EP1507763A1 - Tetrahydroisoquinoline derivatives - Google Patents

Abstract

The invention relates to novel substituted tetrahydroisoquinoline derivatives, methods for the production thereof and the use thereof in medicaments, especially as potent PPAR-delta activating compounds for the prophylaxis and/or treatment of cardiovascular diseases, especially dislipidaemia, coronary heart disease and arteriosclerosis.

Description

Tetrahvdroisochinolin derivatives

The present application relates to new substituted tetrahydroisoquinoline derivatives, processes for their preparation and their use in medicaments, in particular as potent PPAR-delta activating compounds for the prophylaxis and / or treatment of cardiovascular diseases, in particular dyslipidemias, coronary heart diseases and arteriosclerosis.

Despite multiple therapeutic successes, coronary artery disease (CAD) remains a serious public health problem. While treatment with amazement by inhibiting HMG-CoA reductase very successfully lowers the plasma concentration of LDL cholesterol and this leads to a significant reduction in the mortality of high-risk patients, today there are no convincing treatment strategies for the therapy of patients with unfavorable HDL / LDL cholesterol - Ratio and / or hypertriglyceridemia.

Fibrates are the only form of therapy for patients in these risk groups today. They act as weak agonists of the peroxisome proliferator-activated receptor (PPAR) -alpha (Nature 1990, 347, 645-50). A disadvantage of previously approved fibrates is their weak interaction with the receptor, which leads to high daily doses and significant side effects.

For the peroxisome proliferator-activated receptor (PPAR) delta (Mol. Endocrinol. 1992, 6, 1634-41), the first pharmacological findings in animal models indicate that potent PPAR-delta agonists also improve HDL / LDL Cholesterol ratio and hypertriglyceridemia.

WO 00/23407 discloses PPAR modulators for the treatment of obesity, atherosclerosis and / or diabetes. In WO 93/15051 and EP 636 608- Al 1-benzenesulfonyl-1,3-dihydroindol-2-one derivatives with partial phenoxyacetic acid structure are described as vasopressin and / or oxytocin antagonists.

The object of the present invention was to provide new compounds which can be used as PPAR delta modulators.

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

in which

X represents O, S or CH ₂ ,

R ¹ represents halogen, _(Cι-C6) alkoxy, (C ₂ -C ₆₎ alkenyloxy, (C ₃ -C ₇₎ cycloalkoxy, optionally substituted by halogen, (Cι-C ₄₎ -alkyl, trifluoromethyl or ( Cι-C ₄ ) -

Alkoxy substituted benzyloxy

or

represents (C ₆ -Cιo) aryl or 5- to 6-membered heteroaryl with up to three heteroatoms from the series N, O and / or S, which in turn each one to three times, identically or differently, by substituents selected from the group halogen, (-CC ₆ ) alkyl, (-C- ₆ ) alkoxy, trifluoromethyl, trifluoromethoxy, amino, mono- and di- (-C ₆ ) alkylamino may be substituted,

R ² and R ^{3 are the} same or different and independently of one another are hydrogen or (-CC ₆ ) alkyl, which is optionally substituted by phenyl or together with the carbon atom to which they are attached form a 3- to 7-membered, spiro-linked cycloalkyl ring,

R ⁴ and R ^{5 are the} same or different and independently of one another represent hydrogen or (-CC ₆ ) -alkyl,

R ^{6 represents} hydrogen or (C i -C ₆ ) alkyl,

R ^{7 represents} hydrogen or (-CC ₆ ) alkyl,

R ^{8 represents} hydrogen, (C, -C ₆ ) alkyl, (-C-C ₆ ) alkoxy or halogen,

R ⁹ and R ^{10 are the} same or different and independently of one another represent hydrogen or (-CC) alkyl,

and

R ¹ 'represents hydrogen or a hydrolyzable group which can be broken down into the corresponding carboxylic acid,

as well as their pharmaceutically acceptable salts, solvates and solvates of the salts,

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

In the context of the invention in the definition of R ¹ 'means a hydrolyzable

Group is a group that transforms the body in particular

-C (O) 0R '' grouping leads to the corresponding carboxylic acid (R ^u = hydrogen).

Such groups are exemplary and preferably: benzyl, (-CC ₆ ) -alkyl or (C-C ₈ ) -cycloalkyl, each optionally one or more times, identically or differently, by halogen, hydroxy, amino, (-C-C ₆ ) -alkoxy, carboxyl, (-C-C ₆ ) - Alkoxycarbonyl, (-CC ₆ ) -alkoxycarbonylamino or (-C-C ₆ ) alkanoyloxy are substituted, or in particular (-C-C ₄ ) -alkyl, which may be one or more, the same or different, by halogen, hydroxy, amino , (-C-C ₄ ) alkoxy, carboxyl, (-C-C ₄ ) -alkoxycarbonyl, (Cι-C ₄ ) -alkoxycarbonylamino or (Cι-C ₄ ) - alkanoyloxy is substituted.

In the context of the invention, (C ₁ -C ₆ ) -alkyl and (CrC ₄ ) -alkyl stand for a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms. A straight-chain or branched alkyl radical having 1 to 4 carbon atoms is preferred. The following may be mentioned by way of example and preferably: methyl, ethyl, n-propyl,

Isopropyl and t-butyl.

In the context of the invention, (C -C ₆ ) alkenyl and (C -C ₄ ) alkenyl stand for a straight-chain or branched alkenyl radical having 2 to 6 or 2 to 4 carbon atoms. A straight-chain or branched alkenyl radical with 2 to 4 is preferred

Carbon atoms. The following may be mentioned as examples and preferably: vinyl, allyl, isopropenyl and n-but-2-en-l-yl.

(C -C ₈ ) Cycloalkyl stands for a monocyclic cycloalkyl group with 3 to 8 carbon atoms in the context of the invention. Examples and preferably mentioned are: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the context of the invention, (C ₆ -Cιo) aryl represents an aromatic radical with preferably 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

(-C-C ₆ ) alkoxy and (-C-C ₄ ) alkoxy are within the scope of the invention for a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms. A straight-chain or branched alkoxy radical having 1 to 4 carbon atoms is preferred. The following may be mentioned as examples and preferably: methoxy, ethoxy, n-propoxy,

Isopropoxy and t-butoxy. (C2-C ₆₎ -alkenyloxy and (C ₂ -C) alkenyloxy are in the context of the invention a straight-chain or branched alkenyloxy group having 2 to 6 or 2 to 4 carbon atoms. A straight-chain or branched alkenyloxy radical having 2 to 4 carbon atoms is preferred. The following may be mentioned as examples and preferably: vinyloxy, allyloxy, isopropenyloxy and n-but-2-en-1-yloxy.

In the context of the invention, (C -C ₇ ) cycloalkoxy and (C ₅ -C ₆ ) cycloalkoxy represent a monocyclic cycloalkoxy radical having 3 to 7 or 5 to 6 carbon atoms. A cycloalkoxy radical having 5 to 6 carbon atoms is preferred. The following may be mentioned as examples and preferably: cyclopropoxy, cyclobutoxy, cyclopentoxy and cyclohexoxy.

(C l -C ₆₎ - alkoxycarbonyl is in the context of the invention a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms, which is linked via a carbonyl group. A straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms is preferred. The following may be mentioned by way of example and preferably: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl.

(In the context of the invention, C Q-alkoxycarbonylamino represents an amino group with a straight-chain or branched alkoxycarbonyl substituent which has 1 to 6 carbon atoms in the alkoxy radical and is linked via the carbonyl group. An alkoxycarbonylamino radical with 1 to 4 carbon atoms is preferred Examples and preferably mentioned are: methoxycarbonylamino,

Ethoxycarbonylamino, n-propoxycarbonylamino and t-butoxycarbonylamino.

In the context of the invention, (CrC ₆ ) -alkanoyloxy stands for a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, which carries a double-bonded oxygen atom in the 1 position and another one in the 1 position Oxygen atom is linked. Examples that may be mentioned are: acetoxy, propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy, n-hexanoyloxy.

In the context of the invention, mono- (CrC ₆ ) -alkylamino and mono- (CrC ₄ ) -alkylamino represent an amino group with a straight-chain or branched alkyl substituent which has 1 to 6 or 1 to 4 carbon atoms. A straight-chain or branched monoalkylamino radical having 1 to 4 carbon atoms is preferred. Examples and preferably mentioned are: methylamino, ethylamino, n-propylamino, isopropylamino and t-butylamino.

In the context of the invention, di- (C ₁ -C ₆ ) -alkylamino and di- (C 1 -C ₄ ) -alkylamino stand for an amino group with two identical or different straight-chain or branched alkyl substituents, each 1 to 6 or 1 to Have 4 carbon atoms. Straight-chain or branched dialkylamino radicals each having 1 to 4 carbon atoms are preferred. Examples and preferably are:

NN-dimethylamino, NN-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, Nt-butyl-N-methylamino, N-ethyl-Nn-pen- tylamino and Nn-hexyl-N-methylamino.

5- to 6-membered heteroaryl with up to 3 identical or different heteroatoms from the series S, Ν and / or O preferably stands for an aromatic heterocycle in the context of the invention which is via a ring carbon atom of the heteroaromatic, optionally also via a ring nitrogen atom of the heteroaromatic is linked. Examples include: furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl. Are preferred

Pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl.

Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Chlorine or fluorine 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. Like the diastereomers, the racemic forms 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 connections are also within the scope of the

Invention includes.

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 carboxylic 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 are preferred , Ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.

Physiologically acceptable salts can also be salts of the invention

Be compounds with bases, such as 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, for example ethylamine, di- or triethylamine, ethyldiisopropylamine, monoethanolamine, di- or Triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methyl morpholine, 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) in which

X represents O or S,

R ¹ for (C ₂ -C ₄ ) alkenyloxy, (C ₅ -C ₆ ) cycloalkoxy or in particular for halogen or (Cι-C) alkoxy,

or

stands for 6-membered heteroaryl with up to two nitrogen atoms, or in particular for phenyl or benzyloxy, which in turn in each case one to two times, identically or differently, by substituents selected from the group fluorine, chlorine, (CC) -alkyl, (Cι -C ₄ ) alkoxy, trifluoromethyl, trifluoromethoxy, amino, mono- and di- (-C-C ₄ ) alkylamino may be substituted,

R ² and R ^{3 are the} same or different and are independently hydrogen or methyl or ethyl, which may be substituted by phenyl, or together with the carbon atom to which they are attached

Form 4- to 6-membered, spiro-linked cycloalkyl ring,

R ⁴ and R ⁵ each represent hydrogen,

R. 0 represents hydrogen or methyl, R ^{7 represents} hydrogen or methyl,

R ^{8 represents} hydrogen, (-CC ₄ ) -alkyl, (dC ₄ ) -alkoxy, fluorine or chlorine,

R ⁹ and R ^{10 are the} same or different and are independently of one another

Are hydrogen or methyl,

and

R ¹ 'represents hydrogen or (-CC ₄ ) alkyl.

Compounds of the general formula (I) in which

X stands for O,

R ^{1 represents} pyridyl or, in particular, phenyl, which in turn can be substituted once or twice, identically or differently, by substituents selected from the group consisting of fluorine, chlorine, methyl, methoxy, trifluoromethyl, trifluoromethoxy, amino and dimethylamino,

R ^{2 represents} hydrogen or methyl,

R ^{3 represents} methyl or phenethyl,

or

R and R together with the carbon atom to which they are attached form a spiro-linked cyclopentane or cyclohexane ring,

R ⁴ and R ⁵ each represent hydrogen, R ^{6 represents} hydrogen or methyl,

R ^{7 represents} hydrogen or methyl,

R ^{8 represents} methyl,

R ⁹ and R ¹⁰ each represent hydrogen,

and

R ¹ 'represents ethoxy or in particular hydrogen.

The general or preferred radical definitions given above 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, irrespective of the respectively specified combinations of the radicals.

Compounds of the formula (I-A) are of particular importance

in which

R ^{2 represents} hydrogen, R ^{3 represents} methyl or phenethyl,

or

R ² and R ³ both represent methyl or together with the carbon atom to which they are attached form a spiro-linked cyclopentane or cyclohexane ring,

and

1 . 1

R, R and R each have the meaning given above.

In addition, a process for the preparation of the compounds of the general formula (I) according to the invention was found, characterized in that

[A] compounds of the general formula (II)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ each have the meaning given above.

first with a compound of the general formula (III)

in which X, R ⁷ , R ⁸ , R ⁹ and R ¹⁰ each have the meaning given above and

represents benzyl or (-CC ₆ ) alkyl,

in an inert solvent in the presence of a base in compounds of the general formula (I-B)

in which T, X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ each have the meaning given above,

converted, then with acids or bases or, if T is benzyl, also hydrogenolytically to the corresponding carboxylic acids of the general formula (I-C)

in which X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ each have the meaning given above,

implements,

and optionally these carboxylic acids (I-C) are further modified to give compounds of the general formula (I) by known esterification methods,

or

[B] Compounds of the general formula (IV)

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

PG stands for a suitable hydroxyl protective group, such as methyl or benzyl,

first with a compound of the general formula (III) in an inert solvent in the presence of a base in compounds of the general formula (V)

in which PG, T, X, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ each have the meaning given above,

transferred in the next reaction step the protective group PG by suitable methods, for example by treatment with boron tribromide (PG = methyl) or hydrogenolytic (PG = benzyl), to give compounds of the general formula (VI)

in which T, X, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ^{! 0} each have the meaning given above,

removed, and then the compounds of general formula (VI) either

[B- 1] with a compound of the general formula (VII)

R, 1 ¹ 2 -Z (VII), in which R for (C, -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₃ -C ₇ ) cycloalkyl or for optionally by halogen, (Cι-C ₄ ) alkyl, trifluoromethyl or (Cι -C ₄ ) alkoxy substituted benzyl, and

is a suitable leaving group, such as halogen, mesylate or tosylate,

in an inert solvent in the presence of a base to give compounds of the general formula (I-D)

in which T, X, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹² each have the meaning given above,

and this with acids or bases or, if T is benzyl, also hydrogenolytically into the corresponding carboxylic acids of the general formula (I-E)

in which X, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹² each have the meaning given above, or

[B-2] first with trifluoromethanesulfonic anhydride in the presence of a base in compounds of the general formula (VIII)

in which T, X, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ each have the meaning given above,

transferred and this in a coupling reaction with a compound of general formula (IX)

in which

R ^{1 stands} for (C ₆ -Cιo) aryl or 5- to 6-membered heteroaryl with up to three heteroatoms from the series N, O and / or S, which in turn each one to three times, identically or differently, by substituents selected from the group halogen, (Ci

C ₆ ) alkyl, (-C-C ₆ ) alkoxy, trifluoromethyl, trifluoromethoxy, amino, mono- and di- (-C-C ₆ ) alkylamino may be substituted, and

R ^{13 represents} hydrogen or methyl or both radicals together form a CH ₂ CH ₂ or C (CH ₃ ) ₂ -C (CH ₃ ) ₂ bridge, in an inert solvent in the presence of a suitable palladium catalyst and a base to give compounds of the general formula (IB) [cf. e.g. W. Hahnfeld, M. Jung, Pharmazie 1994, 49, 18-20; idem, Liebigs Ann. Chem. 1994, 59-64].

Inert solvents for process step (II) + (III) → (IB) or (IV) + (III) - (V) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, ethyl acetate, acetone, dimethylformamide, dimethylyrrolidine, acetonitrile, acetonitrile, acetonitrile, acetic acid or pyridine. It is also possible to use mixtures of the solvents mentioned. Dichloromethane or

Tetrahydrofuran.

Suitable bases for process step (II) + (III) → (I-B) or (IV) + (III) → (V) are the customary inorganic or organic bases. These preferably include alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate, alkali metal hydrides such as sodium hydride, or organic amines such as pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine , Amine bases such as triethylamine, pyridine or ethyldiisopropylamine are particularly preferred, optionally in the presence of catalytic amounts (approx. 10 mol%) of 4-NN-dimethylaminopyridine or 4-pyrrolidinopyridine.

The base is used in an amount of 1 to 5, preferably 1 to 2.5, mol, based on 1 mol of the compound of the general formula (III). The reaction generally takes place in a temperature range from -20 ° C. to + 100 ° C., preferably from 0 ° C. to + 75 ° C. The reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). Generally one works at normal pressure.

Inert solvents for process step (IB) - »(IC) are, for example, halogenated hydrocarbons such as dichloromethane, 1, 2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol , isopropanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene,

Toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, acetone, dimethylformamide, dimethyl sulfoxide, acetonitrile or N-methylpyrrolidinone. It is also possible to use mixtures of the solvents mentioned. Alcohols such as methanol or ethanol are preferred.

The usual inorganic bases are suitable as bases for process step (I-B) → (I-C). These preferably include alkali hydroxides such as lithium, sodium or potassium hydroxide, or alkali or alkaline earth carbonates such as sodium, potassium or calcium carbonate. Lithium or sodium hydroxide are particularly preferred.

The base is used in an amount of 1 to 5, preferably 1 to 3, mol, based on 1 mol of the compound of the general formula (I-B).

Suitable acids for process step (I-B) → (I-C) are the customary inorganic acids such as, for example, hydrochloric acid or sulfuric acid, or sulfonic acids such as toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid, or carboxylic acids such as trifluoroacetic acid.

The reaction generally takes place in a temperature range from -20 ° C to

+ 100 ° C, preferably from 0 ° C to + 30 ° C. With normal, elevated or reduced pressure can be carried out (for example from 0.5 to 5 bar). Generally one works at normal pressure.

Inert solvents for process step (VI) + (VII) - »(I-D) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or

Diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitro methane, acetone, dimethyl formamide, dimethyl sulfoxide, acetonitrile or N-methyl pyrrolidinone. It is also possible to use mixtures of the solvents mentioned. Dimethylformamide is preferred.

The usual inorganic bases are suitable as bases for process step (VI) + (VII) -> (I-D). These preferably include alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate, or alkali metal hydrides such as sodium or

Potassium hydride. Sodium hydride or potassium carbonate are particularly preferred.

The base is used in an amount of 1 to 5, preferably 1 to 2, mol, based on 1 mol of the compound of the general formula (VI).

The reaction generally takes place in a temperature range from -20 ° C. to + 150 ° C., preferably from 0 ° C. to + 100 ° C. The reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.

Inert solvents for process step (VI) - (VIII) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol ethylene dimethyl ether or diethylene dimethyl ether or diethylene dimethyl ether Benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, acetone, Dimethylformamide, dimethyl sulfoxide, acetonitrile or N-methylpyrrolidinone. It is also possible to use mixtures of the solvents mentioned. Tetrahydrofuran or dichloromethane are preferred.

The usual inorganic or organic bases are suitable as bases for process step (VI) - »(VIII). These preferably include alkali or alkaline earth carbonates such as sodium, potassium or calcium carbonate, or organic amines such as pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine. Triethylamine or ethyldiisopropylamine, particularly in the presence of catalytic amounts (approx. 10 mol%) of 4-N, N-

Dimethylaminopyridine or 4-pyrrolidinopyridine.

The base is used in an amount of 1 to 5, preferably 1 to 2.5, mol, based on 1 mol of the compound of the general formula (VI).

The reaction generally takes place in a temperature range from -20 ° C. to + 150 ° C., preferably from 0 ° C. to + 70 ° C. The reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.

Inert solvents for process step (VIII) + (IX) - (IB) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert. -Butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as

Dimethylformamide, acetonitrile or water. It is also possible to use mixtures of the solvents mentioned. Toluene, dimethylformamide or a mixture of dimethylformamide and water are preferred.

Suitable bases for process step (VIII) + (IX) -> (IB) are the customary inorganic or organic bases. These preferably include alkali or Alkaline earth carbonates such as sodium, potassium or calcium carbonate, alkali phosphates such as sodium or potassium phosphate, or organic amines such as triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine. Sodium or potassium carbonate or potassium phosphate are particularly preferred.

The base is used in an amount of 1 to 5, preferably 1 to 2, mol, based on 1 mol of the compound of the general formula (VIII).

The reaction generally takes place in a temperature range from -20 ° C. to + 150 ° C., preferably from 0 ° C. to + 100 ° C. The reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.

The compounds of the general formula (II) are known or can be prepared analogously to processes known from the literature, for example by adding a compound of the formula (X)

in an inert solvent in the presence of a base with an equivalent

Amount or excess of a compound of the general formula (XI)

R ² -Y (XI),

in which

R, 2 represents (-CC ₆ ) alkyl, which is optionally substituted by phenyl, and Y represents a suitable leaving group, such as halogen, mesylate or tosylate,

or with a compound of formula (XII)

Y- (CH ₂ ) _n -Y (XII),

in which Y has the meaning given above and

n represents the number 2, 3, 4, 5 or 6,

to a compound of the general formula (XIII)

in which R ² and R ^{3 have} the meaning given above, but not both are hydrogen at the same time,

implements this then

[a] in the event that R ⁴ and R ^{5 are} both hydrogen, with the aid of a complex boron or aluminum hydride, such as, for example, lithium aluminum hydride or lithium borohydride, optionally in the presence of trimethylsilyl chloride,

or [b] in the event that R ⁴ and R ^{5 are} each (C ₁ -C ₆ ) -alkyl, in a one-pot reaction or in two substeps with an organometallic compound of the general formula (XIV)

R ⁴ -M (XIV), in which

R ⁴ for (C, -C ₆ ) alkyl and

M represents Li, -Mg-Cl, -Mg-Br or -Mg-I,

to a compound of the general formula (XV)

in which R ² , R ³ , R ⁴ and R ⁵ each have the meaning given above,

reacted, then with formic acid in a compound of general formula

transferred, then in a coupling reaction with a compound of general formula (IX) in an inert solvent in the presence of a suitable Palladium catalyst and a base to a compound of the general formula (XVII)

in which R ¹ , R ² , R ³ , R ⁴ and R ⁵ each have the meaning given above,

reacting this intestine in the presence of an acid with a compound of the general formula (XVIII)

R ⁶ -CHO (XVIII),

in which R ^{6 has} the meaning given above,

with cyclization to a compound of the general formula (XIX)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ each have the meaning given above,

implemented and finally cleaved the formyl group in (XIX) with the aid of a base [for process step (XIII) - »(XV) cf. e.g. A. Giarmis, K. Sandhoff, Angew. Chem. 1989, 101, 220-222; R. Amouroux, GP Axiotis, Synthesis 1981, 270-272; E. Ciganek, J Org. Chem. 1992, 57, 4521-4527; A. Nakazato, T. Kumagai, K. Ohta, S. Chaki. S. Okuyama, K. Tomisawa, J Med. Chem. 1999, 42, 3965-3970; E.FJ. de Vries, P. Steenwinkel, j. Brussee, CG. Kruse, A. van der Gen, J. Org. Chem. 1993, 55, 4315-4325; M. Chastrette, GP Axiotis, Synthesis 1980, 889-890; for process step (XVI) + (IX) → (XVII) cf. e.g. W. Hahnfeld, M. Jung, Pharmazie 1994, 49, 18-20; idem, Liebigs Ann. Chem. 1994, 59-64; for the

Process step (XVII) + (XVIII) → (XIX) cf. e.g. A.P. Venkov, I.I. Ivanov, Synth. Commun. 1993, 23, 1707-1719; B. E. Maryanoff, M.C. Rebarchak, Synthesis 1992, 12, 1245-1248].

Inert solvents for process step (X) + (XI) or (XII) → (XIII) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone. It is also possible to use mixtures of the solvents mentioned. A is preferred

Mixture of diethyl ether and dimethyl sulfoxide.

The usual inorganic or organic bases are suitable as bases for process step (X) + (XI) or (XII) - »(XIII). These preferably include alkali hydroxides such as lithium, sodium or potassium hydroxide, alkali hydrides such as sodium or potassium hydride, or amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide. Potassium hydroxide is particularly preferred.

The base is used in an amount of 1 to 10, preferably 2 to 5 mol, based on 1 mol of the compound of the general formula (X).

The reaction generally takes place in a temperature range from -20 ° C. to + 100 ° C., preferably from 0 ° C. to + 30 ° C. The reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar).

Generally one works at normal pressure. Inert solvents for process step (XV) - »(XVI) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol ethylene or methyl dimethyl or diethylene dimethyl ether Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions. It is also possible to use mixtures of the solvents mentioned. Xylene is preferred (with removal of the water formed during the reaction).

The formic acid is used in this reaction step in an amount of 1 to 5, preferably 1 to 3 mol, based on 1 mol of the compound of the general formula (XV).

The reaction generally takes place in a temperature range from 0 ° C to

+ 150 ° C, preferably from + 20 ° C to + 130 ° C. The reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.

Inert solvents for process step (XVI) + (IX) → (XVII) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol or tert. -Butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, acetonitrile or water. It is also possible to use mixtures of the solvents mentioned. Toluene, dimethylformamide or acetonitrile are preferred.

The usual inorganic or organic bases are suitable as bases for process step (XVI) + (IX) - »(XVII). These preferably include alkali hydroxides such as lithium, sodium or potassium hydroxide, alkali or alkaline earth carbonates such as sodium, potassium or calcium carbonate, alkali phosphates such as sodium or potassium phosphate, or organic amines such as pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine. Sodium or potassium carbonate or potassium phosphate are particularly preferred.

The base is used in an amount of 1 to 5, preferably 2 to 3, mol, based on 1 mol of the compound of the general formula (XVI).

The reaction generally takes place in a temperature range from 0 ° C. to + 150 ° C., preferably from + 20 ° C. to + 100 ° C. The reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.

Inert solvents for process step (XVII) + (XVIII) → (XIX) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane,

Tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions. It is also possible to use mixtures of the solvents mentioned. It is also possible to have the reaction without

Solvent.

The usual inorganic or organic acids are suitable as acids for process step (XVII) + (XVIII) → (XIX). These preferably include hydrochloric acid, sulfuric acid or phosphoric acid, or carboxylic acids such as formic acid,

Acetic acid or trifluoroacetic acid, or sulfonic acids such as toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid. A mixture of acetic acid and trifluoroacetic acid, which is used in large excess and at the same time serves as a solvent, is particularly preferred. The reaction generally takes place in a temperature range from -20 ° C. to + 150 ° C., preferably from + 20 ° C. to + 120 ° C. The reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). Generally one works at normal pressure.

The compounds of the general formula (III) are known or can be prepared analogously to processes known from the literature, for example by adding a compound of the general formula (XX)

in which R ⁷ , R ⁸ and X each have the meaning given above,

first with a compound of the general formula (XXI)

in which R ⁹ , R ¹⁰ and T each have the meaning given above,

in an inert solvent in the presence of a base into a compound of the general formula (XXII)

in which R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , X and T each have the meaning given above,

transferred and then reacted with chlorosulfonic acid [cf. e.g. P. D. Edwards, R.C. Mauger, K.M. Cottrell, F.X. Morris, K.K. Pine, M.A. Sylvester, C.W.

