EP2569309A1 - Hydroxyalkyl benzyl pyrazoles, and use thereof for the treatment of hyperproliferative and angiogenic diseases - Google Patents

Abstract

The invention relates to novel 1-[3-(hydroxyalkyl)benzyl]-1H-pyrazole derivatives, methods for the production thereof, the use thereof for the treatment and/or prevention of diseases, and the use thereof for producing medicaments used for the treatment and/or prevention of diseases, in particular hyperproliferative and angiogenic diseases as well as diseases caused by metabolic adaptation to hypoxic conditions. Such treatments can be administered as monotherapy or in combination with other medicaments or other therapeutic measures.

Description

 HYDROXYALKYLBENZYL-PYRAZOLE AND THEIR USE FOR THE TREATMENT OF

HYPERPROLIFERATIVES AND ANGIOGENIC DISEASES

The present application relates to novel 1- [3- (hydroxyalkyl) benzyl] -lH-pyrazole derivatives, processes for their preparation, their use for the treatment and / or prevention of diseases and their use for the preparation of medicaments for the treatment and / or prevention of diseases, in particular for the treatment and / or prevention of hyperproliferative and angiogenic diseases as well as those diseases which arise through a metabolic adaptation to hypoxic conditions. Such treatments may be monotherapy or in combination with other medicines or other therapeutic measures.

Cancers are the result of uncontrolled cell growth of various tissues. In many cases, the new cells invade existing tissues (invasive growth) or they metastasize to distant organs. Cancers occur in various organs and often have tissue-specific disease courses. Therefore, the term cancer as a generic term describes a large group of defined diseases of various organs, tissues and cell types.

In 2002, 4.4 million people worldwide were diagnosed with tumors of the breast, bowel, ovaries, lungs or prostate. For the same year, approximately 2.5 million deaths were reported as a result of these conditions (Globocan 2002 Report). In the US alone, over 1.25 million new cases and more than 500,000 cancer deaths were predicted for 2005. The majority of these new cases involve cancers of the intestine (~ 100,000), lung (~ 170,000), breast (~ 210,000) and prostate (~ 230,000). A further 15% increase in cancer over the next 10 years is expected (American Cancer Society, Cancer Facts and Figures 2005).

If necessary, early stage tumors may be removed by surgical and radiotherapeutic measures. As a rule, metastatic tumors can only be treated palliatively by chemotherapeutic agents. The goal here is to achieve the optimal combination of improving the quality of life and extending the lifetime.

Chemotherapies often consist of combinations of cytotoxic drugs. The majority of these substances have a binding mechanism to tubulin, or they are compounds that interact with the formation and processing of nucleic acids. More recently, these include enzyme inhibitors that interfere with epigenetic DNA modification or cell cycle progression (eg, histone deacetylase inhibitors, Aurora kinase inhibitors). Since such therapies are toxic, more and more recently, targeted therapies are being used in which specific processes in the cell are blocked, without any high toxic load occurs. These include in particular inhibitors of kinases which inhibit the phosphorylation of receptors and signal transduction molecules. An example of this is imatinib, which is used very successfully for the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). Other examples include EGFR kinase and HER2 blocking substances such as erlotinib and VEGFR kinase inhibitors such as sorafenib and sunitinib, which are used in renal cell carcinoma, liver carcinoma and advanced stages of GIST.

An antibody directed against VEGF has succeeded in extending the life expectancy of colorectal carcinoma patients. Bevacizumab inhibits blood vessel growth, which hinders the rapid expansion of a tumor because it requires a connection to the blood vessel system for a continuously functioning supply and disposal.

One stimulus for angiogenesis is hypoxia, which occurs again and again in solid tumors, as the blood supply due to uncontrolled growth is inadequate. In oxygen depletion, cells convert their metabolism from oxidative phosphorylation to glycolysis to stabilize the ATP level in the cell. This process is controlled by a transcription factor that is up-regulated depending on the oxygen content in the cell. This "hypoxia-induced factor" (HIF) transcription factor is normally removed post translationally by rapid degradation and prevented from being transported to the nucleus. This is done by the hydroxylation of two proline units in the oxygen-degradable domain (ODD) and an asparagine unit near the C-terminus by the enzymes prolyl dehydrogenase and FIH ("factor inhibiting HIF"). Following modification of the proline moieties, HIF can be degraded via the proteasome apparatus via the Hippel Lindau protein (part of a ubiquitin E3 ligase complex) (Maxwell, Wiesener et al., 1999). In the absence of oxygen, breakdown is avoided, the protein is up-regulated and leads to the transcription or blockade of the transcription of numerous (more than 100) other proteins (Semenza and Wang, 1992, Wang and Semenza, 1995).

The transcription factor HIF is formed by the regulated a- and constitutively present aryl hydrocarbon receptor nuclear translocator (ARNT). There are three different species of the α-subunit, la, 2a and 3 a, the latter being more likely to be considered a suppressor (Makino, Cao et al., 2001). The HIF subunits are bHLH (basic helix loop helix) proteins that dimerize via their HLH and PAS (per-Arnt-Sim) domain, which starts their transactivating activity (Jiang, Rue et al., 1996 ). In the major tumor entities, overexpression of the HIF Ι α protein is correlated with increasing blood vessel density and increased VEGF expression (Hirota and Semenza, 2006). At the same time, the glucose metabolism is changed towards glycolysis, and the Krebs cycle is reduced in favor of the production of cell building blocks. This also implies a change in the fat metabolism. Such changes seem to ensure the survival of the tumors. On the other hand, if the activity of HIF is inhibited, then it would be possible to suppress the development of tumors. This has already been observed in several experimental models (Chen, Zhao et al, 2003, Stoeltzing, McCarty et al, 2004, Li, Lin et al, 2005, Mizukami, Jo et al, 2005, Li, Shi et al, 2006). Specific inhibitors of HIF-driven metabolism should therefore be useful as anticancer agents.

WO 2004/089303-A2 describes di-aiyl-substituted pyrazoles as mGluR5 modulators for the treatment of psychiatric disorders. WO-2010/072352-A1 and WO 2010/085584-A1 disclose 3-phenyl-5- (1H-pyrazol-4-yl) -1,4,4-oxadiazole derivatives as sulfinosin-1 - phosphate agonists for the treatment of autoimmune and vascular diseases. WO 2005/030121 -A2 and WO 2007/065010-A2 describe the usefulness of certain pyrazole derivatives for inhibiting the expression of HIF and HIF-regulated genes in tumor cells. In WO 2008/141731 -A2, heteroaryl-substituted N-benzylpyrazoles are disclosed as inhibitors of the HIF-regulation pathway for the treatment of coxious diseases. However, it has been shown that many of these compounds have insufficient inhibitory activity or, because of their pharmacokinetic properties in animal models, allow such a long half-life (> 48 h) in the human body that significant substance accumulation after repeated daily dosing is likely is.

It was therefore an object of the present invention to find new compounds and provide which act on the one hand as potent inhibitors of the transactivating effect of the transcription factor HIF and on the other hand have a pharmacokinetic profile that allows the repeated once daily administration without the simultaneous occurrence of a clinically relevant accumulation. Overall, such properties could lead to a broadening of the clinical applicability of these HIF inhibitors and in particular to facilitate their combinability with other active substances, such as, for example, classical tumor chemotherapeutics. This object is achieved by the compounds according to the invention described below. Structurally, this new group of N-benzylpyrazole derivatives is characterized by a hydroxyalkyl substituent in the 3-position of the benzyl head group, which surprisingly leads to an improved property profile of the compounds. In detail, the present invention relates to compounds of the general formula (I)

in which a group of the formula

stands in which

* denotes the point of attachment with the hydroxyl group, ** denotes the point of attachment to the phenyl ring,

R ^1A and R ^1B independently of one another are hydrogen, deuterium, methyl, hydroxymethyl or trifluoromethyl or are linked to one another and, together with the carbon atom to which they are bonded, are a cyclopropan-1, 1-diyl, cyclobutane-1,1-diyl Form oxetane-3,3-diyl or tetrahydro-2H-pyran-4,4-diyl ring,

R ^2A and R ^{2B are} independently hydrogen, deuterium, methyl or trifluoromethyl, and

R ^3A and R ^3B independently of one another denote hydrogen, fluorine, methyl, hydroxymethyl or trifluoromethyl or and together with the carbon atom to which they are attached, a cyclopropane-l, l -diyl, cyclobutane-l, l -diyl, oxetane-3,3-diyl or tetrahydro-2H-pyran-4 To form 4-diyl ring,

R ^{4 is} trifluoromethoxy, trifluoromethylsulfanyl, trifluoromethylsulfonyl, pentafluorosulfanyl, trimethylsilyl or a group of the formula stands in which

# denotes the point of attachment to the phenyl ring,

R ^5A and R ^5B independently of one another are hydrogen, fluorine, methyl, ethyl, propyl or isopropyl or are linked to one another and, together with the carbon atom to which they are attached, are a cyclopropane-1,1-diyl-, cyclobutane form l, l -diyl, cyclopentane-l, 1-diyl, cyclohexane-l, l -diyl, oxetane-3,3-diyl or tetrahydro-2H-pyran-4,4-diyl ring, and

R ^{6 is} hydrogen, fluorine, methyl, trifluoromethyl, methoxymethyl or ethoxymethyl, and

R ^{7 is} hydrogen, fluorine or methyl, and their salts, solvates and solvates of the salts.

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

A is a group of the formula stands in which

* denotes the point of attachment to the hydroxy group, ** denotes the point of attachment to the phenyl ring, and

R ^2A and R ^{2B are} both hydrogen or deuterium, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfanyl, pentafluorosulfanyl, trimethylsilyl or a group of the formula stands in which

# denotes the point of attachment to the phenyl ring,

R ^5A and R ^{5B are} both methyl or linked together and together with the carbon atom to which they are attached form a cyclopropane-1,1-diyl or tetrahydro-2H-pyran-4,4-diyl ring, and

R ^{6 is} fluorine, methyl or trifluoromethyl, and

R ^{7 is} hydrogen or fluorine, and their salts, solvates and solvates of the salts. Particularly preferred in the context of the present invention are compounds of the formula (I) in which

A is a group of the formula

stands in which

* the point of attachment with the hydroxy group and

** identify the point of attachment with the phenyl ring, R ^{4 represents} trifluoromethoxy, trifluoromethylsulfanyl or a group of the formula stands in which

# denotes the point of attachment to the phenyl ring, and

R ^{7 is} hydrogen, and their salts, solvates and solvates of the salts.

In another aspect, the present invention also encompasses certain prodrugs of the compounds of formula (I). In general, the term "prodrugs" hereby denotes covalent derivatives of the compounds of the formula (I) which themselves may be biologically active or inactive, but are converted during their residence time in the body by, for example, metabolic or hydrolytic routes to compounds of the formula (I). Another object of the present invention are accordingly compounds of the formula (I-PD)

in which

 A, R and R each have the meanings listed above and

 R is a prodrug group of the formula wherein

indicates the point of attachment to the oxygen atom,

Is hydrogen or (C 1 -C ₄ ) -alkyl, and

 R and R independently of one another are hydrogen or methyl, and their salts, solvates and solvates of the salts.

 Preferred in the context of the present invention are compounds of the formula (I-PD) in which

R for a prodrug group of the formula stands in which

## denotes the point of attachment to the oxygen atom and

R ^{8 is} methyl, isopropyl, isobutyl or sec-butyl, and ilire salts, solvates and solvates of the salts.

The compounds of formula (I-PD) are prodrugs of the compounds of formula (I) having good solubility in aqueous or other physiologically acceptable media; They also offer the possibility of salt formation with corresponding bases or acids, which can lead to a further increase in solubility. The compounds of the formula (I-PD) and their salts are therefore particularly suitable for intravenous administration. As a result, other therapeutic applications for these compounds could be developed. Compounds according to the invention are thus the compounds of the formulas (I) and (I-PD) and their salts, solvates and solvates of the salts, the compounds of the formulas (I) and (I-PD) of the formulas below and their salts, Solvates and solvates of the salts and those of the formulas (I) and (I-PD), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as in the of the formulas (I) and (I -PD), the compounds mentioned below are not already salts, solvates and solvates of the salts.

The compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including sol at atropisomers). The present invention therefore includes the enantiomers and diastereoisomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase. If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

The present invention also includes all suitable isotopic variants of the compounds of the invention. An isotopic variant of a compound according to the invention is understood here to mean a compound in which at least one atom within the compound according to the invention is exposed to another atom of the same atomic number but with a different atomic mass than the atomic mass, which usually or predominantly occurs in nature. exchanges. Examples of isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² H (deuterium), ³ H (tritium), ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ 0, ¹⁸ 0, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I and ¹³¹ I. Certain isotopic variants of a compound of the invention, such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example, for the study of the mechanism of action or drug distribution in the body; Due to the comparatively easy production and detectability, compounds labeled with ³ H or ¹⁴ C isotopes in particular are suitable for this purpose. Moreover, the incorporation of isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention. Isotopic variants of the compounds according to the invention can be prepared by generally customary processes known to the person skilled in the art, for example by the methods described below and the rules reproduced in the exemplary embodiments by using corresponding isotopic modifications of the respective reagents and / or starting compounds.

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

Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.

Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms, as exemplified and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, Triethanolamine, dicyclohexylamine, dimethylanine ethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

Solvates in the context of the invention are those fins of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.

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

(In the context of the invention, C 1 -C 4 -alkyl is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms, by way of example and by preference: methyl, ethyl, n-propyl, isopropyl, - butyl, isobutyl, sec-butyl, tert-butyl. butyl.

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

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

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

Another object of the present invention is a process for the preparation of the compounds of formulas (I) and (I-PD), characterized in that initially a N'-hydroxyamidine of the formula (II)

in which R ⁴ and R ^{7 have} the meanings given above, with a pyrazolecarboxylic acid of the formula (III)

in which R ⁴ and R ^{7 have} the meanings given above, then condensing the compound (IV) in the presence of a base with a compound of formula (V)

in which A has the meaning given above,

X is a leaving group such as chlorine, bromine, iodine, mesylate, triflate or tosylate, and

R ^{10 is} hydrogen or a conventional hydroxy protecting group such as acetyl, tetrahydropyranyl, trimethylsilyl, triisopropylsilyl, tert. Butyldimethylsilyl or tert. Butyl (diphenyl) silyl, to give a compound of formula (VI) in which A, R ⁴ , R ⁷ and R ¹⁰ each have the meanings given above, then, if present, the hydroxy protective group R ^{10 is} split off by customary methods and the resulting compound of the formula (I)

in which A, R ⁴ and R ^{7 have} the meanings given above, finally, if desired, with a compound of formula (VII)

R ^P - OH (VII) or an activated form of this compound in which R ^{PD has} the abovementioned meaning, according to known processes, into the prodrug compound of the formula (I-PD)

in which A, R ^PD , R ⁴ and R ^{7 in} each case have the abovementioned meanings, and converting the compounds of the formula (I) or (I-PD) thus obtained, if appropriate, into their enantiomers and / or diastereomers and / or with the corresponding (i) solvents and / or (ii) bases or acids in their solvates, salts and / or solvates of the salts. The condensation reaction (II) + (III) -> (IV) is preferably carried out with the aid of a carbodiimide, such as N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide (EDC), in conjunction with 1-hydroxy-1H-benzotriazole ( HOBt) as the active ester component, or with the aid of a phosgene derivative such as Ι, Γ-carbonyldiimidazole (CDI) in a high-boiling dipolar aprotic solvent such as N, N-dimethylformamide or dimethyl sulfoxide.

The initial coupling step in this reaction is generally carried out in a temperature range from 0 ° C to + 50 ° C; the cyclization to the 1,2,4-oxadiazole is then accomplished by subsequent heating of the reaction mixture to temperatures of + 100 ° C to + 150 ° C. The reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar); usually one works at normal pressure.

Inert solvents for process step (IV) + (V) -> (VI) are, for example, halogenated hydrocarbons, such as dichloromethane, trichloromethane, tetrachloromethane, trichlorethylene or chlorobenzene, ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4 - Dioxane, 1, 2-dimethoxyethane or bis (2-methoxyethyl) ether, hydrocarbons such as benzene, toluene, xylene, pentane, hexane, cyclohexane or petroleum fractions, or dipolar aprotic solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, NN Dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methyl-pyridinol (ΝΜΡ) or pyridine. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to using tetrahydrofuran or 1,4-dioxane. Suitable bases for the reaction (IV) + (V) - »(VI) are customary inorganic or organic bases. These include preferably alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali alcoholates such as sodium or potassium, sodium or potassium ethoxide or sodium or potassium feri.-butoxide, alkali metal hydrides such as sodium or potassium hydride, or amides such as Sodium amide, lithium or potassium bis (trimethylsilyl) amide or Lithiumdiisopro- pylamid. Preferably, potassium tert-butoxide is used. Optionally, the addition of an alkylation catalyst, such as, for example, lithium bromide, sodium or potassium iodide, tetra-n-butylammonium bromide or benzyltriethylammonium chloride, is advantageous.

The reaction is generally carried out in a temperature range from -20 ° C to + 100 ° C, preferably at 0 ° C to + 60 ° C. The reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar); usually one works at normal pressure.

Conventional methods for the removal of a hydroxy-protecting group R ¹⁰ include, for example, in ester derivatives, the basic or acidic hydrolysis or the reaction with organometallics (such as In the case of tetrahydropyranyl ethers, the acid hydrolysis and in the case of silyl ethers likewise the hydrolysis or the treatment with fluorides (such as, for example, potassium or tetra-n-butylammonium fluoride) [cf. eg TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999]. Activated forms of the compound (VII) which are suitable for the introduction of the prodrug group R ^PD [transformation (I) (I-PD)] are, for example, corresponding chlorides or anhydrides, including mixed anhydrides, or else certain ester or amide derivatives. In the remainder of R ^PD further existing hydroxyl or amino groups are expediently present in temporarily protected form and are then released at the end of the reaction sequence by conventional methods. As a protective group for a hydroxy function, benzyl is preferably used in this process step, which is removed again by hydrogenolysis, and as the amino protective group is tert-butoxycarbonyl which can be cleaved off by treatment with a strong acid such as hydrogen chloride or trifluoroacetic acid [see. eg M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, Springer-Verlag, Berlin, 1984; M. Bodanszky, Principles of Peptide Synthesis, Springer-Verlag, Berlin, 1993; TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999; see also the following Reaction Schemes 8-10].

Compounds of the formula (I) according to the invention can alternatively also be prepared by reacting the above-described compound of the formula (IV) first in the presence of a base with a compound of the formula (VIII)

in which X has the meaning given above and

Z generally represents a substituent or a functional group with the aid of which the above-defined hydroxyalkyl group HO-A- can be introduced or built up by subsequent chemical transformations to give a compound of the formula (IX) in which R ⁴ , R ⁷ and Z have the meanings given above, and then converted by taking place by literature methods transformations of the group Z into compounds of formula (I). The reaction (IV) + (VIII) -> ■ (IX) is carried out under similar reaction conditions with respect to solvent, base and temperature, as described above in process step (IV) + (V) -> (VI).

Examples of substituents or functional groups Z in formula (VIII) by means of which the hydroxyalkyl group HO-A- defined above can be introduced or built up are, on the one hand, halides such as bromide or iodide and, on the other hand, a carbonyl group-containing group Radicals such as alkoxycarbonyl, alkoxycarbonylalkyl, hydroxycarbonyl, hydroxycarbonylalkyl, formyl, alkylcarbonyl or alkylcarbonylalkyl. The subject transformations are carried out by known methods known to those skilled in the art and include, for example, reactions such as reduction with complex metal hydrides, 1,2-addition of organometallic compounds (eg Grignard compounds) to carbonyl compounds, hydroxylation, C-alkylation and C-acylation as well as the introduction and removal of temporary protective groups [see also the following Reaction Schemes 1 -7 and the preparation of the embodiments described in detail in the Experimental Part].

The compounds of formulas (II), (III), (V), (VII) and (VIII) are commercially available or described as such in the literature, or they may be published in a manner analogous to those skilled in the art in analogy to the literature Methods are produced. Many detailed instructions and references for the preparation of the starting materials can be found in the Experimental Section in the section on the Preparation of Starting Compounds and Intermediates.

