, 4H; 1.45, t, 3H; 1.68, m, 5H; 2.52, d, 2H; 4.46, quart., 2H; 6.78, dd, IH; 6.92, m, 2H; 7.23, d, IH; 7.86, s, wide,

IH; 7.98, s, 2H; 8.88, s, broad, IH.

Example 87

Ethyl {| ^' 4 - {[ ^' 3- (cyclohexylmethyl) -IH-indol-5-yl] oxy) -3,5-bis (trifluoromethyl) phenyl] amino) (oxo) acetate

Analogously, starting from 253 mg (0.55 mmol) of 4 - {[3- (cyclohexylmethyl) -lH-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) aniline 162 mg ( 48%) ethyl {[4 - {[3- (cyclohexylmethyl) -IH-indol-5-yl] oxy) -3,5-bis (trifluoromethyl) phenyl] amino) (oxo) acetate. 300 MHz 1H NMR (CDC1 ₃ ): 0.92, m, 2H; 1.18, m, 4H; 1.48, t, 3H; 1.63, m, 5H; 2.50, d, 2H; 4.46, quart, 2H; 6.71, dd, IH; 6.80, d, IH; 6.95, m, IH; 7.19, m, IH; 7.83, s, IH; 8.27, s, 2H; 9.09, s, IH.

Example 88

Ethyl - ({3,5-dibromo-4 - [(3-ρentyl-lH-indol-5-yl) oxy] ρhenyl) amino) (oxo) acetate

Analogously, starting from 25 mg (0.06 mmol) of 3,5-dibromo-4 - [(3-pentyl-1H-indol-5-yl) oxy] aniline 30 mg (99%) of ethyl - ({3 , 5-dibromo-4 - [(3-pentyl-lH-indol-5-yl) oxy] phenyl) amino) (oxo) acetate

300 MHz 1H NMR (CDCI ₃ ): 0.88, m, 5H; 1.31, m, 4H; 1.45, t, 3H; 1.65, m, 2H; 2.62, t, 2H; 4.45, quart., 2H; 6.80, dd, IH; 7.89, d, IH; 6.98, m, IH; 7.23, m; 7.83, s, broad, IH; 7.97, s, 2H; 8.88, s, broad, IH.

Example 89

Ethyl oxo {r4 - [(3-pentyl-lH-indol-5-yl) oxy1-3,5-bis (trifluoromethyl) phenyl] amino) acetate,

Analogously, starting from 38.8 mg (0.09 mmol) of 4 - [(3-pentyl-1H-indol-5-yl) oxy] -3,5-bis (trifluoromethyl) aniline 32 mg (66% ) Ethyl oxo {[4 - [(3-pentyl-1H-indol-5-yl) oxy] -3,5-bis (trifluoromethyl) phenyl] amino) acetate.

300 MHz 1H NMR (CDC1 ₃ ): 0.88, m, 5H; 1.31, m, 4H; 1.47, t, 3H; 1.62, .2H; 2.60, t, 2H; 4.46, quart., 2H; 6.73, dd, IH; 6.81, d, IH; 6.97, m, IH; 7.22, d, IH;

7.81, s, IH; 8.24, s, 2H; 9.11, s, IH.

Example 90

Ethyl - ({3,5-dibromo-4 - [(3-butyl-lH-indol-5-yl) oxylphenyl) amino) (oxo) acetate

Analogously, starting from 72 mg (0.14 mmol) of 3,5-dibromo-4 - [(3-butyl-1H-indol-5-yl) oxy] aniline 68 mg (82%) of ethyl - ({3.5 -dibromo-4 - [(3-butyl-1H-indol-5-yl) oxy] phenyl) amino) (oxo) acetate. 300 MHz 1H NMR (CDC1 ₃ ): 0.92, t, 3H; 1.35, m, 2H; 1.45, t, 3H; 1.63, m, 2H; 2.63, t, 2H; 4.45, quart., 2H; 6.78, dd, IH; 6.91, d, IH; 6.99, m, IH; 7.23, d, IH; 7.83, s, IH; 7.98, s, 2H; 8.86, s, IH.

Example 91

Ethyl {4-r (3-butyl-1H-indol-5-yl) oxy] -3,5-bis (trifluoromethyl) phenyl] amino) - (oxo) acetate

Analogously, 49 mg (77%) of ethyl are obtained starting from 44 mg (0.11 mmol) of 4 - [(3-butyl-1H-indol-5-yl) oxy] -3,5-bis (trifluoromethyl) aniline - {[4 - [(3-butyl-1H-indol-5-yl) oxy] -3,5-bis (trifluoromethyl) phenyl] amino} (oxo) acetate.