Scott, S.T. Furlong, Bioorg. Med. Chem. Lett. 2000, 10, 2291-2294].

Inert solvents for process step (XX) + (XXI) → (XXII) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene,

Toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as acetone, dimethylformamide, dimethyl sulfoxide, acetonitrile or N-methylpyrrolidinone. It is also possible to use mixtures of the solvents mentioned. Dimethylformamide or acetone is preferred.

The usual inorganic or organic bases are suitable as bases for process step (XX) + (XXI) - »(XXII). These preferably include alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate, alkali metal hydrides such as sodium hydride, or organic amines such as pyridine, triethylamine,

Ethyl diisopropylamine, N-methylmorpholine or N-methylpiperidine. Potassium carbonate is particularly preferred.

The base is used in an amount of 1 to 5, preferably 1 to 2, mol, based on 1 mol of the compound of the general formula (XX).

The reaction generally takes place in a temperature range from -20 ° C. to + 150 ° C., preferably from 0 ° C. to + 80 ° C. The reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). Generally one works at normal pressure. The compounds of the general formula (IV) can be prepared analogously to processes known from the literature, for example, by adding a compound of the general formula (XXIII)

(XXIII)

in which R ² , R ³ , R ⁴ , R ⁵ and PG each have the meaning given above, either

[a] according to the process steps (XV) -> (XVI) and (XVII) + (XVIII) - »(XIX) described above into a compound of the general formula (XXIV)

in which R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and PG each have the meaning given above,

transferred and then the formyl group in (XXIV) is split off using a base,

or

[b] first with a carboxylic acid or carboxylic acid derivative of the general formula (XXV)

in which R ^{6 has} the meaning given above and

Q represents hydroxy, halogen or the complementary carboxylic anhydride radical,

to a compound of the general formula (XXVI)

_(χχγι

in which R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and PG each have the meaning given above,

implemented, then using a phosphorus chloride, such as

Phosphorus oxychloride, to a compound of the general formula (XXVII)

(XXVII)

cyclized and then reduced with the help of a complex boron or aluminum hydride, such as sodium borohydride [for the process step (XXVI) → (XXVII) cf. e.g. E. Martinez, JC Estevez, RJ Estevez, MC Villaverde, L. Castedo, Tetrahedron Lett. 1998, 39, 1231-1232].

The compounds of the general formula (XXIII) are analogous to the process described above (X) + (XI) or (XII) → (XIII) → (XV) from compounds of the general formula (XXVIII)

(XXVIII) accessible.

The compounds of the general formulas (VII), (IX), (X), (XI), (XII), (XIV), (XVIII), (XX), (XXI), (XXV) and (XXVIII) are commercial available, known from the literature or can be prepared analogously to processes known from the literature.

The processes according to the invention can be illustrated by the following reaction schemes

1-4 are illustrated:

Scheme 1

CIS0 ₃ H

Scheme 2

Scheme 3

Pd °, base, R ⁶ -CHO,

HC ^Q ₂ HR ¹ -B ( ^Q H) ₂ TFA / AcOH

Scheme 4

The compounds of formula (I) according to the invention show a surprising and valuable spectrum of pharmacological activity and can therefore be used as versatile medicaments. In particular, they are suitable for the treatment of coronary artery disease, for myocardial infarction prophylaxis and for the treatment of restenosis after coronary angioplasty or stenting. The compounds of formula (I) according to the invention are preferably suitable for the treatment of arteriosclerosis and hypercholesterolemia, for increasing morbidly low HDL levels and for lowering increased triglyceride and LDL levels. In addition, they can be used for

Treatment of obesity, diabetes, to treat metabolic syndrome (glucose intolerance, hyperinsulinemia, dyslipidemia and hypertension due to insulin resistance), liver fibrosis and cancer.

The new active ingredients can be used alone or in combination with others if necessary

Active substances preferably from the group CETP inhibitors, antidiabetics, antioxidants, cytostatics, calcium antagonists, antihypertensive agents, thyroid hormones and / or thyroid mimetics, inhibitors of HMG-CoA reductase, inhibitors of HMG-CoA reductase expression, squalene synthesis inhibitors, squalene synthesis inhibitors Inhibitors, blood circulation enhancers, platelet aggregation inhibitors, anticoagulants, angiotensin II receptor antagonists, cholesterol absorption inhibitors, MTP inhibitors, aldolase reductase inhibitors, fibrates, niacin, anoretics, lipase inhibitors and / or PPAR-α and PPAR-α and γ agonists can be administered.

The activity of the compounds according to the invention can e.g. Check in vitro using the transactivation assay described in the example section.

The activity of the compounds according to the invention in vivo can e.g. check by the examinations described in the example section.

For the application of the compounds of the general formula (I), all customary application forms come into consideration, that is to say orally, parenterally, by inhalation, nasally, sublingually, rectally, externally, such as, for example, transdermally, or locally, for example in the case of implants or stents. In parenteral administration, intravenous, intramuscular or subcutaneous administration, for example as a subcutaneous depot, is particularly important call. Oral or parenteral administration is preferred. Oral application is very particularly preferred.

The active ingredients can be administered alone or in the form of preparations. For oral application, suitable preparations 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 is 0.5 to 90% by weight, i.e. the active substance should be present in amounts sufficient to achieve the dosage range indicated.

For this purpose, the active substances can be converted into the usual manner in a manner known per se

Preparations are transferred. 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 (eg 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 of body weight are preferably administered per 24 hours.

The following exemplary embodiments explain the invention. The invention is not restricted to the examples.

The percentages in the following tests and examples are, unless stated otherwise, percentages by weight; Parts are parts by weight. Solvent ratios, dilution ratios and concentration details of liquid / liquid mixtures each relate to the volume.

HPLC method 1:

Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm x 2 mm, 3.5 μm; Eluent: A = 5 ml HClO ₄ / l H ₂ O, B = ACN; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min 90% B; Flow: 0.75 ml / min; Temp .: 30 ° C; detection

UV 210 nm

HPLC method 2:

Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm x 2 mm, 3.5 μm; Eluent: A = 5 ml HClO ₄ / l H ₂ O, B = ACN; Gradient: 0 min 2% B, 0.5 min

2% B, 4.5 min 90% B, 9 min 90% B; Flow: 0.75 ml / min; Temp .: 30 ° C; Detection UV 210 nm

LC / MS method 3:

Column: Symmetry C-18, 5 μm, 2.1 x 150 mm; Eluent: A = acetonitrile, B = water + 0.3 g 30% HC1 / 1; Gradient: 0.0 min 2% A → 2.5 min 95% A → 5 min 95% A; Flow:

1.2 ml / min; Temp .: 70 ° C; Detection UV 210 nm

GC / MS method 4:

Device type GC: HP 6890; Column: HP-5, 30 mx 320 μm x 0.25 μm (film thickness); Injector temp .: 250 ° C; Oven temp .: 60 ° C; Gradient: 60 ° C, 1 min → 16 ° C / min → 300 ° C, 1 min; Carrier gas: helium; constant flow: 1.5 mL / min; Ionization: EI / CI positive.

GC / MS Method 5: Device: Varian GC; Column: HP-5, 30 mx 320 μm x 0.25 μm (film thickness);

Injector temp .: 250 ° C; Oven temp .: 60 ° C; Gradient: 60 ° C → 10 ° C / min → 300 ° C, 6 min; Carrier gas: helium; constant flow: 1.5 mL / min; Ionization: EI / CI positive.

GC Method 6: Device: HP 5890 Series 2; Column: DB1, 30 mx 0.25 mm, film thickness 0.25 μm;

Injector temp .: 250 ° C; Gradient: 50 ° C → 10 ° C / min → 320 ° C, 3 min; Detector: FID, temp .: 330 ° C; Injection volume: 1 μl.

Abbreviations:

ACN acetonitrile

DCI direct chemical ionization (for MS)

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

EI electron impact ionization (for MS)

ESI electrospray ionization (for MS)

GC gas chromatography

HPLC high pressure, high performance liquid chromatography

LC-MS liquid chromatography-coupled mass spectroscopy

MS mass spectroscopy

NMR nuclear magnetic resonance spectroscopy

Rf retention index (for DC) RP reverse phase (for HPLC) THF tetrahydrofuran Starting Compounds:

Example 1A

Phenoxyessigsäureethylester

23.53 g (0.25 mol) phenol and 34.55 g (0.25 mol) potassium carbonate are suspended in 100 ml acetone and heated under reflux for 1 hour. A solution of 43.84 g (0.26 mol) of ethyl bromoacetate in 100 ml of acetone is then added dropwise and the mixture is heated under reflux overnight. After cooling down

The mixture is poured onto ice at room temperature and the aqueous phase is extracted three times with methylene chloride. The combined organic phases are dried over sodium sulfate and the solvent is removed in vacuo. 46 g (85% of theory) of the desired product are obtained in 87% purity. GC / MS (Method 4): R, = 7.44 min.

MS (ESIpos): 180 (M) ⁺

Η NMR (200 MHz, CDC1 ₃ ): δ = 1.30 (t, 3H), 4.28 (q, 2H), 4.62 (s, 2H), 6.92 (d, 2H), 7.00 (t, 1H), 7.29 ( t, 2H).

Example 2A 2-methylphenoxyacetic acid ethyl ester

10.81 g (0.10 mol) of 2-methylphenol and 13.82 g (0.10 mol) of potassium carbonate are suspended in 100 ml of N, N-dimethylformamide and stirred at 50 ° C. for 1 hour. Then 18.37 g (0.11 mol) of ethyl bromoacetate are added dropwise and the mixture is stirred at 50 ° C. overnight. After cooling to room temperature, the mixture is concentrated in vacuo, taken up in ethyl acetate and three times with

Washed water. The organic phase is dried over sodium sulfate and freed from the solvent in vacuo. Distillation of the residue in a Kugelrohr gives 18.5 g (95% of theory) of the desired product. GC / MS (Method 5): R _t = 12.50 min. MS (ESIpos): 194 (M) ⁺

1H-NMR (300 MHz, CDC1 ₃ ): δ = 1.29 (t, 3H), 2.29 (s, 3H), 4.26 (q, 2H), 4.62 (s, 2H), 6.70 (d, 1H), 6.89 ( dt, 1H), 7.22 (t, 1H), 7.25 (d, 1H).

Example 3A

2,4-Dimethylphenoxyessigsäureethylester

10.00 g (81.86 mmol) of 2,5-dimethylphenol and 11.31 g (81.86 mmol) of potassium carbonate are suspended in 100 ml of N, N-dimethylformamide and stirred at 50 ° C. for 1 hour. Then 15.04 g (90.04 mmol) of ethyl bromoacetate are added dropwise and the mixture is stirred at 50 ° C. overnight. After cooling to room temperature, the mixture is concentrated in vacuo, taken up in ethyl acetate and washed three times with water. The organic phase is dried over sodium sulfate and freed from the solvent in vacuo. 16.96 g (89% of theory) of the desired product are obtained in 89% purity (HPLC).

HPLC (method 1): R _t = 4.75 min. MS (DCI): 226 (M + NH ₄ ) ⁺ 1H-NMR (300 MHz, CDC1 ₃ ): δ = 1.29 (t, 3H), 2.24 (s, 3H), 2.29 (s, 3H), 4.27 (q, 2H), 4.61 (s, 2H), 6.52 ( s, 1H), 6.71 (d, 1H), 7.02 (d, 1H).

Example 4A

2,3-Dimethylphenoxyessigsäureethylester

10.00 g (81.86 mmol) 2,3-dimethylphenol and 16.97 g (122.78 mmol) potassium carbonate are suspended in 100 ml N, N-dimethylformamide and stirred at 50 ° C for 1 hour. Then 20.51 g (122.78 mmol) of ethyl bromoacetate are added dropwise and the mixture is stirred at 50 ° C. overnight. After cooling to room temperature, the mixture is concentrated in vacuo, taken up in ethyl acetate and washed three times with water. The organic phase is dried over sodium sulfate and freed from the solvent in vacuo. 14 g (82% of theory) of the desired product are obtained.

GC (Method 6): R _t = 12.30 min. MS (DCI): 226 (M + NH ₄ ) ⁺

1H-NMR (200 MHz, CDC1 ₃ ): δ = 1.29 (t, 3H), 2.22 (s, 3H), 2.28 (s, 3H), 4.27 (q, 2H), 4.61 (s, 2H), 6.58 ( d, 1H), 6.81 (d, 1H), 7.03 (t, 1H).

Example 5A

3-Methylphenoxyessigsäureethylester

10.00 g (92.47 mmol) m-cresol and 19.17 g (138.20 mmol) potassium carbonate are suspended in 100 ml N, N-dimethylformamide and stirred at 50 ° C for 1 hour. 23.16 g (138.71 mmol) of ethyl bromoacetate are then added dropwise and the mixture is stirred at 50 ° C. overnight. After cooling to room temperature, the mixture is concentrated in vacuo, taken up in ethyl acetate and washed three times with water. The organic phase is dried over sodium sulfate and freed from the solvent in vacuo. 16.8 g (94% of theory) of the desired product are obtained. GC (Method 6): R _t = 11.05 min. MS (DCI): 212 (M + NH ₄ ) ⁺

Η NMR (200 MHz, CDC1 ₃ ): δ = 1.29 (t, 3H), 2.32 (s, 3H), 4.27 (q, 2H), 4.60 (s, 2H), 6.70 (d, 1H), 6.72 ( s, 1H), 6.80 (d, 1H), 7.18 (t, 1H).

Example 6A

4-Chlorsulfonylphenoxyessigsäureethylester

145.49 g (1.25 mol) of chlorosulfonic acid are added dropwise to a solution of 45.00 g (0.25 mol) of ethyl phenoxyacetate in 100 ml of chloroform at 0 ° C. After addition, the reaction mixture is stirred overnight at room temperature, then added to ice and the aqueous phase is extracted three times with methylene chloride. The combined organic phases are washed three times with water, once with saturated sodium hydrogen carbonate solution and again with water, dried over sodium sulfate and freed from the solvent in vacuo. 50.7 g (73% of theory) of the desired compound are obtained as a crystalline solid.

GC (Method 6): R _t = 11.38 min. MS (ESIpos): 278 (M) ⁺ Η NMR (400 MHz, CDC1 ₃ ): δ - 1.32 (t, 3H), 4.29 (q, 2H), 4.73 (s, 2H), 7.05 (d, 2H), 7.99 (d, 2H).

Example 7A

4-chlorosulfonyl-2-methylphenoxyessigsäureethylester

102.59 g (880.40 mmol) of chlorosulfonic acid are added dropwise to a solution of 17.10 g (88.04 mmol) of ethyl 2-methylphenoxyacetate in 100 ml of chloroform at 0 ° C. The reaction mixture is added overnight after

Stirred at room temperature, then poured onto ice and the aqueous phase extracted three times with methylene chloride. The combined organic phases are three times with water, once with saturated sodium bicarbonate solution. and washed again with water, dried over sodium sulfate and freed from solvent in vacuo. 24.1 g (94% of theory) of the desired compound are obtained as a crystalline solid. GC (Method 6): R _t = 17.53 min. MS (DCI): 310 (M + NH ₄ ) ⁺ Η-NMR (400 MHz, CDC1 ₃ ): δ = 1.32 (t, 3H), 2.38 (s, 3H), 4.29 (q, 2H), 4.76 (s , 2H), 6.80 (d, 1H), 7.83 (s, 1H), 7.85 (d, 1H). Example 8A

4-chlorosulfonyl-2,5-dimethylphenoxyessigsäureethylester

84.44 g (724.67 mmol) of chlorosulfonic acid are added dropwise at 0 ° C. to a solution of 16.90 g (72.47 mmol) of 2,5-dimethylphenoxyacetic acid ethyl ester in 50 ml of chloroform. After addition, the reaction mixture is stirred overnight at room temperature, then added to ice and the aqueous phase is extracted three times with methylene chloride. The combined organic phases are washed three times with water, once with saturated sodium hydrogen carbonate solution and again with water, dried over sodium sulfate and freed from the solvent in vacuo. 23 g (92% of theory) of the desired compound are obtained as an oil. MS (DCI): 324 (M + NH ₄ ) ⁺

1H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.20 (t, 3H), 2.12 (s, 3H), 2.42 (s, 3H), 4.16 (q, 2H), 4.78 (s, 2H), 6.60 (s, 1H), 7.48 (s, 1H).

Example 9A

4-chlorosulfonyl-2,3-dimethylphenoxyessigsäureethylester

39.17 g (336.13 mmol) of chlorosulfonic acid are added dropwise at 0 ° C. to a solution of 14.00 g (67.23 mmol) of 2,3-dimethylphenoxyacetic acid ethyl ester in 150 ml of chloroform. After the addition, the reaction mixture is stirred at room temperature overnight, then poured onto ice and the aqueous phase is thrilled three times with methylene chloride extracted. The combined organic phases are washed three times with water, once with saturated sodium hydrogen carbonate solution and again with water, dried over sodium sulfate and freed from the solvent in vacuo. 19.3 g (94% of theory) of the desired compound are obtained as an oil. GC / MS (Method 4): R _t = 12.55 min.

MS (DCI): 324 (M + NH ₄ ) ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.30 (t, 3H), 2.30 (s, 3H), 2.71 (s, 3H), 4.28 (q, 2H), 4.73 (s, 2H), 6.65 ( d, 1H), 7.94 (d, 1H).

Example 10A 4-Chlorosulfonyl-3-methylphenoxyacetic acid ethyl ester

50.39 g (432.48 mmol) of chlorosulfonic acid are added dropwise to a solution of 16.80 g (86.50 mmol) of ethyl 3-methylphenoxyacetate in 50 ml of chloroform at 0 ° C. After addition, the reaction mixture is stirred overnight at room temperature, then added to ice and the aqueous phase is extracted three times with methylene chloride. The combined organic phases are washed three times with water, once with saturated sodium hydrogen carbonate solution and again with water, dried over sodium sulfate and freed from the solvent in vacuo. 9 g (36% of theory) of the desired compound are obtained as an oil. GC / MS (Method 4): R _t = 11.78 min. MS (DCI): 310 (M + NH ₄ ) ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.31 (t, 3H), 2.74 (s, 3H), 4.28 (q, 2H), 4.70 (s, 2H), 6.80 (d, 1H), 6.90 ( d, 1H), 8.02 (d, 1H). Example 11 A

4-benzyloxybenzonitrile

A suspension of 40.17 g (0.29 mol) of potassium carbonate and 38.70 g (0.29 mol) of 4-hydroxybenzonitrile in 200 ml of acetone is heated under reflux for 1 hour. After cooling to room temperature, 52.20 g (0.31 mol) of benzyl bromide in 100 ml of acetone are added and the reaction mixture is heated under reflux overnight. After cooling to room temperature, the mixture is poured onto water with vigorous stirring, the precipitate formed is filtered off, washed with water and petroleum ether and dried in vacuo at 60.degree. 61.9 g (95% of theory) of the desired product are obtained as a colorless solid. GC: R, = 4.53 min.

1H-NMR (300 MHz, DMSO-d ₆ ): δ - 3.92 (s, 2H), 5.11 (s, 2H), 7.02 (dd, 2H), 7.27 (d, 2H), 7.30-7.48 (m, 5H ).

Example 12A 1- (4-bromophenyl) cyclopentyl nitrile

To a solution of 15.00 g (76.51 mmol) of 4-bromophenylacetonitrile and 17.35 g

(80.34 mmol) 1,4-dibromobutane in 100 ml diethyl ether is added to a suspension of 14.60 g (260.14 mmol) potassium hydroxide in 100 ml dimethyl sulfoxide with stirring and ice cooling. After the addition has ended, the mixture is stirred for 6 hours Stirred at room temperature, then mixed with water and ethyl acetate while cooling, the phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed in vacuo. 19 g (99% of theory) of the desired product are obtained as a colorless oil. HPLC (method 1): R _t = 5.01 min. MS (DCI): 267 (M + NH ₄ ) ⁺

1H-NMR (300 MHz, CDC1 ₃ ): δ = 1.89-2.09 (m, 6H), 2.48 (m, 2H), 7.32 (dt, 2H), 7.51 (dt, 2H).

Example 13A

1 - (4-bromophenyl) cyclohexyl nitrile

Analogously to the production of 1- (4-bromophenyl) cyclopentyl nitrile from 15.00 g

(76.51 mmol) 4-bromophenylacetonitrile, 19.04 g (80.34 mmol) 1,5-dibromopentane and 14.60 g (260.14 mmol) potassium hydroxide in 100 ml diethyl ether and 100 ml dimethyl sulfoxide 20 g (99% of theory) of the desired product as colorless Get oil. HPLC (method 1): R _t = 5.10 min.

MS (ESIpos): 263 (M) ⁺

1H-NMR (300 MHz, CDC1 ₃ ) δ = 1.67-1.93 (m, 8H), 2.13 (dm, 2H), 7.35 (dt, 2H), 7.51 (dt, 2H). Example 14A

2- (4-benzyloxyphenyl) -2-methylpropionitrile

1.00 g (4.48 mmol) [4- (benzyloxy) phenyl] acetonitrile and 1.33 g (9.41 mmol) iodomethane are dissolved in 10 ml diethyl ether and cooled to 0 ° C. 0.85 g (15.23 mmol) of potassium hydroxide are then suspended in 6.36 ml of dimethyl sulfoxide and added, and the mixture is stirred at room temperature overnight. The mixture is poured onto ice and the aqueous phase is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and freed from the solvent in vacuo. The resulting crystals are recrystallized from ethanol. 1.01 g (90% of theory) of the desired product are obtained in 83% purity. HPLC (method 1): R, = 5.07 min. MS (DCI): 269 (M + NH ₄ ) ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.70 (s, 6H), 5.07 (s, 2H), 6.97 (dt, 2H), 7.31-7.45 (m, 7H).

Example 15A 1- (4-Benzyloxyphenyl) cyclobutyl nitrile

11.16 g (50.00 mmol) of [4- (benzyloxy) phenyl] acetonitrile and 10.60 g (52.50 mmol) of 1,3-dibromopropane are dissolved in 100 ml of diethyl ether and cooled to 0 ° C. 9.54 g (170 mmol) of potassium hydroxide are then suspended in 71 ml of dimethyl sulfoxide and added, and the mixture is stirred at room temperature overnight. The mixture is poured onto ice and the aqueous phase is added

Extracted ethyl acetate. The organic phase is dried over sodium sulfate and freed from the solvent in vacuo. The residue is purified over silica gel 60 (mobile phase: methylene chloride and methylene chloride / methanol 100: 5). The clean fractions are combined and the solvent is removed in vacuo. 6.9 g (52% of theory) of the desired product are obtained.

LC / MS (Method 3): R _t = 2.93 min. MS (ESIpos): m / z = 264 (M + H) ⁺

Η NMR (200 MHz, CDC1 ₃ ): δ = 1.94-2.15 (m, 2H), 2.49-2.67 (m, 2H), 2.73-2.89 (m, 2H), 5.07 (s, 2H), 6.99 (i.e. , 2H), 7.29-7.46 (m, 7H).

Example 16A 1- (4-Benzyloxyphenyl) cyclopentyl nitrile

11.16 g (50.00 mmol) [4- (benzyloxy) phenyl] acetonitrile and 11.34 g (52.50 mmol)

1,4-dibromobutane are dissolved in 100 ml of diethyl ether and cooled to 0 ° C. 9.54 g (170 mmol) of potassium hydroxide are then suspended in 71 ml of dimethyl sulfoxide and added, and the mixture is stirred at room temperature overnight. The mixture is poured onto ice and the aqueous phase is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and freed from solvent in vacuo. The residue is recrystallized from ethanol. 11.6 g (84% of theory) of the desired product are obtained.

HPLC (method 1): R _t = 5.22 min.

MS (ESIpos): m / z = 278 (M + H) ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.85-2.10 (m, 6H), 2.39-2.51 (m, 2H), 5.07 (s, 2H),

6.97 (d, 2H), 7.31-7.45 (m, 7H).

Example 17A 1- (4-Benzyloxyphenyl) cyclohexyl nitrile

11.16 g (50.00 mmol) of [4- (benzyloxy) phenyl] acetonitrile and 12.07 g (52.50 mmol) of 1,4-dibromopentane are dissolved in 100 ml of diethyl ether and cooled to 0 ° C. 9.54 g (170 mmol) of potassium hydroxide are then suspended in 71 ml of dimethyl sulfoxide and added, and the mixture is stirred at room temperature overnight. The mixture is poured onto ice and the crystals formed are filtered off, washed with water and ethanol and dried (product fraction 1). The aqueous phase is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and freed from the solvent in vacuo. The residue is over silica gel 60 (eluent: methylene chloride and methylene chloride / methanol

100: 5) cleaned. The clean fractions are combined and the solvent is removed in vacuo (product fraction 2). Together, 10.56 g (72% of theory) of the desired product are obtained. LC / MS (method 3): R, = 3.10 min. MS (DCI): m / z = 309 (M + NH ₄ ) ⁺ 1H-NMR (200 MHz, DMSO-d ₆ ): δ = 1.12-1.42 (m, 2H), 1.45-1.92 (m, 6H), 2.04 (d, 2H), 5.11 (s, 2H), 7.05 (dd , 2H), 7.19-7.55 (m, 7H).

Example 18A

2- (4-methoxy-phenyl) -4-phenylbutanenitrile

20.00 g (135.89 mmol) of 4-methoxyphenylacetonitrile is dissolved in 12 ml of diethyl ether and 26.41 g (19.49 ml; 142.69 mmol) of 2-phenylethyl bromide are added. The mixture is cooled to 0 ° C., then 25.92 g (462 mmol)

Potassium hydroxide suspended in 80 ml of dimethyl sulfoxide with ice cooling and added. The mixture is stirred at room temperature overnight. For working up, the mixture is cooled again and diluted with toluene and water. The phases are separated and the aqueous phase is washed twice more with toluene. The combined organic phases are dried over sodium sulfate, filtered and the solvent is removed in vacuo. The residue is purified over 400 g of silica gel 60 (mobile phase: cyclohexane and cyclohexane / ethyl acetate 98: 2). The clean fractions are combined and the solvent is removed in vacuo. 15.6 g (46% of theory) of the desired product are obtained in 86% purity.

HPLC (method 1): R, = 4.96 min.