The preparation of the compounds of the invention can be exemplified by the following reaction schemes: Scheme 1

 CDI

 or

EDC / HOBt

KO'Bu

KO'Bu

Scheme 2

KO'Bu

EtMgBr

KO'Bu

Scheme 3

Scheme 4

KO'Bu

1 eq. MeMgBr

LiAIH,

Scheme 5

 1. NaH

2. (EtO) ₂ CO

 1. NaH

2nd Mel

NaBH,

-22-

-23 -

Scheme 8

(RO) ₂ P (= 0) CI

or base [(RO) ₂ P (= 0)] ₂ 0

H ₂ , Pd / C or

Me ₃ SiBr

[R = phenyl or benzyi].

Scheme 9

tetrazole

 mCPBA

[see. Y. Watanabe et al, Tetrahedron Lett. 1990, 31 (2), 255-256].

Scheme 10

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

The compounds of the present invention are highly potent inhibitors of the HIF regulatory pathway. In addition, the compounds of the present invention have beneficial pharmacokinetic properties in terms of their volume of distribution and / or clearance and the half-life derived therefrom, making them suitable for repeated once daily dosing. Because of their active profile, the compounds according to the invention are particularly suitable for the treatment of hyperproliferative disorders in humans and in mammals in general. The compounds can inhibit, block, reduce or decrease cell proliferation and cell division and, on the other hand, enhance apoptosis.

The hyperproliferative diseases for the treatment of which the compounds according to the invention can be used include, among others, psoriasis, keloids, scarring and other proliferative diseases of the skin, benign diseases such as benign prostatic hyperplasia (BPH), and in particular the group of tumor diseases. These are under the in particular the following diseases: breast carcinomas and breast tumors (ductal and lobular forms, also in situ), respiratory tumors (small cell and non-small cell carcinoma, bronchial carcinoma), brain tumors (eg of the brainstem and hypothalamus , Astrocytoma, medulloblastoma, ependymoma as well as neuro-ectodermal and pineal tumors), tumors of the digestive organs (esophagus, stomach, gall bladder, small intestine, large intestine, rectum), liver tumors (including hepatocellular carcinoma, cholangiocarcinoma and mixed hepatocellular cholangiocarcinoma), tumors of the head and neck area (larynx, hypopharynx, nasopharynx, oropharynx, lips and oral cavity), skin tumors (squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer and non-melanoma skin cancer), tumors of the soft tissues (including soft tissue sarcomas, osteosarcomas, malignant fibrous Histiocytomas, lymphosarcomas and rhabdomyosarcomas), tumors of the eyes ( including intraocular melanoma and retinoblastoma), tumors of the endocrine and exocrine glands (eg thyroid and parathyroid glands, pancreas and salivary gland), tumors of the urinary tract (bladder, penile, renal, renal pelvis and ureteral tumors) and tumors of the reproductive organs (endometrium , Cervical, ovarian, vaginal, vulvar and uterine carcinomas of the female and prostate and testicular carcinomas of the male). These also include proliferative blood diseases in solid form and as circulating blood cells, such as lymphomas, leukemias and myeloproliferative disorders, for example acute myeloid, acute lymphoblastic, chronic lymphocytic, chronic myelogenous and hairy cell leukemia, as well as AIDS-correlated lymphomas, Hodgkin's lymphomas, Non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma and lymphoma in the central nervous system.

These well-described human diseases can also occur in other mammals with comparable aetiology and be treated there with the compounds of the present invention. The term "treatment" or "treating" is used conventionally within the context of this invention and means the care, care and supervision of a patient with the aim of combating, reducing, alleviating or alleviating a disease or health deviation and improving living conditions that are affected by this disease, such as cancer. The compounds according to the invention act as modulators of the HIF regulation pathway and are therefore also suitable for the treatment of diseases which are associated with a detrimental expression of the HIF transcription factor. This concerns in particular the transcription factors HIF-1 α and HIF-2a. The term "harmful expression of HIF" means a non-normal physiological presence of HIF protein. This may be due to excessive synthesis of the protein (mRNA- or translation-related), by reduced degradation or by insufficient counterregulation in the function of the transcription factor.

HIF-Ια and HIF-2a regulate more than 100 genes. This concerns proteins that play a role in angiogenesis and are therefore directly tumor-relevant, as well as those that influence the glucose, amino acid and lipid metabolism as well as cell migration, metastasis and DNA repair or by suppression of apoptosis survival improve the tumor cells. Others act more indirectly via inhibition of the immune response and upregulation of angiogenic factors in inflammatory cells. HIF also plays an important role in the stem cells, in particular the tumor stem cells, which are reported to have elevated HIF levels. Inhibition of the HIF-regulation pathway by the compounds of the present invention thus also therapeutically influences tumor stem cells which do not have a high proliferation rate and therefore are only insufficiently affected by cytotoxic substances (see Semenza, 2007, Weidemann and Johnson, 2008).

Changes in cellular metabolism by HIF are not exclusive to tumors, but also occur in other hypoxic pathophysiological processes, whether chronic or transient. HIF inhibitors - such as the compounds of the present invention - are therapeutically useful in those contexts in which, for example, adaptation of cells to hypoxic situations causes additional damage, as damaged cells, if not functioning properly, can cause further damage. An example of this is the formation of epileptic foci in partially destroyed tissue after strokes. The same is true of cardiovascular disease when ischemic processes occur in the heart or brain as a result of thromboembolic events, inflammation, wounding, intoxication or other causes. These can lead to damage such as a locally slowed down action potential, which in turn can cause arrhythmias or chronic heart failure. In transient form, e.g. Through apnea, it may under certain circumstances come to an essential increase in blood pressure, which can lead to known sequelae such as stroke and myocardial infarction.

The inhibition of the HIF-regulation pathway as achieved by the compounds according to the invention can therefore also be used in diseases such as cardiac insufficiency, arrhythmia, myocardial infarction, apnea-induced hypertension, pulmonary hypertension, transplantation ischemia, reperfusion damage, stroke and macular degeneration as well as for the recovery of the nerve function be helpful after traumatic injury or severance. Since HIF is one of the factors controlling the transition from an epithelial to a mesenchymal cell type, which is particularly important to the lung and kidney, the compounds of the present invention can also be used to augment HIF-associated lung and kidney fibroses prevent or curb. Other diseases for the treatment of which the compounds according to the invention can be used are inflammatory joint diseases, such as various forms of arthritis, as well as inflammatory bowel diseases, such as, for example, Crohn's disease.

Chugwash polycythemia is mediated by HIF-2a activity during erythropoiesis in, among other places, the spleen. The compounds according to the invention, as inhibitors of the HIF regulatory pathway, are therefore also suitable for suppressing the excessive formation of erythrocytes here and thus for alleviating the effects of this disease.

The compounds of the present invention may also be used to treat diseases associated with excessive or abnormal angiogenesis. These include diabetic retinopathy, ischemic retinal vein occlusion and retinopathy in preterm birth (see Aiello et al., 1994, Peer et al., 1995), age-related macular degeneration (AMD, Lopez et al., 1996), neovascular glaucoma, psoriasis , retrolental fibroplasia, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, /×.yfeni-restenosis and restenosis after vascular implantation.

Increased blood supply is also associated with cancerous neoplastic tissue, leading to accelerated tumor growth. In addition, the growth of new blood and lymph vessels facilitates the formation of metastases and thus the spread of the tumor. New lymphoid and blood vessels are also detrimental to allografts in immune-privileged tissues, such as the eye, which, for example, increases susceptibility to rejection. Compounds of the present invention can therefore also be used to treat any of the aforementioned diseases, e.g. by inhibiting growth or reducing the number of blood vessels. This can be achieved via inhibition of endothelial cell proliferation or other mechanisms to prevent or attenuate vascularization and via reduction of neoplastic cells by apoptosis.

In obesity, HIF-Ι α accumulates in the adipose tissue and thus leads to a HIF-mediated shift in the energy metabolism in the direction of glycolysis, so that more and more glucose is consumed as an energy carrier. At the same time this leads to a reduced fat metabolism and thus to an accumulation of fats in the tissue. The substances according to the invention Therefore, they are also suitable for the treatment of HIF-Ια-mediated accumulation of fats in tissue especially in obesity.

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

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

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

Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention. The compounds according to the invention can be used alone or as needed in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesired and unacceptable side effects. Another object of the present invention are therefore pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases.

For example, the compounds of the present invention can be combined with known anti-hyperproliferative, cytostatic or cytotoxic substances for the treatment of cancers. The combination of the compounds according to the invention with other substances which are commonly used for cancer therapy or else with radiation therapy is therefore particularly indicated since hypoxic regions of a tumor respond only slightly to the said conventional therapies, whereas the compounds of the present invention in particular exert their activity there.

Examples of suitable combination active ingredients are:

Aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole, anzmet, aranesp, arglabine, arsenic trioxide, aromasine, 5-azacytidine, azathioprine, BCG or tice-BCG, bestatin, betamethasone Acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, broxuridine, bortezomib, busulfan, calcitonin, campath, capecitabine, carboplatin, casodex, cefeson, celmoleukin, cerubidine, chlorambucil, cisplatin, cladribine, clodronic acid, cyclophosphamide, cytarabine, dacarbazine, Dactinomycin, DaunoXome, Decadron, Decadron Phosphate, Deles rogen, Denileukin Diftitox, Depomedrol, Deslorelin, Dexrazoxane, Diefhylstübestrol, Diflucan, Docetaxel, Doxifluridine, Doxomicin, Dronabinol, DW-166HC, Eligard, Elitek, Ellence, Emend, Epirubicin, Epoetin-alfa, Epogen, Eptaplatin, Ergamisole, Estrace, Estradiol, Estramustine Sodium Phosphate, Ethinylestradiol, Ethyol, Etidronic Acid, Etopophos, Etoposide, Fadrozole, Farston, Filgrastim, Finasteride, Fligrastim, Floxuridine, Fluconazole, Fludarabine, 5-Fluorodeoxyuridine Monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, formestane, Fosteabin, Fotemustin, fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron-hydroc hlorid, histrelin, hycamtin, hydrocorton, erythro-hydroxynonyladenine, hydiOxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, interferon alpha, interferon-alpha-2, interferon-alpha-2a, interferon-alpha-2β, interferon-alpha-nl, interferon-alpha -n3, interferon-beta, interferon-gamma-1α, interleukin-2, intron A, Iressa, irinotecan, cytril, lentinan sulfate, letrozole, leucovorin, leuprolide, leuprolide acetate, levamisole, levofolic acid calcium salt, levothroid, levoxyl , Lomustine, Lonidamine, Marinol, Mechlorethamine, Mecobalamin, Medroxyprogesterone Acetate, Megestrol Acetate, Melphalan, Menest, 6-Mercaptopurine, Mesna, Methotrexate, Metvix, Miltefosine, Minocycline, Mitomycin C, Mitotane, Mitoxantrone, Modrenal, Myocet, Nedaplatin, Neulasta, Neumega, Neupogen, Nilutamide, Nolvadex, NSC-631570, OCT-43, Octreotide, Ondansetron hydrochloride, Orapred, Oxaliplatin, Paclitaxel, Pediapred, Pegaspargase, Pegasys, Pentostatin, Picibanil, Pilocarpine hydrochloride, Pirarubicin, Plicamycin, Porfimer Nat rium, Prednimustin, Prednisolone, Prednisone, Premarin, Procarbazine, Procrit, Raltitrexed, Rebif, Rhenium-186-etidronate, Rituximab, Roferon-A, Romurtide, Salagen, Sandostatin, Sargramostim, Semustin, Sizofiran, Sobuzoxan, Solu-Medrol, Streptozocin, Strontium 89 chloride, Synthroid, Tamoxifen, Tanisulosine, Tasonermin, Tastolactone, Taxoter, Teceleukin, Temozolomide, Teniposide, Testosterone Propionate, Testred, Thioguanine, Thiotepa, Thyrotropin, Tiludronic Acid, Topotecan, Toremifene, Tositumomab, Tastuzumab, Teosulfan, Tretinoin, Trexal, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, virulizine, zinecard, zinostatin zestran, zofran; ABI-007, Acolbifen, Actimmun, Affinitak, Aminopterin, Arzoxifen, Asoprisnil, Atamestan, Atrasentan, Avastin, CCI-779, CDC-501, Celebrex, Cetuximab, Crisnatol, Cyproterone Acetate, Decitabine, DN-101, Doxorubicin MTC, dSLIM, dutasteride, edotecarin, eflornithine, exatecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium 166-DOTMP, ibandronic acid, interferon gamma, intron PEG, ixabepilone, keyhole limpet hemocyanin, L-651582, lanreotide , Lasofoxifen, Libra, Lonafamib, Miproxifen, Minodronate, MS-209, Liposomal MTP-PE, MX-6, Nafarelin, Nemorubicin, Neovastat, Nolatrexed, Oblimersen, Onko-TCS, Osidem, Paclitaxel polyglutamate, pamidronate disodium, PN-401, QS-21, quazepam, R-1549, raloxifene, ranpirnas, regorafenib, 13-dy-retinoic acid, satraplatin, seocalcitol, sorafenib, T-138067, tarceva, taxoprexin, thymosin alpha-1, tiazofurin, tipifamib, tirapazamine, TLK-286, toremifene, TransMID-107R, valspodar, vapreotide, vatalanib, verteporfin, vinflunine, Z-100, zoledronic acid, and combinations thereof.

In a preferred embodiment, the compounds of the present invention may be combined with anti-hyperproliferative agents, which may be by way of example, without being exhaustive:

Ammoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, bleomycin, busulfan, camptothecin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, 2 ', 2'-difluorodetoxycytidine, docetaxel, Doxorubicin (adriamycin), epirubicin, epothilone and its derivatives, erythro-hydroxynonyladenine, ethinyl estradiol, etoposide, fludarabine phosphate, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil, fluoxymesterone, flutamide, hexamethylmelamine, hydroxyurea, hydroxyprogesterone Caproster, idarubicin, ifosfamide, interferon, irinotecan, leucovorin, lomustine, mechlorethamine, medroxyprogesterone acetate, megestrol acetate, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitotane, mitoxantrone, paclitaxel, pentostatin, N-phosphonoacetyl L-aspartate (PALA), plicamycin, prednisolone, prednisone, procarbazine, raloxifene, semustine, streptozocin, tamoxifen, teniposide, testosterone propionate, thiogua nin, thiotepa, topotecan, trimethylmelamine, uridine, vinblastine, vincristine, vindesine and vinorelbine.

Promisingly, the compounds of the present invention can also be combined with biological therapeutics such as antibodies (eg, Avastin, Rituxan, Erbitux, Herceptin) and recombinant proteins, which additively or synergistically enhance the effects of inhibiting HIF signaling pathway transfer. Inhibitors of the HIF-regulatory pathway, such as the compounds of the present invention, may also produce positive effects in combination with other angiogenesis-targeted therapies, such as Avastin, axitinib, recentin, regorafenib, sorafenib, or sunitinib. Combinations with proteasome and mTOR inhibitors as well as antihormones and steroidal metabolic enzyme inhibitors are particularly suitable because of their favorable side effect profile. In general, the combination of compounds of the present invention with other cytostatic or cytotoxic agents may have the following aims: • improved efficacy in slowing down the growth of a tumor, reducing its size or even eliminating it completely compared to treatment with a single drug;

• the possibility of using the chemotherapeutic agents used in lower doses than in monotherapy;

• the possibility of a more tolerable therapy with fewer side effects compared to a single dose;

• the ability to treat a wider range of tumors;

• achieving a higher response rate to therapy; · A longer survival time of the patients compared to today's standard therapy.

In addition, the compounds of the invention may also be used in conjunction with radiotherapy and / or surgical intervention.

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

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

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

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

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

For the other routes of administration are suitable, for example Inhalation medicines (including powder inhalers, nebulizers), nasal drops, solutions or sprays, lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg plasters), milk, pastes, foams, powdered powders, implants or stents.

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

The compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. Such adjuvants include, but are not limited to, excipients (e.g., microcrystalline cellulose, lactose, mannitol), solvents (eg, liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (e.g., sodium dodecyl sulfate, polyoxysorbitol oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g. Albumin), stabilizers (eg antioxidants such as ascorbic acid), dyes (eg inorganic pigments such as iron oxides) and flavor and / or odoriferous agents. In general, it has proven to be advantageous, when administered parenterally, to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight, in order to achieve effective results. When administered orally, the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight. Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. So In some cases, it may be sufficient to make do with less than the abovementioned minimum quantity, while in other cases the above upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day. The following embodiments illustrate the invention. The invention is not limited to the examples.

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

A. Examples

Abbreviations and acronyms: abs. absolutely

 Ac acetyl

 AIBN 2,2'-azobis (isobutyronitrile)

aq. watery

 Example. Example

 Bu Butyl

about circa, about

 CDI 1, 1'-carbonyldiimidazole

 CI chemical ionization (in MS)

d doublet (by NMR)

d day (s)

 DAST diethylaminosulfur trifluoride

 TLC thin layer chromatography

 DCI direct chemical ionization (in MS)

dd doublet of doublet (by NMR)

 DMAP 4-N, N-dimethylaminopyridine

 DME 1, 2-dimethoxyethane

 DMF N, N-dimethylformamide

 DMSO dimethyl sulfoxide

dt doublet of triplet (by NMR)

d. Th. Of theory (in chemical yield)

 EDC N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride ee enantiomeric excess

 EI electron impact ionization (in MS)

eq. Equivalent (s)

 ESI electrospray ionization (in MS)

 Et ethyl

 GC gas chromatography

h hour (s)

 HOBt 1-Hydroxy-lH-benzotriazole hydrate

 HPLC high pressure, high performance liquid chromatography

^; Pr isopropyl LC-MS liquid chromatography-coupled mass spectrometry

LiHMDS lithium hexamethyldisilazide

 Literature (position)

m multiplet (by NMR)

mCPBA weta-chloroperbenzoic acid

 Me methyl

min minute (s)

 MPLC medium-pressure liquid chromatography (on silica gel;

Called chromatography ")

 Ms methanesulfonyl (mesyl)

 MS mass spectrometry

 NBS N-bromosuccinimide

 ΝΜΡ N-methyl-2-pyrrolidinone

 NMR nuclear magnetic resonance spectrometry

 Pd / C palladium on charcoal

 PEG polyethylene glycol

 Pr Propyl

quart quartet (by NMR)

quint quintet (by NMR)

R _f retention index (at DC)

 RT room temperature

R _t retention time (by HPLC)

s singlet (by NMR)

sept septet (by NMR)

t triplet (by NMR)

 TBAF tetra-n-butylammonium fluoride

^† Bu tert-butyl

 Tf trifluoro-ethylsulfonyl (triflyl)

 TFA trifluoroacetic acid

 THF tetrahydrofuran

 TIPS triisopropylsilyl

 UV ultraviolet spectroscopy

v / v volume to volume ratio (of a solution)

together HPLC. LC / MS and GC / MS methods:

Method 1 (LC / MSV.

Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Gemini 3μ 30 mm x 3.00 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A -> ^■ 3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 ml / min -> 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.

Method 2 (LC / MS):

Instrument: Micromass Quattro Micro MS with HPLC Agilent Series 1 100; Column: Thermo Hypersil GOLD 3μ 20mm x 4mm; Eluent A: 1 l of water + 0.5 ml of 50% strength formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% strength formic acid; Gradient: 0.0 min 100% A -> ^■ 3.0 min 10% A - 4.0 min 10% A -> 4.01 min 100% A (flow 2.5 ml / min) -> 5.00 min 100% A; Oven: 50 ° C; Flow: 2 ml / min; UV detection: 210 nm.

Method 3 (LC / MS):

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex syn ergi 2.5μ MAX-RP 100A Mercury 20mm x 4mm; Eluent A: 1 l of water + 0.5 ml of 50% strength formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A - »0.1 min 90% A -» 3.0 min 5% A -> 4.0 min 5% A - »4.01 min 90% A; Flow: 2 ml / min; Oven: 50 ° C; UV detection: 210 nm. Method 4 (LC / MS):

 Instrument: Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9μ 50mm x 1mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 0.1 min 90% A -> 1.5 min 10% A -> 2.2 min 10% A; Flow: 0.33 ml / min; Oven: 50 ° C; UV detection: 210 nm. Method 5 (LC / MS):

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1 100; Column: Phenomenex Synergi 2.5μ MAX-RP 100A Mercury 20mm x 4mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A - 0.1 min 90% A -> 3.0 min 5% A -> 4.0 min 5% A -> 4.1 min 90% A; Flow: 2 ml / min; Oven: 50 ° C; UV detection: 208-400 nm. Method 6 CLC / MS:

 Instrument: Waters Acquity SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8μ 50mm x 1mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A -> 1.2 min 5% A -> 2.0 min 5% A; Flow: 0.40 ml / min; Oven: 50 ° C; UV detection: 210-400 nm.