300 MHz 1H NMR (CDCI ₃ ): 0.90, t, 3H; 1.30, m, 2H; 1.47, t, 3H; 1.61, m, 2H; 2.61, t, 2H; 4.48, quart., 2H; 6.72, dd, IH; 6.8, d, IH; 6.97, m, IH; 7.21, m, IH; 7.83, s, IH; 8.28, s, 2H; 9.10, s, IH.

Example 92

Ethyl - ({3,5-dibromo-4-r (3-propyl-lH-indol-5-yl) oxy] phenyl) amino) (oxo) acetate,

Analogously, starting from 185 mg (0.44 mmol) of 3,5-dibromo-4- [(3-propyl-1H-indol-5-yl) oxy] aniline, 114 mg (41%) of ethyl - ({ 3,5-dibromo-4 - [(3-propyl-1H-indol-5-yl) oxy] phenyl) amino) - (oxo) acetate

200 MHz 1H NMR (CDC1 ₃ ): 0.96, t, 3H; 1.45, t, 3H; 1.67, m, 2H; 2.61, t, 2H; 4.46, quart., 2H; 6.79, dd, IH; 6.90, d, IH; 6.98, d, IH; 7.20, m, IH; 7.82, s, IH; 7.96, s, 2H; 8.86, s, IH.

Example 93

Ethyl - ({3,5-dibromo-4 - [(3-methyl-lH-indol-5-yl) oxy] ρhenyl) amino) (oxo) acetate,

Analogously, starting from 650 mg (1.64 mmol) of 3,5-dibromo-4- [(3-methyl-1H-indol-5-yl) oxy] aniline, 520 mg (60%) of ethyl ({ 3,5-dibromo-4 - [(3-methyl-1H-indol-5-yl) oxy] phenyl) amino) - (oxo) acetate.

300MHz 1H NMR (CDCI ₃ ): 1.45, t, 3H; 2.25, s, 3H; 4.45, quart., 2H; 6.82, m, 2H; 6.96, d, IH; 7.26, d, IH; 7.81, s, IH; 7.98, s, 2H; 8.88, s, IH.

Example 94 Ethyl ({3,5-dimethyl-4-f (3-propyl-1H-indol-5-yl) oxy] phenyl) amino) (oxo) acetate

Analogously, starting from 120 mg (0.41 mmol) of 3,5-dimethyl-4 - [(3-propyl-1H-indol-5-yl) oxy] aniline, 157 mg (97%) of ethyl - ({3.5 -dimethyl-4 - [(3-propyl-1H-indol-5-yl) oxy] ρhenyl) amino) - (oxo) acetate.

300MHz 1H NMR (CDC1 ₃ ): 0.95, t, 3H; 1.43, t, 3H; 1.62, m, 2H; 2.15, s, 6H; 2.59, t,

2H; 4.41, quarter, 2H; 6.86, m, 2H; 6.95, d, IH; 7.21, d, IH; 7.40, s, 2H; 7.81, s, IH; 8.81, s, IH.

Example 95 tert-Butyl ({4 - [(3-isopropyl-1H-indol-5-yl) oxy] -3,5-dimethylphenyl) amino) (oxo) acetate

Analogously, starting from 200 mg (0.679 mmol) of 4 - [(3-isopropyl-1H-indol-5-yl) oxy] -3,5-dimethylaniline and 151 mg (0.917 mmol) of tert-butyloxalic acid ester chloride 188 mg (65%) tert-butyl ({4 - [(3-isopropyl-1H-indol-5-yl) oxy] -3,5-dimethylphenyl) amino) (oxo) acetate.

300MHz 1H NMR (CDC1 ₃ ): 1.27, d, 6H; 1.61, s, 9H; 2.17, s, 6H; 3.05, m, IH; 6.73, dd, IH; 6.86, d, IH; 6.94, d, IH; 7.21, d, IH; 7.39, s, 2H; 7.78, s, IH; 8.78, s, IH.

Example 96

Isopropyl ({4 - [(3-isopropyl-1H-indol-5-yl) oxy] -3,5-dimethylphenyl) amino) (oxo) acetate

In an analogous manner, starting from 200 mg (0.679 mmol) of 4 - [(3-isopropyl-1H-indol-5-yl) oxy] ~ 3,5-dimethylanilm and 138 (0.917 mmol) of isopropyloxalic acid ester chloride, 247 mg (89 %) Isopropyl ({4 - [(3-isopropyl-lH-indol-5-yl) oxy] -3,5-dimethylphenyl) amino) (oxo) acetate.

300MHz 1H NMR (CDC1 ₃ ): 1.27, d, 6H; 1.41, d, 6H; 2.18, s, 6H; 3.05, m, IH; 5.21. m, IH; 6.72, dd, IH; 6.86, d, IH; 6.93, d, IH; 7.21, d, IH; 7.40, s, 2H; 7.79, s, IH; 8.80, s, IH.