MS (DCI): m / z = 269 (M + NH ₄ ) ⁺

1H-NMR (300 MHz, CDC1 ₃ ): δ = 2.05-2.31 (m, 2H), 2.74-2.85 (m, 2H), 3.64-3.72

(m, 1H), 3.80 (s, 3H), 6.89 (d, 2H), 7.15-7.34 (m, 7H). Example 19A

[1 - (4-bromophenyl) cyclopentyl] methylamine

A solution of 6.27 g (287.84 mmol) lithium borohydride in 50 ml THF is added

Stirring slowly at room temperature with 46.91 g (431.76 mmol) of chlorotrimethylsilane. A solution of 18.00 g (71.96 mmol) of 1- (4-bromophenyl) cyclopentyl nitrile in 10 ml of THF is then added with ice-cooling, the mixture is heated under reflux for 4 h and then stirred at room temperature overnight. Then the mixture is mixed with methanol, made alkaline with 2 N sodium hydroxide solution and the aqueous phase extracted twice with methylene chloride. The combined organic extracts are dried over sodium sulfate, the solvent is removed in vacuo, and the residue obtained is purified by chromatography on silica gel (cyclohexane / ethyl acetate 10: 1 → methylene chloride methanol 100: 5 + ammonia solution). 5.1 g (23% of theory) of the desired product are obtained in 82% strength

Purity as an oil.

HPLC (method 1): R, = 3.91 min. MS (DCI): 254 (M + H) ⁺ 1H-NMR (200 MHz, CDC1 ₃ ): δ = 1.50 (broad, s, 2H), 1.71 (m, 4H), 1.90 (m, 4H), 2.72 ( s, 2H), 7.16 (dt, 2H), 7.42 (dt, 2H). Example 20A

[1 - (4-bromophenyl) cyclohexyl] methylamine

Analogously to the preparation of [l- (4-bromophenyl) cyclopentyl] methylamine, 4.95 g (227.13 mmol) of lithium borohydride, 37.01 g (340.70 mmol) of chlorotrimethylsilane and 20.00 g (75.71 mmol) of l- (4-bromophenyl) cyclohexylnitrile 15.28 g ( 56% of theory) of the desired product in 74% purity (HPLC) as an oil. HPLC (method 1): R _t = 4.11 min. MS (DCI): 254 (M + H) ⁺

Η NMR (400 MHz, CDC1 ₃ ): δ = 1.18 (broad, s, 2H), 1.37 (m, 4H), 1.54 (m, 4H), 2.09 (dd, 2H), 2.68 (s, H), 7.21 (German, 2H), 7.45 (German, 2H).

Example 21A

2- [4- (benzyloxy) phenyl] -2-methylpropylamine

A solution of 28.60 g (113.80 mmol) of 2- [4- (benzyloxy) phenyl] -2-methyl-propanenitrile in 550 ml of tetrahydrofuran is slowly mixed with 114.00 ml of a 1 molar lithium aluminum hydride solution in tetrahydrofuran. It is refluxed for 15 minutes. The reaction mixture is then cooled to 0 ° C. and 20% potassium sodium tartrate solution is added. It is diluted with water and extracted with ethyl acetate. The organic phase becomes saturated

Washed sodium chloride solution, dried over sodium sulfate and freed from solvent in vacuo. The crystalline solid obtained is recrystallized from ethanol. 27.8 g (96% of theory) of the desired product are obtained

99% purity.

HPLC (method 1): R _t = 4.18 min.

MS (DCI): m / z = 273 (M + NH ₄ ) ⁺

Η NMR (400 MHz, CDC1 ₃ ): δ = 0.80-1.1 l (m, 2H), 1.28 (s, 6H), 2.76 (s, 2H), 5.05

(s, 2H), 6.94 (d, 2H), 7.23-7.28 (m, 2H), 7.29-7.46 (m, 5H).

Example 22A

{1 - [4- (Benzyloxy) phenyl] cyclobutyl} methylamine

A supply of 6.90 g (26.20 mmol) of l- [4-

(Benzyloxy) phenyl] cyclobutane carbonitrile in 200 ml of tetrahydrofuran at room temperature added 26.20 ml (26.20 mmol) of a 1 molar lithium aluminum hydride solution in tetrahydrofuran. It is refluxed overnight. The reaction mixture is cooled to 0 ° C. and 20% potassium sodium tartrate solution is added. The resulting solid is filtered off and with water and

Washed ethyl acetate and discarded. The two phases in the filtrate are separated. The aqueous phase is extracted three more times with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed in vacuo. 6.60 g (94% of theory) of the desired product are obtained with a purity of 93%.

HPLC (method 1): R _t = 4.24 min. MS (DCI): m / z = 285 (M + NH ₄ ) ⁺

1H-NMR (200 MHz, DMSO-d ₆ ): δ = 0.90-1.15 (m, 2H), 1.63-2.02 (m, 2H), 2.70 (s,

2H), 5.06 (s, 2H), 6.97 (q, 4H), 7.27-7.50 (m, 5H).

Example 23A {1- [4- (Benzyloxy) phenyl] cyclopentyl} methylamine

36.05 ml (36.05 mmol) of a 1 molar lithium aluminum hydride solution in tetrahydrofuran were added dropwise to argon at a room temperature to a solution of 10.00 g (36.05 mmol) of 1- [4- (benzyloxy) phenyl] cyclopropanecarbonitrile in 100 ml of tetrahydrofuran. It is refluxed overnight. The reaction mixture is cooled to 0 ° C. and 20% potassium sodium tartrate solution is added. The resulting solid is filtered off with suction and washed with water and ethyl acetate and discarded. The two in the mother liquor

Phases are separated. The aqueous phase is extracted three more times with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed in vacuo. It is purified on silica gel 60 (mobile phase: methylene chloride / methanol 100: 2). The clean fractions are combined and the solvent is removed in vacuo. 9.70 g (96% of theory) of the desired product are obtained with 98% purity. HPLC (method 1): R, = 4.32 min. MS (ESIpos): m / z = 282 (M + H) ⁺ Η-NMR (200 MHz, CDC1 ₃ ): δ = 1.07-1.20 (m, 2H), 1.61-1.75 (m, 4H), 1.80-1.93 (m, 4H), 2.70 (s, 2H), 5.05 (s, 2H), 6.93 (d, 2H), 7.19 (d, 2H), 7.29-7.49 (m, 5H). Example 24A

{1 - [4- (benzyloxy) phenyl] cyclohexyl} methylamine

A supply of 8.50 g (29.17 mmol) of l- [4-

(Benzyloxy) phenyl] cyclohexane carbonitrile in 90 ml of tetrahydrofuran at room temperature 29.17 ml (29.17 mmol) of a 1 molar lithium aluminum hydride solution in tetrahydrofuran was added dropwise. It is refluxed overnight. The reaction mixture is cooled to 0 ° C. and 20% potassium sodium tartrate solution is added. The resulting solid is filtered off and with water and

Washed ethyl acetate and discarded. The two phases in the filtrate are separated. The aqueous phase is extracted three more times with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed in vacuo. It is purified on silica gel 60 (mobile phase: methylene chloride, methanol 100: 2). The clean fractions are combined and the solvent is removed in vacuo. 7.20 g (84% of theory) of the desired product are obtained with a purity of 95%. HPLC (method 1): R _t = 4.44 min. MS (ESIpos): m / z = 296 (M + H) ⁺ Η-NMR (200 MHz, CDC1 ₃ ): δ = 1.07-1.21 (m, 2H), 1.64-1.74 (m, 4H), 1.80-1.93

(m, 4H), 2.70 (s, 2H), 5.05 (s, 2H), 6.95 (d, 2H), 7.19 (d, 2H), 7.30-7.49 (m, 5H). Example 25A

2- (4-methoxy-phenyl) -4-phenylbutylamine

31.33 ml (31.33 mmol) of a 1 molar solution of lithium aluminum hydride in tetrahydrofuran were added dropwise to 0.50 ° C. while supplying argon with a solution of 7.50 g (29.84 mmol) of 2- (4-methoxyphenyl) -4-phenylbutanenitrile in 150 ml of tetrahydrofuran. The mixture is allowed to slowly come to room temperature and stirring is continued for 24 hours. The reaction mixture is cooled to 0 ° C with 20%

Potassium sodium tartrate solution was added and washed with water and ethyl acetate. The phases are separated. The ethyl acetate phase is extracted once more with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and freed from the solvent in vacuo. It is cleaned over 200 g of silica gel 60 (mobile phase: cyclohexane / ethyl acetate and later with methylene chloride / ethanol 9: 1). The clean fractions are combined and the solvent is removed in vacuo. 3.35 g (44% of theory) of the desired product are obtained with a purity of 96%. HPLC (method 1): R _t = 4.15 min. MS (ESIpos): m / z = 256 (M + H) ⁺

Η NMR (200 MHz, CDC1 ₃ ): δ - 1.13-1.44 (m, 2H), 1.77-2.04 (m, 2H), 2.42-2.67 (m, 3H), 2.74-3.00 (m, 2H), 3.81 (s, 3H), 6.89 (d, 2H), 7.05-7.32 (m, 7H). Example 26A

2- (4-methoxyphenyl) ethyl acetamide

25.00 g (165.34 mmol) of 2- (4-methoxyphenyl) ethylamine and 70.00 ml of acetic acid are placed in 1 l of xylene. The mixture is boiled on a water separator for 2 hours. The mixture is freed from solvent in vacuo. 31.00 g (97% of theory) of the desired product are obtained. HPLC (method 1): R _t = 3.51 min. MS (DCI): m / z = 211 (M + NH ₄ ) ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ - 1.93 (s, 3H), 2.75 (t, 2H), 3.47 (q, 2H), 3.79 (s, 3H), 5.48 (s, 1H), 6.84 ( d, 2H), 7.10 (d, 2H).

Example 27A

[1 - (4-bromophenyl) cyclopentyl] methylformamide

A solution of 5.10 g (82% pure, 16.45 mmol) of [l- (4-bromophenyl) cyclopentyl] methylamine and 1.52 g (32.91 mmol) of formic acid in 50 ml of xylene are heated under reflux on a water separator for 6 h and then at overnight Room temperature stirred. The mixture is concentrated in vacuo, the residue is taken up in ethyl acetate, the organic phase is washed with sodium hydrogen carbonate solution and dried over sodium sulfate. After removing the Solvent in vacuo gives 4.9 g (99% of theory) of the desired product as a yellow solid.

HPLC (method 1): R _t = 4.52 min.

MS (DCI): 299 (M + NH ₄ ) ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.68-2.00 (m, 8H), 3.22 + 3.44 (d, 2H), 5.10 + 5.30

(broad, s, 1H), 7.11 + 7.18 (dt, 2H), 7.46 (dt, 2H), 8.10 (s, 1H).

Example 28A

[L- (4-Bromophenyl) cyclohexyl] formamide

A solution of 15.28 g (71% pure, 40.59 mmol) of [1- (4-bromophenyl) cyclohexyl] methylamine in 3.74 g (81.18 mmol) of formic acid is mixed with 3 ml of xylene and molecular sieve, heated under reflux for 6 h and then over Stirred at room temperature overnight. Ethyl acetate is added to the mixture, the organic phase is washed with sodium bicarbonate solution, water and saturated sodium chloride solution and dried over sodium sulfate. After removing the solvent in vacuo, the residue is purified on silica gel (cyclohexane / ethyl acetate 1: 1). 4.5 g (77% pure by HPLC, 29% of theory) of the desired product are obtained as a colorless solid. HPLC (method 1): R, = 4.62 min. MS (ESIpos): 296 (M + H) ⁺

Η NMR (200 MHz, CDC1 ₃ ): δ = 1.25-1.80 (m, 8H), 2.10 (m, 2H), 3.19 + 3.40 (d, 2H), 5.02 + 5.23 (broad, s, 1H), 7.18 + 7.23 (d, 2H), 7.50 (d, 2H), 8.10 (s, 1H). Example 29A

2- [4- (benzyloxy) phenyl] -2-methylpropylformamid

27.60 g (0.108 mol) of 2- [4- (benzyloxy) phenyl] -2-methylpropylamine and 124.36 g

(2,702 mol) formic acid are placed in 300 ml of xylene. The mixture is boiled on a water separator for 3 hours. The mixture is concentrated in vacuo and the residue is dissolved in ethyl acetate and extracted with water. The organic phase is washed twice more with water, dried over sodium sulfate and freed from the solvent in vacuo. It is filtered through silica gel 60. The clean fractions are combined and the solvent is removed in vacuo. 24.21 g (79% of theory) of the desired product are obtained with 98% purity. HPLC (method 1): R _t = 4.12 min. MS (DCI): m / z = 301 (M + NH ₄ ) ⁺ 1H-NMR (200 MHz, CDC1 ₃ ): δ - 1.32 (s, 6H), 3.48 (d, 2H), 5.05 (s, 2H) , 6.90-7.01

(dt, 2H), 7.18-7.49 (m, 7H), 7.86 (d, 1H), 8.10 (s, 1H).

Example 30A

{L- [4- (benzyloxy) phenyl] cyclobenzyl} methylformamide

6.60 g (24.68 mmol) {l- [4-benzyloxy) phenyl] cyclobutyl} methylamine and 11.36 g (246.85 mmol) formic acid are placed in 100 ml xylene. The mixture is boiled on a water separator. The mixture is concentrated in vacuo and the residue is dissolved in ethyl acetate and extracted with water. The organic phase is washed twice more with water, dried over sodium sulfate and freed from the solvent in vacuo. 7.20 g (99% of theory) of the desired product are obtained with a purity of 93%. HPLC (method 1): R _t = 4.64 min. MS (DCI): m / z = 313 (M + NH ₄ ) ⁺

1H-NMR (300 MHz, CDC1 ₃ ): δ = 1.80-1.99 (m, 2H), 2.02-2.21 (m, 2H), 3.63 (d, 2H), 5.05 (s, 2H), 6.89-7.01 (m , 2H), 7.29-7.46 (m, 5H), 7.85 (d, 1H), 8.13 (s, 1H).

Example 31A

{L- [4- (benzyloxy) phenyl] cyclopentyl} methylformamide

18.40 g (65.39 mmol) {l- [4-benzyloxy) phenyl] cyclopenyl} methylamine and 75.24 g (1634.70 mmol) formic acid are placed in 200 ml xylene. The mixture is boiled on a water separator. The mixture is concentrated in vacuo and the residue is dissolved in ethyl acetate and extracted with water. The organic phase is washed twice more with water, dried over sodium sulfate and freed from the solvent in vacuo. 20.00 g (99% of theory) of the desired product are obtained with 100% purity. HPLC (method 1): R _t = 4.75 min. MS (ESIpos): m / z = 310 (M + H) ⁺ Η NMR (300 MHz, CDC1 ₃ ): δ = 1.64-1.95 (m, 10H), 3.42 (d, 2H), 5.05 (s, 2H), 6.90-6.99 (m, 2H), 7.10-7.22 (m , 2H), 7.29-7.48 (m, 5H), 7.78 (d, 1H), 8.09 (s, 1H).

Example 32A

{1 - [4- (benzyloxy) phenyl] cyclohexyl} methylformamide

9.20 g (31.14 mmol) {l- [4-benzyloxy) phenyl] cyclophexyl} methylamine and 14.33 g (311.42 mmol) formic acid are placed in 100 ml xylene. The mixture is boiled on a water separator. The mixture is concentrated in vacuo and the residue is dissolved in ethyl acetate and extracted with water. The organic phase is washed twice more with water, dried over sodium sulfate and freed from the solvent in vacuo. 10.62 g (90% of theory) of the desired product are obtained with 85% purity. HPLC (method 1): R _t = 4.83 min. MS (DCI): m / z = 341 (M + NH ₄ ) ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.29-1.70 (m, 8H), 1.95-2.15 (m, 2H), 3.38 (dd, 2H), 5.05 (s, 2H), 6.89-6.97 (m , 2H), 7.11-7.23 (m, 2H), 7.28-7.47 (m, 5H), 7.78 (d, 1H), 8.08 (s, 1H). Example 33A

2- (4-methoxy-phenyl) -4-phenylbutylformamid

3.49 g (13.67 mmol) of 2- (4-methoxyphenyl) -4-phenylbutylamine and 10 ml of formic acid are placed in 200 ml of xylene. The mixture is boiled on a water separator for 3 hours. The mixture is concentrated in vacuo and toluene is added twice to the residue, and the solvent is again removed in vacuo. 3.68 g (95% of theory) of the desired product are obtained with 93%

Purity.

HPLC (method 1): R _t = 4.41 min. MS (DCI): mz = 301 (M + NH ₄ ) ⁺ NMR-NMR (300 MHz, CDC1 ₃ ): δ = 1.79-2.05 (m, 2H), 2.33 (d, 1H), 2.34-2.54 (m, 2H), 2.67-2.80 (m, 1H), 3.15-3.27 (m, 1H), 3.81 (s, 3H), 5.27 (m, 1H), 6.89 (d, 2H), 7.03-

7.30 (m, 7H), 8.04 (s, 1H).

Example 34A

[1 - (1, 1 '-Biphenyl-4-yl) cyclopentyl] methylformamide

A solution of 50 mg (0.07 mmol) bis (triphenylphosphine) palladium dichloride, 500 mg (1.77 mmol) [1- (4-bromophenyl) cyclopentyl] methylformamide and 280 mg (2.30 mmol) benzene boronic acid in 10 ml acetonitrile / DMF (1: 1 ) is heated to 70 ° C for 1 h. Then 2 ml of 2 M sodium carbonate solution are added and the reaction mixture is heated to 100 ° C. overnight. After cooling, the mixture is concentrated in vacuo and the crude product is purified by preparative HPLC. 120 mg (24% of theory) of the desired product are obtained as a colorless solid. HPLC (method 1): R _t = 4.79 min. MS (DCI): 297 (M + NH ₄ ) ⁺ 1H-NMR (200 MHz, CDC1 ₃ ): δ = 1.70-2.08 (m, 8H), 3.29 + 3.50 (d, 2H), 5.20 + 5.35 (broad, s, 1H), 7.30-7.50 (m, 5H), 7.58 (m, 4H), 7.83 (d) + 8.12 (s, 1H).

Example 35A

[1 - (4'-Fluoro-1, 1'-biphenyl-4-yl) cyclopentyl] methylformamide

Analogous to the preparation of [l- (l, l'-biρhenyl-4-yl) cyclopentyl] methylformamide, 500 mg (1,772 mmol) of [l- (4-bromophenyl) cyclopentyl] methylformamide, 50 mg (0.07 mmol) bis ( triphenylphosphine) palladium dichloride and 322 mg (2,304 mmol) of 4-fluorobenzene boronic acid 229 mg (43% of theory) of the desired product obtained as a white solid. HPLC (method 1): R _t = 4.83 min. MS (ESIpos): 298 (M + H) ⁺

Η NMR (300 MHz, d ₆ -DMSO): δ = 1.55-2.00 (m, 8H), 3.10 + 3.31 (d, 2H), 7.23-7.40 (m, 4H), 7.58 (d, 2H), 7.61 -7.73 (m, 3H), 7.92 (d, 1H).

Example 36A

[1 - (4'-Trifluoromethyl-1, 1'-biphenyl-4-yl) cyclopentyl] methylformamide

Analogously to the preparation of [l- (l, r-biphenyl-4-yl) cyclopentyl] methylformamide, 500 mg (1,772 mmol) of [l- (4-bromophenyl) cyclopentyl] methylformamide, 50 mg (0.07 mmol) bis (triphenylphosphine) ) Palladium dichloride and 440 mg (2,304 mmol) 4- (trifluoromethyl) benzene boronic acid 378 mg (61% of theory) of the desired product obtained as a white solid. HPLC (method 1): R, = 5.14 min.

MS (ESIpos): 348 (M + H) ⁺

Η NMR (300 MHz, d ₆ -DMSO): δ = 1.55-2.00 (m, 8H), 3.20 + 3.33 (d, 2H), 7.38 + 7.43 (d, 2H), 7.68 (d, 3H), 7.80 (d, 2H), 7.89 (d, 2H), 7.91 (d, 1H). Example 37A

[1 - (1, 1 '-Biphenyl-4-yl) cyclohexyl] methylformamide

Analogous to the preparation of [l- (l'-biphenyl-4-yl) cyclopentyl] methylformamide, 1.00 g (2.60 mmol) of [l- (4-bromophenyl) cyclohexyl] methylformamide, 100 mg (0.14 mmol) of bis ( triphenylphosphine) palladium dichloride and 317 mg (2.60 mmol) of benzene boronic acid 297 mg (36% of theory) of the desired product as a white solid.

HPLC (method 1): R _t = 4.84 min. MS (DCI): 311 (M + NH ₄ ) ⁺

1H-NMR (300 MHz, d ₆ -DMSO): δ = 1.15-1.70 (m, 8H), 2.00-2.17 (m, 2H), 3.09 + 3.22 (d, 2H), 7.29-7.52 (m, 5H) , 7.60-7.72 (m, 4H), 7.92 (d, 1H).

Example 38A

[1 - (4'-Fluoro-1, 1'-biphenyl-4-yl) cyclohexyl] methylformamide

Analogously to the preparation of [l- (l, r-biphenyl-4-yl) cyclopentyl] methylformamide, 2,086 g (5.42 mmol) of [l- (4-bromophenyl) cyclohexyl] methylformamide, 100 mg (0.14 mmol) of bis (triphenylphosphine) palladium dichloride and 759 mg (5.42 mmol) of 4-fluorobenzeneboronic acid 744 mg (42% of theory) of the desired product obtained as a white solid.

HPLC (method 1): R _t = 4.87 min.

MS (DCI): 329 (M + NH ₄ ) ⁺

Η NMR (200 MHz, d ₆ -DMSO): δ = 1.15-1.70 (m, 8H), 1.95-2.18 (m, 2H), 3.08 +

3.22 (d, 2H), 7.20-7.35 (m, 2H), 7.43 (d, 2H), 7.55-7.77 (m, 5H), 7.92 (d, 1H).

Example 39A

[1 - (4'-Trifluoromethyl-1, 1'-biphenyl-4-yl) cyclohexyl] methylformamide

Analogously to the preparation of [l- (l, r-biphenyl-4-yl) cyclopentyl] methylformamide, 1.00 g (2.60 mmol) of [l- (4-bromophenyl) cyclohexyl] methylformamide, 100 mg (0.14 mmol) of bis (triphenylphosphine ) palladium dichloride and 494 mg (2.60 mmol)

4- (Trifluoromethyl) benzene boronic acid 225 mg (24% of theory) of the desired product obtained as a white solid.

HPLC (method 1): R _t = 5.22 min.

MS (DCI): 379 (M + NH ₄ ) ⁺ 1H-NMR (300 MHz, d ₆ -DMSO): δ = 1.15-1.70 (m, 8H), 2.00-2.20 (m, 2H), 3.10 +

3.23 (d, 2H), 7.50 (d, 2H), 7.60-7.99 (m, 8H). Example 40A

7-methoxy-1-methyl-3,4-dihydroisoquinoline

43.0 g (0.222 mol) of 2- (4-methoxyphenyl) ethyl acetamide are dissolved in 320 ml of toluene under argon, 100 ml of phosphorus oxychloride are added and the mixture is heated under reflux for 3 hours. After cooling to room temperature, the mixture is mixed with ice water and ethyl acetate, made alkaline with 20% sodium hydroxide solution and the aqueous phase extracted three times with diethyl ether. The combined organic extracts are dried over sodium sulfate and freed from the solvent in vacuo. 4.1 g (10% of theory) of the desired product are obtained, which is converted to 7-methoxy-l-methyl-l, 2,3,4-tetrahydroisoquinoline without further characterization (see Example 53A).

Example 41A

7- (benzyloxy) -l, 4,4-trimethyl-3,4-dihydro-2 (lH) -isochinolincarbaldehyd

Under argon, 10.00 g (35.29 mmol) of 2- [4- (benzyloxy) phenyl] -2-methylpropylformamide and 39.46 ml (705.79 mmol) of acetaldehyde in 300 ml of a

Mixture of trifluoroacetic acid / acetic acid (2: 8) submitted and heated to 100 ° C for 4 hours. The mixture is then cooled to room temperature and the acid mixture is distilled off in vacuo. The residue is purified by RP-18 chromatography (aceto nitrile / water / 0.1% acid, gradient). The clean fractions are combined, concentrated in vacuo and dried. 4.41 g (40% of theory) of the desired product are obtained with 100% purity. HPLC (method 1): R, = 4.74 min. MS (DCI): m / z = 327 (M + NH ₄ ) ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.15 (s, 3H), 1.35 (s, 3H), 1.46 (d, 3H), 3.17 (d, 1H), 3.38 (d, 1H), 5.04 ( s, 2H), 5.42 (q, 1H), 6.63-6.91 (m, 2H), 7.22 (d, 2H), 7.28- 7.45 (m, 4H), 8.08 (s, 1H).

Example 42A 7- (Benzyloxy) -4-spirocyclobutyl-3,4-dihydro-2 (1H) isoquinoline carbaldehyde

7.20 g (24.38 mmol) of {l- [4- (benzyloxy) phenyl] cyclobutyl} methylformamide and 1.46 g (48.75 mmol) of formaldehyde in 20 ml of trifluoroacetic acid and 80 ml of acetic acid are introduced under argon. The mixture is boiled under reflux for 3 hours, then cooled, poured onto ice and extracted with methylene chloride. The organic phase is washed twice more with water, once with saturated sodium bicarbonate solution and once with water. The organic phase is then dried over sodium sulfate and concentrated in vacuo and dried. It is purified on silica gel 60 (mobile phase: methylene chloride and cyclohexane / ethyl acetate 1: 1). The clean fractions are combined and the solvent is removed in vacuo. 3.10 g (41% of theory) of the desired product are obtained with 85% purity. HPLC (method 1): R, = 4.84 min.

MS (ESIpos): m / z = 308 (M + H) ⁺ 1H-NMR (200 MHz, CDC1 ₃ ): δ = 1.83-2.41 (m, 6H), 3.70 (d, 2H), 4.57 (d, 2H), 5.04 (s, 2H), 6.63-6.97 (m, 2H ), 7.18-7.58 (m, 6H), 8.27 (d, 1H).