Method 7 (LC / MS:

Device Type MS: Waters ZQ; Device Type HPLC: Agilent 1100 Series; UV DAD; Column: Thermo Hypersil GOLD 3μ 20mm x 4mm; Eluent A: 1 l of water + 0.5 ml of 50% strength formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 100% A -> ^■ 3.0 min 10% A -> ^■ 4.0 min 10% A -> · 4.1 min 100% A (flow 2.5 ml / min); Oven: 55 ° C; Flow: 2 ml / min; UV detection: 210 nm.

Method 8 CLC / MS:

 Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Gemini 3μ 30 mm x 3.00 mm; Eluent A: 1 l of water + 0.5 ml of 50% strength formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A - »■ 2.5 min 30% A -» ■ 3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 ml / min -> 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.

Method 9 iGC / MS:

 Instrument: Micromass GCT, GC 6890; Column: Restek RTX-35, 15 m × 200 μιη x 0.33 μιη; constant flow with helium: 0.88 ml / min; Oven: 70 ° C; Inlet: 250 ° C; Gradient: 70 ° C, 30 ° C / min -> 310 ° C (hold for 3 min).

Method 10 (analytical HPLC):

Instrument: HP 1100 with DAD detection; Column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 μιη; Eluent A: 5 ml perchloric acid (70%) / 1 water, eluent B: acetonitrile; Gradient: 0 min 2% B ^»■ 0.5 min 2% B - 4.5 min 90% B -> 6.5 min 90% B -> 6.7 min 2% B -> 7.5 min 2% B; Flow: 0.75 ml / min; Column temperature: 30 ° C; UV detection: 210 nm.

Method 11 (preparative HPLC):

Column: Grom-Sil 120 ODS-4 HE, 10 μm, 250 mm × 30 mm; Mobile phase and gradient program: acetonitrile / 0.1% aq. Formic acid 10:90 (0-3 min), acetonitrile / 0.1% aq. Formic acid 10: 90- » ^■ 95: 5 (3-27 min), acetonitrile / 0.1% aq. Formic acid 95: 5 (27-34 min), acetonitrile / 0.1% aq. Formic acid 10:90 (34-38 min); Flow: 50 ml / min; Temperature: 22 ° C; UV detection: 254 nm.

Method 12 (preparative HPLC):

 Column: Daiso C18 Bio Spring Column, 10 μm, 300 mm × 100 mm; Eluent and gradient program: water / methanol 80:20 (0-6 min), water / methanol 80:20 -> 20:80 (6-60 min), water / methanol 20:80 (60-95 min), Water / methanol 10:90 (95-105 min), water / methanol 80:20 (105-113 min); Flow: 250 ml / min; Temperature: 25 ° C; UV detection: 240 nm.

Method 13 (preparative HPLC):

 Column: Reprosil-Pur C18, 10 μm, 250 mm × 30 mm; Eluent and gradient program: acetonitrile / 0.1% aq. Formic acid 10:90 (0-3 min), acetonitrile / 0.1% aq. Formic acid 10:90 - »95: 5 (3-27 min), acetonitrile / 0.1%) aq. formic acid 95: 5 (27-34 min), acetonitrile / 0.1%> aq. formic acid 10:90 (34-38 min); Flow: 50 ml / min; Temperature: 22 ° C; UV detection: 254 nm.

Method 14 (preparative HPLC):

 Column: YMC-ODS-AQ, C18, 10 μm, 30 mm × 250 mm; Eluent and gradient program: methanol / 0.1% aq. TFA 50:50 (0: 00-4: 25 min) -> 70:30 (4: 25-4: 50 min) -> 90:10 (4: 50-1 1: 50 min) -> 100: 0 (1: 50-12: 00 min) -> 100: 0 (12: 00-14: 50 min); Flow: 50 ml / min; Temperature: 22 ° C; UV detection: 210 nm.

Method 15 (preparative HPLC):

 Column: YMC-ODS-AQ, C18, 10 μm, 30 mm × 250 mm; Mobile phase and gradient program: methanol / 0.1% aq. TFA 60:40 (0: 00-4: 25 min) 80:20 (4: 25-4: 50 min) 100: 0 (4: 50-1 1: 50 min ) -> 100: 0 (1: 50-14: 50 min); Flow: 50 ml / min; Temperature: 22 ° C; UV detection: 210 nm.

Method 16 (preparative HPLC):

 Column: Sunfire C18 OBD, 5 μιη, 20 mm x 250 mm; Mobile phase: what s he / methanol / 1% aq. TFA 20: 75: 5 (0: 00-7: 00 min); Flow: 25 ml / min; Temperature: 40 ° C; UV detection: 210 nm. Method 17 (preparative HPLC):

Column: Reprosil C18, 10 μm, 250 mm × 30 mm; Mobile phase and gradient program: acetonitrile / 0.1% aq. Ammonia 20:80 (0-3 min), acetonitrile / 0.1% aq. Ammonia 20:80 -> 98: 2 (3-35 min), acetonitrile / 0.1% aq. Ammonia 98: 2 (35-40 min); Flow: 50 ml / min; Temperature: 22 ° C; UV detection: 210 nm. Method 18 (preparative HPLC):

 Column: Sunfire C18 OBD, 5 μηι, 20 mm x 250 mm; Mobile phase: water / acetonitrile / 1% aq. TFA 24:70:06 (0: 00-14: 00 min); Flow: 25 ml / min; Temperature: 40 ° C; UV detection: 210 μm.

Method 19 iGC / MS):

Instrument: Thermo DFS, Trace GC Ultra; Column: Restek RTX-35, 15 m × 200 μιη x 0.33 μιη; constant flow with helium: 1.20 ml / min; Oven: 60 ° C; Inlet: 220 ° C; Gradient: 60 ° C, 30 ° C / min -> 300 ° C (hold for 3.33 min).

For all reactants or reagents, the preparation of which is not explicitly described below, it is true that they were obtained commercially from generally available sources. For all other reactants or reagents, the preparation of which is also not described below and which were not commercially available or obtained from sources that are not generally available, reference is made to the published literature describing their preparation.

Starting Compounds and Intermediates: Example 1A

N'-hydroxy-4- (1,1-trifluoro-2-methyl-2-pi-2-yl) benzenecarboximidamide

Step 1: 2- (4-Bromophenyl) -1,1-trifluoropropan-2-ol

First, a suspension of dichloro (dimethyl) titanium in a heptane / dichloromethane mixture was prepared as follows: 100 ml (100 mmol) of a 1 M solution of titanium tetrachloride in dichloromethane was cooled to -30 ° C., 100 ml (100 mmol) was added dropwise. a 1 M solution of dimethylzinc in heptane and stirred for 30 min at -30 ° C after. Subsequently, this suspension was cooled to -40 ° C and a solution of 10 g (39.5 mmol) l- (4-bromophenyl) -2,2,2-trifluoro -ethanone added in 50 ml of dichloromethane. The mixture was stirred for 5 min at -40 ° C, then allowed to come the temperature to RT and stirred for a further 2 h at RT. While cooling with ice, 50 ml of water were slowly added dropwise and then diluted with a further 300 ml of water. It was extracted twice with dichloromethane, the combined dichloromethane phases were washed once with water, dried over anhydrous magnesium sulfate, filtered and the solvent removed on a rotary evaporator. The residue was purified by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate 85:15). There were obtained 10.5 g (100% of theory) of the title compound, which according to Ή-NMR still residues of solvent were included. 'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7:52 (d, 2H), 7:47 (d, 2H), 1.76 (s, 3H).

LC / MS (Method 1, ESIpos): R _t = 2.27 min, m / z = 268 [M + H] ⁺ . Step 2: 2- (4-Bromophenyl) -1,1,1-trifluoropropan-2-ylmethanesulfonate

3.12 g (78.05 mmol, 60% in mineral oil) of sodium hydride in 45 ml of THF were added under argon, and a solution of 10.5 g (39.03 mmol) of the compound obtained in Example 1A / step 1 in 20 ml of THF was added dropwise RT added. After stirring at RT for 1 h and at 40 ° C. for 30 min, a solution of 8.94 g (78.05 mmol) of methanesulfonyl chloride in 45 ml of THF was added dropwise and the reaction mixture was stirred at 40 ° C. for a further 60 min. Then, 50 ml of water were slowly added dropwise to the mixture, diluted with saturated aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous magnesium sulfate, filtered and the solvent removed on a rotary evaporator. The residue was stirred in hexane and the resulting solid filtered off and dried in vacuo. 12.4 g (92% of theory) of the title compound were obtained.

Ή NMR (400 MHz, CDCl ₃ , δ / ppm): 7.58 (d, 2H), 7.43 (d, 2H), 3.16 (s, 3H), 2.28 (s, 3H).

LC / MS (Method 2, ESIpos): R _t = 2.32 min, m / z = 364 [M + NH ₄ ] ⁺ . Step 3: 1-Bromo-4- (1, 1, 1-trifluoro-2-methyl-2-pi-2-yl) benzene

12.4 g (35.72 mmol) of the compound obtained in Example 1A / Step 2 were initially charged in 250 ml of dichloromethane and the mixture was cooled to 0 ° C. 35.7 ml (71.44 mmol) of a 2 M solution of trimethylaluminum at 0 ° C. were then slowly added dropwise with stirring, then the mixture was allowed to come to RT and stirring was continued for a further 1.5 h at RT. 120 ml of a saturated aqueous sodium bicarbonate solution and then 40 ml of a saturated aqueous sodium chloride solution were added dropwise slowly to the mixture. It was filtered through diatomaceous earth and washed the diatomaceous earth twice with dichloromethane. The combined dichloromethane phases were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and removed the solvent on a rotary evaporator. There were 8.69

Title compound obtained in 95% purity.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7.49 (d, 2H), 7:33 (d, 2H), 1:55 (s, 6H).

LC / MS (Method 3, ESIpos): R _t = 2.54 min, no ionization.

GC / MS (Method 9, EI): R _t = 3.48 min, m / z = 266 [M] ⁺ .

Step 4: 4- (1,1,1-trifluoro-2-methylpropan-2-yl) benzenecarbonitrile

3.34 g (12.50 mmol) of the compound obtained in Example 1 A / Step 3 were dissolved in 2.5 ml of degassed DMF under argon, 881 mg (7.50 mmol) of zinc cyanide and 867 mg (0.75 mmol) of tetrakis (triphenylphosphine) palladium (0). and rinsed overnight at 80 ° C. After cooling to RT, the reaction mixture was diluted with ethyl acetate and filtered solid components. The filtrate was washed twice with 2N aqueous ammonia solution and once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and freed from the solvent on a rotary evaporator. The residue was purified by column chromatography on silica gel (mobile phase: cyclohexane, ethyl acetate 85:15). There was obtained 2.08 g (78% of theory) of the title compound.

H-NMR (400 MHz, CDCl ₃ , δ / ppm): 7.68 (d, 2H), 7.62 (d, 2H), 1.60 (s, 6H).

GC / MS (Method 9, El): R _t = 3.83 min, m / z = 213 [M] ⁺ .

Step 5: N'-Hydroxy-4- (1,1,1-trifluoro-2-methylpropan-2-yl) berizolcarboxiinidamide

A mixture of 2.40 g (1.26 mmol) of the compound of Example 1A / Step 4, 1.72 g (24.77 mmol) of hydroxylamine hydrochloride and 3.45 mL (24.77 mmol) of triethylamine in 60 mL of ethanol was stirred at reflux for 1 h. After cooling to RT, the solvent was removed on a rotary evaporator. The residue was combined with ethyl acetate and the resulting solid was filtered off. The ethyl acetate solution was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. After removal of the solvent, the resulting oil was triturated with petroleum ether. After aspirating the resulting solid and drying in a high vacuum, 2.65 g (96% of theory) of the title compound were obtained. 'H-NMR (400 MHz, CDCL, δ / ppm): 8.0 (s, broad, 1H), 7.62 (d, 2H), 7.52 (d, 2H), 4.88 (s, broad, 2H), 1.60 ( s, 6H).

LC / MS (Method 2, ESIpos): R _t = 1.34 min, m / z = 247 [M + H] ⁺ . Example 2A

4- (2-fluoro propan-2-yl) -N'-hydroxybenzenecarboximidamide

4- (2-fluoro propan-2-yl) benzenecarbonitrile

To a solution of 1.00 g (6.20 mmol) of 4- (2-hydroxypropan-2-yl) benzenecarbonitrile [obtained from 4- (propan-2-yl) benzene carbonitrile according to JL Tucker et al, Synth. Comm. 2006, 36 (15), 2145-2155] in 20 ml of dichloromethane were added 1.20 g (7.44 mmol) of diethylaminosulfur trifluoride (DAST) at a temperature of 0 ° C. The reaction mixture was stirred for 2 h at RT and then diluted with water and extracted with dichloromethane. The organic phase was washed with water, dried over anhydrous magnesium sulfate and filtered. After removing the Solvent on a rotary evaporator, the residue was purified by MPLC (silica gel, eluent: cyclohexane / ethyl acetate 95: 5). 675 mg (67% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7.57 (d, 2H), 7:48 (d, 2H), 1.72 (s, 3H), 1.68 (s, 3H). LC / MS (Method 2, ESIpos): R _t = 2.12 min, m / z = 163 [M + H] ⁺ .

Step 2: 4- (2-fluoropropan-2-yl) -N'-hydroxybenzenecarboximidamide

According to the procedure described under Example 1A / step 5, from 675 mg (4.14 mmol) of the compound from Example 2A / step 1, 756 mg (93% of theory) of the title compound were obtained. 'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7.62 (d, 2H), 7:41 (d, 2H), 4.89 (s, broad, 2H), 1.72 (s, 3H), 1.68 (s, 3H).

LC / MS (Method 2, ESIpos): R _t = 1.04 min, m / z = 197 [M + H] ⁺ . Example 3A

N'-hydroxy-4 - benzenecarboximidamide [(trifluoromethyl) sulfonyl]

4.60 g (19.56 mmol) of 4 - [(trifluoromethyl) sulfonyl] benzenecarbonitrile [W. Su, Tetrahedron. Lett. 1994, 35 (28), 4955-4958] 5.08 g (97% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.26 (s, 1H), 8.13 (dd, 4H), 6.12 (s, 2H). LC / MS (Method 2, ESIpos): R, = 1.57 min, m / z = 269 [M + H] ⁺ . Example 4A

4- (3-fluorooxetane-3-yl) -N'-hydroxybenzenecarboximidamide

Under inert conditions, a solution of 5.0 g (21.8 mmol) 4-iodobenzonitrile in 100 ml of anhydrous THF was added dropwise at -40 ° C with 11 ml (21.8 mmol) of a 2 M solution of isopropyl magnesium chloride in diethyl ether. After the mixture had been stirred at the same temperature for 1.5 h, it was cooled to -78 ° C and cannulatively added to a solution of 2.95 g (32.7 mmol, 80% in dichloromethane) of 3-oxooxetane also cooled to -78 ° C [G. Wuitschik et al, Angew. Chem. Int. Ed. Engl. 2006, 45 (46), 7736-7739] in 100 ml of anhydrous THF. After completion of the addition, the reaction mixture was stirred for 10 min at -78 ° C, then for 2 h at 0 ° C and finally for 30 min at RT. It was then mixed with a few ml of saturated aqueous ammonium chloride solution. Subsequently, the solvent was largely removed on a rotary evaporator. The resulting residue was diluted with 200 ml of water and extracted three times with about 200 ml of ethyl acetate. The combined organic extracts were washed successively with water and saturated brine. After drying over anhydrous magnesium sulfate, it was filtered and the solvent removed on a rotary evaporator. The crude product obtained was purified by crystallization from cyclohexane / ethyl acetate 10: 1. 2.42 g (63% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-cL, δ / ppm): 7.88 (d, 2H), 7.80 (d, 2H), 6.63 (s, 1H), 4.79 (d, 2H), 4.65 (d, 2H ). HPLC (Method 10): R _t = 3.09 min.

MS (DCI, NH _3): m / z = 193 [M + NH _4] ^+.

Step 2: 4- (3-Fluorooxetan-3-yl) benzenecarbonitrile

Under inert conditions, a suspension of 600 mg (3.43 mmol) of the compound from Example 4A / step 1 in 55 ml of dichloromethane was added dropwise at -78 ° C. to a solution of 662 mg (4.11 mmol) of diethylaminosulfur trifluoride (DAST) in 5 ml of dichloromethane , After 30 min at -78 ° C, the reaction mixture was heated very quickly to -20 ° C with the aid of an ice / water bath. After about 30 seconds, 20 ml of 1 M sodium hydroxide solution were added and the mixture was allowed to warm to rt. After dilution with 150 ml of water was extracted three times with about 50 ml of diethyl ether. The combined organic extracts were dried over anhydrous magnesium sulfate. After filtration, the solvent was removed on a rotary evaporator. The crude product was purified by MPLC (silica gel, eluent: cyclohexane / ethyl acetate 8: 1). 495 mg (82% of theory) of the title compound were obtained. 'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7.76 (d, 2H), 7.73 (d, 2H), 5.15 (dd, 2H), 4.81 (dd, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.59 min, m / z = 178 [M + H] ⁺ .

Step 3: 4- (3-Fluorooxetan-3-yl) -N'-hydroxybenzenecarboximidamide

450 mg (2.54 mmol) of the compound from Example 4A / Step 2 gave 470 mg (86% of theory) of the title compound by the method described under Example 1 A / Step 5. 'H-NMR (400 MHz, DMSO-de, δ / ppm): 9.71 (s, 1H), 7.77 (d, 2H), 7.54 (d, 2H), 5.87 (broad s, 2H), 4.97 (dd, 2H), 4.91 (dd, 2H).

HPLC (Method 10): R _t = 2.64 min.

MS (DCI, NH _3): m / z = 211 [M + H] ^+. LC / MS (Method 2, ESIpos): R _t = 0.80 min, m / z = 211 [M + H] ⁺ .

Example 5A

4- (4-fluoro tetrahydro-2H-pyran-4-yl) -N'-hydroxybenzenecarboximidamide

Step 1: 4- (4-Hydroxytetrahydro-2H-pyran-4-yl) benzenecarbonitrile

25.0 g (109 mmol) of 4-iodobenzonitrile with 16.4 g (164 mmol) of tetrahydro-4H-pyran-4-one were added to 7.56 g (34% of theory) of the method described under Example 4A / step 1 Title compound implemented. ¹ H-NMR (400 MHz, DMSO-de, δ / ppm): 7.80 (d, 2H), 7.70 (d, 2H), 5.30 (s, 1H), 3.81-3.70 (m, 4H), 2.02-1.94 (m, 2H), 1.51-1.48 (m, 2H).

HPLC (Method 10): R _t = 3.35 min.

MS (DCI, NH ₃ ): m / z = 204 [M + H] ⁺ , 221 [M + NH ₄ ] Step 2: 4- (4-fluorotetrahydro-2H-pyran-4-yl) benzenecarbonitrile

Following the procedure described in Example 4A / Step 2, 6.5 g (31.98 mmol) of the compound from Example 5A / Step 1 were converted to 3.73 g (57% of theory) of the title compound. 'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7.68 (d, 2H), 7.50 (d, 2H), 3.98-3.83 (m, 4H), 2:23 to 2:05 (m, 2H), 1.91- 1.85 (m, 2H).

HPLC (Method 10): R _t = 4.04 min.

MS (DCI, NH _3): m / z = 223 [M + NH _4] ^+.

Step 3: 4- (4-fluorotetrahydro-2H-pyran-4-yl) -N'-hydroxybenzenecarboximidamide

3.5 g (17.05 mmol) of the compound from Example 5A / step 2 gave 3.57 g (88% of theory) of the title compound by the method described under Example 1A / step 5.

Ti NMR (500 MHz, DMSO-de, δ / ppm): 9.64 (s, 1H), 7.70 (d, 2H), 7.44 (d, 2H), 5.81 (s, 2H), 3.88-3.83 (m, 2H), 3.73-3.67 (m, 2H), 2.23-2.06 (m, 2H), 1.87-1.81 (m, 2H). HPLC (Method 10): R _t = 3.06 min.