Example 97 2-Hydroxyethyl {| ^" 4- {r3- (4-fluorobenzyl) -IH-mdol-5-ylloxy) -3,5-bis (trifluoromethyl) phenyl] amino) (oxo) acetate

5 mg of sodium are dissolved in ethanediol under argon. 65 mg (0.11 mmol) of ethyl - {[4 - {[3- (4-fluorobenzyl) -1H-indol-5-yl] oxy} -3,5-bis (trifluoromethyl) phenyl] amino) are added. (oxo) acetate, stirred for 3 hours at room temperature and poured the reaction mixture into water. It is extracted with dichlorometane, torcknet over sodium sulfate and removes the solvent in a vacuum. Chromatographic purification (cyclohexane / ethyl acetate = 1: 1) gives 15 mg (22%) 2-hydroxyethyl {[4 - {[3- (4-fluorobenzyl) -lH-indol-5-yl] oxy} -3, 5-bis (trifluoro-methyl) phenyl] amino} (oxo) acetate.

300 MHz 1H-ΝMR (CDC1 ₃ ): 3.95, s, 2H; 4.03, t, 2H; 4.51, t, 2H; 6.41, d, IH; 6.80, dd, IH; 6.90, m, 2H; 7.12, m, 2H; 7.23, IH; 7.90, s, IH; 8.21, s, 2H; 9.14, s IH.

The following examples are prepared in accordance with the preceding examples and in accordance with the general description of the process.

Example no.

174

175

176

177

178

Claims

claims

Compounds of the general formula (I),

in which

represents O, S, CH ₂ , CHF or CF ₂ ,

R ¹ and R ^{2 are} identical or different and represent hydrogen, halogen, (C _j - C ₆ ) alkyl, CF ₃ , CHF ₂ , CH ₂ F, vinyl or (C ₃ -C ₇ ) cycloalkyl, at least one of the two substituents is not equal to hydrogen and is ortho to the bridge bond,

R ³ for a head group with optionally derivatized carboxyl radical,

R ⁴ and R ^{5 are the} same or different and each represents hydrogen, hydroxy, halogen, cyano, Νitro, (C _j -C ^ alkyl, or the rest of the formula ΝR ¹⁸ R ¹⁹ , where R ¹⁸ and R ^{19 are the} same or are different and each represent hydrogen, phenyl, benzyl, (C ^ -Cg) alkyl, (Cι-C6) alkoxy or (Cß-Cg ^ cycloalkyl, which in turn, if necessary, are mono- or polysubstituted by halogen, hydroxy, amino, ( C _r C ₄ ) alkoxy, -CO-O (C ₁ -C ₄ ) alkyl, -NH-CO-O (C _r C ₄ ) alkyl, -O-CO- (C ₁ -C4) alkyl , a heterocycle or phenyl which is optionally substituted by halogen or hydroxy,

R ^{6 represents} halogen or represents hydrogen, hydroxy, OR ¹⁰ , NR ⁿ R ¹² , (C _r C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₆ -Cι ₀ ) aryl, or for a saturated, unsaturated or aromatic 5- to 10-membered hetero- Cycle with up to four identical or different heteroatoms from the series S, O and / or N, the abovementioned radicals optionally being substituted by one, two or three identical or different substituents from the group halogen, hydroxy, cyano, nitro, amino, CF. ₃ , (C _j -Cg) alkyl, optionally substituted by R ²³

(C _r C ₆ ) alkoxy, (C ₃ -C ₈ ) cycloalkyl, -OCO-R ¹³ , -CO-O-R14, -CO-NR ¹⁵ R ¹⁶ , -NHCOR ¹⁷ or -NHCOOR ^{17 are} substituted, where R ¹ », RU. Rl ² , Rl ³ , Rl _s Rl5 _{; R} 16 _{3 R} 17 _{and R} ^{23 are the} same or different and each represents hydrogen, phenyl, benzyl, (Ci-Cg) - alkyl, (-C-Cö) alkoxy or (C ₃ -C ₈ ) cycloalkyl, which in turn optionally one or more times by halogen, hydroxy, amino, (C _r C ₄ ) alkoxy, -CO-O (C _r C ₄ ) alkyl, -NH-CO-O (C _r C ₄ ) - alkyl, -O -CO- (-C-C ₄ ) alkyl, a heterocycle or optionally substituted by halogen or hydroxy substituted phenyl, or for the rest

stands in what

R ²⁰ and R ²¹ together with the carbon atom to which they are attached form a carbonyl group or are each the same or different and are hydrogen, halogen, hydroxyl, (C _r C ₆ ) -alkyl, (C _r C ₆ ) -alkoxy or the rest -NR ¹⁵ R ¹⁶ and