Example 43A

7- (benzyloxy) -4-spirocyclopentyl-3,4-dihydro-2 (lH) -isochinolincarbaldehyd

20.00 g (64.64 mmol) of {l- [4- (benzyloxy) phenyl] cyclopentyl} methylformamide and 3.88 g (129.28 mmol) of formaldehyde in 35 ml of trifluoroacetic acid and 135 ml of acetic acid are introduced under argon. The mixture is boiled under reflux for 30 minutes, then cooled, poured onto ice and extracted with methylene chloride. The organic phase is washed once more with water, twice with saturated sodium bicarbonate solution, twice with water and once with saturated sodium chloride solution. The organic phase is then dried over sodium sulfate and concentrated in vacuo and dried. It is over silica gel 60

(Solvent: methylene chloride) cleaned. The clean fractions are combined and the solvent is removed in vacuo. 20.50 g (99% of theory) of the desired product are obtained. HPLC (method 1): R _t = 4.44 min. MS (ESIpos): m / z = 322 (M + H) ⁺

1H-NMR (200 MHz, CDC1 ₃ ): δ = 1.42-2.03 (m, 8H), 3.44 (d, 2H), 4.60 (d, 2H), 5.07 (s, 2H), 6.62-7.00 (m, 2H) ), 7.33-7.51 (m, 6H), 8.25 (d, 1H). Example 44A

7- (benzyloxy) -4-spirocyclohexyl-3,4-dihydro-2 (lH) -isochinolincarbaldehyd

10.00 g (27.82 mmol) of {1- [4- (benzyloxy) phenyl] cyclohexyl} methylformamide and 1.65 g (55.03 mmol) of formaldehyde in 20 ml of trifluoroacetic acid and 80 ml of acetic acid are introduced under argon. The mixture is boiled under reflux for 30 minutes, then cooled, poured onto ice and extracted with methylene chloride. The organic phase is washed twice more with water, once with saturated sodium bicarbonate solution and once with water. The organic phase is then dried over sodium sulfate and concentrated in vacuo and dried. It is purified on silica gel 60 (mobile phase: methylene chloride and cyclohexane / ethyl acetate 1: 1). The clean fractions are combined and the solvent is removed in vacuo. 7.20 g (72% of theory) of the desired product are obtained with a purity of 92%. HPLC (method 1): R, = 5.05 min. MS (ESIpos): mz = 336 (M + H) ⁺

Η NMR (200 MHz, CDC1 ₃ ): δ = 1.10-1.87 (m, 10H), 3.59 (d, 2H), 4.58 (d, 2H), 5.03 (s, 2H), 6.61-7.01 (m, 2H ), 7.21-7.48 (m, 6H), 8.24 (d, 1H). Example 45A

7-phenyl-4-spirocyclopentyl-3,4-dihydro-2 (lH) -isochinolincarbaldehyd

A mixture of 103 mg (0.369 mmol) [l- (l, l'-biphenyl-4-yl) cyclopentyl] methylformamide and 55 μl (0.737 mmol) 37% formaldehyde solution is mixed with 8 ml acetic acid and 2 ml trifluoroacetic acid , Heated under reflux for 4 h and stirred overnight at room temperature. Then the mixture is mixed with water and ethyl acetate, the organic phase is washed with sodium hydrogen carbonate solution and water, dried over sodium sulfate and in vacuo

Free solvent. 110 mg (94% of theory) of the desired product are obtained as a colorless oil in 92% purity (HPLC). HPLC (method 1): R _t = 4.95 min. MS (ESIpos): 292 (M + H) ⁺ 1H-NMR (300 MHz, CDC1 ₃ ): δ = 1.65-2.15 (m, 8H), 3.38 + 3.60 (s, 2H), 4.64 + 4.77

(s, 2H), 7.36 (m, 3H), 7.44 (m, 3H), 7.55 (d, 2H), 8.19 + 8.33 (s, 1H).

Example 46A

7- (4-fluorophenyl) -4-spirocyclopentyl-3, 4-dihydro-2 (1 H) -isoquinoline carbaldehyde

Analogously to the preparation of 7-phenyl-4-spirocyclopentyl-3,4-dihydro-2 (lH) -isoquinoline carbaldehyde, 210 mg (0.706 mmol) are converted into [1- (4'-fluoro-l, r-biphenyl-4 - yl) cyclopentyl] methylformamide and 42.4 mg (0.523 mmol) 37% formaldehyde solution in 16 ml acetic acid and 4 ml trifluoroacetic acid 170 mg (51% of theory) of the desired product as a colorless oil in 66% purity obtained (HPLC). LC / MS (method 3): R, = 2.93 min. MS (ESIpos): 310 (M + H) ⁺

1H-NMR (300 MHz, CDC1 ₃ ): δ = 1.70-2.05 (m, 8H), 3.38 + 3.60 (s, 2H), 4.62 + 4.76 (s, 2H), 7.11 (m, 2H), 7.30-7.45 (m, 2H), 7.46-7.59 (m, 3H), 8.19 + 8.34 (s, 1H).

Example 47A

4-spirocyclopentyl-7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1H) isoquinoline carbaldehyde

Analogously to the preparation of 7-phenyl-4-spirocyclopentyl-3,4-dihydro-2 (lH) -isoquinoline carbaldehyde, 259 mg (0.746 mmol) are converted into [1- (4'-trifluoromethyl-l, l'-biphenyl- 4-yl) cyclopentyl] methylformamide and 121 mg (1,491 mmol) 37%

Formaldehyde solution in 24 ml acetic acid and 6 ml trifluoroacetic acid 237 mg (73% of theory) of the desired product obtained as a colorless oil in 81% purity

(HPLC).

HPLC (method 1): R, = 5.18 min.

MS (DCI): 377 (M + NH ₄ ) ⁺

1H-NMR (200 MHz, d ₆ -DMSO): δ = 1.58-1.98 (m, 8H), 3.42 + 3.49 (s, 2H), 4.66 +

4.70 (s, 2H), 7.37-7.65 (m, 3H), 7.75-7.95 (m, 4H), 8.21 + 8.30 (s, 1H). Example 48A

7-bromo-4-spirocyclohexyl-3, 4-dihydro-2 (1 H) -isoquinoline carbaldehyde

Analogously to the preparation of 7-phenyl-4-spirocyclopentyl-3,4-dihydro-2 (lH) -isoquinoline carbaldehyde, 1.23 g (2.95 mmol) of [l- (4-bromophenyl) cyclohexyl] methylformamide and 479 mg ( 5.90 mmol) 37% formaldehyde solution in 40 ml acetic acid and 10 ml trifluoroacetic acid 1.22 g (99% of theory) of the desired product obtained as a colorless oil in 74% purity (HPLC). LC / MS (method 3): R, = 2.84 min. MS (ESIpos): 308 (M + H) ⁺

Η NMR (300 MHz, d ₆ -DMSO): δ = 1.40-1.80 (m, 10H), 3.60 + 3.62 (s, 2H), 4.56 + 4.59 (s, 2H), 7.12-7.49 (m, 3H) , 8.18 + 8.24 (s, 1H).

Example 49A

7-phenyl-4-spirocyclohexyl-3,4-dihydro-2 (lH) -isochinolincarbaldehyd

Analogously to the preparation of 7-phenyl-4-spirocyclopentyl-3,4-dihydro-2 (lH) -isoquinoline carbaldehyde, from 265 mg (0.90 mmol) [l- (l, l'-biphenyl-4-yl) - cyclohexyl] methylformamide and 147 mg (1.81 mmol) 37% formaldehyde solution in 24 ml acetic acid and 6 ml trifluoroacetic acid 235 mg (61% of theory) of the desired product as a colorless oil in 69% purity (HPLC ). LC / MS (Method 3): R _t = 3.01 min. MS (ESIpos): 294 (M + H) ⁺ .

Example 50A

7- (4-Fluo henyl) -4-spirocyclohexyl-3,4-dihydro-2 (1H) isoquinoline carbaldehyde

Analogously to the preparation of 7-phenyl-4-spirocyclopentyl-3,4-dihydro-2 (1H) -isoquinoline carbaldehyde, 680 mg (2.18 mmol) are [1- (4'-fluoro-l, l'-biphenyl- 4- yl) cyclohexyl] methylformamide and 350 mg (4.37 mmol) 37% formaldehyde solution in 40 ml acetic acid and 10 ml trifluoroacetic acid 770 mg (99% of theory) of the desired product as a colorless oil in 91% Purity obtained (HPLC). HPLC (method 1): R _t - 5.20 min. MS (DCI): 341 (M + NH ₄ ) ⁺

1H-NMR (300 MHz, CDC1 ₃ ): δ = 1.25-1.85 (m, 10H), 3.65 + 3.85 (s, 2H), 4.66 + 4.78 (s, 2H), 7.12 (m, 2H), 7.26 (m , 2H), 7.40-7.59 (m, 3H), 8.23 + 8.39 (s, 1H).

Example 51A

4-spirocyclohexyl-7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1H) isoquinoline carbaldehyde

Analogously to the preparation of 7-phenyl-4-spirocyclopentyl-3,4-dihydro-2 (1H) -isoquinoline carbaldehyde, 212 mg (0.59 mmol) [1- (4'-trifluoromethyl-1, - biphenyl-4- yl) cyclohexyl] methylformamide and 95 mg (1.17 mmol) 37% formaldehyde solution in 12 ml acetic acid and 3 ml trifluoroacetic acid. 218 mg (94% of theory) of the desired product were obtained as a colorless oil in 94% purity (HPLC).

HPLC (method 1): R _t = 4.38 min. MS (ESIpos): 374 (M + H) ⁺

1H-NMR (300 MHz, CDC1 ₃ ): δ = 1.25-1.95 (m, 10H), 3.61 + 3.83 (s, 2H), 4.63 + 4.78 (s, 2H), 7.27-7.35 (m, IH), 7.42 -7.55 (m, 2H), 7.62-7.72 (m, 4H), 8.20 + 8.34 (s, IH).

Example 52A

7-methoxy-4- (2-phenylethyl) -3,4-dihydro-2 (lH) -isochinolincarbaldehyd

A mixture of 3.60 g (12.70 mmol) of 2- (4-methoxyphenyl) -4-phenylbutylformamide and 2.18 g (25.41 mmol) of formaldehyde solution is mixed with 150 ml of trifluoroacetic acid / acetic acid mixture (2: 8). The mixture is heated under reflux for 2 h. The mixture is then freed from the solvent in vacuo and water and ethyl acetate are added. The organic phase is washed once with water and once with saturated sodium chloride solution, dried over sodium sulfate and freed from the solvent in vacuo. It is purified using preparative HPLC. 2.35 g (62% of theory) of the desired product are obtained in 83% purity. HPLC (method 1): R _t = 4.65 min.

MS (DCI): 313 (M + NH ₄ ) ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 2.60-2.94 (m, 4H), 3.43-3.70 (m, 2H), 3.78 (s, 3H), 4.29-4.56 (m, 2H), 5.01 (d , IH), 6.54-6.69 (m, IH), 6.72-6.83 (m, IH), 7.01-7.09 (m, 2H), 7.12-7.36 (m, 4H), 8.12 (s, IH).

Example 53A

7-methoxy-1-methyl-1, 2,3,4-tetrahydroisoquinoline

2.80 g (15.98 mmol) 7-methoxy-l-methyl-3,4-dihydroisoquinoline in 140 ml

Methanol is mixed with 665 mg (17.58 mmol) sodium borohydride at room temperature and stirred for 1 hour. The mixture is then mixed with water and ethyl acetate, the aqueous phase is extracted twice with ethyl acetate and the combined organic extracts are dried over sodium sulfate. After removal of the solvent in vacuo, 2.70 g (95% of theory) of the desired

Product. MS (ESIpos): mz = 178 (M + H) ⁺ Η NMR (300 MHz, CDC1 ₃ ): δ = 1.43 (d, 2H), 2.70 (m, IH), 2.96 (m, IH), 3.23 (dt, IH), 3.48 (m, IH), 3.78 ( s, 3H), 4.05 (m, IH), 6.70 (m, 2H), 6.99 (d, IH).

Example 54A

7- (benzyloxy) - 1,4,4-trimethyl-1,3,4,4-tetrahydroisoquinoline

2.20 g (7.11 mmol) 7- (benzyloxy) -l, 4,4-trimethyl-3,4-dihydro-2 (lH) -isoquinoline-carbaldehyde are dissolved in 30 ml ethanol and at room temperature with 22 ml 2 molar sodium hydroxide. Solution added. It is refluxed overnight. For working up, the mixture is cooled and diluted with methylene chloride and water. The organic phase is washed twice more with water and saturated sodium chloride solution, dried over sodium sulfate and freed from the solvent in vacuo. 1.65 g (83% of theory) of the desired product with 90% purity are obtained.

HPLC (method 3): R, = 1.94 min. MS (ESIpos): m / z = 282 (M + H) ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.22 (s, 3H), 1.26 (s, 3H), 1.44 (d, 3H), 1.66 (s, IH), 2.84 (dd, 2H), 5.02 ( s, 2H), 6.69-6.85 (m, 2H), 7.20-7.46 (m, 6H).

Example 55A 7- (Benzyloxy) -4-spirocyclobutyl-l, 2,3,4-tetrahydroisoquinoline

3.10 g (10.08 mmol) of 7- (benzyloxy) -4-spirocyclobutyl-3,4-dihydro-2 (1H) -isoquinoline carbaldehyde are dissolved in 30 ml of ethanol and 32 ml of 2 molar sodium hydroxide solution are added at room temperature. It is refluxed overnight. For working up, the mixture is cooled and diluted with ethyl acetate and water. The organic phase is washed with saturated sodium bicarbonate solution, dried over sodium sulfate and freed from the solvent in vacuo. 2.70 g (79% of theory) of the desired product are obtained with 82% purity. HPLC (method 1): R _t = 4.21 min. MS (DCI): m / z = 297 (M + NH ₄ ) ⁺

1H-NMR (300 MHz, CDC1 ₃ ): δ = 1.62 (s, IH), 1.94-2.08 (m, 4H), 2.24-2.37 (m, 2H), 3.12 (s, 2H), 3.95 (s, 2H ), 5.02 (s, 2H), 6.53-6.92 (m, 2H), 7.24-7.52 (m, 6H).

Example 56A

7- (benzyloxy) -4-spirocyclopentyl-l, 2,3,4-tetrahydroisoquinoline

20.50 g (63.78 mmol) 7- (benzyloxy) -4-spirocyclopentyl-3,4-dihydro-2 (1H) -isoquinoline carbaldehyde are dissolved in 200 ml ethanol and at room temperature with 191 ml (382.68 mmol) 2 molar sodium hydroxide. Solution added. It gets under Reflux cooked. For working up, the mixture is cooled and diluted with methylene chloride and water. The aqueous phase is extracted three more times with methylene chloride. The combined organic phases are combined and washed with saturated sodium hydrogen carbonate solution, dried over sodium sulfate and freed from the solvent in vacuo. You get

19.47 g (76% of theory) of the desired product with a purity of 73%. HPLC (method 1): R _t = 4.45 min. MS (ESIpos): m / z = 294 (M + H) ⁺

Η NMR (200 MHz, CDC1 ₃ ): δ = 1.60-1.94 (m, 9H), 2.86 (s, 2H), 3.99 (s, 2H), 5.02 (s, 2H), 6.50-6.89 (m, 2H ), 7.10-7.49 (m, 6H).

Example 57A

7- (benzyloxy) -4-spirocyclohexyl-l, 2,3,4-tetrahydroisoquinoline

3.10 g (9.24 mmol) 7- (benzyloxy) -4-spirocyclohexyl-3,4-dihydro-2 (1H) -isoquinoline carbaldehyde are dissolved in 100 ml ethanol and at room temperature with 28 ml (55.45 mmol) 2 molar sodium hydroxide. Solution added. It is cooked under reflux. For working up, the mixture is cooled and diluted with methylene chloride and water. The aqueous phase is three times with

Extracted methylene chloride. The combined organic phases are combined and washed with saturated sodium hydrogen carbonate solution, dried over sodium sulfate and freed from the solvent in vacuo. 2.83 g (86% of theory) of the desired product are obtained with 86% purity. HPLC (method 1): R _t = 4.46 min.

MS (ESIpos): m / z = 308 (M + H) ⁺ 1H-NMR (200 MHz, CDC1 ₃ ): δ = 1.22-1.98 (m, 11H), 3.08 (s, 2H), 3.95 (s, 2H), 5.01 (s, 2H), 6.52-6.91 (m, 2H ), 7.17-7.48 (m, 6H).

Example 58A

7-phenyl-4-spirocyclopentyl-l, 2,3,4-tetrahydroisoquinoline

A solution of 107 mg (0.37 mmol) of 7-phenyl-4-spirocyclopentyl-3,4-dihydro-2 (1H) isoquinoline carbaldehyde in 10 ml of ethanol is mixed with 0 ml of 2.2 M (2.20 mmol) of 1 M sodium hydroxide solution and after addition, stirred at 70 ° C. for 6 hours. After cooling to room temperature, the mixture is mixed with water and ethyl acetate, the aqueous phase is extracted with ethyl acetate, the combined organic phases are washed with saturated sodium hydrogen carbonate solution and dried over sodium sulfate. After removing the solvent in vacuo, 52 mg (54% of theory) of the desired product are obtained in 98% purity. HPLC (method 1): R, = 4.30 min. MS (ESIpos): 264 (M + H) ⁺

Η NMR (200 MHz, CDC1 ₃ ): δ = 1.65-1.98 (m, 8H), 2.40 (broad, s, IH), 2.89 (s, 2H), 4.09 (s, 2H), 7.20 (m, IH ), 7.30-7.49 (m, 5H), 7.51-7.61 (m, 2H). Example 59A

7- (4-Fluoφhenyl) -4-spirocyclopentyl-l, 2,3,4-tetrahydroisoquinoline

Analogously to the preparation of 7-phenyl-4-spirocyclopentyl-l, 2,3,4-tetrahydroisoquinoline, 7- (4-fluophenyl) -4-spirocyclopentyl-3,4-dihydro-2 is obtained from 170 mg (0.55 mmol) (1H) -isoquinoline carbaldehyde and 3.0 ml (3.30 mmol) 1 M sodium hydroxide solution in

10 ml ethanol 101 mg (65% of theory) of the desired product in 100%

Purity won.

HPLC (method 1): R _t = 4.36 min.

MS (ESIpos): 282 (M + H) ⁺

1H-NMR (200 MHz, CDC1 ₃ ): δ = 1.68-1.98 (m, 8H), 2.76 (s, IH), 2.88 (s, 2H), 4.06

(s, 2H), 7.06-7.13 (m, 3H), 7.33-7.36 (m, IH), 7.48-7.56 (m, 3H).

Example 60A

4-spirocyclopentyl-7- [4- (trifluoromethyl) phenyl] -l, 2,3,4-tetrahydroisoquinoline

Analogous to the preparation of 7-phenyl-4-spirocyclopentyl-1,2,3,4-tetrahydroisoquinoline, 7- [4- (trifluoromethyl) phenyl] -4-spiro- Cyclopentyl-3,4-dihydro-2 (1H) -isoquinolinecarbaldehyde and 4.93 ml (4.93 mmol) of 1 M sodium hydroxide solution in 6 ml of ethanol 380 mg (96% of theory) of the desired product in 92% purity. LC / MS (Method 3): R _t = 1.99 min. MS (ESIpos): 332 (M + H) ⁺ .

Example 61A

7-bromo-4-spirocyclohexyl-l, 2,3,4-tetrahydroisoquinoline

Analogously to the preparation of 7-phenyl-4-spirocyclopentyl-l, 2,3,4-tetrahydroisoquinoline, 1.13 g (2.71 mmol) of 7-bromo-4-spirocyclohexyl-3,4-dihydro-2 (1H) - isoquinoline carbaldehyde and 8.14 ml (16.28 mmol) of 2 M sodium hydroxide solution in 30 ml of ethanol after purification by HPLC 390 mg (36% of theory) of the desired product in 71% purity.

HPLC (method 1): R _t = 4.17 min. MS (ESIpos): 280 (M + H) ⁺

1H-NMR (200 MHz, CDC1 ₃ ): δ = 1.23-1.85 (m, 11H), 3.07 (s, IH), 3.94 (s, 2H), 7.12 (m, IH), 7.26 (m, 2H).

Example 62A

7-phenyl-4-spirocyclohexyl-l, 2,3,4-tetrahydroisoquinoline

Analogously to the production of 7-phenyl-4-spirocyclopentyl-l, 2,3,4-tetrahydroisoquinoline, 7-phenyl-4-spirocyclohexyl-3,4-dihydro-2 (1H) - isoquinoline carbaldehyde and 3.7 ml (3.70 mmol) of 1 M sodium hydroxide solution in 6 ml of ethanol after purification by HPLC 40 mg (27% of theory) of the desired product in 98% purity. LC / MS (method 3): R, = 1.94 min. MS (ESIpos): 278 (M + H) ⁺ .

Example 63A

7- (4-Fluoφhenyl) -4-spirocyclohexylpentyl-l, 2,3,4-tetrahydroisoquinoline

Analogously to the preparation of 7-phenyl-4-spirocyclopentyl-1,2,3, 4-tetrahydroisoquinoline, 700 (2.16 mmol) 7- (4-fluoφhenyl) -4-spirocyclohexyl-3,4-dihydro-2 (lH) -isoquinoline carbaldehyde and 13.0 ml (13.00 mmol) of 1 M sodium hydroxide solution in 10 ml of ethanol after purification over silica gel 140 mg (22% of theory) of the desired product in 91% purity. HPLC (method 1): R, = 4.50 min.

MS (ESIpos): 296 (M + H) ⁺ 1H-NMR (200 MHz, CDC1 ₃ ): δ = 1.23-1.90 (m, 11H), 3.12 (s, IH), 4.06 (s, 2H), 7.02-7.19 (m, 3H), 7.32-7.60 (m , 4H).

Example 64A

4-spirocyclohexyl-7- [4- (trifluoromethyl) phenyl] -l, 2,3,4-tetrahydroisoquinoline

Analogously to the preparation of 7-phenyl-4-spirocyclopentyl-1,2,3,4-tetrahydroisoquinoline, 7- [4- (trifluoromethyl) phenyl] -4-spirocyclopentyl-3, 4-dihydro-2 (1H) -isoquinolinecarbaldehyde and 3.40 ml (3.40 mmol) 1 M sodium hydroxide solution in 10 ml ethanol 195 mg (99% of theory) of the desired product in 69% purity. LC / MS (Method 3): R _t = 2.04 min. MS (ESIpos): 346 (M + H) ⁺ .

Example 65A

7-methoxy-4- (2-phenylethyl) - 1, 2,3, 4-tetrahydroisoquinoline

Analogously to the preparation of 7-phenyl-4-spirocyclopentyl-l, 2,3,4-tetrahydroisoquinoline, 2.30 g (7.79 mmol) of 7-methoxy-4- (2-phenylethyl) -3,4-dihydro- 2 (1H) isoquinoline carbaldehyde and 23.6 ml of 2N sodium hydroxide solution in 100 ml

Ethanol (4 hours at 60 ° C) 1.9 g (92% of theory) of the desired product in 62% purity.

HPLC (method 1): R _t = 4.18 min.

MS (ESIpos): 268 (M + H) ⁺

Η NMR (200 MHz, CDC1 ₃ ): δ = 1.87-2.10 (m, 2H), 2.58-2.82 (m, 4H), 3.11 (q, 2H),

3.77 (s, 3H), 3.97 (s, 2H), 6.49-6.58 (m, IH), 6.68-6.77 (m, IH), 7.12-7.36 (m, 6H).

Example 66A

Ethyl (4 - {[7- (hydroxy) -4-methyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate

A solution of 1.90 g (4.38 mmol) of ethyl (4 - {[7- (methoxy) -4-methyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate (Example 2 ) in 34 ml of methylene chloride is added at -70 ° C with 0.70 ml (7.45 mmol) of a 1.7 M boron tribromide solution in methylene chloride and then for 1 hour

Temperature stirred. Another 1.86 g (7.45 mmol) of 99% boron tribromide are added, the reaction mixture is warmed to 0 ° C. and stirred at this temperature for 1 hour. 4 ml of methanol are then added and the mixture is diluted with water and ethyl acetate, the aqueous phase is extracted with ethyl acetate and the combined organic extracts are dried over sodium sulfate. After constriction in

Vacuum and cleaning of the crude product on silica gel (mobile phase: cyclohexane - Cyclohexane / ethyl acetate 3: 2) gives 1.80 g (98% of theory) of the desired product.

HPLC (method 1): R, = 4.56 min. MS (ESIpos): 420 (M + H) ⁺ 1H-NMR (300 MHz, CDC1 ₃ ): δ = 1.28 (t, 3H), 1.46 (d, 3H), 2.23 (s, 3H), 2.57 (m,

2H), 3.39 (ddd, IH), 3.81 (dddd, IH), 4.25 (q, 2H), 4.64 (s, 2H), 4.72 (s, IH), 5.04 (q, IH), 6.51 (d, IH ), 6.60 (dd, IH), 6.64 (d, IH), 6.84 (d, IH), 7.55 (s, IH), 7.56 (dd, IH).

Example 67A Ethyl (4- {[7- (hydroxy) -1,4,4-trimethyl-3,4-dihydro-2 (1 H) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate

Under argon, 2.00 g (3.72 mmol) of ethyl- (4 - {[7- (benzyloxy) -l, 4,4-trimethyl-

3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate (Example 3) in 50 ml of ethanol and 10 ml of tetrahydrofuran. 2.35 g (37.2 mmol) of ammonium formate are added, the mixture is stirred briefly and then 0.30 g of 10% palladium-on-carbon are added. It is stirred overnight at room temperature. For working up, the mixture is diluted with methylene chloride and suction filtered through diatomaceous earth. Water is added to the filtrate, the aqueous phase is extracted with methylene chloride, the combined organic extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and the solvent is removed in vacuo. 1.68 g (99% of theory) of the desired product are obtained with 99% purity.

LC / MS (Method 3): R _t = 4.79 min. MS (ESIpos): 448 (M + H) ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.23-1.33 (m, 9H), 2.32 (s, 3H), 3.11 (d, IH), 3.47 (d, IH), 4.27 (q, 2H), 4.70 (s, 2H), 4.78 (s, IH), 5.04 (q, IH), 6.47 (d, IH), 6.65-6.75 (m, 2H), 7.14 (d, IH), 7.62-7.71 (m, 2H).