MS (DCI, NH _3): m / z = 239 [M + H] ^+.

LC / MS (Method 4, ESIpos): R _t = 0.40 min, m / z = 239 [M + H] ⁺ . Example 6A

4-cyclohexyl-N'-hydroxybenzenecarboximidamide

Analogously to the process described under Example 1A / step 5, 240 mg (1.29 mmol) of 4-cyclohexylbenzenecarbonitrile [E. Riguet et al, J. Organomet. Chem., 2001, 624 (1-2), 376-379], 252 mg (89% of theory) of the title compound were obtained. ¹ H-NMR (400 MHz, DMSO-de, δ / ppm): 9.51 (s, 1H), 7.56 (d, 2H), 7.20 (d, 2H), 5.72 (s, broad, 2H), 2.52-2.48 (m, 1H), 1.81-1.74 (m, 4H), 1.73-1.67 (m, 1H), 1.45-1.31 (m, 4H), 1.28-1.19 (m, 1H). LC / MS (Method 5, ESIpos): R _t = 1.24 min, m / z = 219 [M + H] ⁺ . Example 7A

N'-hydroxy-4- (pentafluoro-λ ⁶ -sulfanyl) benzenecarboximidamide

Analogously to the process described under Example 1A / step 5, from 5.00 g (21.8 mmol) 4- (pentafluoro- ^6- sulfanyl) benzenecarbonitrile [PJ. Crowley et al., Chimia 2004, 58 (3), 138- 142]. 5.50 g (96% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 9.99 (s, 1H), 7.94-7.85 (m, 4H), 6.00 (s, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.49 min, m / z = 263 [M + H] Example 8A

N'-hydroxy-4 - [(trifluoromethyl) sulfanyl] ^ benzolcarboxin DAMID

Analogously to the process described under Example 1A / step 5, 5.98 g (25.6 mmol) of 4 - [(trifluoromethyl) sulfanyl] benzenecarbonitrile gave 5.98 g (97% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 9.90 (s, 1H), 7.80 (d, 2H), 7.72 (d, 2H), 5.94 (s, 2H). LC / MS (Method 2, ESIpos): R _t = 1.42 min, m / z = 237 [M + H] ⁺ . Example 9A N'-hydroxy-4- (trimethylsilyl) benzenecarboximidamide

Analogously to the process described under Example 1A / step 5, from 2.10 g (11.9 mmol) of 4- (trimethylsilyl) benzenecarbonitrile [P. Raddo et al., J. Chem. Soc. Chem. Commun. 1984 (3), 159-160] 2.20 g (91% purity, 80% of theory) of the title compound. 'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7.95 (s, broad, 1H), 7.60 (d, 2H), 7:55 (d, 2H), 4.86 (s, broad, 2H), 0:27 ( s, 9H).

LC / MS (Method 6, ESIpos): R _t = 0.75 min, m / z = 209 [M + H] ⁺ . Example 10A

4- (1-fluorocyclobutyl) -N'-hydroxybenzenecarboximidamide

4- (1-hydroxycyclobutyl) benzenecarbonitrile

Analogously to the procedure described under Example 4A / step 1 were from 15.00 g (65.5 mmol) of 4-iodobenzonitrile, 34.4 ml (68.8 mmol) of isopropylmagnesium chloride solution (2 M in diethyl ether) and 7.4 ml (98.2 mmol) of cyclobutanone 9.47 g (83% of theory) of the title compound. The product was purified by MPLC (silica gel, mobile phase: cyclohexane / ethyl acetate 10: 1 → 4: 1).

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7.67 (d, 2H), 7.62 (d, 2H), 2:58 to 2:51 (m, 2H), 2:44 to 2:37 (m, 2H), 2.23- 2.04 (m, 2H), 1.83-1.72 (m, 1H).

HPLC (Method 10): R _t = 3.47 min.

MS (DCI, NH _3): m / z = 191 [M + NH _4] ^+.

Step 2: 4- (1-fluorocyclobutyl) benzenecarbonitrile

Analogously to the process described under Example 4A / Step 2, from 2.00 g (1.5 mmol) of the compound from Example 10A / Step 1 and 1.8 ml (13.9 mmol) of diethylaminosulfur trifluoride (DAST) 1.39 g (69% of theory) of th .) Of the title compound. The product was purified by MPLC (silica gel, mobile phase: cyclohexane / ethyl acetate 10: 1 ^→ 5: 1). 'H-NMR (400 MHz, CDC1 ₃ , δ / ρρηι): 7.69 (d, 2H), 7.57 (d, 2H), 2.78-2.62 (m, 2H), 2.58-2.48 (m, 2H), 2.20- 2.09 (m, 1H), 1.87-1.75 (m, 1H).

GC / MS (Method 9, EIpos): R _t = 4.71 min, m / z = 155 [M-HF] ⁺ .

Step 3: 4- (1-Fluorocyclobutyl) -N'-hydroxybenzenecarboximidamide

Analogously to the process described under Example 1 A / Step 5, starting from 1.25 g (7.13 mmol) of the compound from Example 10A / Step 2, 1.16 g of the title compound (78% of theory) were obtained.

'H-NMR (400 MHz, CDCl ₃ , δ / ppm): 7.67 (d, 2H), 7.50 (d, 2H), 4.87 (s, broad, 2H), 2.72-2.52 (m, 5H), 2.16- 2.05 (m, 1H), 1.82-1.71 (m, 1H).

HPLC (Method 10): R _t = 3.17 min.

MS (DCI, NH _3): m / z = 209 [M + H] ^+.

Example IIA

N'-hydroxy-4- (tetrahydro-2H-pyran-4-yl) berizolcarboxirnidamid

Step 1: 4- (Tetrahydro-2H-pyran-4-yl) benzonitrile

A solution of 2.91 g (19.8 mmol) of 4-cyanophenylboronic acid [M. Nishimura et al, Tetrahedron 2002, 58 (29), 5779-5788] in 20 ml of isopropanol was charged with 186 mg (0.594 mmol) of nickel (II) iodide, 90 mg (0.594 mmol) of 2-aminocyclohexanol hydrochloride hydrochloride and 3.63 g (19.8 mmol) of sodium hexamethyldisilazide. The suspension thus obtained was stirred for 5 min at RT under an argon atmosphere. Then, 2.1 g (9.90 mmol) of 4-iodotetrahydropyran [Heuberger et al., J. Chem. Soc. 1952, 910] added. After the reaction mixture had been stirred for 15 h at a temperature of 75 ° C, it was cooled to RT and largely freed from inorganic salts with dichloromethane by filtration over about 50 g of silica gel. The crude product was purified by MPLC (silica gel, eluent: dichloromethane). There were thus obtained 986 mg (53% of theory) of the title compound.

Ή NMR (400 MHz, CDCl ₃ , δ / ρρηι): 7.60 (d, 2H), 7.32 (d, 2H), 4.12-4.07 (m, 2H), 3.56-3.50 (m, 2H), 2.87-2.79 (m, 1H), 1.86-1.73 (m, 4H). GC / MS (Method 9, EIpos): R _t = 5.97 min, m / z = 187 [M] ⁺ .

Step 2: N'-Hydoxy-4- (tetrahydro-2H-pyran-4-yl) benzenecarboximidamide

Analogously to the process described under Example 1A / step 5, 480 mg (2.56 mmol) of the compound from Example I IA / step 1 were converted to 525 mg (93% of theory) of the title compound. 'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7:58 (d, 2H), 7.26 (d, 2H), 6.79 (broad, 1H), 4.82 (s, broad, 2H), 4:11 to 4:05 ( m, 2H), 3.57-3.50 (m, 2H), 2.83-2.74 (m, 1H), 1.87-1.73 (m, 4H).

LC / MS (Method 2, ESIpos): R _t = 0.92 min, m / z = 221 [M + H] ⁺ . Example 12A

N'-hydroxy-4-isobutylbenzolcarboximidamid

Step 1: 4-Isobutylbenzonitrile

Under inert, oxygen-free conditions, a mixture of 5.0 g (23.5 mmol) 1-bromo-4-isobutylbenzene, 3.14 g (26.7 mmol) zinc cyanide, 963 mg (2.35 mmol) dicyclohexyl- (2 ', 6'-dimethoxybiphenyl) 2-yl) phosphine and 1.08 g (1.17 mmol) of tris (dibenzylideneacetone) dipalladium in 230 ml of DMF / water (99: 1) for 1 h at 120 ° C heated. After cooling to RT, it was diluted with about 1000 ml of water and extracted three times with about 150 ml of ethyl acetate each time. The combined organic extracts were washed successively with water and saturated brine. After drying over anhydrous magnesium sulfate, it was filtered and the filtrate was freed from the solvent on a rotary evaporator. The residue obtained was purified by suction filtration through silica gel with cyclohexane / ethyl acetate 10: 1 as eluent. 3.04 g (81% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 _3, δ / ppm) 7.56 (d, 2H), 7.23 (d, 2H), 2:53 (d, 2H), 1.94-1.83 (m, 1H), 0.90 (d, 6H).

GC / MS (Method 9, EIpos): R _t = 4.05 min, m / z = 159 [M] ⁺ . Step 2: N'-hydroxy-4-isobutyl-anizolecarboximidamide

Analogously to the process described under Example 1A / Step 5, 3.03 g (19.0 mmol) of the compound from Example 12A / Step 1 were converted to 3.39 g (93% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 9.53 (s, 1H), 7.57 (d, 2H), 7.14 (d, 2H), 5.74 (broad, 2H), 2.46 (d, 2H ), 1.89-1.79 (m, 1H), 0.87 (d, 6H). LC / MS (Method 6, ESIpos): R _t = 0.68 min, m / z = 193 [M + H] ⁺ .

Example 13A

N'-hydroxy-4-isopropylbenzolcarboximidamid

Analogously to the process described under Example 1A / step 5, 4.65 g (94% purity, 71% of theory) of the title compound were obtained from 5.00 g (34.4 mmol) 4-isopropylbenzonitrile.

Ή NMR (400 MHz, DMSO-c 8 / ppm): 9.53 (s, 1H), 7.58 (d, 2H), 7.23 (d, 2H), 5.74 (s, broad, 2H), 2.89 (sept. 1H), 1.20 (d, 6H).

LC / MS (Method 4, ESIpos): R _t = 0.64 min, m / z = 179 [M + H] ⁺ . Example 14A N'-hydroxy-4- [1- (methoxymethyl) cyclobutyl] benzenecarboximidamide

Step 1: Ethyl 1 - (4-bromophenyl) cyclobutanecarboxylate

A solution of 10.0 g (41.1 mmol) of ethyl 4-bromophenylacetate in 250 ml of anhydrous THF was admixed at 0 ° C. with 45 ml (45.2 mmol) of a 1 M solution of lithium hexamethyldisilazide in THF. After 15 minutes, 5.4 ml (53.5 mmol) of 1,3-dibromopropane were added. The reaction mixture was allowed to warm to RT and stirred at this temperature for 1 h. It was then cooled again to 0 ° C and treated with another 45 ml (45.2 mmol) Lithiumhexamethyldisilazid solution (1 M in THF). Thereafter, it was heated again to RT. After 1 h, the reaction was stopped by adding about 10 ml of saturated aqueous ammonium chloride solution. The THF was largely removed on a rotary evaporator. It was diluted with water and extracted with ethyl acetate. The organic extract was washed successively with water and saturated brine. After drying over anhydrous magnesium sulfate, it was filtered and the filtrate was freed from the solvent on a rotary evaporator. The crude product thus obtained was roughly purified by suction filtration over about 300 g of silica gel with cyclohexane / ethyl acetate 3: 1 as the eluent. This gave 7.1 g (44% of theory, 73% purity) of the title compound, which was reacted further in this form.

Ή NMR (400 MHz, CDCl ₃ , δ / ppm): 7.44 (d, 2H), 7.17 (d, 2H), 4.10 (quart, 2H), 2.85-2.79 (m, 2H), 2.49-2.41 (m , 2H), 2.10-1.98 (m, 1H), 1.91 -1.81 (m, 1H), 1.18 (t, 3H).

MS (DCI, NH _3): m / z = 300/302 [M + NH _4] ^+. LC / MS (Method 2, ESIpos): R _t = 2.70 min, m / z = 283/285 [M + H] ⁺ .

Step 2: [1- (4-Bromophenyl) cyclobutyl] methanol

7.20 g (25.4 mmol) of the compound from Example 14A / Step 1 were dissolved in 150 ml of anhydrous THF and treated dropwise at 0 ° C. with 25 ml (25 mmol) of a 1 M solution of lithium aluminum hydroxide. hydrolyzed in THF. Upon completion of the addition, the ice / water bath was removed and stirring continued at RT. After 1 h, the reaction was stopped by - initially cautious - adding about 450 ml of saturated aqueous ammonium chloride solution. It was then extracted with ethyl acetate. After drying the organic extract over anhydrous magnesium sulfate, followed by filtration, the solvent was removed on a rotary evaporator. There were obtained 6.04 g (88% of theory, 90% purity) of the title compound.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7.43 (d, 2H), 7:02 (d, 2H), 3.72 (d, 2H), 2:33 to 2:20 (m, 4H), 2:13 to 2:01 ( m, 1H), 1.93-1.83 (m, 1H).

MS (DCI, NH _3): m / z = 258/260 [M + NH _4] ^+. GC / MS (Method 9, ESIpos): R _t = 5.77 min, m / z = 240/242 [M] ⁺ .

Step 3: 1 Bromo-4- [1- (methoxymethyl) cyclobutyl] benzene

A solution of 7.0 g (29.0 mmol) of the compound from Example 14A / step 2 in 120 ml of anhydrous DMF was admixed at about 5 ° C. with 1.28 g (31.9 mmol) of a 60% suspension of sodium hydride in mineral oil. After stirring at this temperature for 1 h, 2.2 ml (34.8 mmol) of methyl iodide were added. The reaction mixture was allowed to warm to rt and stirring continued for 15 h. Subsequently, the reaction mixture was concentrated on a rotary evaporator to a volume of about 20 ml. About 500 ml of water were added and the mixture extracted three times with about 200 ml of diethyl ether. The combined organic extracts were washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration and removal of the solvent on a rotary evaporator, the crude product obtained was purified by suction filtration over about 200 g of silica gel with cyclohexane / ethyl acetate 50: 1 as eluent. There were obtained 4.92 g (66% of theory) of the title compound.

'H-NMR (400 MHz, CDCl ₃ , δ / ppm): 7.41 (d, 2H), 7.04 (d, 2H), 3.48 (s, 2H), 3.27 (s, 3H), 2.32-2.22 (m, 4H), 2.12-2.00 (m, 1H), 1.90-1.80 (m, 1H).

MS (DCI, NH _3): nvz = 272/274 [M + NH _4] ^+.

GC / MS (Method 9, ESIpos): R _t = 5.25 min, m / z = 254/256 [M] Step 4: 4- [1- (methoxymethyl) cyclobutyl] benzonitrile

Analogously to the process described under Example 12A / Step 1, 4.80 g (18.8 mmol) of the compound from Example 14A / Step 3 gave 1.82 g (48% of theory) of the title compound.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7:58 (d, 2 H), 7.24 (d, 2H), 3:52 (s, 2H), 3.26 (s, 3H), 2.34- 2.24 (m, 4H), 2.16-2.03 (m, 1H), 1.92-1.83 (m, 1H).

LC / MS (Method 4, ESIpos): R _t = 1.22 min, m / z = 202 [M + H] ⁺ .

Step 5: N'-hydroxy-4- [1- (methoxymethyl) cyclobutyl] benzenecarboximidamide

Analogously to the process described under Example 1A / Step 5, 2.04 g (96% of theory) of the title compound were obtained from 1.82 g (9.04 mmol) of the compound from Example 14A / Step 4.

'H-NMR (400 MHz, CDCl ₃ , 8 / ppm): 7.55 (d, 2H), 7.20 (d, 2H), 7.10 (broad, 1H), 4.83 (broad, 2H), 3.51 (s, 2H) , 3.27 (s, 3H), 2.36-2.25 (m, 4H), 2.12-2.01 (m, 1H), 1.90-1.81 (m, 1H).

LC / MS (Method 6, ESIpos): R _t = 0.61 min, m / z = 235 [M + H] ⁺ .

Example 15A

N'-hydroxy-4- [1- (trifluoromethyl) cyclopropyl] benzenecarboximidamide

Step 1: 1-Bromo-4- [1- (trifluoromethyl) cyclopropyl] benzene

Activated zinc bromide on montmorillonite was initially prepared as follows: 7.0 g (31.1 mmol) of zinc bromide were placed in 225 ml of methanol in a 1 liter flask and 28.2 g of montmorillonite K10 were added. Subsequently, the suspension was stirred for 1 h at RT. It was then evaporated to dryness on a rotary evaporator. The remaining fine powder was heated under low vacuum (about 500 mbar) for 1 hour in a sand bath to 200 ° C bath temperature and then allowed to cool under argon. The title compound was then prepared as follows: 49.63 g (267 mmol) of 1-phenyl-1- (trifluoromethyl) cyclopropane were initially charged in 1.25 liters of pentane and montmorillonite was added to the activated zinc bromide obtained above. Then, the reaction vessel was externally packed with aluminum foil to reduce the incidence of light. 137 ml (2.67 mol) of bromine were slowly added dropwise with stirring. The reaction mixture was then stirred at RT for 16 h in the dark. Then, under ice-cooling, 1 liter of saturated aqueous sodium sulfite solution was dropwise added thereto. The solids were filtered off with suction and washed twice with pentane. After phase separation, the filtrate was extracted twice more with 1 liter of pentane. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and freed from the solvent on a rotary evaporator under only a slight vacuum. There were obtained 77.18 g (92% purity, 100% of theory) of the title compound.

Ή NMR (400 MHz, CDCl ₃ , δ / ρρηι): 7.47 (d, 2H), 7.33 (s, 2H), 1.37-1.34 (m, 2H), 1.03-0.98 (m, 2H).

GC / MS (Method 9, ESIpos): R _t = 3.43 min, m / z = 264/266 [M] ⁺ . Step 2: 4- [1- (trifluoromethyl) cyclopropyl] benzonitrile

A solution of 75.0 g (283 mmol) of the compound of Example 15A / Step 1 in a mixture of 990 ml of DMF and 10 ml of water was deoxygenated by repeated application of a weak vacuum and argon gasification. Then, 37.87 g (322 mmol) of zinc cyanide and 32.69 g (28.3 mmol) of tetrakis (triphenylphosphine) palladium (0) were added. The reaction mixture was then heated to 120 ° C for 5 h. After cooling to RT was filtered off from the undissolved and the residue washed with a little DMF. The filtrate was then freed from the solvent on a rotary evaporator. The resulting crude product was dissolved in 1.5 liters of ethyl acetate and washed twice with 500 ml of saturated ammonium chloride solution and once with 500 ml of saturated sodium chloride solution. After drying the organic phase over anhydrous magnesium sulfate was filtered and the filtrate was concentrated on a rotary evaporator. The resulting oil was purified by suction filtration over 175 g silica gel with cyclohexane / ethyl acetate 40: 1 as eluent. After evaporation of the product fractions and drying in a high vacuum, 49.7 g (83% of theory) of the title compound were obtained.

Ή NMR (400 MHz, CDCl ₃ , δ / ppm): 7.65 (d, 2H), 7.57 (d, 2H), 1.46-1.42 (m, 2H), 1.09-1.03 (m, 2H).

GC / MS (Method 9, ESIpos): R _t = 3.79 min, m / z = 211 [M] ⁺ .

Step 3: N'-hydroxy-4- [1- (trifluoromethyl) cyclopropyl] benzenecarboximidamide

A solution of 20.0 g (94.7 mmol) of the compound from Example 15A / Step 2 in 500 ml of ethanol was admixed with 14.48 g (208 mmol) of hydroxylammonium chloride and 29 ml (208 mmol) of triethylamine. The reaction mixture was heated at reflux for 2 h. Subsequently, about half of the solvent was removed on a rotary evaporator. The remaining remainder was 1.5 Liter of water, and the resulting suspension was stirred for 20 min at RT. The solid was then filtered off with suction, washed with a little cold water and dried under high vacuum. For further purification, it was stirred with a mixture of 120 ml of pentane and 30 ml of dichloromethane. After further suction filtration and drying of the solid, 15.79 g (68% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-d _ß, δ / ppm): 9.68 (s, 1H), 7.67 (d, 2H), 7:46 (d, 2H), 5.83 (s, broad, 2H), 1.36- 1.32 (m, 2H), 1.15-1.1 1 (m, 2H).