R ²² for hydrogen, hydroxy, OR ¹⁰ , NR ⁿ R ¹² , (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl, or for a saturated, unsaturated or aromatic 5- to 10-membered heterocycle with up to four identical or different heteroatoms from the series S, O and / or N, where the above radicals mentioned optionally by one, two or three identical or different substituents from the group halogen, hydroxy, cyano, nitro, amino, CF ₃ , (Cj-Cg) - alkyl, optionally substituted by R ²³ (Cj-Cg) - alkoxy, (C ₃ -C ₈ ) cycloalkyl, -OCO-R ¹³ , -CO-OR ¹⁴ , -CO-NR ¹⁵ R ¹⁶ ,

-NHCOR ¹⁷ or -NHCOOR ^{17 are} substituted, where R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ^{23 are the} same or different and each represents hydrogen, phenyl, benzyl, (C _r C ₆ ) -alkyl, (C _r C ₆ ) -alkoxy or (C ₃ -C ₈ ) -cycloalkyl, which in turn may be repeated one or more times

Halogen, hydroxy, amino, (C _r C ₄ ) alkoxy, -CO-O (C _r C ₄ ) alkyl, -NH-CO-O (C _r C ₄ ) alkyl, -O-CO- (C _r C ₄ ) -alkyl, a heterocycle or phenyl which is optionally substituted by halogen or hydroxy,

R ^{7 represents} hydrogen or an acyl group which can be split off under physiological conditions to form an NH function, preferably represents hydrogen or acetyl,

and their salts.

2. Nerbindungen of the general formula (I) according to claim 1

in which

represents O, S, CH ₂ , CHF or CF ₂ , Rl and R ^{2 are the} same or different and represent hydrogen, halogen, (C _r C ₆ ) alkyl, CF ₃ , CHF ₂ , CH ₂ F, vinyl or (C ₃ -C ₇ ) cycloalkyl, at least one of which the two substituents are not equal to hydrogen and are in the ortho position to the bridge bond,

R ³ for a head group of the formula

A- (CH ₂ ) _n - (CO) _m -R8, wherein

A represents CH ₂ , O, S, CO or ΝR ⁹ , in which R ^{9 is} hydrogen, or (C ₃ -C ₈ ) -cycloalkyl or represents the group - (CH ₂ ) _n - (CO) _m -O- (C _r C ₄ ) -alkyl,

n stands for a number from 0 to 3,

m represents 1 or 2,

R8 for hydrogen, hydroxy, ORl °, NR ^Ü Rl ² , (C _r C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (Cg-Cιo) aryl, or for a saturated, unsaturated or aromatic 5 is a 10-membered heterocycle with up to four identical or different heteroatoms from the series S, O and / or Ν, the aforementioned radicals optionally being substituted by one, two or three identical or different substituents from the group

Halogen, hydroxy, cyano, Νitro, amino, CF ₃ , (-C-Cg) alkyl, optionally substituted by R ²³ (C _r C ₆ ) - alkoxy, (C ₃ -C ₈ ) cycloalkyl, -OCO-Rl ^3rd , -CO-O-Rl ⁴ , -CO-ΝRl ⁵ Rl ⁶ , -NHCORl ⁷ or -NHCOORl ^{"7 are} substituted, where R ¹⁰ , RU, Rl, Rl ³ , RI ⁴ , R15, Rl6, RI ⁷ and R ^{23 are the} same or different and each represents hydrogen, phenyl, benzyl, (C _r C ₆ ) -alkyl, (C _r C ₆ ) -alkoxy or (C ₃ -C ₈ ) -cycloalkyl, which in turn may be mono- or polysubstituted by halogen, hydroxy, amino, (C1-C4) -alkoxy, -CO-O (-C ~ C ₄ ) alkyl, -NH-CO-O (C _r C ₄ ) alkyl, -O-CO- (C _r C ₄ ) alkyl, a heterocycle or optionally by halogen or

Hydroxy substituted phenyl are substituted,

R ⁴ and R ^{5 are the} same or different and each represents hydrogen,

Hydroxy, halogen, cyano, nitro, (Cj-) - alkyl, or the rest of the formula NRl ⁸ Rl ⁹ are available, where Rl ^§ and R ^{i9 are} those specified for Rl °

Have meanings and can be identical or different with this substituent,

R ^{6 represents} halogen or has the meaning given for R ⁸ and is identical or different with this substituent or for the rest

stands in what

R ²⁰ and R ²ⁱ together with the carbon atom to which they are attached form a carbonyl group or are each the same or different and are hydrogen, halogen, hydroxy, (C _r C ₆ ) alkyl, (C _r C ₆ ) alkoxy or the rest -NRl ⁵ Rl ⁶ and

R ^{22 has} the meaning of R ⁸ and is the same or different with it, R ^{7 represents} hydrogen or an acyl group which can be split off under physiological conditions to form an NH function, preferably represents hydrogen or acetyl,

and their salts.