Example 68A

Ethyl {4 - [(7-hydroxy-4-spirocyclobutyl-3,4-dihydro-2 (1H) -isoquinolinyl) sulfonyl] -2-methylphenoxy} acetate

Under argon, 0.77 g (1.44 mmol) of ethyl (4 - {[7- (benzyloxy) -4-spirocyclobutyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate (Example 4 ) in 10 ml of ethanol and 2 ml of tetrahydrofuran. 0.91 g (14.42 mmol) of ammonium formate is added, the mixture is stirred briefly and then 0.06 g of 10% palladium on carbon is added. It is stirred overnight at room temperature. For working up, the batch is suctioned off over kieselguhr. Water, ethyl acetate and saturated sodium chloride solution are added to the filtrate and the aqueous phase is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and freed from the solvent in vacuo. 0.69 g (84% of theory) of the desired product are obtained with a purity of 78%. LC / MS (Method 3): R _t = 2.83 min. MS (ESIpos): m / z = 446 (M + H) ⁺

Η NMR (200 MHz, CDC1 ₃ ): δ = 1.30 (t, 3H), 1.90-2.20 (m, 4H), 2.20-2.35 (m, 2H), 2.36 (s, 3H), 3.26 (s, 2H) ), 4.10 (s, 2H), 4.28 (q, 2H), 4.70 (s, 2H), 6.45 (d, IH), 6.73 (dd, IH), 6.79 (d, IH), 7.40 (d, IH) , 7.55 (d, IH), 7.57 (d, IH). Example 69A

Ethyl {4 - [(7-hydroxy-4-spirocyclopentyl-3,4-dihydro-2 (1H) -isoquinolinyl) sulfonyl] -2-methylphenoxy} acetate

1.65 g (3.00 mmol) of ethyl (4 - {[7- (benzyloxy) -4-spirocyclopentyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate ( Example 5) taken up in 20 ml of ethanol and 4 ml of tetrahydrofuran. 1.89 g (30.02 mmol) of ammonium formate are added, the mixture is stirred briefly and then 0.09 g of 10% palladium on carbon is added. It is stirred overnight at room temperature. For working up, the batch is suctioned off over kieselguhr. Water, ethyl acetate and saturated sodium chloride solution are added to the filtrate and the aqueous phase is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and freed from the solvent in vacuo. The residue is purified over silica gel 60 (mobile phase: cyclohexane / ethyl acetate 3: 1). The clean fractions are combined and the solvent is removed in vacuo. 1.33 g (96% of theory) of the desired product are obtained with 98% purity. HPLC (method 1): R, = 4.98 min. MS (ESIpos): mz = 460 (M + H) ⁺ 1H-NMR (200 MHz, CDC1 ₃ ): δ = 1.30 (t, 3H), 1.82 (s, 8H), 2.35 (s, 3H), 2.97 ( s

2H), 4.12 (s, 2H), 4.27 (q, 2H), 4.71 (s, 2H), 6.44 (d, IH), 6.68 (dd, IH), 6.78 (d, IH), 7.13 (d IH) , 7.63, (s, IH), 7.64 (d, IH). Example 70A

Ethyl {4 - [(7-hydroxy-4-spirocyclohexyl-3,4-dihydro-2 (1H) -isoquinolinyl) sulfonyl] -2-methylphenoxy} acetate

Under argon, 3.70 g (6.56 mmol) of ethyl (4 - {[7- (benzyloxy) -4-spirocyclohexyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate ( Example 6) taken up in 40 ml of ethanol and 20 ml of tetrahydrofuran. 4.14 g (65.64 mmol) of ammonium formate are added, the mixture is stirred briefly and then 0.16 g is added

Add 10% palladium on carbon. It is stirred overnight at room temperature. For working up, the batch is suctioned off over kieselguhr. Water, ethyl acetate and saturated sodium chloride solution are added to the filtrate and the aqueous phase is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and freed from the solvent in vacuo. You get

3.00 g (94% of theory) of the desired product with 98% purity. HPLC (method 1): R _t = 5.07 min. MS (ESIpos): m / z = 474 (M + H) ⁺ 1H-NMR (200 MHz, CDC1 ₃ ): δ = 1.30 (t, 3H), 1.52-1.85 (m, 10H), 2.09 (s, IH ), 2.37 (s, 3H), 3.22 (s, 2H), 4.12 (s, 2H), 4.32 (q, 2H), 4.75 (s, 2H), 6.50 (d, IH), 6.72 (dd,

IH), 6.82 (d, IH), 7.25 (d, IH), 7.68 (s, IH), 7.70 (d, IH). Example 71A

Ethyl (4 - {[7-hydroxy-4- (2-phenylethyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} - 2-methylphenoxy) acetate

1.78 g (3.40 mmol) of ethyl (4 - {[7-methoxy-4- (2-phenylethyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate (Example 17) dissolved in 35.6 ml dichloromethane. The solution is cooled to -78 ° C. and mixed with 7.81 ml (5.78 mmol) of a 0.74 molar boron tribromide solution in dichloromethane. Stir in the cold for an hour, then stir in for an hour

0 ° C and for one hour at room temperature. For working up, it is cooled again to 0 ° C. and diluted with ethyl acetate and water. The aqueous phase is extracted twice more with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and the solvent is removed in vacuo. The residue is purified by preparative HPLC. The clean fractions are combined and the solvent is removed in vacuo. 1.46 g (84% of theory) of the desired product are obtained with 100% purity. HPLC (method 1): R _t = 5.03 min. MS (ESIpos): mz = 510 (M + H) ⁺ Η-NMR (300 MHz, CDC1 ₃ ): δ = 1.32 (t, 3H), 1.84-1.97 (m, IH), 2.00-2.06 (m, IH )

2.32 (s, 3H), 2.59-2.91 (m, 4H), 3.72-3.80 (m, IH), 3.85 (d, IH), 4.26 (q, 2H), 4.47 (d, IH), 4.68 (s, 2H), 4.75 (s, IH), 6.46-6.51 (m, IH), 6.59-6.66 (m, IH), 6.76 (d, IH), 6.94 (d, IH ), 7.13-7.32 (m, 5H), 7.61-7.68 (m, 2H).

Example 72A

Ethyl (2-methyl- {[7- {[(trifluoromethyl) sulfonyl] oxy} -4-methyl-3,4-dihydro-2 (1 H) -isoquinolinyl] sulfonyl} phenoxy) acetate

Under argon, 1.87 g (4.46 mmol) of ethyl {4 - [(7-hydroxy-4-methyl-3,4-dihydro-2 (1H) -isoquinolinyl) sulfonyl] -2-methylphenoxy} acetate (Example 66A) are converted into 25 ml of pyridine dissolved and 2.52 g (8.92 mmol) of trifluoromethanesulfonic anhydride slowly added at 0 ° C. The mixture is allowed to come to room temperature and stirred overnight and water and ethyl acetate are added to the reaction mixture. The aqueous phase is extracted twice with ethyl acetate, the combined organic phases are washed twice with 1 M hydrochloric acid, dried over sodium sulfate and freed from the solvent in vacuo. 2.20 g (86% of theory) of the desired product are obtained with a purity of 96%. HPLC (method 1): R _t = 5.33 min. MS (ESIpos): 552 (M + H) ⁺ 1H-NMR (300 MHz, CDC1 ₃ ): δ = 1.28 (t, 3H), 1.46 (d, 3H), 2.23 (s, 3H), 2.62 (m,

2H), 3.37 (ddd, IH), 3.90 (dddd, IH), 4.25 (q, 2H), 4.73 (s, 2H), 5.14 (q, IH), 6.63 (d, IH), 6.96 (d, IH ), 7.03 (dd, IH), 7.05 (d, IH), 7.55 (s, IH), 7.57 (dd, IH). Example 73A

Ethyl (2-methyl - {[7 - {[(trifluoromethyl) sulfonyl] oxy} -l, 4,4-trimethyl-3,4-dihydro-2 (1 H) -isoquinolinyl] sulfonyl} phenoxy) acetate

1.68 g (3.75 mmol) of ethyl {4 - [(7-hydroxy-l, 4,4-trimethyl-3,4-dihydro-2 (lH) -isoquinolinyl) sulfonyl] -2-methylphenoxy} acetate ( Example 67 A) dissolved in 20 ml of pyridine, and 2.12 g (7.51 mmol) of trifluoromethanesulfonic anhydride were slowly added at 0 ° C. The mixture is allowed to come to room temperature and stirred overnight, 0.42 g (1.52 mmol) of trifluoromethanesulphonic anhydride are added again at 0 ° C. and the mixture is stirred again at room temperature for 2 hours. The reaction mixture is mixed with water and ethyl acetate, the aqueous phase is extracted twice with ethyl acetate, the combined organic phases are washed twice with 1 M hydrochloric acid, dried over sodium sulfate and the solvent is removed in vacuo. 1.90 g (77% of theory) of the desired product are obtained with 89% purity. HPLC (method 1): R, = 5.61 min. MS (ESIpos): 580 (M + H) ⁺ 1H-NMR (300 MHz, CDC1 ₃ ): δ = 1.25-1.33 (m, 9H), 2.33 (s, 3H), 3.12 (d, IH), 3.52 ( d, IH), 4.27 (q, 2H), 4.69 (s, 2H), 5.11 (q, IH), 6.74 (d, IH), 6.91 (d, IH), 7.09 (dd,

IH), 7.35 (d, IH), 7.63-7.70 (m, 2H). Example 74A

Ethyl (2-methyl - {[4-spirocyclobutyl-7 - {[(trifluoromethyl) sulfonyl] oxy} -3,4-dihydro-2 (1 H) -isoquinolinyl] sulfonyl} phenoxy) acetate

Under argon, 0.68 g (1.19 mmol) of ethyl {4 - [(7-hydroxy-4-spirocyclobutyl-3,4-dihydro-2 (1H) -isoquinolinyl) sulfonyl] -2-methylphenoxy} acetate (Example 68A) are added 50 ml of methylene chloride dissolved. 0.27 g (2.62 mmol) of triethylamine are added dropwise and the mixture is cooled to 0.degree. Then 0.37 g (1.31 mmol) of trifluoromethanesulfonic anhydride are added dropwise. Allow to come to room temperature and stir overnight. The mixture is concentrated in vacuo and the residue is purified on silica gel 60 (mobile phase: cyclohexane / ethyl acetate 3: 1). The clean fractions are combined and the solvent is removed in vacuo. 0.49 g (71% of theory) of the desired product with 95% purity is obtained.

LC / MS (Method 3): R _t = 3.18 min.

MS (ESIpos): m / z = 578 (M + H) ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.30 (t, 3H), 2.04-2.21 (m, 6H), 2.36 (s, 3H), 3.31

(s, 2H), 4.18 (s, 2H), 4.27 (q, 2H), 4.71 (s, 2H), 6.80 (d, IH), 6.92 (d, IH), 7.16 (dd, IH), 7.59- 7.71 (m, 3H).

Example 75A

Ethyl (2-methyl - {[4-spirocyclopentyl-7 - {[(trifluoromethyl) sulfonyl] oxy} -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate

7.30 g (15.88 mmol) of ethyl {4 - [(7-hydroxy-4-spirocyclopentyl-3,4-dihydro-2 (lH) -isoquinolinyl) sulfonyl] -2-methylphenoxy} acetate (Example 69A) are added under argon (Example 69A) 70 ml of methylene chloride dissolved. 3.54 g (34.95 mmol) of triethylamine are added dropwise and the mixture is cooled to 0.degree. 4.93 g (17.47 mmol) of trifluoromethanesulfonic anhydride are then added dropwise. Allow to come to room temperature and stir overnight. The mixture is concentrated in vacuo and the residue is purified on silica gel 60 (mobile phase: methylene chloride). The clean fractions are combined and the solvent is removed in vacuo. 4.90 g (52% of theory) of the desired product are obtained with a purity of 92%. HPLC (method 2): R _t = 5.69 min. MS (ESIpos): m / z = 592 (M + H) ⁺

Η NMR (200 MHz, CDC1 ₃ ): δ = 1.30 (t, 3H), 1.72-1.99 (m, 8H), 2.36 (s, 3H), 2.99 (s, 2H), 4.19 (s, 2H), 4.28 (q, 2H), 4.71 (s, 2H), 6.79 (d, IH), 6.91 (d, IH), 7.09 (dd, IH), 7.34 (d, IH), 7.57-7.69 (m, 2H) ,

Example 76A

Ethyl (2-methyl - {[4-spirocyclohexyl-7 - {[(trifluoromethyl) sulfonyl] oxy} -3,4-dihydro-2 (1 H) -isoquinolinyl] sulfonyl} phenoxy) acetate

Under argon, 0.65 g (1.37 mmol) of ethyl {4 - [(7-hydroxy-4-spirocyclohexyl-3,4-dihydro-2 (1H) -isoquinolinyl) sulfonyl] -2-methylphenoxy} acetate (Example 70A) are added 5 ml of methylene chloride dissolved. 0.31 g (0.42 ml; 3.02 mmol) of triethylamine is added dropwise and the mixture is cooled to 0 ° C. Then 0.43 g (1.51 mmol) of trifluoromethanesulfonic anhydride are added dropwise. Allow to come to room temperature and stir overnight. The mixture is concentrated in vacuo and the residue is purified on silica gel 60 (mobile phase: methylene chloride). The clean fractions are combined and the solvent is removed in vacuo. 0.83 g (97% of theory) of the desired product with 97% purity are obtained.

HPLC (method 1): R _t = 5.84 min. MS (ESIpos): m / z - 606 (M + H) ⁺

1H-NMR (300 MHz, CDC1 ₃ ): δ = 1.30 (t, 3H), 1.54-1.88 (m, 10H), 2.36 (s, 3H), 3.25 (s, 2H), 4.19 (s, 2H), 4.27 (q, 2H), 4.71 (s, 2H), 6.80 (d, IH), 6.92 (d, IH), 7.10 (dd, IH), 7.44 (d, IH), 7.62-7.70 (m, 2H) ,

Example 77A

Ethyl (2-methyl-4 - {[4- (2-phenylethyl) -7 - {[(trifluoromethyl) sulfonyl] oxy} -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate

0.66 g (1.30 mmol) of ethyl (4 - {[7-hydroxy-4- (2-phenylethyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate ( Example 71 A) dissolved in 68.46 g (865.46 mmol) pyridine and cooled to 0 ° C. 0.73 g (2.60 mmol) of trifluoromethanesulfonic anhydride are added dropwise and the mixture is then stirred overnight at room temperature. It is cooled again to 0 ° C., a further 0.07 g (0.26 mmol) of trifluoromethanesulfonic anhydride is added dropwise and the mixture is then stirred for a further 30 minutes at room temperature. Since educt is still present, the mixture is cooled again to 0 ° C. and 0.07 g (0.26 mmol) of trifluoromethanesulfonic anhydride is again added. After 30 minutes at 0 ° C, the mixture is warmed to room temperature again for 2 hours. to

Working up is diluted with ethyl acetate and water and the phases are separated. The organic phase is washed once more with 1N hydrochloric acid, dried over sodium sulfate, filtered and freed from the solvent in vacuo. 1.02 g (quant.) Of the desired product with 100% purity is obtained. HPLC (method 1): R _t = 5.87 min.

MS (ESIpos): m / z = 641 (M + H) ⁺

Η NMR (200 MHz, CDC1 ₃ ): δ = 1.30 (t, 3H), 1.82-2.02 (m, IH), 2.04-2.23 (m, IH), 2.34 (s, 3H), 2.55-2.97 (m , 4H), 3.87 (d, 2H), 4.27 (q, 2H), 4.59 (d, IH), 4.70 (s, 2H), 6.71-6.83 (m, IH), 6.90-7.00 (m, IH), 7.02-7.09 (m, IH), 7.15-7.37 (m, 6H), 7.59-7.70 (m, 2H).

EXAMPLES

example 1

Ethyl (4 - {[7-bromo-4-spirocyclohexyl] -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate

To a solution of 390 mg (1.39 mmol) of 7-bromo-4-spirocyclohexyl-l, 2,3,4-tetra-hydroisoquinoline, 310 mg (3.06 mmol) of triethylamine and 17 mg (0.139 mmol) of 4-dimethylaminopyridine in 5 ml A solution of 407 mg (1.39 mmol) of ethyl 4-chlorosulfonyl-2-methylphenoxyacetate in 5 ml of tetrahydrofuran is added to tetrahydrofuran at 0 ° C. and the mixture is stirred at room temperature overnight. Then the mixture is mixed with water and ethyl acetate, the aqueous phase is extracted with ethyl acetate and the combined organic phases are dried over sodium sulfate. After purification via preparative HPLC, one obtains

400 mg (54% of theory) of the desired product. LC / MS (Method 3): R _t = 3.29 min. MS (ESIpos): m / z = 536 (M + H) ⁺ 1H-NMR (300 MHz, CDC1 ₃ ): δ = 1.30 (t, 3H), 1.45-1.88 (m, 10H), 2.37 (s, 3H ), 3.22 (s, 2H), 4.14 (s, 2H), 4.28 (q, 2H), 4.71 (s, 2H), 6.79 (d, IH), 7.14 (d, IH), 7.22 (d,

IH), 7.31 (dd, IH), 7.64 (s, IH), 7.65 (d, IH). Example 2

Ethyl (4 - {[7- (methoxy) -4-methyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate

To a solution of 3.80 g (21.44 mmol) of 7- (methoxy) -4-methyl-l, 2,3,4-tetrahydroisoquinoline in 1 ml of methylene chloride and 65 ml of pyridine, a solution of 3,138 g ( 10.72 mmol) of ethyl 4-chlorosulfonyl-2-methylphenoxyacetate in 65 ml of methylene chloride were added and the mixture was stirred at room temperature overnight. For working up, it is diluted with ethyl acetate and water and the aqueous phase is extracted. The combined organic phases are washed with 1 M hydrochloric acid, dried over sodium sulfate and freed from the solvent in vacuo. After purification by preparative HPLC, 1.8 g (19% of theory) of the desired product are obtained.

HPLC (method 1): R _t = 5.02 min. MS (ESIpos): 434 (M + H) ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.28 (t, 3H), 1.48 (d, 3H), 2.23 (s, 3H), 2.57 (m, 2H), 3.41 (m, IH), 3.60 ( s, 3H), 3.79 (m, IH), 4.25 (q, 2H), 5.08 (q, IH), 6.58 (d, IH), 6.68 (m, 2H), 6.89 (d, IH), 7.55 (s , IH), 7.57 (d, IH). Example 3

Ethyl (4 - {[7- (benzyloxy) -1,4,4-trimethyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate

A solution of 2.14 is added to a solution of 1.63 g (6.10 mmol) 7- (benzyloxy) -l, 4,4-trimethyl-1,2,3,4-tetrahydroisoquinoline in 5 ml methylene chloride and 20 ml pyridine at 0 ° C g (7.32 mmol) of ethyl 4-chlorosulfonyl-2-methylphenoxyacetate in 15 ml of methylene chloride was added and the mixture was stirred at room temperature overnight. For working up, it is diluted with ethyl acetate and water and extracted. The combined organic phases are washed with 1 M hydrochloric acid, dried over sodium sulfate and freed from the solvent in vacuo. After purification by preparative HPLC, 2.06 g (63% of theory) of the desired product are obtained.

HPLC (method 1): R _t = 5.38 min.

MS (ESIpos): 538 (M + H) ⁺

1H-NMR (300 MHz, CDC1 ₃ ): δ = 1.23-1.33 (m, 9H), 2.32 (s, 3H), 3.12 (d, IH), 3.47

(d, IH), 4.27 (q, 2H), 4.70 (s, 2H), 5.01 (s, 2H), 5.06 (q, IH), 6.60 (d, IH), 6.72 (d, IH), 6.84 ( dd, IH), 7.19 (d, IH), 7.32-7.45 (m, 5H), 7.66 (s, IH), 7.67 (m, IH). Example 4

Ethyl (4 - {[7- (benzyloxy) -4-spirocyclobutyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate

0.39 g (3.89 mmol) of triethylamine and a spatula tip of 4-dimethylaminopyridine are added to a solution of 0.60 g (1.77 mmol) of 7- (benzyloxy) -4-spirocyclobutyl-l, 2,3,4-tetrahydroisoquinoline in methylene chloride. The mixture is stirred for 5 minutes at room temperature and then cooled to 0 ° C. 0.57 g (1.94 mmol) of ethyl 4-chlorosulfonyl-2-methylphenoxyacetate are dissolved in methylene chloride and added dropwise. The mixture is allowed to come to room temperature and stirred overnight. For working up, it is diluted with ethyl acetate and water and extracted. The organic phase is dried over sodium sulfate and freed from the solvent in vacuo. 0.90 g (83% of theory) of the desired product are obtained.

HPLC (method 2): R, = 5.44 min.

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.19-1.35 (m, 6H), 1.91-2.40 (m, 6H), 3.28 (s, 2H), 4.13 (d, 2H), 4.27 (q, 2H ), 4.69 (s, 2H), 5.01 (s, 2H), 6.75-6.81 (m, 2H), 7.24-7.49 (m, 7H), 7.64-7.71 (m, 2H). Example 5

Ethyl (4- {[7- (benzyloxy) -4-spirocyclopentyl-3,4,4-dihydro-2 (1 H) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate

To a solution of 5.00 g (17.04 mmol) 7- (benzyloxy) -4-spirocyclopentyl-1,2,3,4-tetrahydroisoquinoline in 50 ml methylene chloride are added 3.79 g (37.49 mmol) triethylamine and 20.8 mg (0.17 mmol) 4- Dimethylaminopyridine added. The mixture is stirred for 5 minutes at room temperature and then cooled to 0 ° C. 5.49 g (18.75 mmol) of 4-chlorosulfonyl-2-methylphenoxyacetic acid ethyl ester are dissolved in 25 ml of methylene chloride and added dropwise. The mixture is allowed to come to room temperature and stirred. For working up, it is diluted with ethyl acetate and water and extracted. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed in vacuo. 8.80 g (94% of theory) of the desired product are obtained. HPLC (method 1): R _t = 5.51 min. MS (ESIpos): m / z = 550 (M + H) ⁺ NMR-NMR (300 MHz, CDC1 ₃ ): δ = 1.52 (s, 3H), 1.74-1.89 (m, 8H), 2.34 (m, 3H ), 4.15 (s, 2H), 4.27 (q, 2H), 4.69 (s, 2H), 5.00 (s, 2H), 6.58 (d, IH), 6.75-6.86 (m, 2H), 7.17

(d, IH), 7.27-7.43 (m, 5H), 7.59-7.67 (m, 2H). Example 6

Ethyl (4 - {[7- (benzyloxy) -4-spirocyclohexyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate

To a solution of 0.70 g (2.28 mmol) 7- (benzyloxy) -4-spirocyclohexyl-l, 2,3,4-tetrahydroisoquinoline in 3 ml methylene chloride, 0.51 g (5.01 mmol) triethylamine and 27.82 mg (0.23 mmol) 4- Dimethylaminopyridine added. The mixture is stirred for 5 minutes at room temperature and then 0.67 g (2.28 mmol) of ethyl 4-chlorosulfonyl-2-methylphenoxyacetate dissolved in 2 ml

Methylene chloride added dropwise. The mixture is left to stir at room temperature overnight. For working up, it is diluted with methylene chloride and water and extracted. The aqueous phase is extracted three times with methylene chloride. The combined organic phases are dried over sodium sulfate and the solvent is removed in vacuo. The residue is over silica gel 60

(Solvent: methylene chloride) cleaned. The clean fractions are combined and the solvent is removed in vacuo. 0.82 g (64% of theory) of the desired product is obtained. HPLC (method 2): R _t = 5.94 min. MS (ESIpos): mz = 564 (M + H) ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.29 (t, 3H), 1.52 (s, 4H), 1.57-1.84 (m, 6H), 2.35 (s, 3H), 3.22 (s, 2H), 4.15 (s, 2H), 4.27 (q, 2H), 4.70 (s, 2H), 5.00 (s, 2H), 6.59 (d, IH), 6.75-6.87 (m, 2H), 7.27-7.42 (m, 6H), 7.63-7.70 (m, 2H). Example 7

Ethyl (2-methyl-4 - {[4-spirocyclopentyl-7-phenyl] -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate

Analogously to the preparation of ethyl (4 - {[7- (benzyloxy) -4-spirocyclopentyl-3,4-dihydro-2 (lH) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate, from 26 mg (0.10 mmol) 7-Phenyl-4-spirocyclopentyl-l, 2,3,4-tetrahydroisoquinoline, 22 mg (0.22 mmol) triethylamine, 1.2 mg (0.01 mmol) 4-dimethylaminopyridine and 28.9 mg (0.10 mmol) 4-chlorosulfonyl-2-methylphenoxyacetic acid ethyl ester in 6 ml

Tetrahydrofuran 41 mg (63% of theory) of the desired product. LC / MS (Method 3): R _t = 3.36 min. MS (ESIpos): m / z = 520 (M + H) ⁺ NMR-NMR (200 MHz, DMSO-d ₆ ): δ = 1.20 (t, 3H), 1.66-1.92 (m, 8H), 2.28 (s , 3H), 2.99 (s, 2H), 4.17 (q, 2H), 4.19 (s, 2H), 4.95 (s, 2H), 7.09 (d, IH), 7.26-7.57 (m,

6H), 7.55-7.75 (m, 4H).

Example 8

Ethyl (2-methyl-4 - {[7- [4-fluorophene] -4-spirocyclopentyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate

Analogously to the preparation of ethyl (4 - {[7- (benzyloxy) -4-spirocyclopentyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate, 46 mg (0.16 mmol) are 7- (4-Fluoφhenyl) -4-spirocyclopentyl-l, 2,3,4-tetrahydroisoquinoline, 33 mg (0.33 mmol) triethylamine, 2.0 mg (0.02 mmol) 4-dimethylaminopyridine and 47.9 mg (0.16 mmol) 4-chlorosulfonyl- 2-methylphenoxyacetic acid ethyl ester in 6 ml of tetrahydrofuran 67 mg (51% of theory) of the desired product. LC / MS (method 3): R, = 3.31 min. MS (ESIpos): mz = 538 (M + H) ⁺ .

Example 9

Ethyl (2-methyl-4 - {[4-spirocyclopentyl-7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate

Analogously to the preparation of ethyl (4 - {[7- (benzyloxy) -4-spirocyclopentyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate, 156 mg (0.46 mmol) are obtained from 7- [4- (Trifluoromethyl) phenyl] -4-spirocyclopentyl-l, 2,3,4-tetrahydroisoquinoline, 101 mg (1.00 mmol) triethylamine, 5.6 mg (0.05 mmol) 4-dimethylaminopyridine and 133.4 mg ( 0.46 mmol) 4-chlorosulfonyl-2-methylphenoxyacetic acid, ethyl ester in 6 ml of tetrahydrofuran 252 mg (81% of theory) of the desired product. HPLC (method 1): R, = 6.10 min. MS (ESIpos): m / z = 588 (M + H) ⁺ 1H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.20 (t, 3H), 1.71-1.92 (m, 8H), 2.29 (s, 3H), 2.97 (d, 2H), 4.12-4.25 (m , 4H), 4.94 (s, 2H), 7.10 (d, IH), 7.45 (d, IH), 7.51-7.54 (m, IH), 7.59 (d, IH), 7.62-7.71 (m, 2H), 7.83 (dd, 4H).