LC / MS (Method 4, ESIpos): R _t = 0.80 min, m / z = 245 [M + H] ⁺ .

Example 16A 3 -fluoro-N'-hydroxy-4- (trifluoromethoxy) benzenecarboximidamide

Analogously to the process described under Example 1 A / step 5, 5.7 g (99% of theory) of the title compound were obtained from 5.0 g (23.9 mmol) of 3-fluoro-4- (nifluoromethoxy) benzonitrile.

Ή-NM (400 MHz, CDCl ₃ , 8 / ppm): 7.53-7.49 (dd, 1H), 7.45-7.41 (m, 1H), 7.37-7.31 (t, 1H), 4.87 (s, broad, 2H) ,

LC / MS (Method 6, ESIpos): R _t = 0.74 min, m / z = 239 [M + H] ⁺ .

Example 17A

N'-hydroxy-3-methyl-4- (trifluonnethoxy) benzolcarboxiiriidamid

3-methyl-4- (trifluoromethoxy) benzonitrile

Analogously to the process described under Example 12A / step 1, 3.55 g (90% purity, 81% of theory) of the title compound were obtained from 5.00 g (19.6 mmol) of 3-methyl-4- (trifluoromethoxy) bromobenzene.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7:59 (d, 1H), 7:53 (dd, 1H), 7.31 (d, 1H), 2:36 (s, 3H).

GC / MS (Method 9, DCI / NH ₃ ): R, = 2.58 min, m / z = 201 [M] ⁺ .

Step 2: N'-hydroxy-3-methyl-4- (trifluoromiethoxy) benzenecarboximidanide

Analogously to the process described under Example 1A / Step 5, from 2.50 g (12.4 mmol) of the compound from Example 17A / Step 1, 2.36 g (87% purity, 70% of theory) of the title compound were obtained.

LC / MS (Method 6, ESIpos): R _t = 0.67 min, m / z = 235 [M + H] ⁺ . Example 18A 4- [1- (ethoxymethyl) cyclobutyl] -N'-hydroxybenzenecarboximidamide

1-Bromo-4- [1- (ethoxymethyl) cyclobutyl] benzene

Analogously to the process described under Example 14A / Example 3, 1.28 g (77% of theory) of the title compound were obtained from 1.50 g (6.22 mmol) of the compound from Example 14A / Step 2 and 557 μΐ (7.46 mmol) of bromoethane.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7.40 (d, 2H), 7:05 (d, 2H), 3.51, (s, 2H), 3:38 (quart, 2H), 2:29 to 2:24 (m, 4H), 2.11-2.00 (m, 1H), 1.89-1.79 (m, 1H), 1.10 (t, 3H).

GC / MS (Method 9, ESIpos): R _t = 5.37 min, m / z = 268/270 [M] ⁺ .

Step 2: 4- [1- (ethoxymethyl) cyclobutyl] benzonitrile

Analogously to the process described under Example 12A / step 1, 1.16 g (4.29 mmol) of the compound from Example 18A / Step 1 gave 0.64 g (69% of theory) of the title compound.

'H-NMR (400 MHz, CDCI _3, δ / ppm): 7:59 (d, 2H), 7.27 (d, 2H), 3:54 (s, 2H), 3:37 (quart, 2H), 2:31 to 2:27 (m, 4H), 2.16-2.03 (m, 1H), 1.91-1.82 (m, 1H), 1.08 (t, 3H).

LC / MS (Method 6, ESIpos): R, = 1.18 min, m / z = 216 [M + H] Step 3: 4- [1 - (Ethoxymethyl) cyclobutyl] -N'-hydroxybenzenecarboximidamide

Analogously to the process described under Example 1A / Step 5, from 635 mg (2.95 mmol) of the compound from Example 18A / Step 2, 725 mg (90% purity, 90% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 9.55 (s, 1H), 7.58 (d, 2H), 7.14 (d, 2H), 5.79 (broad, 2H), 3.50 (s, 2H ), 3.35 (quart, 2H), 2.23-2.20 (m, 4H), 2.08-1.97 (m, 1H), 1.82-1.73 (m, 1H), 1.03 (t, 3H).

LC / MS (Method 6, ESIpos): R _t = 0.67 min, m / z = 249 [M + H] ⁺ . Example 19A

N'-hydroxy-4- [1- (methoxymethyl) cyclopentyl] benzenecarboximidamide

Step 1: Ethyl 1 - (4-bromophenyl) cyclopentanecarboxylate

Analogously to the process described under Example 14A / Step 1, 75.0 g (308 mmol) of ethyl (4-bromophenyl) acetate and 47.5 ml (401 mmol) of 1, 4-dibromobutane were mixed with 100 g (98% of theory, approx 90% purity) of the title compound, which was further reacted in this form.

GC / MS (Method 9, EIpos): R _t = 6.22 min, m / z = 296/298 [M] ⁺ . Step 2: [1- (4-Bromophenyl) cyclopentyl] methanol

100.0 g (336 mmol) of the compound from Example 19A / Step 1 were dissolved in 1800 ml of anhydrous THF and treated dropwise at 0 ° C with 337 ml (337 mmol) of a 1 M solution of lithium aluminum hydride in THF. Upon completion of the addition, the ice / water bath was removed and stirring continued at RT. After 1 h, the reaction was stopped by - initially cautious - adding about 100 ml of saturated aqueous ammonium chloride solution. Subsequently, most of the THF was removed on a rotary evaporator. The resulting residue was partitioned between 1.5 liters of 2 M hydrochloric acid and ethyl acetate. After phase separation, the organic extract was dried over anhydrous magnesium sulfate. After filtration, the solvent was removed on a rotary evaporator. The resulting residue was chromatographed over 1.5 kg of silica gel with cyclohexane / ethyl acetate 95: 5-> 80:20 as the eluent. 45.7 g (53% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d _ß, δ / ppm): 7:44 (d, 2H), 7.23 (d, 2H), 4.62 (t, 1 H) 3.33 (d, 2H), 1.97-1.90 ( m, 2H), 1.72-1.56 (m, 6H). MS (DCI, NH _3): m / z = 272/274 [M + NH _4] ^+.

GC / MS (Method 9, EIpos): R _t = 6.34 min, m / z = 254/256 [M] ⁺ .

Step 3: 1 Bromo-4- [1- (methoxymethyl) cyclopentyl] benzene

Analogously to the process described under Example 14A / Step 3, from 10.0 g (39.1 mmol) of the compound from Example 19A / Step 2 and 2.9 ml (43.1 mmol) of iodomethane 9.52 g (90% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDCl ₃ , δ / ppm): 7.40 (d, 2H), 7.19 (d, 2H), 3.33 (s, 2H), 3.22 (s, 3H), 2.00- 1.94 (m, 2H), 1.87-1.79 (m, 2H), 1.76-1.66 (m, 4H).

GC / MS (Method 9, EIpos): R _t = 5.78 min, m / z = 268/270 [M] ⁺ .

Step 4: 4- [1 - (Methoxymethyl) cyclopentyl] benzonitrile

Analogously to the process described under Example 12A / Step 1, 2.00 g (18.6 mmol) of the compound from Example 19A / Step 3 gave 2.21 g (55% of theory) of the title compound.

'H-NMR (400 MHz, CDCI _3, δ / ppm): 7:58 (d, 2H), 7:42 (d, 2H), 3:35 (s, 2H), 3.22 (s, 3H), 2.05- 1.99 (m, 2H), 1.88-1.70 (m, 6H).

LC / MS (Method 4, ESIpos): R _t = 1.31 min, m / z = 216 [M + H] ⁺ . Step 5: N'-hydroxy-4- [1- (methoxymethyl) cyclopentyl] benzenecarboximidamide

Analogously to the process described under Example 1A / Step 5, 2.17 g (10.1 mmol) of the compound from Example 19A / Step 4 gave 2.32 g (93% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ppm): 9.53 (s, 1H), 7.56 (d, 2H), 7.29 (d, 2H), 5.73 (broad, 2H), 3.32 (s, 2H ), 3.12 (s, 3H), 1.97-1.90 (m, 2H), 1.82-1.75 (m, 2H), 1.73-1.58 (m, 4H). LC / MS (Method 6, ESIpos): R, = 0.69 min, m / z = 249 [M + H] ⁺ . Example 20A

3-fluoro-N'-hydoxy "oxy-4- [1- (methoxymethyl) cyclobutyl] benzenecarboximidamide

Step 1: Ethyl (4-bromo-2-fluorophenyl) acetate

A solution of 50.0 g (0.215 mol) of 4-bromo-2-fluorophenylacetic acid in 500 ml of ethanol was treated with 100 .mu.l of concentrated sulfuric acid and then heated to reflux for 16 h. After cooling to RT, the solvent was removed as far as possible on a rotary evaporator. The residue obtained was taken up in 500 ml of ethyl acetate and washed with 250 ml of saturated aqueous sodium bicarbonate solution. After drying over anhydrous magnesium sulfate, it was filtered and the filtrate was evaporated to dryness. There were obtained 53.2 g (90% of theory, 95% purity) of the title compound.

GC / MS (Method 9, EIpos): R _t = 4.74 min, m / z = 260/262 [M] ⁺ . Step 2: Ethyl 1- (4-bromo-2-fluorophenyl) cyclobutanecarboxylate

Analogously to the process described under Example 14A / Step 1, from 53.0 g (0.202 mol) of the compound from Example 20A / Step 1 and 26.8 ml (0.264 mol) of 1,3-dibromopropane 67.6 g (75% purity, 82% of theory) of the title compound, which was reacted further in this form.

LC / MS (Method 6, ESIpos): R _t = 1.31 min, m / z = 301/303 [M + H] ⁺ . Step 3: [1- (4-Bromo-2-fluorophenyl) cyclobutyl] methanol

Analogously to the process described under Example 14A / Step 2, from 67.6 g (0.150 mol) of the compound from Example 20A / Step 2, 23.9 g (85% purity, 50% of theory) of the title compound were prepared. In contrast to the procedure described under Example 14A / Step 2, it was necessary during the work-up to add as much 2M hydrochloric acid after addition of the saturated ammonium chloride solution until a clear aqueous phase was reached.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 7.38 (dd, 1H), 7.32 (dd, 1H), 7.02 (t, 1H), 4.80 (t, 1H), 3.57 (d, 2H), 2.24-2.19 (m, 4H), 2.07-1.95 (m, 1H), 1.83-1.74 (m, 1H).

Step 4: 4-Bromo-2-fluoro-1- [(methoxymethyl) cyclobutyl] benzene

Analogously to the process described under Example 14A / Step 3, 12.8 g (49.4 mmol) of the compound from Example 20A / Step 3 and 3.7 ml (59.3 mmol) of methyl iodide were reacted to 12.6 g (93% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 7.39 (dd, 1H), 7.33 (dd, 1H), 7.06 (t, 1H), 3.53 (s, 2H), 3.18 (s, 3H ), 2.32-2.17 (m, 4H), 2.12-2.01 (m, 1H), 1.85-1.75 (m, 1H). GC / MS (Method 9, EIpos): R, = 5.04 min, m / z = 272/274 [M] ⁺ . Step 5: 3-Fluoro-4- [1- (methoxymethyl) cyclobutyl] benzonitrile

Analogously to the process described under Example 12A / Step 1, from 12.60 g (46.1 mmol) of the compound from Example 20A / Step 4, 7.01 g (63% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 7.72 (dd, IH), 7.62 (dd, IH), 7.30 (t, IH), 3.59 (s, 2H), 3.18 (s, 3H ), 2.36-2.20 (m, 4H), 2.15-2.03 (m, IH), 1.86-1.77 (m, IH).

Step 6: 3-Fluoro-N'-hydroxy-4- [1- (methoxymethyl) cyclobutyl] benzenecarboximidamide

Analogously to the process described under Example 1A / Step 5, 2.04 g (90% purity, 86% of theory) of the title compound were obtained from 5.00 g (22.8 mmol) of the compound from Example 20A / Step 5.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 9.69 (s, IH), 7.43 (dd, IH), 7.33 (dd, IH), 7.10 (t, IH), 5.83 (s, broad , 2H), 3.55 (s, 2H), 3.18 (s, 3H), 2.34-2.19 (m, 4H), 2.12-2.01 (m, IH), 1.84-1.77 (m, IH).

LC / MS (Method 6, ESIpos): R _t = 0.70 min, m / z = 253 [M + H] ⁺ .

Example 21A

3-Fluoro-N'-hydroxy-4- (1,1-trifluoro-2-methylpropan-2-yl) benzenecarboximidamide H ₃ C CH ₃

1 - [4-Bromo-2-fluoro-3 - (trimethylsilyl) phenyl] -2,2,2-trifluoroethanone

To a solution of 17.60 g (124 mmol) of 2,2,6,6-tetramethylpiperidine in 110 ml of THF under argon was at -20 ° C bath temperature 78 ml (125 mmol) of a 1.6 M solution of / i-butyllithium in hexane slowly added dropwise. After stirring for 30 minutes at -20 ° C, the mixture was further cooled to -70 ° C bath temperature and with a solution of 28.0 g (1 13 mmol) (2-bromo-6-fluorophenyl) - (trimethyl) silane [obtained from Bromo-3-fluorobenzene and chloro (trimethyl) silane according to S. Lulinski et al., J. Org. Chem. 2003, 68 (24), 9384-9388] in 30 ml of THF. After 1 h of stirring at -70 ° C bath temperature 17.70 g (124.6 mmol) of ethyl trifluoroacetate were added dropwise at -70 ° C. The mixture was then allowed to slowly rise to RT and stirred for an additional hour at RT. Thereafter, saturated aqueous ammonium chloride solution was added and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate phases were washed once with sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. There were obtained 42.0 g (82% purity, 89% of theory) of the title compound.

GC / MS (Method 9, EIpos): R _t = 3.92 min, nVz = 342/344 [M] ⁺ .

Step 2: 1 - (4-Bromo-2-fluorophenyl) -2,2,2-trifluoro-ethanone

To a solution of 42.0 g (100 mmol, purity 82%) of the compound from Example 21A / Step 1 in 140 ml of THF was added at RT 120 ml (120 mmol) of a 1 M solution of tetra-n-butylammonium fluoride in THF , After stirring for 30 min at RT, the mixture was diluted with ethyl acetate and washed once with water. The aqueous phase was back-extracted once with ethyl acetate. The combined organic phases were then washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue obtained was purified by flash chromatography (silica gel, mobile phase: cyclohexane-> cyclohexane / ethyl acetate 95: 5). After removal of the solvent, 18.90 g (92% purity, 64% of theory) of the title compound were obtained. 'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7.78 (t, 1H), 7:49 (dd, 1H), 7:45 (dd, 1H).

GC / MS (Method 9, EIpos): R _t = 2.63 min, m / z = 270/272 [M] ⁺ .

Step 3: 2- (4-Bromo-2-fluorophenyl) -1,1,1-trifluoropropan-2-ol

First, a suspension of dichloro (dimethyl) titanium in a heptane / dichloromethane mixture was prepared as follows: 160 mL (160 mmol) of a 1M solution of titanium tetrachloride in dichloromethane was cooled to -30 ° C, then 160 mL (160 mL) was added dropwise mmol) of a 1 M solution of dimethylzinc in heptane and the mixture was stirred for 30 minutes at -30 ° C after. The suspension was then cooled to -40 ° C. and a solution of 19.4 g (65.9 mmol, purity 92%) of the compound from Example 21 A / Step 2 in 80 ml of dichloromethane was added. The mixture was stirred for a further 5 minutes at -40 ° C., then the bath temperature was brought to RT and stirred for a further 2 hours at RT. While cooling with ice, 80 ml of water were then slowly added dropwise and then diluted with a further 250 ml of water. It was extracted twice with 250 ml of dichloromethane, the combined dichloromethane phases were washed once with 350 ml of water, dried over anhydrous magnesium sulfate, filtered and the solvent removed on a rotary evaporator. It was 23.7 g (> 100%) d. Th.) Of a residue containing the title compound in a purity of 92%> according to 'H-NMR and was further reacted in this form.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7:52 (t, 1H), 7:34 (dd, 1H), 7.29 (dd, 1H), 3.06-2.99 (m, 1H), 1.86 (s, 3H). LC / MS (Method 6, ES Ineg): R _t = 1.08 min, m / z = 331/333 [M-H + HC0 ₂ H]

GC / MS (Method 19, EIpos): R _t = 3.61 min, m / z = 286/288 [M] ⁺ .

Step 4: 2- (4-Bromo-2-fluorophenyl) -1,1,1-trifluo-2-propanolanilane sulfonate

To a suspension of 6.08 g of sodium hydride (60% in mineral oil, 152 mmol) in 90 ml of THF was added at RT a solution of 23.7 g (75.9 mmol, purity 92%) of the compound from Example 21A / step 3 in 40 ml of THF dripped. After 1 h of stirring at RT and a further 30 min at 40 ° C, a solution of 11.8 ml (151.91 mmol) of methanesulfonyl chloride was added dropwise in 90 ml of THF and the mixture then stirred at 40 ° C for 1 h. It was then slowly added dropwise 100 ml of water. The mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue thus obtained was stirred with pentane. The solid was filtered off, washed once with pentane and dried in air. There were obtained 25.6 g (92% of theory) of the title compound. 'H-NMR (400 MHz, CDC1 ₃ , δ / ρρηι): 7.42 (t, 1H), 7.37 (dd, 1H), 7.32 (dd, 1H), 3.19 (s, 3H), 2.33 (s, 3H) ,

LC / MS (Method 4, ESIpos): R _t = 1.34 min, m / z = 382/384 [M + NH ₄ ] ⁺ .

Step 5: 4-Bromo-2-fluoro-1 - (1,1-trifluoro-2-methylpropan-2-yl) benzene

To a solution of 25.6 g (70.1 mmol) of the compound from Example 21A / step 4 in 480 ml of dichloromethane at 0 ° C were added slowly with stirring 70 ml (140 mmol) of a 2 M solution of trimethylaluminum in heptane. The bath temperature was allowed to come to RT and the mixture stirred for 1 h at RT. Thereafter, 230 ml of a saturated aqueous solution were slowly added Sodium bicarbonate solution and 75 ml of a saturated aqueous sodium chloride solution was added. The mixture was filtered through kieselguhr and the filter residue was washed twice with dichloromethane. The filtrate combined with the washing solution was washed once with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. There were obtained 18.77 g (94% of theory) of the title compound.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7:32 to 7:24 (m, 3H), 1.63 (s, 6H).

GC / MS (Method 9, EIpos): R, = 2.99 min, m / z = 283/285 [M] ⁺ .

Step 6: 3-Fluoro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) benzonitrile

To a solution of 10.0 g (35.1 mmol) of the compound from Example 21A / Step 5 in 50 ml of DMF under argon was added 2.47 g (21 mmol) of zinc cyanide and 2.43 g (2.10 mmol) of tetrakis (triphenylphosphine) palladium (O) , The mixture was stirred at 80 ° C overnight. After cooling to RT, the solid present was filtered off and washed with a little DMF. The filtrate and the washing were combined and concentrated. The residue was purified by column chromatography (silica gel, eluent: cyclohexane ethyl acetate 95: 5). There were obtained 5.40 g (67% of theory) of the title compound.

'H-NMR (400 MHz, CDCl ₃ , 8 / ppm): 7.57 (t, 1H), 7.45 (dd, 1H), 7.38 (dd, 1H), 1.67 (s, 6H). GC / MS (Method 9, EIpos): R _t = 3.22 min, m / z = 231 [M] ⁺ .

Step 7: 3-Fluoro-N'-hydroxy-4- (1,1,1-trifluoro-2-methylpipan-2-yl) benzenecarboximidamide

Analogously to the process described under Example 1A / Step 5, from 5.40 g (23.36 mmol) of the compound from Example 21A / Step 6 5.81 g (94% of theory) of the title compound were obtained.

¹ H-NMR (400 MHz, CDCl ₃ , δ / ppm): 7.46 (t, 1H), 7.41-7.31 (m, 2H), 4.84 (s, broad, 2H), 1.65 (s, 6H).