3. Nerbindungen of the general formula (I) according to claim 1,

in which

Z represents O, CH ₂ or CF ₂ ,

Rl and R ^{2 are the} same or different and represent hydrogen, fluorine, chlorine,

Bromine, (C _r C ₄ ) alkyl, CF ₃ , CHF ₂ , CH ₂ F, ninyl or (C ₃ -C ₆ ) cycloalkyl, with at least one of the two substituents not equal to hydrogen and in the ortho position Bridge binding stands,

R ³ for a head group with optionally derivatized carboxyl radical, of the formula

A- (CH ₂ ) _n - (CO) _m -R ⁸ ,

wherein

A represents CH ₂ , O or ΝR ⁹ , where R ^{9 is} hydrogen, (C _r C ₄ ) -

Is alkyl or (C ₃ -C7) cycloalkyl or represents the group - (CH ₂ ) _n - (CO) _m -O- (C _r C ₄ ) alkyl,

n represents the number 0 or 1,

m represents the number 1 or 2, R ⁸ for hydrogen, hydroxy, OR ¹⁰ , NR ^Ü Rl ² , (C _r C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (Cg-Cio ^ aryl, or for a saturated, unsaturated or aromatic 5 is a 10-membered heterocycle with up to four identical or different heteroatoms from the series S, O and / or N, the abovementioned hydrocarbon radicals and heterocycles optionally being substituted by one, two or three identical or different substituents from the group halogen, Hydroxy, cyano, nitro, amino, CF ₃ , (C _r C ₄ ) alkyl, (C _r C ₄ ) alkoxy, (C _r C ₄ ) -

Alkoxyphenyl, (C ₃ -C ₈ ) cycloalkyl, -O-CO-Rl ³ , -CO-O-Rl ⁴ , -CO-NR15R1 ⁶ , -NHCORI ⁷ or -NHCOORI ^{7 are} substituted, where Rl °, R, R ² , R ¹³ , R ¹⁴ , R ¹⁵ , Rl ⁶ and R ^{17 are the} same or different and each represents hydrogen, benzyl, (-C-Cg) alkyl or (C ₃ -C ₈ ) cycloalkyl, which in turn, if appropriate single or multiple through fluorine, chlorine, hydroxy, amino, -CO-O (C _r C ₄ ) -alkyl, -NH-CO-O (C _r C ₄ ) -alkyl, -O-CO- (C _r C) Alkyl, imidazolyl, hydroxyphenyl or (C _] -C) alkoxy are substituted,

R ⁴ and R ^{5 are the} same or different and each represents hydrogen, halogen or (C ₁ -C ₄ ) alkyl,

R ^{6 represents} chlorine, fluorine, bromine or has the meaning given for R ⁸ and is the same or different with the above substituent or for the rest

stands, in which R ²⁰ and R ² 1 together with the carbon atom to which they are attached form a carbonyl group, or are in each case identical or different and for hydrogen, halogen, hydroxy, (C _r C ₄ ) alkyl, (C _r C ₄ ) - Alkoxy or the radical -NR ⁵ Rl6 and

R ^{22 has} the meaning of R ⁸ and is the same or different with it,

R ^{7 represents} hydrogen,

and their salts.

4. Nerbindungen of general formula (I) according to claim 1, in which

Z represents CH ₂ or oxygen,

Rl and R ^{2 are} identical or different and represent methyl, ethyl, propyl, isopropyl, chlorine, bromine, CF ₃ , ninyl or cyclopropyl, both substituents being in the ortho position to the bridge bond,

R ³ for the group -O- (CH ₂ ) _n -CO-R ⁸ or for the group ΝR ⁹ - (CH ₂ ) _n - (CO) _m -R ⁸ , each of which is in the para position to the bridge bond, where

R ⁹ -CH ₂ -CO-O- (C _r C ₄ ) alkyl substituted (C _r C ₄ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, -CO-CO-O- (C _r C ₄ ) Means alkyl or hydrogen,

m represents the number 1 or in particular 2, n represents the number 1 or 0,

R ⁸ for methyl, ethyl, n-propyl, isopropyl, n-, i-, s- or t-butyl, n-pentyl or n-hexyl, thiophenyl, pyridyl or for the groups -CH ₂ -O-benzyl, ORl ° or NR ^{! l} R ¹² stands,

where R 1 is hydrogen, or straight-chain or branched alkyl optionally substituted by hydroxyl having up to 7 carbon atoms, where R ⁿ and R ^{12 are the} same or different and are

Hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy, n-hexoxy or straight-chain or branched alkyl having up to 6 carbon atoms, where Alkyl, in turn, is optionally mono- or polysubstituted, identically or differently, by hydroxy, -CO-O (C _r C ₄ ) -alkyl, -NH-CO-O (C _r C ₄ ) -alkyl, imidazolyl and / or hydroxyphenyl,