Example 10 Ethyl (2-methyl-4 - {[7-phenyl-4-spirocyclohexyl] -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate

Analogous to the preparation of ethyl (4 - {[7- (benzyloxy) -4-spirocyclopentyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate, 35 mg (0.10 mmol) 7-phenyl-4-spirocyclohexyl-l, 2,3,4-tetrahydroisoquinoline, 22.5 mg (0.22 mmol) triethylamine, 1.2 mg (0.01 mmol) 4-dimethylaminopyridine and 29.6 mg (0.10 mmol) 4-chlorosulfonyl-2-methylphenoxyacetic acid ethyl ester in 6 ml of tetrahydrofuran 69 mg (94% of theory) of the desired product.

LC / MS (Method 3): R _t = 3.45 min. MS (ESIpos): m / z = 534 (M + H) ⁺ .

Example 11

Ethyl (2-methyl-4 - {[7- [4-fluorophene] -4-spirocyclohexyl-3,4-dihydro-2 (1H) - isoquinolinyl] sulfonyl} phenoxy) acetate

Analogously to the preparation of ethyl (4 - {[7- (benzyloxy) -4-spirocyclopentyl-3,4-dihydro-2 (lH) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate, 70 mg (0.24 mmol) 7- (4-Fluoφhenyl) -4-spirocyclohexyl-l, 2,3,4-tetrahydroisoquinoline, 52.8 mg (0.52 mmol) triethylamine, 2.9 mg (0.02 mmol) 4-dimethylaminopyridine and 69.4 mg (0.24 mmol) 4-chlorosulfonyl- 2-methylphenoxyacetic acid ethyl ester in 6 ml

Tetrahydrofüran 110 mg (72%. Th.) Of the desired product. HPLC (method 1): R _t = 6.20 min. MS (ESIpos): mz = 552 (M + H) ⁺ 1H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.30 (t, 3H), 1.44-1.84 (m, 10H), 2.30 (s, 3H ), 3.21 (s, 2H), 4.12-4.26 (m, 4H), 4.95 (s, 2H), 7.06-7.16 (m, IH), 7.20-7.33 (m, 2H),

7.38-7.58 (m, 3H), 7.61-7.75 (m, 4H).

Example 12

Ethyl (4 - {[4-spirocyclohexyl-7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1H) - isoquinolinyl] sulfonyl} phenoxy) acetate

Analogous to the preparation of ethyl (4 - {[7- (benzyloxy) -4-spirocyclopentyl-3,4-dihydro-2 (lH) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate, 40 mg (0.12 mmol) 7- [4- (Trifluoromethyl) phenyl] -4-spirocyclohexyl-l, 2,3,4-tetrahydroisoquinoline, 25.8 mg (0.25 mmol) triethylamine, 1.4 mg (0.01 mmol) 4-dimethylaminopyridine and 32.3 mg ( 0.12 mmol) of 4-chlorosulfonylphenoxyacetic acid ethyl ester in 6 ml of tetrahydrofuran 75 mg (99% of theory) of the desired product. HPLC (method 2): R, = 6.02 min. MS (ESIpos): mz = 588 (M + H) ⁺ Η-NMR (200 MHz, DMSO-d ₆ ): δ = 1.21 (t, 3H), 1.37-1.86 (m, 10H), 3.22 (s, 2H )

4.09-4.26 (m, 4H), 4.94 (s, 2H), 7.19 (d, 2H), 7.57 (d, 2H), 7.75-7.95 (m, 5H), 8.09 (d, 2H).

Example 13

Ethyl (2-methyl-4 - {[4-spirocyclohexyl-7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate

Analogous to the preparation of ethyl (4 - {[7- (benzyloxy) -4-spirocyclopentyl-3,4-dihydro-2 (lH) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate, 40 mg (0.12 mmol) 7- [4- (Trifluoromethyl) phenyl] -4-spirocyclohexyl-l, 2,3,4-tetrahydroisoquinoline, 25.8 mg (0.25 mmol) triethylamine, 1.4 mg (0.01 mmol) 4-dimethylaminopyridine and 33.9 mg ( 0.12 mmol) 4-chlorosulfonyl-2-methylphenoxyacetic acid, ethyl ester in 6 ml of tetrahydrofuran 68 mg (98% of theory) of the desired product. HPLC (method 1): R, = 6.21 min. MS (ESIpos): m / z = 602 (M + H) ⁺

1H-NMR (200 MHz, DMSO-d ₆ ): δ = 1.21 (t, 3H), 1.44-1.83 (m, 10H), 2.94 (s, 3H), 3.22 (s, 2H), 4.08-4.25 (m , 4H), 4.96 (s, 2H), 6.58 (d, IH), 7.11 (d, IH), 7.49-7.62 (m, 2H), 7.65-7.95 (m, 5H), 8.03-8.14 (m, IH ).

Example 14

Ethyl (3-methyl-4 - {[4-spirocyclohexyl-7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1 H) -isoquinolinyl] sulfonyl} phenoxy) acetate

Analogously to the preparation of ethyl (4 - {[7- (benzyloxy) -4-spirocyclopentyl-3,4-dihydro-2 (lH) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate, 65 mg (0.19 mmol) 7- [4- (Trifluoromethyl) phenyl] -4-spirocyclohexyl-1, 2,3,4-tetrahydroisoquinoline, 41.9 mg (0.41 mmol) triethylamine, 2.3 mg (0.02 mmol) 4-dimethylaminopyridine and 55.1 mg (0.19 mmol ) 4-Chlorosulfonyl-3-methylphenoxyacetate in 6 ml of tetrahydrofuran 26 mg (23% of theory) of the desired product. HPLC (method 1): R, - 6.27 min. MS (ESIpos): m / z = 602 (M + H) ⁺

1H-NMR (200 MHz, DMSO-d ₆ ): δ = 1.21 (t, 3H), 1.44-1.83 (m, 10H), 2.56 (s, 3H), 3.40 (s, 2H), 4.18 (q, 2H ), 4.37 (s, 2H), 4.92 (s, 2H), 7.04 (m, 2H), 7.60 (m, 3H), 7.75-7.93 (m, 5H).

Example 15

Ethyl (2,5-dimethyl-4 - {[4-spirocyclohexyl-7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1 H) -isoquinolinyl] sulfonyl} phenoxy) acetate

Analogous to the preparation of ethyl (4 - {[7- (benzyloxy) -4-spirocyclopentyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate from 65 mg

(0.19 mmol) 7- [4- (trifluoromethyl) phenyl] -4-spirocyclohexyl-l, 2,3,4-tetrahydroisoquinoline, 41.9 mg (0.41 mmol) triethylamine, 2.3 mg (0.02 mmol) 4-dimethylaminopyridine and 57.7 mg (0.19 mmol) of 4-chlorosulfonyl-2,6-dimethylphenoxyacetic acid ethyl ester in 6 ml of tetrahydrofuran 27 mg (23% of theory) of the desired product. HPLC (method 1): R _t = 6.55 min.

MS (ESIpos): mz = 616 (M + H) ⁺

Η NMR (200 MHz, DMSO-d ₆ ): δ = 1.20 (t, 3H), 1.25-1.83 (m, 10H), 2.25 (s, 3H),

2.54 (s, 3H), 3.37 (s, 2H), 4.18 (q, 2H), 4.34 (s, 2H), 4.93 (s, 2H), 6.96 (s, IH), 7.60

(s, 3H), 7.72-7.95 (m, 5H).

Example 16

Ethyl (2,3-dimethyl-4 - {[4-spirocyclohexyl-7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate

Analogous to the preparation of ethyl (4 - {[7- (benzyloxy) -4-spirocyclopentyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetate, 64 mg (0.19 mmol) 7- [4- (Trifluoromethyl) phenyl] -4-spirocyclohexyl-l, 2,3,4-tetrahydro-isoquinoline, 41.3 mg (0.41 mmol) triethylamine, 2.3 mg (0.02 mmol) 4-dimethylaminopyridine and 56.8 mg ( 0.19 mmol) of 4-chlorosulfonyl-2,3-dimethylphenoxyacetic acid ethyl ester in 6 ml of tetrahydrofuran 29 mg (25% of theory) of the desired product. HPLC (method 1): R _t = 6.53 min. MS (ESIpos): m / z = 616 (M + H) ⁺

Η NMR (200 MHz, DMSO-d ₆ ): δ = 1.22 (t, 3H), 1.35-1.83 (m, 10H), 2.19 (s, 3H), 2.52 (s, 3H), 3.42 (s, 2H) ), 4.18 (q, 2H), 4.38 (s, 2H), 4.94 (s, 2H), 6.98 (d, IH), 7.49 (s, 3H), 7.74-7.94 (m, 5H). Example 17

Ethyl (4- {[7-methoxy-4- (2-phenylethyl) -3,4-dihydro-2 (1 H) -isoquinolinyl] sulfonyl} ■ 2-methylphenoxy) acetate

1.60 g (3.89 mmol) of 7-methoxy-4- (2-phenylethyl) -1,2,3,4-tetrahydroisoquinoline are dissolved in 16 ml of dichloromethane and 23.47 g (24.0 ml; 296.73 mmol) of pyridine and supplied to 0 ° with the addition of argon C cooled. 2.27 g (7.78 mmol) of ethyl 4-chlorosulfonyl-2-methylphenoxyacetate are dissolved in 8 ml of dichloromethane and the solution is added dropwise. The mixture is allowed to slowly come to room temperature and is stirred overnight. For working up, the mixture is diluted with ethyl acetate and water and the phases are separated. The organic phase is washed twice more with 1N hydrochloric acid, dried over sodium sulfate, filtered and freed from the solvent in vacuo. The residue is purified by preparative HPLC in 2 shots. The clean fractions are combined and the solvent is removed in vacuo. 1.78 g (87% of theory) of the desired product are obtained. HPLC (method 1): R _t = 5.50 min. MS (ESIpos): mz = 524 (M + H) ⁺

1H-NMR (200 MHz, CDC1 ₃ ): δ = 1.29 (t, 3H), 1.56 (s, 2H), 2.33 (s, 3H), 2.60-2.94 (m, 4H), 3.75 (s, 3H), 3.87 (d, 2H), 4.27 (q, 2H), 4.52 (d, IH), 4.69 (s, 2H), 6.51-6.59 (m, IH), 6.67-6.81 (m, 2H), 7.00 (d, IH), 7.16-7.35 (m, 5H), 7.62-7.71 (m, 2H) Example 18

Ethyl (2-methyl-4 - {[4-methyl-7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1H) - isoquinolinyl] sulfonyl} phenoxy) acetate

A suspension of 200 mg (0.363 mmol) of ethyl- (2-methyl - {[7 - {[(trifluoromethyl) - sulfonyl] oxy} -4-methyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate, 86.1 mg (0.453 mmol) 4- (trifluoromethyl) phenylboronic acid, 564 mg (1.813 mmol)

Potassium phosphate trihydrate and 8.4 mg (0.007 mmol) tetrakis (triphenylphosphine) - palladium in 2 ml of toluene is heated under reflux under argon for 2 hours. After cooling to room temperature, stirring is continued for 2 days. Then ethyl acetate and water are added, the aqueous phase is extracted twice with ethyl acetate, the combined organic phases are dried over sodium sulfate and concentrated. To

Purification by HPLC gives 92 mg (46%> d. Th.) Of the desired product. HPLC (method 1): R, - 5.37 min. MS (ESIpos): 548 (M + H) ⁺ Η-NMR (300 MHz, CDC1 ₃ ): δ = 1.26 (t, 3H), 1.52 (d, 3H), 2.23 (s, 3H), 2.62-2.85 ( m, 2H), 3.45 (ddd, IH), 3.89 (dddd, IH), 4.25 (q, 2H), 4.64 (s, 2H), 5.20 (q, IH),

6.66 (d, IH), 7.09 (d, IH), 7.27 (dd, IH), 7.35 (dd, IH), 78.57 (m, 2H), 7.62 (d, 2H), 7.68 (s, IH), 7.70 (d, IH). Example 19

Ethyl (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoro-phenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate

A suspension of 220 mg (0.380 mmol) of ethyl- (2-methyl - {[7 - {[(trifluoromethyl) - sulfonyljoxy} - 1,4,4-trimethyl-3,4,4-dihydro-2 (1 H) -isoquinolinyl ] sulfonyl} phenoxy) - acetate, 66.4 mg (0.474 mmol) 4-fluoφhenylboronic acid, 590 mg (1.898 mmol) potassium phosphate trihydrate and 8.8 mg (0.008 mmol) tetrakis (triphenylphosphine) - palladium in 5 ml toluene is under argon for 2 hours Reflux heated. To

Cooling, a further 13.2 mg (0.094 mmol) of 4-fluoro-phenylboronic acid and 1.8 mg (0.0016 mmol) of tetrakis (triphenylphosphine) palladium are added and the mixture is refluxed for 3 hours. After cooling to room temperature, ethyl acetate and water are added, the aqueous phase is extracted twice with ethyl acetate, and the combined organic phases are dried over sodium sulfate and concentrated. To

Purification by HPLC gives 114 mg (57% of theory) of the desired product. HPLC (method 1): R, = 5.65 min. MS (ESIpos): 526 (M + H) ⁺ 1H-NMR (300 MHz, CDC1 ₃ ): δ = 1.23-1.37 (m, 12H), 2.33 (s, 3H), 3.18 (d, IH), 3.54 ( d, IH), 4.27 (q, 2H), 4.69 (s, 2H), 5.16 (q, IH), 6.75 (d, IH), 7.08-7.16 (m,

3H), 7.35 (d, IH), 7.35 (s, IH), 7.46-7.51 (m, 2H), 7.68-7.71 (m, 2H). Example 20

Ethyl (2-methyl-4- {[1,4,4-trimethyl-7- (4-methoxyphenyl) -3,4-dihydro-2 (1 H) -isoquinolinyl] sulfonyl} phenoxy) acetate

Analogous to the preparation of ethyl (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoro-phenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate from 220 mg (0.380 mmol) of ethyl- (2-methyl- {[7- {[(trifluoromethyl) sulfonyl] oxy} - 1,4,4-trimethyl-3,4,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl } phenoxy) acetate, 86.5 mg (0.514 mmol) 4-methoxyphenylboronic acid, 590 mg (1.898 mmol) potassium phosphate trihydrate and

10.68 mg (0.00816 mmol) of tetrakis (triphenylphosphine) palladium in 5 ml of toluene after purification by HPLC 149 mg (73% of theory) of the desired product. HPLC (method 1): R _t = 5.58 min. MS (ESIpos): 538 (M + H) ⁺ Η-NMR (300 MHz, CDC1 ₃ ): δ = 1.23-1.37 (m, 12H), 2.32 (s, 3H), 3.18 (d, IH),

3.53 (d, IH), 3.85 (s, 3H), 4.27 (q, 2H), 4.69 (s, 2H), 5.16 (q, IH), 6.74 (d, IH), 6.95 (d, 2H), 7.17 (d, IH), 7.30-7.39 (m, 2H), 7.47 (d, 2H), 7.69 (m, 2H).

Example 21 Ethyl (2-methyl-4 - {[1,4,4-trimethyl-7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate

Analogous to the preparation of ethyl (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -

3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate are made from 220 mg (0.380 mmol) of ethyl (2-methyl- {[7- {[(trifluoromethyl) sulfonyl] oxy} - 1, 4 , 4-trimethyl-3, 4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate, 108.1 mg (0.514 mmol) 4-

(Trifluoromethyl) phenylboronic acid, 590 mg (1,898 mmol) potassium phosphate trihydrate and 10.6 mg (0.00816 mmol) tetrakis (triphenylphosphine) palladium in 5 ml toluene after purification via HPLC 171 mg (78% of theory) of the desired product.

HPLC (method 1): R _t = 5.61 min.

MS (ESIpos): 576 (M + H) ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.23-1.38 (m, 12H), 2.33 (s, 3H), 3.18 (d, IH),

3.56 (d, IH), 4.27 (q, 2H), 4.69 (s, 2H), 5.18 (q, IH), 6.75 (d, IH), 7.22 (d, IH), 7.37-

7.44 (m, 2H), 7.61-7.71 (m, 6H).

Example 22

Ethyl (2-methyl-4 - {[4-spirocyclobutyl-7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate

To 0.10 g (0.17 mmol) of ethyl- (2-methyl - {[4-spirocyclobutyl-7- {[(trifluoromethyl) - sulfonyl] oxy} -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -phenoxy ) acetate in 5 ml of toluene, 41.0 mg (0.22 mmol) of 4-trifluoromethylphenylboronic acid and 23.0 mg (0.17 mmol) of potassium carbonate are added. The mixture is flooded with argon for 15 minutes and then a spatula tip of tetrakis (triphenylphosphine) - palladium (O) is added. It is refluxed overnight. It is cooled and the mixture is freed from the solvent in vacuo. It is purified on silica gel 60 (mobile phase: cyclohexane / ethyl acetate 5: 1). The clean fractions are combined and the solvent is removed in vacuo. 30 mg (30% of theory) of the desired product are obtained.

HPLC (method 1): R, = 5.97 min.

MS (ESIpos): m / z = 574 (M + H) ⁺

Η NMR (200 MHz, CDC1 ₃ ): δ = 1.30 (t, 3H), 1.99-2.44 (m, 6H), 2.37 (s, 3H), 3.35

(s, 2H), 4.22 (s, 2H), 4.26 (q, 2H), 4.71 (s, 2H), 6.80 (d, 2H), 7.22 (m, 2H), 7.50 (dd, IH), 7.60- 7.76 (m, 6H).

Example 23

Ethyl (2-methyl-4 - {[4-spirocyclobutyl-7- [4- (trifluoromethoxy) phenyl] -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate

To 0.10 g (0.17 mmol) of ethyl- (2-methyl - {[4-spirocyclobutyl-7 - {[(trifluoromethyl) - sulfonyl] oxy} -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -phenoxy ) acetate in 5 ml of toluene, 71.3 mg (0.35 mmol) of 4-trifluoromethoxyphenylboronic acid and 35.9 mg (0.26 mmol) of potassium carbonate are added. The mixture is flooded with argon for 15 minutes and then 10 mg (0.01 mmol) of tetrakis (triphenylphosphine) are added. palladium (O). It is boiled under reflux for 2 days. It is cooled and the mixture is freed from the solvent in vacuo. It is purified on silica gel 60 (mobile phase: cyclohexane / ethyl acetate 5: 1). The clean fractions are combined and the solvent is removed in vacuo. 37 mg (36% of theory) of the desired product are obtained.

HPLC (method 1): R _t = 6.17 min. MS (ESIpos): m / z - 590 (M + H) ⁺

1H-NMR (300 MHz, CDC1 ₃ ): δ = 1.29 (t, 3H), 2.04-2.27 (m, 4H), 2.30-2.47 (m, 2H), 2.36 (s, 3H), 3.35 (s, 2H) ), 4.21-4.32 (m, 4H), 4.70 (s, 2H), 6.79 (d, IH), 7.17 (d, IH), 7.26-7.29 (m, 2H), 7.45 (dd, IH) 7.53 (d , 2H) 7.64 (d, IH), 7.67 (s, IH), 7.69 (m,

IH).

Example 24

Ethyl (2-methyl-4 - {[7- [3-fluorophene] -4-spirocyclopentyl-3,4-dihydro-2 (1H) - isoquinolinyl] sulfonyl} phenoxy) acetate

To 0.15 g (0.25 mmol) of ethyl- (2-methyl - {[4-spirocyclopentyl-7 - {[(trifluoromethyl) - sulfonyl] oxy} -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -phenoxy ) acetate in 5 ml of toluene, 70.95 mg (0.51 mmol) of 3-fluoφhenylboronic acid and 52.56 mg (0.38 mmol) of potassium carbonate are added. The mixture is flooded with argon for 15 minutes and then 13.4 mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium (O) are added. It is refluxed overnight. It is cooled and the mixture is freed from the solvent in vacuo. It is purified on silica gel 60 (mobile phase: cyclohexane / ethyl acetate 5: 1). The clean fractions will be combined and freed from solvent in vacuo. 121 mg (89% of theory) of the desired product are obtained. HPLC (method 1): R, = 5.89 min. MS (ESIpos): m / z = 538 (M + H) ⁺ NMR-NMR (200 MHz, CDC1 ₃ ): δ = 1.30 (t, 3H), 1.75-2.02 (m, 8H), 2.36 (s, 3H ), 3.03

(s, 2H), 4.20-4.37 (m, 4H), 4.71 (s, 2H), 6.75-6.85 (m, IH), 6.94-7.09 (m, IH), 7.15- 7.22 (m, 2H), 7.30 -7.48 (m, 4H) 7.61-7.74 (m, 2H).

Example 25

Ethyl 1- (2-methyl-4- {[7- [4-methoxypheny 1] -4-spirocyclopentyl-3,4, dihydro-2 (1 H) -isoquinolinyl] sulfonyl} phenoxy) acetate

To 0.15 g (0.25 mmol) of ethyl- (2-methyl - {[4-spirocyclopentyl-7 - {[(trifluoromethyl) - sulfonyl] oxy} -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -phenoxy ) acetate in 5 ml

Toluene is given 77.05 mg (0.51 mmol) of 4-methoxyphenylboronic acid and 52.56 mg (0.38 mmol) of potassium carbonate. The mixture is flooded with argon for 15 minutes and then 13.4 mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium (O) are added. It is refluxed overnight. It is cooled and the mixture is freed from the solvent in vacuo. It is about

Silica gel 60 (mobile phase: cyclohexane / ethyl acetate 5: 1) cleaned. The clean fractions are combined and the solvent is removed in vacuo. 84 mg (60% of theory) of the desired product are obtained. HPLC (method 1): R, = 5.81 min. MS (ESIpos): m / z = 550 (M + H) ⁺ Η NMR (200 MHz, CDC1 ₃ ): δ = 1.29 (t, 3H), 1.73-2.00 (m, 8H), 2.36 (s, 3H), 3.02 (s, 2H), 3.84 (s, 3H), 4.18-4.37 (m, 4H), 4.71 (s, 2H), 6.72-6.84 (m, IH), 6.90-7.00 (m, 2H), 7.17 (s, IH), 7.27-7.51 (m, 4H), 7.62-7.74 (m, 2H).

Example 26

Ethyl (2-methyl-4- {[7- [3-methoxyphenyl] -4-spirocyclopentyl-3,4,4-dihydro-2 (1 H) -isoquinolinyl] sulfonyl} phenoxy) acetate

To 0.15 g (0.25 mmol) of ethyl- (2-methyl - {[4-spirocyclopentyl-7 - {[(trifluoromethyl) - sulfonyl] oxy} -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -phenoxy ) acetate in 5 ml of toluene, 77.05 mg (0.51 mmol) of 3-methoxyphenylboronic acid and 52.56 mg (0.38 mmol) of potassium carbonate are added. The mixture is flooded with argon for 15 minutes and then 13.4 mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium (O) are added. It is refluxed overnight. It is cooled and the mixture is freed from the solvent in vacuo. It is purified on silica gel 60 (mobile phase: cyclohexane / ethyl acetate 5: 1). The clean fractions are combined and the solvent is removed in vacuo. 98 mg (70% of theory) of the desired product are obtained. HPLC (method 1): R _t = 5.91 min.

MS (ESIpos): m / z = 550 (M + H) ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.29 (t, 3H), 1.79-1.96 (m, 8H), 2.36 (s, 3H), 3.04 (s, 2H), 3.85 (s, 3H), 4.22-4.31 (m, 4H), 4.70 (s, 2H), 6.76-6.82 (m, IH), 6.87 (dd, IH), 7.02-7.07 (m, IH), 7.08-7.13 (m, IH), 7.18-7.22 (m, IH), 7.28-7.36 (m, 2H), 7.38-7.44 (m, IH), 7.62-7.70 (m, 2H). Example 27

Ethyl (2-methyl-4 - {[4-spirocyclopentyl-7- [3- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate

To 0.15 g (0.25 mmol) of ethyl- (2-methyl - {[4-spirocyclopentyl-7 - {[(trifluoromethyl) - sulfonyl] oxy} -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -phenoxy ) acetate in 5 ml of toluene, 96.31 mg (0.51 mmol) of 3-trifluoromethylphenylboronic acid and 52.56 mg (0.38 mmol) of potassium carbonate are added. The mixture is flooded with argon for 15 minutes and then 13.4 mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium (O) are added. It is boiled under reflux for 6 hours. It is cooled and the mixture is freed from the solvent in vacuo. The desired product is obtained in a mixture with the starting material, and cleaning takes place at the carboxylic acid stage (see Example 44). LC / MS (method 3): R, = 3.40 min.

MS (ESIpos): mz = 588 (M + H) ⁺ .

Example 28

Ethyl (2-methyl-4 - {[7- [4-methylphenyl] -4-spirocyclopentyl-3,4-dihydro-2 (1H) - isoquinolinyl] sulfonyl} phenoxy) acetate

To 0.15 g (0.25 mmol) of ethyl- (2-methyl - {[4-spirocyclopentyl-7 - {[(trifluoromethyl) - sulfonyl] oxy} -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -phenoxy ) acetate in 5 ml of toluene, 68.94 mg (0.51 mmol) of 4-methylphenylboronic acid and 52.56 mg (0.38 mmol) of potassium carbonate are added. The mixture is flooded with argon for 15 minutes and then 13.4 mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium (O) are added. It is refluxed overnight. It is cooled and the mixture is freed from the solvent in vacuo. It is purified on silica gel 60 (mobile phase: cyclohexane / ethyl acetate 5: 1). The clean fractions are combined and the solvent is removed in vacuo. You get

116 mg (86% of theory) of the desired product. HPLC (method 1): R _t = 6.22 min. MS (ESIpos): m / z = 534 (M + H) ⁺ NMR-NMR (300 MHz, CDC1 ₃ ): δ = 1.29 (t, 3H), 1.79-1.97 (m, 8H), 2.36 (d, 6H ), 3.03 (s, 2H), 4.22-4.32 (m, 4H), 4.70 (s, 2H), 6.79 (d, IH), 7.17-7.21 (m, 2H), 7.23 (s,

2H), 7.31 (d, IH), 7.39-7.60 (m, 2H), 7.63-7.66 (m, 2H).