LC / MS (Method 6, ESIpos): R _t = 0.77 min, m / z = 265 [M + H] ⁺ . Example 22A

5- (5-methyl-lH-pyrazol-3-yl) -3- [4- (trifluoromethoxy) phenyl] -l, 2,4-oxadiazole

Method A:

A solution of 15.3 g (0.121 mol) of 5-methyl-1H-pyrazole-3-carboxylic acid in 600 ml of anhydrous DMF was washed successively at RT with 23.3 g (0.121 mol) EDC, 16.4 g (0.121 mol) HOBt and 26.7 g (0.121 mol) of N'-hydroxy-4- (trifluoromiethoxy) benzenecarboximidamide. The mixture was stirred initially at RT for 2 h and then at 140 ° C. for 5 h. After cooling, it was diluted with 2 liters of water and extracted three times with 1 liter of ethyl acetate. The combined organic extracts were washed successively with water and saturated brine. After drying over anhydrous magnesium sulfate, it was filtered and the solvent removed on a rotary evaporator. The crude product obtained was purified by suction filtration through a filter slide filled with silica gel (eluent: cyclohexane / ethyl acetate 5: 1 ^→ 1: 1). The product fractions were combined and the solvent removed on a rotary evaporator so far that the product was just beginning to precipitate. The precipitation was completed at RT. By filtration and further concentration of the mother liquor two fractions solid were obtained, which were combined and dried under high vacuum. In total, 19.7 g (52% of theory) of the title compound were obtained in this way. Method B:

To a suspension of 20.25 g (125 mmol) of Ι, Γ-carbonyldiimidazole (CDI) in 75 ml of anhydrous DMF, a solution of 15.0 g (1 19 mmol) of 5-methyl-1H- was added at RT within 15 min. pyrazole-3-carboxylic acid was added dropwise in 75 ml of anhydrous DMF. After the mixture was stirred at RT for 1 h 45 min, 26.19 g (1 19 mmol) of N'-hydroxy-4- (trifluoromethoxy) benzenecarboximidamide were added. Subsequently, the reaction mixture was heated to 1 10 ° C for 4 h. After cooling, most of the solvent was removed on a rotary evaporator. The residue was added with 800 ml of water and stirred for a few minutes. The undissolved product was filtered off with suction and washed with diethyl ether. From the filtrate, the ether phase was separated and the aqueous phase extracted once more with diethyl ether. The combined ethereal extracts were mixed with 25 ml of methanol and the previously extracted product was suspended therein. After stirring for a few minutes, it was again filtered off with suction. The residue was dried under high vacuum to give a first fraction of the title compound (8.79 g). The filtrate was mixed with the same volume of water and shaken out. After phase separation, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and finally freed from the solvent on a rotary evaporator. After drying the residue in a high vacuum, a second fraction of the title compound was obtained in this way (24.43 g). In total, 33.32 g (90% of theory) of the title compound were obtained in this way.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 10.64 (broad, 1 H), 8.23 (d, 2H), 7:34 (d, 2H), 6.82 (s, 1 H) 2.46 (s, 3H).

HPLC (Method 10): R _t = 4.72 min. MS (DCI, NH ₃ ): m / z = 31 1 [M + H] ⁺ . LC / MS (Method 4, ESIpos): R _t = 1.28 min, m / z = 31 1 [M + H] ⁺ . Example 23A

5- (5-Methyl-1H-pyrazol-3-yl) -3- [4- (1,1,2-trifluoro-2-methylpropan-2-yl) -phenyl] -1,2,4-oxadiazole

Analogously to the process described under Example 22A (Method A), 7.57 g (60.0 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 14.8 g (60.0 mmol) of the compound from Example 1 A were dissolved in 14.7 g (73% of theory) Th.) Of the title compound. For workup was here after finished Reaction the product precipitated by stirring the reaction mixture in ice water, filtered off, washed with water and dried under high vacuum.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.80 (s, broad, 1H), 8.17 (d, 2H), 7.63 (d, 2H), 6.83 (s, 1H), 2.46 (s , 3H), 1.63 (s, 6H). LC / MS (Method 4, ESIpos): R _t = 1.34 min, m / z = 337 [M + H] ⁺ .

Example 24A

3- [4- (2-fluoro propan-2-yl) phenyl] -5- (5-methyl-lH-pyrazol-3-yl) -l, 2,4-oxadiazole

Analogously to the process described under Example 22A (Method A), 3.15 g (25.0 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 4.91 g (25.0 mmol) of the compound from Example 2A were admixed with 5.0 g (68% of theory). Th.) Of the title compound. For workup, the product was precipitated by stirring the reaction mixture into ice water, filtered off, washed with water and dried under high vacuum after completion of the reaction.

'H-NMR (400 MHz, DMSO-ds, δ / ppm): 13.54 (s, broad, 1H), 8.08 (d, 2H), 7.62 (d, 2H), 6.81 (s, 1H), 2.33 ( s, 3H), 1.72 (s, 3H), 1.68 (s, 3H).

LC / MS (Method 2, ESIpos): R _t = 2.19 min, m / z = 287 [M + H] ⁺ .

Example 25A

5- (5-Methyl-1H-pyrazol-3-yl) -3- {4 - [(trifluoromethyl) sulfonyl] phenyl} -1, 2,4-oxadiazole

Analogously to the process described under Example 22A (Method A), 2.37 g (18.7 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 5.03 g (18.7 mmol) of the compound from Example 3A were admixed with 3.4 g (51% of theory). Th.) Of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 13.62 (s, broad, 1H), 8.49 (d, 2H), 8.38 (d, 2H), 6.83 (s, 1H), 2.34 (s , 3H).

LC / MS (Method 4, ESIpos): R _t = 1.25 min, m / z = 359 [M + H] ⁺ .

Example 26A

5- (5-methyl-lH-pyrazol-3-yl) -3- [4- (trimethylsilyl) phenyl] -l, 2,4-oxadiazole

Analogously to the process described under Example 22A (Method A), from 2.52 g (20.0 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 4.63 g (20.0 mmol, 90% purity) of the compound from Example 9A 4.67 g ( 78% of theory) of the title compound. For workup, the product was precipitated by stirring the reaction mixture into ice water, filtered off, washed with water and dried under high vacuum after completion of the reaction. 'H-NMR (400 MHz, CDC1 _3, δ / ppm): 11.3 (s, broad, 1H), 8.12 (d, 2H), 7.63 (d, 2H), 6.81 (s, 1H), 2:43 (s, 3H), 0.31 (s, 9H).

LC / MS (Method 3, ESIpos): R _t = 2.39 min, m / z = 299 [M + H] ⁺ . Example 27A

5- (5-methyl-lH-pyrazol-3-yl) -3- [4- (trifluoromethyl) phenyl] -l, 2,4-oxadiazole

Analogously to the process described under Example 22A (Method A), from 2.40 g (19.0 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 3.88 g (19.0 mmol) of N'-hydroxy-4- (trifluoromethyl) -benzenecarboximidamide 3.95 g (71% of theory) of the title compound. For workup, the product was precipitated by stirring the reaction mixture into 500 ml of ice water, filtered off, washed with water and dried under high vacuum after completion of the reaction.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 10:52 (broad, 1H), 8:32 (d, 2H), 7.77 (d, 2H), 6.82 (s, 1H), 2.63 (s, 3H) ,

LC / MS (Method 6, ESIpos): R _t = 1.11 min, m / z = 295 [M + H] ⁺ . Example 28A 5- (5-Methyl-1H-pyrazol-3-yl) -3- [4- (tetrahydro-2H-pyran-4-yl) -phenyl] -1,4,4-oxadiazole

Analogously to the process described under Example 22A (Method A), from 469 mg (3.72 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 820 mg (3.72 mmol) of the compound from Example 11A, 450 mg of the title compound were stirred up of the crude product in acetonitrile and a further 97 mg of the title compound after purification of the mother liquor by preparative HPLC (Method 11) (total yield 47% of theory).

'H-NMR (400 MHz, DMSO-de, δ / ppm): 13.52 (s, 1H), 8.01 (d, 2H), 7.49 (d, 2H), 6.79 (s, 1H), 3.99-3.95 (m , 2H), 3.49-3.42 (m, 2H), 2.92-2.84 (m, 1H), 2.34 (s, 3H), 1.77-1.65 (m, 4H).

LC / MS (Method 6, ESIpos): R _t = 0.98 min, m / z = 311 [M + H] ⁺ . Example 29A

3- [3-Fluoro-4- (trifluoromethoxy) phenyl] -5- (5-methyl-1H-pyrazol-3-yl) -1,2,4-oxadiazole

Analogously to the process described under Example 22A (Method A), 2.0 g (15.9 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 3.78 g (15.9 mmol) of the compound from Example 16A were added to 3.15 g (92% purity, 56% of theory) of the title compound. The product in this case was not obtained via a chromatographic purification but by washing the crude product with water and pentane and then drying in vacuo.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 12.0-9.5 (broad, 1H), 8.10-7.97 (m, 2H), 7:46 to 7:41 (t, 1 H), 6.81 (s, 1 H ), 2.47 (s, 3H).

LC / MS (Method 6, ESIpos): R _t = 1.16 min, m / z = 329 [M + H] ⁺ . Example 30A

5- (5-Methyl-1H-pyrazol-3-yl) -3- {4- [1- (trifluoromethyl) cyclopropyl] -phenyl} -1, 2,4-oxadiazole

Method A. ^¬

Analogously to the process described under Example 22A (Method A), 1.19 g (9.42 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 2.30 g (9.42 mmol) of the compound from Example 15A were added to 1.05 g (62% of theory). Th.) Implemented the title compound. The crude product was purified by preparative HPLC (Method 13).

Method B:

To a suspension of 6.75 g (41.6 mmol) of Ι, Γ-carbonyldiimidazole (CDI) in 25 ml of anhydrous DMF at RT within 15 min, a solution of 5.0 g (36.6 mmol) of 5-methyl-lH-pyrazole-3-carboxylic acid added dropwise in 25 ml of anhydrous DMF. After the mixture was stirred for 1 h 45 min at RT, 9.68 g (39.6 mmol) of the compound from Example 15A were added. Subsequently, the reaction mixture was heated to 1 10 ° C for 2.5 h. After cooling to RT were added slowly with vigorous stirring 800 ml of water, whereby the product precipitated. The solid was filtered off with suction and washed with a little cold water. The still moist crude product was recrystallized from a boiling mixture of 300 ml of ethanol and 350 ml of water. There were obtained 1.03 g (83% of theory) of the title compound. 'H-NMR (400 MHz, CDC1 _3, 8 / ppm): 4.11 (s, broad, 1 H), 8.16 (d, 2H), 7.60 (d, 2H), 6.82 (s, 1H), 2:45 (s , 3H), 1.43-1.40 (m, 2H), 1.11-1.07 (m, 2H).

LC / MS (Method 6, ESIpos): R _t = 1.14 min, m / z = 335 [M + H] ⁺ .

Example 31A

3- {3-Fluoro-4- [1- (methoxymethyl) cyclobutyl] phenyl} -5- (5-methyl-1H-pyrazol-3-yl) -1,2,4-oxadiazole

Analogously to the process described under Example 22A (Method A), 2.50 g (19.8 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 5.0 g (19.8 mmol) of the compound from Example 20A were admixed with 2.07 g (30% of theory). Th.) Of the title compound.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 10.80 (broad, 1H), 7.91 (dd, 1H), 7.80 (dd, 1 H), 7.24 (t, 1H), 6.80 (s, 1H ), 3.67 (s, 2H), 3.29 (s, 3H), 2.45 (s, 3H), 2.48-2.31 (m, 4H), 2.19-2.07 (m, 1H), 1.95- 1.86 (m, 1H).

LC / MS (Method 4, ESIpos): R, = 1.34 min, m / z = 343 [M + H] ⁺ . Example 32A

3- {4- [1- (ethoxymethyl) cyclobutyl] phenyl} -5- (5-methyl-1H-pyrazol-3-yl) -1, 2,4-oxadiazole

Analogously to the process described under Example 22A (Method A), 368 mg (2.92 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 725 mg (2.92 mmol) of the compound from Example 18A were converted into 608 mg (60% of theory). Th.) Of the title compound.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 1 1.13 (broad, 1H), 8.10 (d, 2H), 7.30 (d, 2H), 6.81 (s, 1H), 3:58 (s, 2H ), 3.39 (quart, 2H), 2.45 (s, 3H), 2.41-2.29 (m, 4H), 2.15-2.04 (m, 1H), 1.92-1.83 (m, 1H), 1.10 (t, 3H).

LC / MS (Method 2, ESIpos): R _t = 2.52 min, m / z = 339 [M + H] ⁺ . Example 33A

3- {4- [1- (methoxymethyl) cyclopentyl] phenyl} -5- (5-methyl-1H-pyrazol-3-yl) -1, 2,4-oxadiazole

Analogously to the process described under Example 22A (Method A), 1.18 g (9.34 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 2.32 g (9.34 mmol) of the compound from Example 19A were mixed with 1.31 g (41% of theory). Th.) Of the title compound.

'H-NMR (400 MHz, CDCl ₃ , δ / ppm): 10.82 (broad, 1H), 8.10 (d, 2H), 7.46 (d, 2H), 6.80 (s, 1H), 3.41 (s, 2H) , 3.23 (s, 3H), 2.43 (s, 3H), 2.07-2.00 (m, 2H), 1.97-1.89 (m, 2H), 1.78-1.71 (m, 4H).

LC / MS (Method 6, ESIpos): R _t = 1.19 min, m / z = 339 [M + H] ⁺ .

Example 34A

5- (5-Methyl-1H-pyrazol-3-yl) -3 - [3-methyl-4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazole

Analogously to the process described under Example 22A (Method A), 1.50 g (11.9 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 2.79 g (11.9 mmol) of the compound from Example 17A were admixed with 1.81 g (94% purity, 44% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 13.56 (broad, 1H), 8.12 (s, 1H), 8.02 (d, 1H), 7.54 (d, 1H), 6.81 (s, 1H ), 2.39 (s, 3H), 2.35 (s, 3H).

LC / MS (Method 6, ESIpos): R _t = 1.17 min, m / z = 325 [M + H] ⁺ .

Example 35A

3 - [4- (3-Fluorooxetane-3-yl) phenyl] -5- (5-methyl-1H-pyrazol-3-yl) -1,2,4-oxadiazole

Analogously to the process described under Example 22A (Method A), 300 mg (2.38 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 500 mg (2.38 mmol) of the compound from Example 4A were admixed with 204 mg (28%) of theory , Th.) Of the title compound. The crude product in this case was not purified by chromatography but by crystallization from ethanol.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.27 (d, 2H), 7.72 (d, 2H), 6.81 (s, 1H), 5:05 (dd, 2H), 5.01, (dd, 2H) , 2.47 (s, 3H).

LC / MS (Method 2, ESIpos): R _t = 1.93 min, m / z = 301 [M + H] ⁺ .

Example 36A

5- (5-Methyl-1H-pyrazol-3-yl) -3- {4 - [(trifluoromethyl) sulfanyl] phenyl} -1,4,4-oxadiazole

Analogously to the process described under Example 22A (Method A), from 600 mg (4.76 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 1.12 g (4.76 mmol) of the compound from Example 8A 485 mg (31% of theory) of the title compound. The crude product in this case was not purified by chromatography but by crystallization from ethanol.

¹ H-NMR (400 MHz, CDCl ₃ , δ / ppm): 10.60 (broad, IH), 8.23 (d, 2H), 7.79 (d, 2H), 6.81 (s, 2.47 (s, 3H).

LC / MS (Method 6, ESIpos): R _t = 1.17 min, m / z = 327 [M + H] ⁺ . Example 37A

3- (4-Cyclohexyl-phenyl) -5- (5-methyl-lH-pyrazol-3-yl) -l, 2,4-oxadiazole

Analogously to the process described under Example 22A (Method A), from 6.66 g (52.8 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 11.54 g (52.8 mmol) of the compound from Example 6A 9.02 g (55%) of theory , Th.) Of the title compound. The crude product in this case was not purified by chromatography but by crystallization from ethanol.

Ή NMR (400 MHz, CDCl ₃ , δ / ppm): 10.91 (s, broad, IH), 8.09 (d, 2H), 7.33 (d, 2H), 6.81 (s, IH), 2.61-2.52 (m , IH), 2.45 (s, 3H), 1.95-1.82 (m, 4H), 1.80-1.73 (m, IH), 1.52-1.34 (m, 4H), 1.33-1.21 (m, IH).

LC / MS (Method 6, ESIpos): R _t = 1.31 min, m / z = 309 [M + H] ⁺ .

Example 38A

5- (5-Methyl-1H-pyrazol-3-yl) -3- [4- (pentafluoro-λ ⁶ -sulfanyl) phenyl] -1,4,4-oxadiazole

Analogously to the process described under Example 22A (Method A), 1.58 g (12.5 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 3.28 g (12.5 mmol) of the compound from Example 7A were mixed with 2.87 g (65% of theory). Th.) Of the title compound. For workup, the product was precipitated by stirring the reaction mixture into ice water, filtered off, washed with water and dried under high vacuum after completion of the reaction.

'H-NMR (400 MHz, CDC1 ₃ , δ / ρρηι): 11.0 (s, broad, 1H), 8.29 (d, 2H), 7.89 (d, 2H), 6.82 (s, 1H), 2.46 (s, 3H).

LC / MS (Method 6, ESIpos): R _t = 1.13 min, m / z = 353 [M + H] ⁺ . Example 39A 3- (4-Isobutylphenyl) -5- (5-methyl-1H-pyrazol-3-yl) -1,4,4-oxadiazole

A solution of 2.0 g (15.9 mmol) 5-methyl-1H-pyrazole-3-carboxylic acid in 80 mL anhydrous DMF was added sequentially with 3.19 g (16.7 mmol) EDC, 2.55 g (16.7 mmol) HOBt and 3.35 g (17.4 mmol). the compound of Example 12A added. It was stirred for 1 h at RT, before being heated to 140 ° C for 30 min. After cooling to RT, the solvent was largely removed on a rotary evaporator. The residue was treated with about 500 ml of water, and it was extracted three times with about 200 ml of diethyl ether. The combined organic extracts were washed successively with water and saturated brine. After drying over anhydrous magnesium sulfate, it was filtered and the filtrate was evaporated on a rotary evaporator. The resulting residue was purified by MPLC (silica gel, eluent: cyclohexane / ethyl acetate 2: 1). After concluding stirring with about 50 ml of pentane, 1.7 g (38% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDCl ₃ , δ / ρρηι): 10.84 (broad, 1H), 8.08 (d, 2H), 7.27 (d, 2H), 6.81 (s, 1H), 2.54 (d, 2H ), 2.44 (s, 3H), 1.97-1.87 (m, 1H), 0.93 (d, 6H). LC / MS (Method 7, ESIpos): R _t = 2.59 min, m / z = 283 [M + H] Example 40A

3- {4- [1- (methoxymethyl) cyclobutyl] phenyl} -5- (5-methyl-1H-pyrazol-3-yl) -1, 2,4-oxadiazole

Analogously to the process described under Example 39A, 1.08 g (8.52 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 2.0 g (8.52 mmol) of the compound from Example 14A were added to 1.87 g (46% of th Title compound implemented. For MPLC purification of the crude product, a mobile phase gradient of cyclohexane / ethyl acetate (5: 1-> 1: 1) was used.

Tl-NMR (400 MHz, CDC1 _3, δ / ppm): 1 1:57 (broad, 1 H), 8.10 (d, 2H), 7.30 (d, 2H), 6.81 (s, 1 H), 3:57 (s, 2H), 3.29 (s, 3H), 2.45 (s, 3H), 2.41-2.28 (m, 4H), 2.15-2.03 (m, 1H), 1.93-1.84 (m, 1H). LC / MS (Method 4, ESIpos): R, = 1.28 min, m / z = 325 [M + H] ⁺ .

Example 41A

3- (4-Isopropylphenyl) -5- (5-methyl-1H-pyrazol-3-yl) -1, 2,4-oxadiazole

Analogously to the process described under Example 39A, 2.0 g (15.9 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 3.1.1 g (17.4 mmol) of the compound from Example 13A were added to 2.20 g (52% of theory). the title compound implemented.

'H-NMR (400 MHz, CDC, δ / ppm): 8.10 (d, 2H), 7.36 (d, 2H), 6.81 (s, 1H), 2.97 (sept, 1H), 2.43 (s, 3H), 1.29 (d, 6H).