R ⁴ and R ^{5 represent} methyl, fluorine or chlorine or hydrogen,

R ⁶ for hydrogen, hydroxy, ORl °, NR Rl ² , methyl ethyl, n-propyl, isopropyl, n-, i-, s- or t-butyl, (C ₃ -Cö) cycloalkyl, (C6-Cιn) Aryl, or for a saturated, unsaturated or aromatic 5- to 10-membered heterocycle with up to three identical or different

Heteroatoms from the series S, O and / or N, the aforementioned hydrocarbon radicals and heterocycles optionally being substituted by one, two or three identical or different substituents from the group halogen, hydroxy, cyano, nitro, amino, CF ₃ , (C _r C ₄₎ -alkyl, (C _r C ₄₎ - _alkoxy, (C ₃ -C ₈₎ -cycloalkyl, O-CO-R ^13,

-CO-OR ¹⁴ , -CO-NR ¹⁵ Rl ⁶ or -NHCOORl ^{"7 are} substituted, wherein Rl °, U, Rl ² , Rl ³ , Rl ⁴ , Rl ⁵ , Rl ⁶ and R ^{i7 are the} same or different and each represents hydrogen, benzyl, (Cι-C ₄ ) - alkyl or (C ₃ -C _Ö ) - Are cycloalkyl, which in turn are optionally substituted by amino or (Cj-C ₄ ) alkoxy,

or for the rest

in which

R ²⁰ and R 1 together with the carbon atom to which they are attached form a carbonyl group, or are each the same or different and are hydrogen, halogen, hydroxy,

(C _r C ₄ ) alkyl, (C _r C ₄ ) alkoxy or the radical -NRl ⁵ Rl ⁶ and

R ²² for hydrogen, hydroxy, OR, NR ^Ü Rl ² , (C _r C ₄ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl, or for a saturated, unsaturated or aromatic 5- to 10-membered heterocycle having up to three identical or different heteroatoms from the series S, O and / or N, the abovementioned hydrocarbon radicals and heterocycles optionally being substituted by one, two or three identical or different substituents from the group Halogen, hydroxy, cyano, nitro, amino, CF ₃ , (Ci) alkyl, (C _r C ₄ ) alkoxy, (C ₃ -C ₈ ) -

Cycloalkyl, O-CO-R ³ , -CO-O-Rl ⁴ , -CO-NR ⁵ Rl6 or -NHCOOR ^{7 are} substituted, where Rl °, R ¹¹ , Rl ² , R ⁱ³ , R ¹⁴ , Rl ⁵ , Rl ⁶ and Rl ^{"7 are the} same or different and each represents hydrogen, benzyl, (C _r C ₄ ) alkyl or (C ₃ -C ₆ ) cycloalkyl stand, which in turn are optionally substituted by amino or (-CC ₄ ) - alkoxy,

R ^{7 represents} hydrogen,

and their salts.

Compounds of the general formula (I)

represents O, S, CH ₂ , CHF or CF ₂ ,

Rl and R ^{2 are the} same or different and represent hydrogen, halogen, (C _j - C ₆ ) alkyl, CF ₃ , CHF ₂ , CH ₂ F, ninyl or (C ₃ -C ₇ ) cycloalkyl, at least one is not equal to hydrogen for both substituents and is in the ortho position to the bridge bond,

R ³ for a head group with optionally derivatized carboxyl radical, preferably for a group of the formula

A- (CH ₂ ) _n - (CO) _m -R ⁸ , wherein

A represents CH ₂ , O, S, CO or ΝR ⁹ , in which R ^{9 is} hydrogen, (C _r C ₆ ) -alkyl or (C ₃ -C ₈ ) -cycloalkyl, n stands for a number from 0 to 3,

m represents 1 or 2,

R ⁸ for hydrogen, hydroxy, OR ¹⁰ , NR ^Ü Rl ² , (C _r C ₈ ) - alkyl,

(C ₃ -Cg) cycloalkyl, (C6-Cιo) aryl, or for a saturated, unsaturated or aromatic 5- to 10-membered heterocycle with up to four identical or different heteroatoms from the series S, O and / or N is, the aforementioned hydrocarbon radicals and heterocycles optionally by one, two or three identical or different substituents from the group halogen, hydroxy, cyano, nitro, amino, CF ₃ , (C _r C ₆ ) - alkyl, (C _r C ₆ ) - Alkoxy, (C ₃ -C ₈ ) - cycloalkyl, OCO-Rl ³ , -CO-O-Rl ⁴ , CO-NRl ⁵ Rl ⁶ or -NHCOORI ⁷ , where Rl °, Rl 1, Rl ² , R ⁱ³ , R,

Rl ⁵ , Rl ⁶ and Rl ^{"7 are the} same or different and each represents hydrogen, benzyl, (C _r C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl, which in turn may be substituted by amino or (C1-C4 ) - alkoxy are substituted,