Example 29

Ethyl (2-methyl-4- {[7- [3-methylphenyl] -4-spirocyclopentyl-3,4,4-dihydro-2 (1 H) -isoquinolinyl] sulfonyl} phenoxy) acetate

To 0.15 g (0.25 mmol) of ethyl- (2-methyl - {[4-spirocyclopentyl-7 - {[(trifluoromethyl) - sulfonyl] oxy} -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -phenoxy ) acetate in 5 ml of toluene, 68.94 mg (0.51 mmol) of 3-methylphenylboronic acid and 52.56 mg

(0.38 mmol) potassium carbonate. The batch is run for 15 minutes with argon flooded and then 13.4 mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium (O) are added. It is refluxed overnight. It is cooled and the mixture is freed from the solvent in vacuo. It is purified on silica gel 60 (mobile phase: cyclohexane / ethyl acetate 5: 1). The clean fractions are combined and the solvent is removed in vacuo. You get

126 mg (93% of theory) of the desired product. HPLC (method 1): R, = 6.10 min. MS (ESIpos): m / z = 534 (M + H) ⁺

1H-NMR (200 MHz, CDC1 ₃ ): δ = 1.29 (t, 3H), 1.80-1.97 (m, 8H), 2.38 (d, 6H), 3.03 (s, 2H), 4.20-4.33 (m, 4H ), 4.71 (s, 2H), 6.79 (d, IH), 7.11-7.18 (m, IH), 7.18-7.22

(m, IH), 7.29-7.36 (m, 4H), 7.38-7.46 (m, IH), 7.62-7.71 (m, 2H).

Example 30

Ethyl (2-methyl-4 - {[4-spirocyclopentyl-7- [4- (trifluoromethoxy) phenyl] -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate

To 0.15 g (0.25 mmol) of ethyl- (2-methyl - {[4-spirocyclopentyl-7 - {[(trifluoromethyl) - sulfonyl] oxy} -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -phenoxy ) acetate in 5 ml of toluene, 104.4 mg (0.51 mmol) of 4-trifluoromethoxyphenylboronic acid and 52.6 mg (0.38 mmol) of potassium carbonate are added. The mixture is flooded with argon for 15 minutes and then 13.4 mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium (O) are added. It is refluxed overnight. It is cooled and the mixture is freed from the solvent in vacuo. It is purified on silica gel 60 (mobile phase: cyclohexane / ethyl acetate 5: 1). The clean ones Fractions are combined and the solvent is removed in vacuo. You get

133 mg (87% of theory) of the desired product.

HPLC (method 1): R, = 6.30 min.

MS (ESIpos): mz = 604 (M + H) ⁺

1H-NMR (300 MHz, CDC1 ₃ ): δ = 1.29 (t, 3H), 1.56-1.80 (m, 8H), 2.36 (s, 3H), 3.04

(s, 2H), 4.26 (s, 2H), 4.28 (q, 2H), 4.69 (s, 2H), 6.79 (d, IH), 7.18 (d, IH), 7.24 (d,

2H), 7.33 (d, IH), 7.39 (dd, IH), 7.52 (d, 2H), 7.55 (s, IH), 7.57 (d, IH).

Example 31

Ethyl (2-methyl-4 - {[4-spirocyclopentyl-7- [3- (trifluoromethoxy) phenyl] -3,4-dihydro-2 (1 H) -isoquinolinyl] sulfonyl} phenoxy) acetate

To 0.15 g (0.25 mmol) of ethyl- (2-methyl - {[4-spirocyclopentyl-7 - {[(trifluoromethyl) - sulfonyl] oxy} -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -phenoxy ) acetate in 5 ml

104.42 mg (0.51 mmol) of 3-trifluoromethoxyphenylboronic acid and 52.56 mg (0.38 mmol) of potassium carbonate are added to toluene. The mixture is flooded with argon for 15 minutes and then 13.4 mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium (O) are added. It is refluxed overnight. It is cooled and the mixture is freed from the solvent in vacuo. It is purified on silica gel 60 (mobile phase: cyclohexane / ethyl acetate 5: 1). The clean fractions are combined and the solvent is removed in vacuo. 143 mg (93% of theory) of the desired product are obtained. HPLC (method 1): R, = 6.27 min. MS (ESIpos): m / z = 604 (M + H) ⁺ Η NMR (300 MHz, CDC1 ₃ ): δ = 1.29 (t, 3H), 1.80-1.88 (m, 8H), 2.36 (s, 3H), 3.04 (s, 2H), 4.21-4.32 (m, 4H ), 4.70 (s, 2H), 6.79 (d, IH), 7.14-7.20 (m, 2H), 7.31-7.46 (m, 5H), 7.63-7.69 (m, 2H).

Example 32

Ethyl (2-methyl-4 - {[4- (2-phenylethyl) -7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1 H) -isoquinolinyl] sulfonyl} phenoxy) acetate

0.209 g (0.33 mmol) of ethyl- (2-methyl-4 - {[4- (2-phenylethyl) -7- {[(trifluoromethyl) sulfonyl] oxy} -3, 4-dihydro-2 (1 H ) -isoquinolinyl] - sulfonyl} phenoxy) acetate and 77.3 mg (0.41 mmol) 4-trifluoromethylphenylboronic acid dissolved in 1.74 ml dioxane. The flask is evacuated three times and each filled with argon. 7.53 mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium (O) and 506.8 mg (1.63 mmol) of potassium phosphate trihydrate are added. The evacuation process is repeated two more times. The mixture is heated to reflux for 2 hours and the mixture is left to stand overnight. For working up, the phosphate is decanted off and the supernatant is concentrated in vacuo. The residue is dissolved in dichloromethane and it is purified on silica gel 60 (mobile phase: dichloromethane). The clean fractions are combined and in vacuo freed from the solvent. 159 mg (76% of theory) of the desired product are obtained.

HPLC (method 1): R, = 6.43 min. MS (ESIpos): mz = 638 (M + H) ⁺ NMR-NMR (300 MHz, CDC1 ₃ ): δ = 1.29 (t, 3H), 2.04 (s, IH), 2.08-2.22 (m, IH), 2:34

(s, 3H), 2.65-2.79 (m, IH), 2.81-2.95 (m, 3H), 3.81-3.89 (m, IH), 3.98 (d, IH), 4.27 (q, 2H), 4.61 (s , IH), 4.64-4.71 (s, 2H), 6.77 (d, 2H), 7.17-7.34 (m, 6H), 7.35-7.41 (m, IH), 7.57-7.72 (m, 6H).

Example 33 (2-Methyl-4 - {[4-methyl-7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1H) - isoquinolinyl] sulfonyl} phenoxy) acetic acid

A solution of 75.0 mg (0.137 mmol) of ethyl- (2-methyl-4 - {[4-methyl-7- (4-fluorophenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy ) Acetate in 1 ml of ethanol is mixed with 1 ml (2.0 mmol) of 2 M sodium hydroxide solution and stirred overnight at room temperature. The mixture is then concentrated in vacuo, acidified with 1N hydrochloric acid and stirred overnight. The resulting precipitate is filtered off and dried in vacuo. 58 mg (79% of theory) of the desired product are obtained as a colorless solid. HPLC (method 1): R, = 5.22 min. MS (ESIpos): 520 (M + H) ⁺ 1H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.42 (d, 3H), 2.12 (s, 3H), 2.60-2.78 (m, 2H), 3.43 (ddd, IH), 3.79 (ddd, IH), 4.75 (s, 2H), 5.16 (q, IH), 6.92 (d, IH), 7.13 (d, IH), 7.46 (dd, IH), 7.59 (d, 3H), 7.79 (d, IH), 7.80 (s, IH), 7.86 (s, IH), 7.88 (d, IH), 13.08 (broad, s, IH) , Example 34

(2-Methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid

A solution of 80.0 mg (0.152 mmol) of ethyl- (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoro-phenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl } phenoxy) acetate in 2 ml

Ethanol is mixed with 1 ml (2.0 mmol) of 2 M sodium hydroxide solution and stirred overnight at room temperature. The mixture is then concentrated in vacuo, acidified with 1N hydrochloric acid and stirred for 1 hour. The resulting precipitate is filtered off and dried in vacuo. 60 mg (79% of theory) of the desired product are obtained as a colorless solid.

HPLC (method 1): R _t = 5.17 min. MS (ESIpos): 498 (M + H) ⁺

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.14 (s, 3H), 1.19 (d, 3H), 1.31 (s, 3H), 2.28 (s, 3H), 3.13 (d, IH), 3.57 (d, IH), 4.82 (s, 2H), 5.09 (q, IH), 7.02 (d, IH), 7.27 (t, 2H), 7.43 (d, 2H), 7.45 (s, IH), 7.65 -7.72 (m, 4H), 13.20 (broad, s, IH). Example 35

(2-Methyl 1-4- {[1,4,4-trimethyl-7- (4-methoxyphenyl) -3,4-dihydro-2 (1 H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogously to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid from 121.0 mg (0.225 mmol) ethyl (2-methyl-4 - {[1,4-trimethyl-7- (4-methoxyphenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate and 1 ml (2.0 mmol) of 2 M sodium hydroxide solution in 2 ml of ethanol 103 mg (90% of theory) of the desired product.

HPLC (method 1): R _t = 5.10 min. MS (ESIpos): 510 (M + H) ⁺ 1H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.13 (s, 3H), 1.19 (d, 3H), 1.30 (s, 3H), 2.26 ( s, 3H), 3.13 (d, IH), 3.56 (d, IH), 4.82 (s, 2H), 5.08 (q, IH), 7.00 (d, 2H), 7.02 (d, IH),

7.38 (s, IH), 7.42 (s, 2H), 7.58 (d, 2H), 7.63-7.70 (m, 2H), 13.21 (broad, s, IH).

Example 36

(2-Methyl-4 - {[1,4,4-trimethyl-7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1H) - isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogously to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid from 141.0 mg

(0.245 mmol) ethyl- (2-methyl-4 - {[1,4-trimethyl-7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy ) acetate and 1.5 ml (3.0 mmol) 2 M

Sodium hydroxide solution in 2 ml of ethanol 126 mg (94% of theory) of the desired product.

HPLC (method 1): R, = 5.38 min.

MS (ESIpos): 548 (M + H) ⁺

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.15 (s, 3H), 1.20 (d, 3H), 1.32 (s, 3H), 2.26 (s,

3H), 3.15 (d, IH), 3.58 (d, IH), 4.79 (s, 2H), 5.12 (q, IH), 7.01 (d, IH), 7.49 (d, IH),

7.55 (s, 2H), 7.67 (d, IH), 7.69 (s, IH), 7.79 (d, 2H), 7.89 (d, 2H), 13.28 (broad, s,

IH).

Example 37 (2-Methyl-4- {[4-spirocyclobutyl-7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1 H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogously to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid from 30.0 mg (0.052 mmol) ethyl (2-methyl-4 - {[4-spirocyclobutyl-7- [4- (trifluoromethyl) phenyl] - 3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate and 0.12 ml (0.12 mmol) 1 M sodium hydroxide solution in 8 ml ethanol after purification over silica gel (cyclohexane ethyl acetate 1: 1) 10 mg (35% of theory) of the desired product.

HPLC (method 1): R _t = 5.40 min. MS (ESIpos): 548 (M + H) ⁺

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.15 (s, 3H), 1.20 (d, 3H), 1.32 (s, 3H), 2.26 (s,

3H), 3.15 (d, IH), 3.58 (d, IH), 4.79 (s, 2H), 5.12 (q, IH), 7.01 (d, IH), 7.49 (d, IH),

7.55 (s, 2H), 7.67 (d, IH), 7.69 (s, IH), 7.79 (d, 2H), 7.89 (d, 2H), 13.28 (broad, s,

IH).

Example 38

(2-Methyl-4 - {[4-spirocyclopentyl-7-phenyl] -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogously to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid from 41.0 mg

(0.079 mmol) ethyl (2-methyl-4 - {[4-spirocyclopentyl-7-phenyl-3,4-dihydro-2 (1H) - isoquinolinyl] sulfonyl} phenoxy) acetate and 0.16 ml (0.16 mmol) 1 M Caustic soda in

5 ml ethanol after cleaning over silica gel (cyclohexane / ethyl acetate 1: 1 -

Methylene chloride / methanol 10: 1) 30 mg (77% of theory) of the desired product.

LC MS (method 3): R _t = 3.11 min.

MS (ESIpos): 492 (M + H) ⁺

Η NMR (400 MHz, DMSO-d ₆ ): δ - 1.70-1.95 (m, 8H), 2.29 (s, 3H), 2.97 (s, 2H),

4.20 (s, 2H), 4.79 (s, 2H), 7.07 (d, IH), 7.33 (t, IH), 7.37-7.47 (m, 4H), 7.51 (dd,

IH), 7.60-7.69 (m, 5H). Example 39

(2-Methyl-4 - {[7- [4-fluoφhenyl] -4-spirocyclopentyl-3,4-dihydro-2 (1H) - isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogously to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid from 67.0 mg (0.083 mmol) ethyl (2-methyl-4- {[4-spirocyclopentyl-7- (4-fluoro) phenyl-3, 4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate and 0.20 ml (0.20 mmol) 1 M sodium hydroxide solution in 5 ml ethanol after purification over silica gel (cyclohexane / ethyl acetate

1: 1 → methylene chloride methanol 10: 1) and HPLC 7 mg (16% of theory) of the desired product. HPLC (method 1): R _t = 5.38 min. MS (ESIpos): 510 (M + H) ⁺ Η-NMR (300 MHz, DMSO-d ₆ ): δ = 1.68-1.95 (m, 8H), 2.29 (s, 3H), 2.98 (s, 2H),

4.20 (s, 2H), 4.82 (s, 2H), 7.08 (d, IH), 7.22-7.34 (m, 3H), 7.40 (d, IH), 7.41 (s, IH), 7.49 (dd, IH) , 7.54 (d, IH), 7.62-7.70 (m, 3H), 13.13 (broad, s, IH).

Example 40

(2-Methyl-4 - {[7- [3-fluoφhenyl] -4-spirocyclopentyl-3,4-dihydro-2 (1H) - isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogously to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid from 93.0 mg (0.173 mmol) ethyl (2-methyl-4- {[4-spirocyclopentyl-7- (3-fluoro) phenyl-3, 4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate and 0.259 ml (0.259 mmol) 1 M sodium hydroxide solution in 5 ml of ethanol after extraction of the aqueous phase with ethyl acetate and removal of the solvent in vacuo, 88 mg (99% of theory) of the desired product. HPLC (method 1): R, = 5.49 min. MS (ESIpos): 510 (M + H) ⁺

Η NMR (200 MHz, DMSO-d ₆ ): δ = 1.70-1.91 (m, 8H), 2.29 (s, 3H), 2.96 (s, 2H), 4.17 (s, 2H), 4.84 (s, 2H ), 7.00 (d, 2H), 7.07 (d, IH), 7.36 (d, IH), 7.38 (s, IH), 7.46 (d, IH), 7.57 (d, 2H), 7.66 (d, IH) , 7.68 (s, IH), 13.19 (broad, s, IH).

Example 41

(2-Methyl-4 - {[7- [4-methoxyphenyl] -4-spirocyclopentyl-3,4-dihydro-2 (1H) - isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogously to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (lH) -isoquinolinyl] sulfonyl} phenoxy) acetic acid from 53.0 mg (0.096 mmol) ethyl (2-methyl-4 - {[4-spirocyclopentyl-7- (4-methoxy) phenyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate and 0.145 ml ( 0.145 mmol) 1

M sodium hydroxide solution in 5 ml ethanol after extraction of the aqueous phase with ethyl acetate and removal of the solvent in vacuo 47 mg (93% of theory) of the desired

Product won.

HPLC (method 1): R _t = 5.41 min.

MS (ESIpos): 522 (M + H) ⁺

1H-NMR (200 MHz, DMSO-d ₆ ): δ = 1.72-1.93 (m, 8H), 2.28 (s, 3H), 2.97 (s, 2H),

3.34 (s, 3H), 4.19 (s, 2H), 4.80 (s, 2H), 7.05 (d, IH), 7.17 (m, IH), 7.36-7.60 (m,

6H), 7.65 (d, IH), 7.67 (s, IH), 13.35 (broad, s, IH).

Example 42

(2-Methyl-4 - {[7- [3-methoxyphenyl] -4-spirocyclopentyl-3,4-dihydro-2 (1H) - isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogously to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluθφhenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid from 68.0 mg (0.124 mmol) ethyl (2-methyl-4- {[4-spirocyclopentyl-7- (3-methoxy) phenyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate and 0.186 ml (0.186 mmol) 1

M sodium hydroxide solution in 5 ml of ethanol after extraction of the aqueous phase with ethyl acetate and removal of the solvent in vacuo 61 mg (95% of theory) of the desired product. HPLC (method 1): R _t = 5.42 min. MS (ESIpos): 522 (M + H) ⁺ 1H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.72-1.91 (m, 8H), 2.29 (s, 3H), 2.98 (s, 2H), 3.81 (s, 3H), 4.20 (s, 2H) ), 4.81 (s, 2H), 6.90 (dd, IH), 7.07 (d, IH), 7.17 (dd, IH), 7.18 (dd, IH), 7.33 (d, IH), 7.39 (d, IH) , 7.44 (d, IH), 7.51 (dd, IH), 7.66 (dd, IH), 7.67 (s, IH).

Example 43

(2-Methyl-4 - {[4-spirocyclopentyl-7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1H) - isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogously to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid from 200.0 mg

(0.34 mmol) ethyl (2-methyl-4- {[4-spirocyclopentyl-7- (4-trifluoromethyl) phenyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate and 0.70 ml ( 0.70 mmol) 1 M

Sodium hydroxide solution in 10 ml of ethanol after extraction of the aqueous phase with ethyl acetate,

Remove the solvent in vacuo and clean over silica gel

(Methylene chloride / methanol 20: 1) 133 mg (70% of theory) of the desired product were obtained.

HPLC (method 1): R _t = 5.60 min.

MS (ESIpos): 560 (M + H) ⁺

1H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.72-1.92 (m, 8H), 2.29 (s, 3H), 2.98 (s, 2H),

4.21 (s, 2H), 4.82 (s, 2H), 7.07 (d, IH), 7.46 (d, IH), 7.52 (d, IH), 7.59 (dd, IH),

7.66 (dd, IH), 7.68 (s, IH), 7.79 (d, 2H), 7.86 (d, 2H). Example 44

(2-Methyl-4 - {[4-spirocyclopentyl-7- [3- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1H) - isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogously to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid from 142.0 mg (0.242 mmol) ethyl (2-methyl-4- {[4-spirocyclopentyl-7- (3-trifluoromethyl) phenyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate and 0.48 ml (0.48 mmol) 1 M sodium hydroxide solution in 3 ml ethanol after extraction of the aqueous phase with ethyl acetate,

Removal of the solvent in vacuo and cleaning over silica gel (methylene chloride / methanol 20: 1) 87 mg (64% of theory) of the desired product. HPLC (method 1): R _t = 5.60 min. MS (ESIpos): 560 (M + H) ⁺

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.72-1.92 (m, 8H), 2.29 (s, 3H), 2.99 (s, 2H), 4.21 (s, 2H), 4.83 (s, 2H ), 7.03-7.13 (m, 2H), 7.43 (d, IH), 7.56 (s, IH), 7.59 (dd, IH), 7.63-7.72 (m, 3H), 7.95 (m, 2H).

Example 45 (2-Methyl-4- {[7- [4-methylphenyl] -4-spirocyclopentyl-3, 4-dihydro-2 (1 H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogous to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid from 86.0 mg (0.161 mmol) ethyl (2-methyl-4 - {[4-spirocyclopentyl-7- (4-methyl) phenyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate and 0.24 ml (0.24 mmol) 1 M sodium hydroxide solution in 3 ml ethanol after extraction of the aqueous phase with ethyl acetate and removal of the solvent in vacuo, 78 mg (96% of theory) of the desired product. HPLC (method 1): R, = 5.71 min. MS (ESIpos): 506 (M + H) ⁺

Η NMR (200 MHz, CDC1 ₃ ): δ = 1.75-2.02 (m, 8H), 2.35 (s, 3H), 2.38 (s, 3H), 3.03 (s, 2H), 4.26 (s, 2H), 4.78 (s, 2H), 6.82 (d, IH), 7.20 (s, IH), 7.23 (d, 2H), 7.30 (d, IH), 7.40 (s, IH), 7.42 (d, 2H), 7.68 (s, IH), 7.69 (d, IH).

Example 46

(2-Methyl-4 - {[7- [3-methylphenyl] -4-spirocyclopentyl-3,4-dihydro-2 (1H) - isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogously to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid from 94.0 mg (0.176 mmol) ethyl (2-methyl-4 - {[4-spirocyclopentyl-7- (3-methyl) phenyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate and 0.26 ml (0.26 mmol) 1 M sodium hydroxide solution in 3 ml ethanol after extraction of the aqueous phase with ethyl acetate, drying over sodium sulfate and removal of the solvent, 86 mg (97% of theory) of the desired product were obtained. HPLC (method 1): R _t = 5.66 min. MS (ESIpos): 506 (M + H) ⁺

1H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.70-1.93 (m, 10H), 2.29 (s, 3H), 2.35 (s, 3H), 2.98 (s, 2H), 4.20 (s, 2H) ), 4.82 (s, 2H), 7.08 (d, IH), 7.13 (d, IH), 7.30 (t, IH), 7.38- 7.47 (m, 4H), 7.50 (dd, IH), 7.66 (d, IH), 7.68 (s, IH).

Example 47

(2-Methyl-4- {[4-spirocyclopentyl-7- [4- (trifluoromethoxy) phenyl] -3,4-dihydro-2 (1 H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogously to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid from 94.0 mg

(0.156 mmol) ethyl (2-methyl-4- {[4-spirocyclopentyl-7- (4-trifluoromethoxy) phenyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate and 0.23 ml ( 0.23 mmol) of 1 M sodium hydroxide solution in 3 ml of ethanol after extraction of the aqueous phase with ethyl acetate, drying over sodium sulfate and removal of the solvent, 86 mg (96% of theory) of the desired product were obtained.

HPLC (method 1): R, = 5.73 min. MS (ESIpos): 576 (M + H) ⁺

Η NMR (200 MHz, CDC1 ₃ ): δ = 1.75-2.00 (m, 8H), 2.35 (s, 3H), 3.03 (s, 2H), 4.27 (s, 2H), 4.77 (s, 2H), 6.81 (d, IH), 7.16 (s, IH), 7.23 (d, 2H), 7.35 (s, IH), 7.38 (d, IH), 7.52 (d, 2H), 7.66 (s, IH), 7.68 (d, IH).

Example 48

(2-Methyl-4 - {[4-spirocyclopentyl-7- [3- (trifluoromethoxy) phenyl] -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogously to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid from 91.0 mg (0.151 mmol) ethyl (2-methyl-4- {[4-spirocyclopentyl-7- (3-trifluoromethoxy) phenyl-3,4-dihydro-2 (lH) -isoquinolinyl] sulfonyl} phenoxy) acetate and 0.23 ml (0.23 mmol) 1 M sodium hydroxide solution in 3 ml of ethanol after extraction of the aqueous phase with ethyl acetate, drying over sodium sulfate and removal of the solvent in vacuo, 85 mg (98% of theory) of the desired product. HPLC (method 1): R, = 5.64 min. MS (ESIpos): 576 (M + H) ⁺

Η NMR (200 MHz, CDC1 ₃ ): δ = 1.75-2.00 (m, 8H), 2.36 (s, 3H), 3.02 (s, 2H), 4.26 (s, 2H), 4.78 (s, 2H), 6.81 (d, IH), 7.19 (m, 2H), 7.30-7.48 (m, 5H), 7.68 (s, IH), 7.69 (d, IH).

Example 49 (4 - {[7-bromo-4-spirocyclohexyl] -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} -2-methylphenoxy) acetic acid

Analogously to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid from 35.0 mg (0.065 mmol) ethyl (2-methyl-4 - {[7-bromo-4-spirocyclohexyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate and 0.13 ml (0.13 mmol ) 1 M sodium hydroxide solution in 2 ml of ethanol after extraction of the aqueous phase with ethyl acetate, drying over sodium sulfate and removal of the solvent in vacuo, 33 mg (99% of theory) of the desired product. LC / MS (method 3): R, = 3.05 min. MS (ESIpos): 508 (M + H) ⁺

1H-NMR (200 MHz, CDC1 ₃ ): δ = 1.45-1.90 (m, 10H), 2.36 (s, 3H), 3.22 (s, 2H), 4.15 (s, 2H), 4.78 (s, 2H), 6.81 (d, IH), 7.14 (d, IH), 7.25 (s, IH), 7.31 (dd, IH), 7.65 (s, IH), 7.68 (d, IH).

Example 50

(4 - {[4-Spirocyclohexyl-7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1H) - isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogously to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid from 68.0 mg (0.116 mmol) ethyl (4 - {[4-spirocyclohexyl-7- (4-trifluoromethyl) phenyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate and 0.23 ml (0.23 mmol) 1 M sodium hydroxide solution in 5 ml ethanol after additional addition of 0.10 ml (0.10 mmol) 1 M sodium hydroxide solution, stirring for 2 days, extraction of the aqueous phase with ethyl acetate, removal of the solvent in vacuo and cleaning over silica gel (methylene chloride / methanol 100: 1 → 10: 1) 12 mg (15% of theory) of the desired product were obtained.

HPLC (method 1): R, = 5.57 min. MS (ESIpos): 560 (M + H) ⁺

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.45-1.85 (m, 10H), 3.22 (s, 2H), 4.19 (s, 2H), 4.70 (s, 2H), 7.13 (d, 2H ), 7.55 (d, IH), 7.58 (s, IH), 7.75-7.90 (m, 7H).

Example 51 (2-Methyl-4 - {[7-phenyl-4-spirocyclohexyl] -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogously to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluθφhenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid, 53.4 mg (0.100 mmol) ethyl (2-methy 1-4- {[4-spirocyclohexyl-7-ρhenyl-3, 4-dihydro-2 (1 H) -isoquinolinyl] sulfonyl} phenoxy) acetate and 0.20 ml (0.20 mmol ) 1 M sodium hydroxide solution in 5 ml of ethanol after extraction of the aqueous phase with ethyl acetate, drying over sodium sulfate and removal of the solvent in vacuo and cleaning over Silica gel (cyclohexane / ethyl acetate 3: 1 → methylene chloride / methanol 10: 1) 30 mg

(59% of theory) of the desired product.

HPLC (method 1): R, = 5.53 min.