LC / MS (Method 7, ESIpos): R _t = 2.42 min, m / z = 269 [M + H] ⁺ . Example 42A

3- (4-Ferrogen-butylphenyl) -5- (5-methyl-1H-pyrazol-3-yl) -1,2,4-oxadiazole

Analogously to the process described under Example 39A, 2.50 g (19.8 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 4.19 g (21.8 mmol) of 4-iert. -Butyl-N'-hydroxy-benzenecarboximidamide to 2.60 g (46% of theory) of the title compound.

'H-NMR (400 MHz, CDCl ₃ , δ / ppm): 1 10.08 (s, broad, 1H), 8.10 (d, 2H), 7.51 (d, 2H), 6.81 (s, 1H), 2.46 (s, 3H), 1.37 (s, 9H).

LC / MS (Method 6, ESIpos): R _t = 1.21 min, m / z = 283 [M + H] ⁺ . Example 43A

3- [4- (4-Fluoro-tetrahydro-2H-pyran-4-yl) -phenyl] -5- (5-methyl-1H-pyrazol-3-yl) -1,4,4-oxadiazole

A solution of 4.30 g (34.1 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid in 20 ml of anhydrous DMF was added at RT within about 15 minutes to a suspension of 5.81 g (35.8 mmol) of 1,1'-carbonyldiimidazole added dropwise in 25 ml of anhydrous DMF. After the mixture was stirred for 105 min at RT, 8.12 g (34.1 mmol) of the compound from Example 5A were added. Then, the reaction mixture was heated at 110.degree. C. for 5 hours. After cooling to RT, the mixture was stirred slowly into 800 ml of water. The precipitated product was filtered off with suction and washed with water. Subsequently, the moist crude product was recrystallized from 430 ml of ethanol. After filtration and drying, the crystal fraction gave 8.3 g (74% of theory) of the Title compound. Another fraction was obtained by concentrating the mother liquor (1.69 g, 85% purity, 13% of theory).

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 10.73 (broad, 1 H), 8.20 (d, 2H), 7:52 (d, 2H), 6.81 (s, 1 H), 4.00-3.88 ( m, 4H), 2.45 (s, 3H), 2.30-2.11 (m, 2H), 1.98-1.91 (m, 2H). LC / MS (Method 8, ESIpos): R _t = 4.24 min, m / z = 329 [M + H] ⁺ .

Example 44A

3- [4- (l-Fluorcyclobutyl) phenyl] -5- (5-methyl-lH-pyrazol-3-yl) -l, 2,4-oxadiazole

Analogously to the process described under Example 43A, 2.50 g (19.8 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 4.13 g (19.8 mmol) of the compound from Example 10A were mixed with 4.41 g (75% of theory). the title compound. After stirring the batch in water, the mixture was extracted three times with about 200 ml of ethyl acetate. The combined organic extracts were washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, the crude product was purified by crystallization from ethanol.

'H-NMR (400 MHz, CDCI _3, δ / ppm): 1 1:36 (broad, 1H), 8.20 (d, 2H), 7.60 (d, 2H), 6.82 (s, 1H), 2.77-2.54 (m , 4H), 2.47 (s, 3H), 2.19-2.08 (m, 1H), 1.87-1.77 (m, 1H).

LC / MS (Method 6, ESIpos): R _t = 1.07 min, m / z = 299 [M + H] ⁺ .

Example 45A 3- [3-Fluoro-4- (1,1,2-trifluoro-2-methylpropan-2-yl) phenyl] -5- (5-methyl-1H-pyrazol-3-yl) -1, 2 , 4-oxadiazole

Analogously to the process described under Example 39A, 2.71 g (21.5 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 5.68 g (21.5 mmol) of the compound from Example 21A were added to 4.36 g (95% purity, 54% of theory) Th.) Of the title compound implemented. 'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7.94 (d, 1 H), 7.88 (d, 1H), 7:57 (t, 1H), 6.81 (s, 1H), 2:45 (s, 3H ), 1.69 (s, 6H).

LC / MS (Method 6, ESIpos): R _t = 1.16 min, m / z = 355 [M + H] ⁺ . Example 46A

3- (2-hydroxypropane-2-yl) benzylmethansulfonat

2- [3- (hydroxymethyl) phenyl] propan-2-ol

To a suspension of 500 mg (2.78 mmol) of 3- (2-hydroxypropan-2-yl) benzoic acid in 10 ml of THF was slowly added 1.5 ml (3.47 mmol) of a 2.4 M solution of lithium aluminum hydride in THF. The mixture was then heated for 2 h at 80 ° C bath temperature. After cooling to RT was treated with 50 ml of 1 N hydrochloric acid and tert three times with 30 ml. Butyl methyl ether extracted. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Drying of the residue in vacuo afforded 455 mg (97% purity, 99% of theory) of the title compound. Ή-NMR (400 MHz, CDCl ₃ , δ / ppm): 7.51 (s, 1H), 7.42 (d, 1H), 7.34 (t, 1H), 7.25 (d, 1H), 4.71 (s, 2H), 1.59 (s, 6H).

LC / MS (Method 6, ESIpos): R _t = 0.57 min, m / z = 149 [M + HH ₂ 0] ⁺ . Step 2: 3 - (2-Hydroxypropan-2-yl) benzylmethanesulfonate

To a solution of 873 mg (5.25 mmol) of the compound from Example 46A / Step 1 in 50 ml of dichloromethane was added under argon 1.1 ml (7.88 mmol) of triethylamine at RT, followed by 1.01 g (5.78 mmol) of methanesulfonic anhydride at 0 ° C. After stirring at RT for 1 h, the mixture was washed successively with 100 ml of aqueous ammonium chloride solution and 100 ml of sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated. Drying of the residue in vacuo gave 1.13 g (88% of theory) of the title compound.

Ή NMR (400 MHz, CDCL, δ / ppm): 7.56 (s, 1H), 7.51 (d, 1H), 7.39 (t, 1H), 7.32 (d, 1H), 5.25 (s, 2H), 2.94 (s, 3H), 1.59 (s, 6H). LC / MS (Method 6, ESIpos): R, = 0.74 min, m / z = 227 [M + HH ₂ 0] ⁺ .

Example 47A

1 - (3 - {[(methylsulfonyl) oxy] methyl} phenyl) cyclopropylacetate

Step 1: 1 - [3 - ({[tert-butyl (dimethyl) silyl] oxy} methyl) phenyl] cyclopropanol

Preparation of solution A: 12.32 g (70.7 mmol) of [(1-ethoxycyclopropyl) oxy] (trimethyl) silane were admixed with 60 ml of methanol and one drop of concentrated hydrochloric acid and stirred at RT overnight. Subsequently, the solvent was removed at RT and a vacuum of not less than 30 mbar on a rotary evaporator. There were obtained 6.26 g (61.27 mmol) of 1-ethoxycyclopropanol, which were dissolved in 80 ml of THF. This solution was then cooled to -70 ° C. under argon and 30.6 ml (61.27 mmol) of a 2 M solution of ethylmagnesium chloride in THF were added. Thereafter, the cold bath was removed and the solution was stirred without cooling until reaching an internal temperature of 0 ° C.

Preparation of solution B: To a solution of 19.40 g (55.70 mmol) of tert. -Butyl [(3-iodobenzyl) oxy] dimethylsilane in 280 ml of THF under argon at -40 ° C were added 47.1 ml (61.27 mmol) of a 1.3 M solution of isopropylmagnesium chloride-lithium chloride complex in THF and the mixture was stirred for 1 h stirred at -40 ° C.

After preparation of the two solutions solution B was added at 0 ° C with solution A. Subsequently, the reaction mixture was heated under reflux for 1 h. After cooling to RT, saturated aqueous ammonium chloride solution was added and tert. Butyl methyl ether extracted. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, eluent: cyclohexane - ^{> ■} cyclohexane / ethyl acetate 85:15). After removal of the solvent, 9.55 g (60% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDCL, δ / ppm): 7.32-7.24 (m, 2H), 7.22-7.16 (m, 2H), 4.74 (s, 2H), 2.36 (s, 1H), 1.26 (dd , 2H), 1.06 (dd, 2H), 0.94 (s, 9H), 0.1 1 (s, 6H).

MS (DCI, NH _3): m / z = 296 [M + NH _4] ^+.

Step 2: 1 - [3 - ({[tert-butyl (dimethyl) silyl] oxy} methyl) phenyl] cyclopropylacetate

To a solution of 9.55 g (34.3 mmol) of the compound from Example 47A / Step 1 in 100 ml of THF at RT was added 21.4 ml (42.87 mmol) of a 2 M solution of ethylmagnesium chloride in THF followed immediately by 3.0 ml (42.87 mmol) of acetyl chloride given. After stirring for 5 min at RT the mixture was added with saturated aqueous ammonium chloride solution and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. 11.25 g (94% purity, 96% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, CDCl ₃ , δ / ρρηι): 7.30-7.24 (m, 2H), 7.20-7.13 (m, 2H), 4.72 (s, 2H), 2.04 (s, 3H), 1.31-1.25 (m, 2H), 1.24-1.18 (m, 2H), 0.94 (s, 9H), 0.09 (s, 6H).

MS (DCI, NH _3): m / z = 338 [M + NH _4] ^+.

Step 3: 1- [3- (Hydioxymethyl) phenyl] cyclopropylacetate

To a solution of 11.25 g (32.82 mmol, purity 94%) of the compound from Example 47A / Step 2 was added at RT 65.6 ml (65.6 mmol) of a 1 M solution of tetra-n-butylammonium fluoride in THF. The mixture was stirred at RT for 30 min, then diluted with ethyl acetate and washed once with water. The aqueous phase was back-extracted once with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. 8.0 g (80% pure, 95% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7:24 to 7:12 (m, 5H), 4:58 (s, 2H), 1.95 (s, 3H), 1.22-1. 17 (m, 2H), 1.16-1.10 (m, 2H).

Step 4: 1- (3- {[(Methylsulfonyl) oxy] methyl} phenyl) cyclopropylacetate

2.8 ml (37.24 mmol) of methanesulphonic acid chloride were added dropwise at 0 ° C. to a solution of 8.0 g (31.03 mmol, purity 80%) of the compound from Example 47A / Step 3 and 5.6 ml (40.34 mmol) of triethylamine in 90 ml of THF. The mixture was then warmed slowly to RT, stirred for 10 min at RT and then diluted with ethyl acetate. The mixture was washed once with water, and the aqueous phase was back-extracted once with ethyl acetate. The United organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue obtained was purified by flash chromatography (silica gel, mobile phase: cyclohexane / ethyl acetate 95: 5 ^→ 70:30). After removal of the solvent and drying of the residue in vacuo, 8.45 g (95% purity, 91% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7:39 to 7:27 (m, 4H), 5.22 (s, 2H), 2.90 (s, 3H), 2:06 (s, 3H), 1:35 to 1:28 ( m, 2H), 1.27-1.20 (m, 2H).

LC / MS (Method 4, ESIpos): R _t = 1.02 min, m / z = 285 [M + H] ⁺ . Example 48A 3 - (2-hydroxy-2-methylpropyl) benzylmethanesulfonate

Step 1: 1 - (3-Bromophenyl) -2-methylpropan-2-ol

A solution of 15.0 g (65.5 mmol) of methyl (3-bromophenyl) acetate in 600 ml of anhydrous THF was added dropwise at 0 ° C with 55 ml (164 mmol) of a 3 M solution of methylmagnesium chloride in THF. After completion of the addition, the mixture was stirred for 1 h at 0 ° C. Subsequently, the ice / water bath was removed and stirring continued overnight at RT. Then, about 1.2 liters of saturated aqueous ammonium chloride solution were added and the mixture was extracted three times with about 200 ml of ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally freed from the solvent in vacuo. The residue obtained was purified by suction filtration through silica gel with cyclohexane / ethyl acetate 10: 1 → 1: 1 as eluent. 8.04 g (53% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDCI _3, δ / ppm): 7:41 to 7:37 (m, 2H), 7:20 to 7:13 (m, 2H), 2.73 (s, 2H), 1:32 (s, 1H), 1.23 ( s, 6H). GC / MS (Method 9, EIpos): R _t = min, m / z = 210/212 [MH ₂ 0]

3- (2-hydroxy-2-methylpropyl) benzaldehyde

A solution of 2.50 g (10.9 mmol) of the compound from Example 48A / Step 1 in 100 ml of anhydrous THF was added dropwise at -78 ° C. with 13.7 ml (21.8 mmol) of n-butyllithium solution (1.6 M in hexane) , After completion of the addition, the mixture was stirred for a further 30 minutes at -78 ° C before, also at -78 ° C, 2.6 ml (32.8 mmol) of anhydrous N, N-dimethylformamide were added. Subsequently, the cold bath was removed and stirring continued overnight at RT. It was then mixed with about 100 ml of saturated aqueous ammonium chloride solution and extracted three times with about 100 ml of ethyl acetate. The combined organic extracts were washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally freed of solvent in vacuo. The crude product thus obtained was purified by MPLC (silica gel, eluent: cyclohexane / ethyl acetate 2: 1). 1.15 g (59% of theory) of the title compound were obtained. 'H-NMR (400 MHz, CDC1 ₃ , δ / ρρηι): 10.01 (s, 1H), 7.79-7.74 (m, 2H), 7.53-7.47 (m, 2H), 2.86 (s, 2H), 1.25 ( s, 6H).

GC / MS (Method 9, EIpos): R, = 4.76 min, m / z = 160 [MH ₂ 0] ⁺ .

Step 3: 1 - [3 - (Hydroxymethyl) phenyl] -2-methylpropan-2-ol A solution of 1.07 g (6.00 mmol) of the compound from Example 48A / Step 2 in 30 mL of anhydrous THF was added dropwise at 0 ° C with 6.0 mL (6.0 mmol) of lithium aluminum hydride solution (1.0 M in THF). After the end of the addition, the mixture was stirred at RT for a further 1 h. Then, carefully added 1-2 ml of saturated aqueous ammonium chloride solution and then about 30 ml of ethyl acetate. As much anhydrous magnesium sulfate was added as needed to completely take up the aqueous phase. After filtration, the filtrate was subjected to rotation freed of steamer solvent and the residue dried under high vacuum. There were obtained 1.09 g (100% of theory) of the title compound.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7.31 (t, 1H), 7.25 (dd, 1H), 7.22 (dd, 1H), 7.14 (dd, 1H), 4.69 (s, broad, 2H), 2.78 (s, 2H), 1.79 (broad, 1H), 1.41 (s, broad, 1H), 1.23 (s, 6H). GC / MS (Method 9, EIpos): R, = 5.00 min, m / z = 162 [MH ₂ 0] ⁺ .

3- (2-hydroxy-2-methylpropyl) benzylmethansulfonat

A solution of 1.05 g (5.83 mmol) of the compound from Example 48A / Step 3 and 1.2 ml (8.74 mmol) of triethylamine in 60 ml of anhydrous dichloromethane was treated at 0 ° C with 1.12 g (6.41 mmol) of methanesulfonic anhydride. The mixture was stirred for 1 h at RT. Subsequently, the reaction mixture was transferred to a separating funnel and washed successively briskly with half-saturated aqueous ammonium chloride solution and water. After drying over anhydrous magnesium sulfate, it was filtered and the filtrate was freed from the solvent on a rotary evaporator. 1.5 g (99% of theory) of the title compound were obtained. MS (DCI, NH _3): m / z = 276 [M + NH _4] ^+.

Example 49A

Ethyl 2- [3 - (bromomethyl) phenyl] -2-methylpropanoate

Ethyl-2-methyl-2- (3-methylphenyl) propanoate

10.0 g (56.1 mmol) of ethyl t-tolylacetate and 15.9 g (12 mmol) of methyl iodide were dissolved in 300 ml of abs. Submitted THF and cooled to about -70 ° C. 6.93 g (61.7 mmol) of potassium were added. Butylate added and stirred for 1 h without further cooling. The mixture was then cooled again to about - 70 ° C, gave again 6.93 g (61.7 mmol) of potassium tert. Butylate added and stirred for another hour without cooling. The reaction was then diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was freed from the solvent on a rotary evaporator. 9.7 g (76% of theory) of the title compound were obtained.

GC / MS (Method 9, EIpos): R _t = 4.23 min, m / z = 206 [M] ⁺ . Step 2: Ethyl 2- [3- (bromomethyl) phenyl] -2-methylpropanoate

3.70 g (17.9 mmol) of the compound from Example 49A / Step 1 were initially charged in 55 ml of acetonitrile, with 3.19 g (17.9 mmol) of N-bromosuccinimide and 29 mg (0.18 mmol) of 2,2'-azobis-2-methylpropanenitrile (AIBN) and heated to reflux overnight. The mixture was then freed from the solvent on a rotary evaporator, the residue was suspended in pentane and the solid was separated by filtration. The filtrate was freed from the solvent on a rotary evaporator. The residue obtained was a yellow oil which still contained educt but was reacted directly without further purification.

Yield: 4.64 g (64% of theory, 71% purity according to GC / MS) GC / MS (Method 9, EIpos): R _t = 5.71 min, m / z = 284/286 [M] ⁺ . Example 50A

3 - (1 - {[(Triisopropylsilyl) oxy] methyl} cyclopropyl) benzylmethanesulfonate

Step 1: Methyl 1 - (3-Bromophenyl) cyclopropanecarboxylate

A solution of 10.0 g (43.6 mmol) of methyl (3-bromophenyl) acetate in 250 ml of anhydrous THF was added at 0 ° C with 48 ml (48.0 mmol) of a 1 M solution of lithium hexamethyldisilazide (LiHMDS) in THF. After 15 min at 0 ° C, 4.9 ml (56.7 mmol) of 1,2-dibromoethane were added. The ice / water bath was removed and stirred at RT for 1 h. It was then cooled again to 0 ° C. and treated with a further 48 ml (48.0 mmol) of the LiHMDS solution. After completion of the addition, stirring was continued at RT for 63 h. Then, the reaction mixture was treated with about 250 ml of saturated aqueous ammonium chloride solution and extracted three times with about 200 ml of ethyl acetate. The combined organic extracts were washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally freed of solvent in vacuo. The residue obtained was purified by suction filtration through silica gel with cyclohexane / ethyl acetate 20: 1 as eluent. There was obtained 6.24 g (56% of theory) of the title compound. 'H-NMR (400 MHz, CDCL, δ / ppm): 7.50 (m, 1H), 7.39 (m, 1H), 7.27 (m, 1H), 7.19 (m, 1H), 3.63 (s, 3H), 1.62-1.60 (m, 2H), 1.20-1.17 (m, 2H).

GC / MS (Method 9, EIpos): R _t = 5.27 min, m / z = 254/256 [M] ⁺ .

[1- (3-Bromophenyl) cyclopropyl] methanol

A solution of 3.50 g (13.7 mmol) of the compound from Example 50A / Step 1 in 70 ml of anhydrous THF was added at -78 ° C with 13.7 ml (13.7 mmol) of a 1 M solution of lithium aluminum hydride in THF. After stirring for 1 h, the reaction mixture was admixed with about 3 ml of saturated aqueous ammonium chloride solution and allowed to warm to RT. It was then diluted with about 80 ml of ethyl acetate and then added as much anhydrous magnesium sulfate that the aqueous phase was completely absorbed. After filtration, the filtrate was concentrated and the residue was purified by MPLC (silica gel, mobile phase: cyclohexane -> ^■ cyclohexane / ethyl acetate 5: 1). 1.37 g (44% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7:52 (s, 1H), 7:36 (d, 1 H), 7.29 (d, 1 H), 7.18 (t, 1 H), 3.66 (d , 2H), 1.44 (t, 1H), 0.91-0.84 (m, 4H). GC / MS (Method 9, EIpos): R, = 5.26 min, m / z = 226/228 [M] ⁺ .

Step 3: {[1- (3-Bromophenyl) cyclopropyl] methoxy} (triisopropyl) silane

A solution of 1.34 g (5.90 mmol) of the compound of Example 50A / Step 2 and 948 mg (8.85 mmol) of 2,6-lutidine in 25 mL of anhydrous dichloromethane was added at -50 ° C with 1.55 mL (6.19 mmol) triisopropylsilyl triflate added. After 30 minutes, the cold bath was removed and stirring continued for 1 h at RT. Then it was mixed with about 50 ml of water and extracted three times with about 50 ml of ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally freed from the solvent in vacuo. The residue obtained was purified by MPLC (silica gel, eluent: cyclohexane / ethyl acetate 5: 1). 1.93 g (85% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDCI _3, δ / ppm): 7:52 (s, 1H), 7.31 (d, 1H), 7.27 (d, 1H), 7.13 (t, 1H), 3.74 (s, 2H) , 1.02 (m, 3H), 0.99 (d, 18H), 0.91-0.89 (m, 2H), 0.78-0.75 (m, 2H).