R ⁴ and R ^{5 are the} same or different and each represents hydrogen,

Hydroxy, halogen, cyano, nitro, (C1-C4) alkyl, or the rest of the

Formula NR ¹⁸ R ¹⁹ , where R ¹⁸ and R ^{19 are} those given for R ¹⁰

Have meaning and can be identical or different with this substituent,

R ^{6 has} the meaning given for R ⁸ and is identical or different with this substituent or for the rest

stands in what

R ²⁰ and R ² 1 together represent oxygen, or are each the same or different and represent hydrogen, halogen, hydroxy, (C _r C ₆ ) alkyl, (C _r C ₆ ) alkoxy or the radical -N l ⁵ Rl ⁶ stand and

R ^{22 has} the meaning of R ⁸ and is the same or different with it,

R ^{7 represents} hydrogen or an acyl group which can be split off under physiological conditions to form an NH function, preferably represents hydrogen or acetyl,

and their salts.

6. Nerbindungen of formula (I) according to claim 5,

in which

Z represents O, CH ₂ or CF ₂ ,

Rl and R ^{2 are the} same or different and are hydrogen, fluorine, chlorine, bromine, (C _r C ₄ ) alkyl, CF ₃ , CHF ₂ , CH ₂ F, ninyl or (C ₃ -C ₆ ) cycloalkyl where at least one of the two substituents is not hydrogen and is ortho to the bridge bond, in particular both substituents are not hydrogen and both are ortho,

R ³ for a head group with optionally derivatized carboxyl radical, preferably for a group of the formula A- (CH ₂ ) _n - (CO) _m -R ⁸ , which is para to the bridge bond,

wherein

represents CH ₂ , O or NR ⁹ , where R ^{9 is} hydrogen, (C _r C ₄ ) alkyl or (C ₃ -C ₇ ) cycloalkyl,

n represents 0 or 1,

m represents 1 or 2,

R ⁸ for hydrogen, hydroxy, ORl °, NR ^Ü R ² , (C _r C ₆ ) alkyl, (C -C) cycloalkyl, (C6-Cj) aryl, or for a saturated, unsaturated or aromatic 5- to 10-membered heterocycle with up to four identical or different heteroatoms from the series S, O and / or N, the abovementioned hydrocarbon radicals and heterocycles optionally being replaced by one, two or three identical or different ones

Substituents from the group halogen, hydroxy, cyano, nitro, amino, CF ₃ , (C _r C ₄ ) - alkyl, (C _r C ₄ ) - alkoxy, (C ₃ -C ₈ ) - cycloalkyl, O-CO-Rl ³ , -CO-O-Rl ⁴ , -CO-NRl ⁵ Rl ⁶ or -NHCOORI ^{7 are} substituted, where R ¹⁰ , R ^Ü , Rl, R ^{! 3} , R ¹⁴ , Rl ⁵ , R ⁱ⁶ and Rl ^{7 are the} same or are different and each for

Are hydrogen, benzyl, (C _r C ₄ ) -alkyl or (C ₃ -C ₆ ) -cycloalkyl, which in turn are optionally substituted by amino or (CC ₄ ) - alkoxy,

R ⁴ and R ^{5 are the} same or different and each represents hydrogen, halogen or (-CC) alkyl, R ^{6 has} the meaning given for R ⁸ and is the same or different with the above substituent or for the rest

stands, in which

R ²⁰ and R ² 1 together represent oxygen, or are each the same or different and represent hydrogen, halogen, hydroxy, (C _r C ₄ ) alkyl, (C _r C ₄ ) alkoxy or the radical -NRl ⁵ Rl ⁶ stand and

R ^{22 has} the meaning of R ⁸ and is the same or different with it,

R ^{7 represents} hydrogen,

and their salts.

Nerbindungen of formula (I) according to claim 5, in which

Z represents oxygen or CH ₂ ,

Rl and R ^{2 are} identical or different and represent methyl, ethyl, propyl, isopropyl, chlorine, bromine, CF ₃ , ninyl or cyclopropyl, both substituents being in the ortho position to the bridge bond,

R ³ for the group -ΝR ⁹ - (CO) _m -R ⁸ or the group -O- (CH ₂ ) _n -CO-R ⁸ is in para position to the bridge bond, where R ^{9 is} hydrogen, (C _r C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,

m represents 2,

n stands for 1,

R ⁸ for (-C-C ₆ ) alkyl _. Pyridyl, ORl ° or NR ^{1 l} R ¹² ,

where R 1 °, R and R 1 are hydrogen, benzyl, (C _r C ₄ ) alkyl or (C ₃ -C 6) cycloalkyl,

R ⁴ and R ^{5 represent} hydrogen, methyl, fluorine or chlorine,

R ⁶ for hydrogen, hydroxy, OR ¹⁰ , NR ^Ü Rl ² , (C _r C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (Cg-C ^ -Ary-, or for a saturated, unsaturated or aromatic 5- to 10-membered heterocycle having up to three identical or different heteroatoms from the series S, O and / or N, the abovementioned hydrocarbon radicals and heterocycles optionally being substituted by one, two or three identical or different substituents from the group halogen, Hydroxy, cyano,