MS (ESIpos): 506 (M + H) ⁺

1H-NMR (300 MHz, CDC1 ₃ ): δ = 1.45-1.90 (m, 10H), 2.35 (s, 3H), 3.29 (s, 2H), 4.26

(s, 2H), 4.77 (s, 2H), 6.82 (d, IH), 7.23 (d, 2H), 7.35-7.47 (m, 3H), 7.51 (d, 2H), 7.59

(m, IH), 7.69 (s, IH), 7.70 (d, IH).

Example 52

(2-Methyl-4 - {[7- [4-fluoφhenyl] -4-spirocyclohexyl-3,4-dihydro-2 (1H) - isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogously to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid from 106.0 mg

(0.192 mmol) ethyl (2-methyl-4- {[4-spirocyclohexyl-7- (4-fluoro) phenyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate and 0.40 ml ( 0.40 mmol) of 1 M sodium hydroxide solution in 5 ml of ethanol after extraction of the aqueous phase with ethyl acetate, drying over sodium sulfate and removal of the solvent, 94 mg (86% of theory) of the desired product were obtained.

HPLC (method 1): R _t = 5.53 min. MS (ESIpos): 524 (M + H) ⁺

Η NMR (400 MHz, DMSO-d ₆ ): δ = 1.45-1.80 (m, 10H), 2.29 (s, 3H), 3.21 (s, 2H), 4.17 (s, 2H), 4.80 (s, 2H) ), 7.07 (d, IH), 7.15 (d, IH), 7.18 (d, IH), 7.41 (s, IH), 7.49 (d, IH), 7.52 (d, IH), 7.62-7.72 (m, 4H). Example 53

(2-Methyl-4 - {[4-spirocyclohexyl-7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1H) - isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogously to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid from 840.0 mg

(1,396 mmol) ethyl- (2-methyl-4- {[4-spirocyclohexyl-7- (4-trifluoromethyl) phenyl-

3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate and 1.68 ml (1.68 mmol) 1

M sodium hydroxide solution in 10 ml ethanol after extraction of the aqueous phase

Ethyl acetate, drying over sodium sulfate, removal of the solvent in vacuo and purification via HPLC 570 mg (71% of theory) of the desired product.

HPLC (method 1): R _t = 5.69 min.

MS (ESIpos): 574 (M + H) ⁺

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.45-1.83 (m, 10H), 2.29 (s, 3H), 3.21 (s, 2H),

4.20 (s, 2H), 4.83 (s, 2H), 7.09 (d, IH), 7.55 (s, IH), 7.58 (s, 2H), 7.70 (d, IH), 7.72

(s, IH), 7.79 (d, 2H), 7.88 (d, 2H). Example 54

(3-Methyl-4 - {[4-spirocyclohexyl-7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1H) - isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogously to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (lH) -isoquinolinyl] sulfonyl} phenoxy) acetic acid from 19.0 mg (0.032 mmol) ethyl (3-methyl-4 - {[4-spirocyclohexyl-7- (4-trifluoromethyl) phenyl-3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate and 0.10 ml (0.10 mmol) 1 M sodium hydroxide solution in 5 ml ethanol 13 mg (72% of theory) of the desired product.

HPLC (method 1): R, = 5.75 min. MS (ESIpos): 574 (M + H) ⁺ 1H-NMR (200 MHz, DMSO-d ₆ ): δ = 1.40-1.83 (m, 10H), 2.56 (s, 3H), 3.30 (s, 2H), 4.36 (s, 2H), 4.78 (s, 2H), 6.98 (d, IH), 7.02 (s, IH), 7.60 (s, 2H), 7.63 (m, IH), 7.75-

7.95 (m, 5H).

Example 55

(2,5-Dimethyl-4 - {[4-spirocyclohexyl-7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1 H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogous to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (lH) -isoquinolinyl] sulfonyl} phenoxy) acetic acid from 24.0 mg

(0.039 mmol) ethyl- (2,6-dimethyl-4- {[4-spirocyclohexyl-7- (4-trifluoromethyl) phenyl-

3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate and 0.12 ml (0.12 mmol) 1

M sodium hydroxide solution in 5 ml of ethanol 21 mg (92% of theory) of the desired product.

HPLC (method 1): R, = 5.88 min.

MS (ESIpos): 588 (M + H) ⁺

Η NMR (200 MHz, DMSO-d ₆ ): δ = 1.45-1.80 (m, 10H), 2.23 (s, 3H), 2.50 (s, 3H),

3.30 (s, 2H), 4.32 (s, 2H), 4.70 (s, 2H), 6.89 (s, IH), 7.59 (s, 2H), 7.70 (s, IH), 7.80

(d, 2H), 7.89 (d, 2H).

Example 56 (2,3-Dimethyl-4 - {[4-spirocyclohexyl-7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-

2 (lH) -isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogously to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (lH) -isoquinolinyl] sulfonyl} phenoxy) acetic acid from 25.0 mg

(0.041 mmol) ethyl- (2,3-dimethyl-4- {[4-spirocyclohexyl-7- (4-trifluoromethyl) phenyl-

3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate and 0.12 ml (0.24 mmol) 2

M sodium hydroxide solution in 5 ml ethanol 17 mg (71% of theory) of the desired product.

HPLC (method 1): R _t = 5.90 min.

MS (ESIpos): 588 (M + H) ⁺

Η NMR (200 MHz, DMSO-d ₆ ): δ = 1.40-1.80 (m, 10H), 2.19 (s, 3H), 2.53 (s, 3H),

3.30 (s, 2H), 4.37 (s, 2H), 4.77 (s, 2H), 6.93 (d, IH), 7.58 (m, 3H), 7.74-7.95 (m,

5H).

Example 57

(2-Methyl-4 - {[4- (2-phenylethyl) -7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1H) - isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogous to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid, 0.12 g (0.19 mmol) ethyl- (2-methyl-4 - {[4- (2-phenylethyl) -7- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl } phenoxy) acetate with 2 ml of 2N sodium hydroxide solution in 5 ml Ethanol stirred for 3 hours at room temperature. For working up, the mixture is concentrated in vacuo and the residue is taken up in diethyl ether and water. The phases are separated and the aqueous phase is acidified with 1N hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases are combined and dried over sodium sulfate, filtered and freed from the solvent in vacuo. The crude yield is purified on a 3 g silica gel cartridge (mobile phase: dichloromethane and dichloromethane / ethyl acetate 95: 5). The clean fractions are combined and the solvent is removed in vacuo. 85 mg (73% of theory) of the desired product are obtained. HPLC (method 1): R _t = 5.73 min. MS (DCI): 627 (M + NH ₄ ) ⁺

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.87-1.99 (m, 2H), 2.26 (s, 3H), 2.60-2.84 (m, 2H), 2.87-2.97 (m, 2H), 3.68 -3.79 (m, IH), 3.97 (d, IH), 4.54 (d, IH), 4.82 (s, 2H), 7.02-7.09 (m, IH), 7.13-7.36 (m, 6H), 7.49-7.59 (m, 2H), 7.63-7.72 (m, 2H), 7.78 (d, 2H), 7.86 (d, 2H), 12.98-13.26 (m, IH).

Example 58

Ethyl (2-methyl-4 - {[1,4,4-trimethyl-7- [4- (dimethylamino) phenyl] -3,4-dihydro-2 (1 H) -isoquinolinyl] sulfonyl} phenoxy) acetate

Analogous to the preparation of ethyl (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoro-phenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate ( Example 19) from 220 mg (0.380 mmol) of ethyl- (2-methyl - {[7 - {[(trifluoromethyl) sulfonyl] oxy} -l, 4,4-trimethyl-3,4-dihydro-2 (lH) -isoquinolinyl] sulfonyl} phenoxy) acetate, 125.3 mg (0.759 mmol) 4- (dimethylamino) phenylboronic acid, 590 mg (1.898 mmol) potassium phosphate trihydrate and 35 mg (0.030 mmol) tetrakis (triphenylphosphine) palladium in 5 ml toluene after purification via HPLC 53 mg (25% of theory) of the desired product. HPLC (method 1): R _t = 4.66 min. MS (ESIpos): 551 (M + H) ⁺

1H-NMR (400 MHz, CDC1 ₃ ): δ = 1.17 (s, 3H), 1.29 (t, 3H), 1.31 (s, 3H), 1.35 (d, 3H), 2.31 (s, 3H), 2.99 ( s, 6H), 3.18 (d, IH), 3.51 (d, IH), 4.27 (q, 2H), 4.69 (s, 2H), 5.17 (q, IH), 6.72 (d, IH), 6.79 (d , 2H), 7.17 (d, IH), 7.30 (d, IH), 7.38 (dd, IH), 7.43 (d, 2H), 7.68 (s, IH), 7.69 (d, IH).

Example 59

Ethyl (2-methyl-4 - {[1,4,4-trimethyl-7- [4- (trifluoromethoxy) phenyl] -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate

Analogous to the preparation of ethyl (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoro-phenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetate ( Example 19) from 220 mg (0.380 mmol) of ethyl- (2-methyl - {[7 - {[(trifluoromethyl) sulfonyl] oxy} -l, 4,4-trimethyl-3,4-dihydro-2 (lH) -isoquinolinyl] sulfonyl} phenoxy) acetate, 195.4 mg (0.948 mmol) 4- (trifluoromethoxy) phenylboronic acid, 590 mg (1.898 mmol) potassium phosphate trihydrate and 17.4 mg (0.016 mmol) tetrakis (triphenylphosphine) palladium in 5 ml toluene after purification HPLC 147 mg (65% of theory) of the desired product.

HPLC (method 1): R, = 5.89 min. MS (ESIpos): 592 (M + H) ⁺ Η NMR (300 MHz, CDC1 ₃ ): δ = 1.20 (s, 3H), 1.29 (t, 3H), 1.33 (s, 3H), 1.33 (d, 3H), 2.31 (s, 3H), 3.18 ( d, IH), 3.54 (d, IH), 4.27 (q, 2H), 4.69 (s, 2H), 5.17 (q, IH), 6.74 (d, IH), 7.18 (d, IH), 7.26 (d , 2H), 7.37 (d, 2H), 7.53 (d, 2H), 7.68 (s, IH), 7.69 (d, IH).

Example 60

(2-Methyl-4 - {[1,4,4-trimethyl-7- [4- (dimethylamino) phenyl] -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogously to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid (Example 34 ) are made

40.0 mg (0.073 mmol) of ethyl- (2-methyl-4 - {[l, 4,4-trimethyl-7- [4- (dimethylamino) phenyl] -3,4-dihydro-2 (lH) -isoquinolinyl] sulfonyl} phenoxy) acetate and 0.50 ml (1.50 mmol) 2 M sodium hydroxide solution in 1 ml ethanol 31 mg (82% of theory) of the desired

Product won.

HPLC (method 1): R _t = 4.86 min.

MS (ESIpos): 523 (M + H) ⁺ Η-NMR (200 MHz, DMSO-d ₆ ): δ = 1.13 (s, 3H), 1.19 (d, 3H), 1.29 (s, 3H), 2.26 ( s

3H), 2.99 (s, 6H), 3.11 (d, IH), 3.55 (d, IH), 4.83 (s, 2H), 5.08 (q, IH), 6.99-7.11 (m,

2H), 7.35-7.48 (m, 3H), 7.58 n (d, 2H), 7.61-7.71 (m, 3H). Example 61

(2-Methyl-4 - {[1,4,4-trimethyl-7- [4- (trifluoromethoxy) phenyl] -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid

Analogously to the preparation of (2-methyl-4 - {[1,4,4-trimethyl-7- (4-fluoφhenyl) -3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl} phenoxy) acetic acid (Example 34 ) are made

130.0 mg (0.219 mmol) ethyl- (2-methyl-4 - {[l, 4,4-trimethyl-7- [4- (trifluoromethoxy) phenyl] -3,4-dihydro-2 (lH) -isoquinolinyl] sulfonyl} phenoxy) acetate and 1.0 ml (2.0 mmol) 2 M sodium hydroxide solution in 2 ml ethanol 106 mg (86% of theory) of the desired

Product won.

HPLC (method 1): R _t = 5.42 min.

MS (ESIpos): 564 (M + H) ⁺ 1H-NMR (200 MHz, DMSO-d ₆ ): δ = 1.15 (s, 3H), 1.20 (d, 3H), 1.31 (s, 3H), 2.26 ( s

3H), 3.13 (d, IH), 3.58 (d, IH), 4.79 (s, 2H), 5.11 (q, IH), 7.00 (d, IH), 7.39-7.57

(m, 5H), 7.67 (d, IH), 7.69 (s, IH), 7.77 (d, 2H).

Example A

Cellular Transactivation Assay:

Test principle:

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

Since mammalian cells contain different endogenous nuclear receptors, which could complicate a clear interpretation of the results, an established one

Chimeric system used in which the ligand binding domain of the human PPARδ receptor is fused to the DNA binding domain of the yeast transcription factor GAL4. The resulting GAL4-PPARδ chimera is co-transfected and stably expressed in CHO cells with a reporter construct.

cloning:

The GAL4-PPARδ expression construct contains the ligand binding domain of PPARδ (amino acids 414-1326), which is PCR-amplified and cloned into the vector pcDNA3.1. This vector already contains the GAL4-DNA binding domain (amino acids 1-147) of the vector pFC2-dbd (Stratagene). The

Reporter construct, which contains five copies of the GAL4 binding site, upstream of a thymidine kinase promoter, leads to the expression of Firefly luciferase (Photinus pyralis) after activation and binding of GAL4-PPARδ.

Transactivation Assay (Luciferase Reporter):

CHO (Chinese hamster ovary) cells are in CHO-A-SFM medium (GIBCO), supplemented with 2.5% fetal calf serum and 1% penicillin / streptomycin (GIBCO), with a cell density of 2 x 10 ³ cells per well in one 384 well plate (Greiner) sown. After culturing for 48 hours at 37 ° C, the cells are stimulated. For this purpose, the substances to be tested are taken up in the medium mentioned above and added to the cells. After a stimulation time of 24 For hours, the luciferase activity is measured using a video camera. The measured relative light units result in a sigmoid stimulation curve depending on the substance concentration. The EC o values are calculated using the GraphPad PRISM computer program (version 3.02).

The compounds according to the invention of Examples 18-22, 28, 30, 32-37, 41, 43, 45, 47, 50-57, 60 and 61 show EC ₅₀ values from 1 to 100 nM in this test.

Example B

Test descriptions for the detection of pharmacologically active substances which increase the HDL cholesterol (HDL-C) in the serum of transgenic mice which are transfected with the human ApoAl gene (hApoAl) or the metabolic syndrome of obese ob, ob mice influence and lower their blood glucose concentration:

The substances which are to be investigated for their HDL-C-increasing effect in vivo are administered orally to male transgenic hApoAl mice. The animals were randomly assigned to groups with the same number of animals, usually n = 7-10, one day before the start of the experiment. During the entire experiment

Animals drinking water and feed ad libitum available. The substances are administered orally once a day for 7 days. For this purpose, the test substances are dissolved in a solution of Solutol HS 15 + ethanol + saline solution (0.9%) in a ratio of 1 + 1 + 8 or in a solution of Solutol HS 15 + saline solution (0.9%>) in a ratio of 2 + 8. The dissolved substances are applied in a volume of 10 ml / kg body weight with a throat probe. 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, each mouse is used to determine ApoAl,

Serum cholesterol, HDL-C and serum triglycerides (TG) blood by puncturing the retroorbital venous plexus taken (previous value). The animals are then given the test substance for the first time using a pharyngeal tube. 24 hours after the last substance application, ie on the 8th day after the start of treatment, blood is again taken from each animal to determine the same parameters by puncturing the retroorbital venous plexus. The blood samples are centrifuged, and after the serum has been obtained, cholesterol and TG are determined photometrically using an EPOS Analyzer 5060 (Eppendorf-Gerätebau, Netheler & Hinz GmbH, Hamburg). The determination is carried out using commercially available enzyme tests (Boehringer Mannheim, Mannheim).

To determine the HDL-C, the non-HDL-C fraction is precipitated with 20% PEG 8000 in 0.2 M glycine buffer pH 10. The cholesterol is determined from the supernatant in a 96-well perforated plate using commercially available reagent (Ecoline 25, Merck, Darmstadt) using UN photometry (BIO-TEK Instruments, USA).

The human mouse ApoAl is determined using a sandwich ELISA method using a polyclonal anti-human ApoAl and a monoclonal anti-human ApoAl antibody (Biodesign International, USA). The quantification is carried out UV-photometrically (BIO-TEK Instruments, USA) with peroxidase-coupled anti-mouse IGG antibodies (KPL, USA) and peroxidase substrate (KPL, USA).

The effect of the test substances on the HDL-C concentration is determined by subtracting the measured value of the first blood sample (previous value) from the measured value of the second blood sample (after treatment). There are differences of all

HDL-C values of a group averaged and compared with the mean of the differences of the control group.

Statistical evaluation is carried out using Student's t-test after the variances have been checked for homogeneity. Substances which increase the HDL-C of the treated animals statistically significantly (p <0.05) by at least 15% compared to that of the control group are considered to be pharmacologically active.

In order to be able to test substances for their influence on a metabolic syndrome, animals with an insulin resistance and increased blood glucose levels are used. For this purpose, C57B1 / 6J Lep <ob> mice are treated according to the same protocol as the transgenic ApoAl mice. Serum lipids are determined as described above. In addition, serum glucose is determined as a parameter for blood glucose in these animals. The serum glucose is enzymatic on an EPOS

Analyzer 5060 (see above) was determined using commercially available enzyme tests (Boehringer Mannheim).

A blood glucose-lowering effect of the test substances is obtained by subtracting the measured value of the 1st blood sample from an animal (previous value) from the measured value of the 2nd

Blood collection from the same animal (after treatment) was determined. The differences of all serum glucose 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 the variances have been checked for homogeneity.

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

Claims

claims

1. Compounds of the general formula (I)

in which

X represents O, S or CH ₂ ,

R ¹ for halogen, (C _t -C ₆ ) alkoxy, (C ₂ -C ₆ ) alkenyloxy, (C ₃ -C ₇ ) -

Cycloalkoxy, optionally substituted by halogen, (-CC ₄ ) alkyl, trifluoromethyl or (-C-C ₄ ) alkoxy-substituted benzyloxy

or

stands for (C ₆ -Cιo) aryl or 5- to 6-membered heteroaryl with up to three heteroatoms from the series N, O and / or S, which in turn are selected one to three times, identically or differently, by substituents the group halogen, _(Cι-C6) alkyl, _(Cι-C6) alkoxy, trifluoromethyl, trifluoromethoxy, amino, mono- and di _(Cι-C6) - alkylamino may be substituted,

9 7

R and R are the same or different and are independent of each other for

Are hydrogen or (-CC ₆ ) -alkyl, which is optionally substituted by phenyl, or together with the carbon atom to which they are attached form a 3- to 7-membered, spiro-linked cycloalkyl ring, R ⁴ and R ^{5 are the} same or different and independently of one another represent hydrogen or (-CC ₆ ) -alkyl,

R ^{6 represents} hydrogen or (-CC ₆ ) alkyl,

R ^{7 represents} hydrogen or (-CC ₆ ) alkyl,

R ^{8 represents} hydrogen, (GC ₆ ) alkyl, (-C-C ₆ ) alkoxy or halogen,

R ⁹ and R ^{10 are the} same or different and are independently of one another

Are hydrogen or (G-C) -alkyl,

and

R ^{1 1 represents} hydrogen or a hydrolyzable group which can be broken down into the corresponding carboxylic acid,

and their pharmaceutically acceptable salts, solvates and solvates of the salts.

2. Compounds of general formula (I), according to claim 1, in which

X represents O or S,

R ¹ for (C ₂ -C) alkenyloxy, (C ₅ -C ₆ ) cycloalkoxy or for halogen or

(C _r C ₄ ) alkoxy,

or

stands for 6-membered heteroaryl with up to two nitrogen atoms, or for phenyl or benzyloxy, which in turn each one to twice, the same or different, by substituents selected from the group fluorine, chlorine, (-CC) -alkyl, (GC ₄ ) -alkoxy, trifluoromethyl, trifluoromethoxy, amino, mono- and di- (-C-C ₄ ) -alkylamino can be substituted

9 7 •

R and R are the same or different and are independent of each other for

Is hydrogen or represents methyl or ethyl, which may be substituted by phenyl, or together with the carbon atom to which they are attached form a 4- to 6-membered, spiro-linked cycloalkyl ring,

R ⁴ and R ⁵ each represent hydrogen,

R ^{6 represents} hydrogen or methyl,

R ^{7 represents} hydrogen or methyl,

R ^{8 represents} hydrogen, (QC ₄ ) alkyl, (GC ₄ ) alkoxy, fluorine or chlorine,

R ⁹ and R ^{10 are the} same or different and independently of one another represent hydrogen or methyl,

and

R ¹ 'represents hydrogen or (GC ₄ ) alkyl,

and their pharmaceutically acceptable salts, solvates and solvates of the salts. Compounds of the general formula (I) according to Claim 1, in which

X stands for O,

R ^{1 represents} pyridyl or phenyl, which in turn can be substituted once or twice, identically or differently, by substituents selected from the group consisting of fluorine, chlorine, methyl, methoxy, trifluoromethyl, trifluoromethoxy, amino and dimethylamino

R ^{2 represents} hydrogen or methyl,

R ^{3 represents} methyl or phenethyl,

or

R ² and R ³ together with the carbon atom to which they are attached form a spiro-linked cyclopentane or cyclohexane ring,

R ⁴ and R ⁵ each represent hydrogen,

R ^{6 represents} hydrogen or methyl,

R ^{7 represents} hydrogen or methyl,

R ^{8 represents} methyl,

R ⁹ and R ¹⁰ each represent hydrogen,

and

R ^: 'represents ethoxy or hydrogen, and their pharmaceutically acceptable salts, solvates and solvates of the salts.

Compounds of the general formula (I) according to one of Claims 1 to

3,

in which

R ⁴ , R ⁵ , R ⁹ , R ^{10 represent} hydrogen,

X represents oxygen,

R ^{8 represents} 2-methyl,

R ^{2 represents} hydrogen,

R ^{3 represents} methyl or phenethyl,

or

9 7

R and R both represent methyl or together with the carbon atom to which they are attached form a spiro-linked cyclopentane or cyclohexane ring,

and

R ¹ , R ⁶ and R ⁷ each have the meanings given in Claims 1 to 3, and their pharmaceutically acceptable salts, solvates and solvates of the salts.

5. Compounds of the general formula (I) according to claim 4,

in which

R ^{2 represents} hydrogen,

R ^{3 represents} methyl or phenethyl,

or

9 7

R and R both represent methyl or, together with the carbon atom to which they are attached, a spiro-linked one

Form a cyclopentane or cyclohexane ring,

as well as their pharmaceutically acceptable salts, solvates and solvates of the salts.

6. A process for the preparation of the compounds of general formula (I) as defined in claim 1, characterized in that

[A] compounds of the general formula (II)

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

first with a compound of the general formula (III)

in which X, R ⁷ , R ⁸ , R ⁹ and R ¹⁰ each have the meanings given in claim 1 and

represents benzyl or (GC ₆ ) alkyl,

in an inert solvent in the presence of a base in compounds of the general formula (I-B)

in which T, X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ each have the meanings given in Claim 1,

transferred, then with acids or bases or, if T is benzyl, also hydrogenolytically to the corresponding carboxylic acids of the general formula (IC)

in which X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ^J and R ¹⁰ each have the meanings given in Claim 1,

implements,

and optionally these carboxylic acids (I-C) are further modified to give compounds of the general formula (I) by known esterification methods,

or

[B] Compounds of the general formula (IV)

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

PG stands for a suitable hydroxyl protective group, such as methyl or benzyl, first with a compound of the general formula (III) in an inert solvent in the presence of a base in compounds of the general formula (V)

in which PG, T, X, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ each have the meanings given in Claim 1,

transferred in the next reaction step the protective group PG by suitable methods, for example by treatment with boron tribromide (PG = methyl) or hydrogenolytic (PG = benzyl), to give compounds of the general formula (VI)

in which T, X, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ each have the meanings given in Claim 1,

removed, and then the compounds of general formula (VI) either [B1] with a compound of the general formula (VII)

R, 12 -Z (VII),

in which

R ^{12 is} for (-C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₃ -C ₇ ) cycloalkyl or for optionally by halogen, (GC ₄ ) alkyl, trifluoromethyl or (Cι-C ₄ ) -alkoxy substituted benzyl, and

Z a suitable leaving group, such as halogen,

Mesylate or tosylate means

in an inert solvent in the presence of a base to give compounds of the general formula (I-D)

in which T, X, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹² each have the meanings given in Claim 1,

and this is reacted with acids or bases or, if T is benzyl, also hydrogenolytically into the corresponding carboxylic acids of the general formula (IE)

in which X, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹² each have the meanings given in Claim 1,

or

[B-2] first with trifluoromethanesulfonic anhydride in the presence of a base in compounds of the general formula (VIII)

in which T, X, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ each have the meanings given in Claim 1,

transferred and this in a coupling reaction with a compound of general formula (IX)

in which R ^{1 represents} (C ₆ -Cιo) aryl or 5- to 6-membered heteroaryl with up to three heteroatoms from the series N, O and / or S, which in turn each one to three times, identically or differently, by substituents selected from the group halogen, (C _\ - C ₆ ) -alkyl, (-C-C ₆ ) -alkoxy, trifluoromethyl, trifluoromethoxy, amino, mono- and di- (-C-C ₆ ) -alkylamino can be substituted, and

R ^{13 represents} hydrogen or methyl or both radicals together form a CH ₂ CH ₂ or C (CH ₃ ) ₂ -C (CH ₃ ) ₂ bridge,

in an inert solvent in the presence of a suitable palladium catalyst and a base to give compounds of the general formula (I-B).

7. Compounds of formula (I), as defined in claims 1 to 6, for the prevention and treatment of diseases.

8. Medicament containing at least one compound of formula (I) as defined in claim 1 or 6, and inert, non-toxic, pharmaceutically suitable carriers, auxiliaries, solvents, vehicles, emulsifiers and / or dispersants.

9. Use of compounds of formula (I) and medicaments, which are defined in claims 1 to 8, for the prevention and treatment of

Diseases.

10. Use of compounds of formula (I), as defined in claims 1 to 6, for the manufacture of medicaments.

11. Use of compounds of formula (I), as defined in claims 1 to 6, for the manufacture of medicaments for the prevention and treatment of coronary heart diseases, dyslipidemia and arteriosclerosis, for myocardial infarction prophylaxis and for the treatment of restenosis after coronary angioplasty or Stenting.

12. A method for the prevention and treatment of diseases, characterized in that compounds of the formula (I), as defined in claims 1 and 6, are allowed to act on living beings.