Nitro, amino, CF ₃ , (C _r C ₄ ) - alkyl, (C _r C ₄ ) - alkoxy, (C ₃ -C ₈ ) - cycloalkyl, O-CO-Rl ³ , -CO-O-Rl ⁴ , -CO-NRl ⁵ Rl ⁶ or -NHCOOR ^{i7 are} substituted, wherein Rio, Rü, Rl ² , Rl ³ , Rl ⁴ , Rl5, Rl6 and Rl ^{7 are the} same or different and each for hydrogen, benzyl, (-C-C ₄ ) -Alkyl or (C ₃ -Cö) -cycloalkyl, which in turn are optionally substituted by amino or (-C-C ₄ ) alkoxy,

or for the rest

in which

R ²⁰ and R ²ⁱ together represent oxygen, or are each the same or different and represent hydrogen, halogen, hydroxyl,

(C _r C ₄ ) alkyl, (C _r C ₄ ) alkoxy or the radical -NR ⁱ⁵ Rl ⁶ and

R ²² for hydrogen, hydroxy, OR ¹⁰ , N Rl ² , (C _r C ₄ ) alkyl, (C ₃ -C6) cycloalkyl, (C -Cj) aryl, or for a saturated, unsaturated or aromatic 5- to 10-membered heterocycle with up to three identical or different heteroatoms from the series S, O and / or N, the aforementioned hydrocarbon radicals and heterocycles optionally being replaced by one, two or three identical or different ones

Substituents from the group halogen, hydroxy, cyano, nitro, amino, CF ₃ , (C _r C ₄ ) - alkyl, (C _r C ₄ ) - alkoxy, (C ₃ -C ₈ ) - cycloalkyl, O-CO-Rl ³ , -CO-O-Rl ⁴ , -CO-NRl ⁵ Rl ⁶ or -NHCOORI ^{7 are} substituted, where Rl °, Rü, Rl ² , R ⁱ³ , Rl ⁴ , Rl ⁵ , Rl ⁶ and R ^{i7 are the} same or different are and each for

Are hydrogen, benzyl, (C _r C ₄ ) -alkyl or (C ₃ -C ₆ ) -cycloalkyl, which in turn are optionally substituted by amino or (C _j - C4) -alkoxy,

R ^{7 represents} hydrogen,

and their salts.

8. Ner process for the preparation of Nerbindungen of general formula (I) as defined in claim 1, characterized in that reactive indole Derivatives of the general formula (II) with reactive phenyl derivatives of the general formula (III)

(II) (HI) (IV)

wherein the substituents Rl, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meanings given in claim 1 and

R ³ 'has the meaning given for R ³ or stands for NO, NH ₂ or NPG, where PG stands for a protective group,

X and Y each represent groups of opposite reactivity,

Z 'has the meaning given for Z or represents CHOH,

if appropriate in the presence of inert solvents and catalysts and if appropriate with isolation of the intermediates of the general formula (IN), or directly to Nerbindungen of formula (I).

9. compounds of the formula (IN)

in which Rl, R ² , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meanings given in Claim 1,

Z 'has the meaning given for Z in claim 1 or represents CHOH and

R ³ 'has the meaning given for R ³ in claim 1 or represents NO ₂ , NH ₂ or NPG,

with the proviso that when Z 'is CH ₂ , R ³ ' is not NO ₂ ,

and that if

Z 'represents CH ₂ ,

R ³ 'represents NH ₂ ,

Rl and R ^{2 represent} (C _r C ₄ ) alkyl,

R ⁴ and R ⁵ stand for H and R ^{6 stands} for (C ₃ -C 6) cycloalkyl substituted with amino,

R ⁷ does not represent hydrogen.

10. Medicament containing at least one compound of general formula (I) according to at least one of claims 1 to 8.

11. A process for the production of medicaments, characterized in that at least one compound of the general formula (I) according to at least one of claims 1 to 8 is converted into a suitable application form with auxiliaries and excipients.

12. Use of the compounds of the general formula (I) according to at least one of claims 1 to 8 for combating diseases.

13. Use of Nerbindungen of general formula (I) according to at least one of claims 1 to 8 in the treatment and / or

Prophylaxis of atherosclerosis and hypercholesterolemia.

14. Use of compounds of the general formula (I) according to at least one of claims 1 to 8 for the manufacture of medicaments for the prophylaxis and / or treatment of disease forms which are natural

Thyroid hormone can be treated.

15. Use of compounds of the general formula (I) according to at least one of claims 12 to 14 in combination with other medicaments.

16. Medicament containing at least one compound of the general formula (I) according to at least one of claims 1 to 8 and carriers, auxiliaries, solvents, vehicles, emulsifiers and / or dispersants.