GC / MS (Method 9, EIpos): R, = 6.87 min, m / z = 339/341 [M-'Pr] ⁺ . Step 4: 3 - (1 - {[(Triisopropylsilyl) oxy] methyl} cyclopropyl) benzaldehyde

Analogously to the process described under Example 48A / Step 2, from 1.92 g (5.01 mmol) of the compound from Example 50A / Step 3 and corresponding amounts of 77-butyllithium and N, N-dimethylformamide 1.48 g (88% of th.) of the title compound after MPLC purification (silica gel, eluent: cyclohexane / ethyl acetate 10: 1).

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 10.00 (s, 1H), 7.89 (s, 1H), 7.72 (d, 1H), 7.65 (d, 1H), 7:43 (t, 1H) , 3.79 (s, 2H), 1.01 (sept, 3H), 0.98 (d, 18H), 0.96-0.94 (m, 2H), 0.83-0.81 (m, 2H). GC / MS (Method 9, EIpos): R _t = 7.00 min, m / z = 289 [M- ^! Pr] ⁺ .

Step 5: [3 - (1 - {[(Triisopropylsilyl) oxy] methyl} cyclopropyl) phenyl] methanol

Analogously to the process described under Example 50A / Step 2, 1.10 g (78% of theory) of the title compound were obtained from 1.40 g (4.21 mmol) of the compound from Example 50A / Step 4 and the corresponding amount of lithium aluminum hydride. Chromatographic purification of the product was omitted here.

'H-NMR (400 MHz, CDCl ₃ , δ / ppm): 7.38 (s, 1H), 7.31-7.25 (m, 2H), 7.20 (d, 1H), 4.67 (d, 2H), 3.79 (s, 2H), 1.60 (t, 1H), 1.02 (sept, 3H), 1.00 (d, 18H), 0.93-0.90 (m, 2H), 0.77-0.75 (m, 2H).

GC / MS (Method 9, EIpos): R _t = 7.18 min, m / z = 291 [M- ^! Pr] ⁺ . Step 6: 3 - (1 - {[(Triisopropylsilyl) oxy] methyl} cyclopropyl) benzylmethanesulfonate

Analogously to the process described under Example 48A / Step 4, from 1.01 g (100%) of 820 mg (2.45 mmol) of the compound from Example 50A / Step 5 and corresponding amounts of triethylamine and methanesulfonic anhydride. Th.) Of the title compound. 'H-NMR (400 MHz, CDC1 ₃ , δ / ρρηι): 7.42 (s, 1H), 7.40 (d, 1H), 7.32 (t, 1H), 7.25 (d, 1H), 5.21 (s, 2H) , 3.77 (s, 2H), 2.91 (s, 3H), 1.02 (sept, 3H), 0.98 (d, 18H), 0.93-0.91 (m, 2H), 0.79-0.76 (m, 2H). LC / MS (Method 6, ESIpos): R, = 1.59 min, m / z = 413 [M + H] ⁴

MS (DCI, NH _3): m / z = 430 [M + NH _4].

Example 51A

Dideutero [(triisopropylsilyl) oxy] methyl} cyclopropyl) benzylmethansulfonat

[1- (3-Bromophenyl) cyclopropyl] -1,1-dideuteromethanol

Analogously to the process described under Example 50A / Step 2, 3.50 g (13.7 mmol) of the compound from Example 50A / Step 1 were reacted with lithium aluminum deuteride (instead of lithium aluminum hydride) to give 1.39 g (44% of theory) of the title compound.

Ti-NMR (400 MHz, CDC1 _3, 8 / ppm): 7:51 (s, 1H), 7:36 (d, 1H), 7.29 (d, 1H), 7.18 (t, 1H), 1:43 (s, 1H), 0.90-0.86 (m, 4H).

GC / MS (Method 9, EIpos): R _t = 5.26 min, m / z = 228/230 [M] ⁺ .

Step 2: ({[1- (3-Bromophenyl) cyclopropyl] -1,1-dideuteromethyl} oxy) (triisopropyl) silane

Analogously to the process described under Example 50A / Step 3, 1.38 g (6.02 mmol) of the compound from Example 51 A / Step 1 were reacted with triisopropylsilyl triflate to give 2.03 g (88% of theory) of the title compound. 'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7:52 (s, 1H), 7.31 (d, 1H), 7.27 (d, 1H), 7.13 (t, 1H), 1:03 (m, 3H) , 1.00 (d, 18H), 0.91-0.88 (m, 2H), 0.78-0.75 (m, 2H).

GC / MS (Method 9, EIpos): R _t = 6.86 min, m / z = 341/343 [M- ^; Pr] ⁺ .

Step 3: 3 - (1 - {[(Triisopropylsilyl) oxy] dideuteromethyl} cyclopropyl) benzaldehyde

Analogously to the process described under Example 48A / Step 2, from 2.01 g (5.23 mmol) of the compound from Example 51 A / Step 2 and corresponding amounts of n-butyllithium and N, N-dimethylformamide 1.75 g (100% of theory) of Title compound obtained.

Ή NMR (400 MHz, CDCl ₃ , δ / ppm): 10.00 (s, 1H), 7.89 (s, 1H), 7.72 (d, 1H), 7.64 (d, 1H), 7.43 (t, 1H), 1.01 (sept, 3H), 0.98 (d, 18H), 0.97-0.93 (m, 2H), 0.83-0.81 (m, 2H).

GC / MS (Method 9, EIpos): R _t = 7.00 min, m / z = 291 [M- ^; Pr] ⁺ .

[3 - (1 - {[(triisopropylsilyl) oxy] dideuteromethyl} cyclopropyl) phenyl] methanol

Analogously to the process described under Example 50A / Step 2, from 1.74 g (5.21 mmol) of the compound from Example 51A / Step 3 and the corresponding amount of lithium aluminum hydride 1.45 g (83% of theory) of the title compound were obtained after MPLC purification (Silica gel, eluent: cyclohexane / ethyl acetate 10: 1).

'H-NMR (400 MHz, CDCl ₃ , δ / ppm): 7.37 (s, 1H), 7.30-7.25 (m, 2H), 7.20 (d, 1H), 4.67 (d, 2H), 1.60 (t, 1H), 1.02 (sept, 3H), 1.00 (d, 18H), 0.93-0.90 (m, 2H), 0.77-0.75 (m, 2H). GC / MS (Method 9, EIpos): R _t = 7.18 min, m / z = 293 [M-Pr] Step 5: 3 - (1 - {[(Triisopropylsilyl) oxy] dideuteromethyl} cyclopropyl) benzylmethanesulfonate

Analogously to the process described under example 48A / step 4, from 1.18 g (3.51 mmol) of the compound from example 51A / step 4 and corresponding amounts of triethylamine and methanesulfonic anhydride 1.46 g (100% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7:42 (s, 1H), 7:40 (d, 1H), 7:32 (t, 1H), 7.25 (d, 1H), 5.21 (s, 2H) , 2.91 (s, 3H), 1.02 (sept, 3H), 0.98 (d, 18H), 0.93-0.90 (m, 2H), 0.79-0.76 (m, 2H).

LC / MS (Method 6, ESIpos): R _t = 1.59 min, m / z = 415 [M + H] ⁺ .

MS (DCI, NH _3): m / z = 432 [M + NH _4] ^+. Example 52A

2- [3 - (bromomethyl) phenyl] -2,2-difluoroethanol

Step 1: Ethyl difluoro (3-methylphenyl) acetate

To a solution of 23.35 g (107 mmol) of 3-iodotoluene in 110 ml of DMSO at RT under argon was added 25.0 g (123 mmol) of ethyl bromo (difluoro) acetate and 41.0 g (225 mmol) of copper bronze (90/10 copper). Tin alloy). The reaction mixture was then stirred at 50 ° C for 16 h. After cooling to RT, the mixture was added to 200 ml of 1 N hydrochloric acid and treated with 100 ml of ethyl acetate. Existing solids were filtered off and the filtrate was extracted by shaking twice with 50 ml each of 1 N hydrochloric acid and 50 ml of ethyl acetate. The combined organic Phases were washed once each with 200 ml of water and 200 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, mobile phase: isohexane / ethyl acetate 98: 2 ^{→ 90:10} ). After removal of the solvent, 21.41 g (54% of theory) of the title compound were obtained. 'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7:43 to 7:38 (m, 2H), 7:37 to 7:21 (m, 2H), 4.30 (quart, 2H), 2:40 (s, 3H), 1.31 ( t, 3H).

GC / MS (Method 9, EIpos): R _t = 3.72 min, m / z = 214 [M] ⁺ .

Step 2: 2,2-Difluoro-2- (3-methylphenyl) ethanol

To a solution of 8.57 g (40.0 mmol) of the compound from Example 52A / Step 1 in 70 ml of ethanol was added slowly at RT under argon 1.51 g (40 mmol) of sodium borohydride. After stirring for 30 min at RT, the reaction mixture was slowly tert with 300 ml. Butyl methyl ether and 300 ml of 1 N hydrochloric acid. The aqueous phase was then back-extracted once with 200 ml of tert-butyl methyl ether. The combined organic phases were dried over sodium sulfate, filtered and concentrated at just enough vacuum on a rotary evaporator at RT. There were obtained 7.17 g (> 100% of theory) of a residue containing the target compound as well as residues of solvent.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7:35 to 7:24 (m, 3H), 3.96 (t, 2H), 2:40 (s, 3H). GC / MS (Method 9, EIpos): R _t = 3.32 min, m / z = 172 [M] ⁺ . Step 3: 2- [3- (Bromomethyl) phenyl] -2,2-difluoroethanol

To a solution of 6.88 g (about 40 mmol) of the compound from example 52A / step 2 in 150 ml of acetonitrile at RT 7.47 g (42.0 mmol) of N-bromosuccinimide and 328 mg (2.00 mmol) of 2,2'-azobis 2-methylpropanenitrile (AIBN). The mixture was heated to 80 ° C bath temperature for 6 hours heated. After cooling to RT, the solvent was removed and the residue was stirred with a mixture of 100 ml of pentane and 50 ml of ethyl acetate. The solid was filtered off and washed twice with 15 ml of the 2: 1 mixture of pentane and ethyl acetate. The filtrate and the washings were combined, washed once each with 200 ml of saturated aqueous sodium sulfite solution and 200 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. This gave 9.72 g (70% purity, 68% of theory) of the title compound, which was reacted further in this form.

'H-NMR (400 MHz, CDC, δ / ppm): 7.56-7.42 (m, 4H), 4.51 (s, 2H), 3.98 (m, 2H). GC / MS (Method 9, EIpos): R _t = 5.06 min, m / z = 250 [M] ⁺ . Example 53A

Ethy 1- [3 - (bromomethyl) phenyl] (difluoro) acetate

To a solution of 4.64 g (21.7 mmol) of the compound of Example 52A / Step 1 in 110 mL of acetonitrile was added 4.05 g (22.74 mmol) of N-bromosuccininide and 178 mg (1.08 mmol) of 2,2'-azobis-2-methylpropanenitrile ( AIBN). The mixture was heated for 2.5 h at 80 ° C bath temperature. After cooling to RT, the solvent was removed and the residue was stirred with 30 ml of ethyl acetate and 60 ml of pentane. The solid was filtered off and washed twice with 10 ml of pentane. The filtrate was combined with the washing phases, washed successively with 100 ml of 10% aqueous sodium thiosulfate solution, 100 ml of water and 100 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated. There were obtained 5.56 g (70% purity, 62% of theory) of the title compound, which was reacted further in this form.

'H-NMR (400 MHz, CDC1 _3, 8 / ppm): 7.64 (s, 1H), 7:58 to 7:28 (m, 3H), 4:51 (s, 2H), 4.31 (quart, 2H), 1.31 (t, 3H).

GC / MS (Method 9, EIpos): R _t = 5.24 min, m / z = 282 [M] ⁺ . Example 54A

Methyl 3 - [(5-methyl-3 - {3 - [4- (1,1-trifluoro-2-methylpropan-2-yl) -phenyl] -1,2,4-oxadiazol-5-yl} - 1H-pyrazol-1-yl) methyl] benzoate

Method A:

 1.0 g (2.97 mmol) of the compound from Example 23A and 0.82 g (3.56 mmol) of methyl 3-bromomethyl-benzoate were dissolved in 30 ml of abs. Dissolved THF, with ice bath cooling with 0.37 g (3.27 mmol) of potassium tert. butyl acetate and stirred overnight at RT. It was then treated with water, and it was extracted three times with about 50 ml of ethyl acetate. The combined organic extracts were washed with brine. After drying over anhydrous magnesium sulfate, it was filtered and the filtrate was concentrated on a rotary evaporator. The residue was chromatographed on silica gel (mobile phase: cyclohexane / ethyl acetate 4: 1). 0.74 g (51% of theory) of the title compound were obtained.

Method B:

 A solution of 10.0 g (29.7 mmol) of the compound from Example 23A and 8.86 g (38.6 mmol) of methyl 3-bromomethylbenzoate in 300 ml of anhydrous 1,4-dioxane was treated at 0 ° C. with 3.67 g (32.7 mmol) of solid potassium fert. butyl acetate and then stirred for 15 h at RT. Thereafter, about 600 ml of water were added, and it was extracted three times with about 250 ml of ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally freed from the solvent on a rotary evaporator. The crude product was stirred in a mixture of 50 ml of pentane and 5 ml of diisopropyl ether for 30 min at RT. The solid was filtered off, the filtrate discarded and the residue stirred once more in pentane / diisopropyl ether as described. After re-filtration and drying of the residue under high vacuum, 1.0 g (72% of theory, 95% purity) of the title compound was obtained.

Ή MR (400 MHz, DMSO-de, δ / ppm): 8.10 (d, 2H), 7.91 (d, 1H), 7.84 (s, 1H), 7.77 (d, 2H), 7.55 (t, 1H) , 7.47 (d, 1H), 6.96 (s, 1H), 5.61 (s, 2H), 3.85 (s, 3H), 2.34 (s, 3H), 1.61 (s, 6H). LC / MS (Method 6, ESIpos): R _t = 1.38 min, m / z = 485 [M + H] Example 55A

2,2,2-trifluoro-1- {3 - [(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -l, 2,4-oxadiazo

1 -yl) methyl] phenyl} ethanone

A solution of 600 mg (1.14 mmol) of the compound from Example 81A in 25 ml of anhydrous THF was treated rapidly at -20 ° C. with 2.6 ml (3.42 mmol) of a 1 .3 M solution of isopropylmagnesium chloride / lithium chloride complex in THF , After 4 min, the reaction mixture was cooled to about -40 ° C and then added in one portion with 644 μΐ (4.56 mmol) of trifluoroacetic anhydride. After the reaction mixture had been stirred at -40 ° C. for 10 minutes, 1 ml of saturated aqueous ammonium chloride solution was added and the mixture was warmed to RT. Then, it was mixed with about 100 ml of water and extracted three times with about 50 ml of ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally freed from the solvent on a rotary evaporator. The residue obtained was coarsely prepurified by MPLC (about 50 g of silica gel, eluent: cyclohexane / ethyl acetate 4: 1). After evaporation of the product fraction, the residue was stirred in a mixture of 25 ml of pentane and 1 ml of dichloromethane. The product was filtered off with suction and finally dried under high vacuum. This gave 233 mg (39% of theory, 95% purity) of the title compound.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.25 (d, 2H) 8.02 (d, 1H), 7.90 (s, 1H), 7:55 (t, 1H), 7.50 (d, 1H) , 7.33 (d, 2H), 6.86 (s, 1H), 5.53 (s, 2H), 2.32 (s, 3H).

LC / MS (Method 6, ESIpos): R, = 1.22 min, no ionization.

Example 56A

Methyl 3 - [(5-methyl-3- {3- [4- (tetrahydro-2H-pyran-4-yl) phenyl] -1,4,4-oxadiazol-5-yl} -1H-pyrazole-1 -yl) methyl] benzoate

A solution of 175 mg (0.564 mmol) of the compound of Example 28A and 168 mg (0.733 mmol) of methyl 3-bromomethylbenzoate in 6 mL of anhydrous THF was added at 0 ° C with 70 mg (0.620 mmol) of solid potassium butoxide and then stirred for 4 h at RT. Thereafter, the reaction was terminated by the addition of 2 drops of water, and methanol was added until all solid components had just gone into solution. This solution was then purified directly by preparative HPLC (method 11). 208 mg (80% of theory) of the title compound were isolated.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.15 (d, 2H), 7.98 (d, 1H), 7.89 (s, 1H), 7:42 (t, 1H), 7:34 (d, 2H) , 7.33 (d, 1H), 6.82 (s, 1H), 5.50 (s, 2H), 4.13-4.08 (m, 2H), 3.91 (s, 3H), 3.54 (dt, 2H), 2.87-2.79 ( m, 1H), 2.28 (s, 3H), 1.92-1.78 (m, 4H).

LC / MS (Method 6, ESIpos): R _t = 1.24 min, m / z = 459 [M + H] ⁺ .

Example 57A

Methyl 3 - ({3- [3- (4-tert-butylphenyl) -1,2,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) benzoate

A solution of 500 mg (1.77 mmol) of the compound of Example 42A and 81 1 mg (3.54 mmol) of methyl 3-bromomethylbenzoate in 15 ml of anhydrous THF was added at 0 ° C with 298 mg (2.66 mmol) of solid potassium tertiary. butyl acetate and then stirred for 15 h at RT. Thereafter, about 45 ml of water were added, and it was extracted three times with about 20 ml of ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally removed on a rotary evaporator from the solution medium freed. From the crude product, 493 mg (64% of theory) of the title compound were obtained by MPLC (silica gel, eluent: cyclohexane / ethyl acetate 5: 1).

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.13 (d, 2H), 7.98 (d, 1H), 7.89 (s, 1H), 7.50 (d, 2H), 7:42 (t, 1H) , 7.33 (d, 1H), 6.83 (s, 1H), 5.50 (s, 2H), 3.91 (s, 3H), 2.28 (s, 3H), 1.37 (s, 9H). LC / MS (Method 6, ESIpos): R _t = 1.41 min, m / z = 431 [M + H] ⁺ .

Example 58A

Methyl 3 - {[3- (3 - {4- [1- (methoxymethyl) cyclobutyl] phenyl} -1,2,4-oxadiazol-5-yl) -5-methyl-1H-pyrazol-1-yl] methyl} benzoate

Analogously to the process described under Example 57A, from 325 mg (1.00 mmol) of the compound from Example 40A and methyl 3-bromomethylbenzoate, 206 mg (44% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDCI _3, δ / ppm): 8.14 (d, 2H), 7.98 (d, 1H), 7.90 (s, 1H), 7:42 (t, 1H), 7:33 (d, 1H) , 7.30 (d, 2H), 6.83 (s, 1H), 5.50 (s, 2H), 3.91 (s, 3H), 3.55 (s, 2H), 3.28 (s, 3H), 2.43-2.28 (m, 4H ), 2.28 (s, 3H), 2.15-2.03 (m, 1H), 1.93-1.83 (m, 1H).

LC / MS (Method 6, ESIpos): R _t = 1.38 min, m / z = 473 [M + H] ⁺ .

Example 59A

Methyl 3 - {[3- (3 - {3-fluoro-4- [1 - (methoxymethyl) cyclobutyl] phenyl} -1,2,4-oxadiazol-5-yl) -5-methyl-1H-pyrazole 1 -yl] methyl} benzoate

- HO -

Analogously to the process described under Example 57A, from 350 mg (1.02 mmol) of the compound from Example 31A and methyl 3-bromomethylbenzoate, 233 mg (46% of theory) of the title compound were obtained.

¹ H NMR (400 MHz, CDC1 ₃ , δ / ρρηι): 7.99 (d, IH), 7.93 (dd, IH), 7.89 (s, IH), 7.83 (dd, IH), 7.43 (t, IH) , 7.33 (d, IH), 7.23 (d, IH), 6.83 (s, IH), 5.51 (s, 2H), 3.91 (s, 3H), 3.67 (s, 2H), 3.28 (s, 3H), 2.48-2.40 (m, 2H), 2.37-2.30 (m, 2H), 2.28 (s, 3H), 2.19-2.07 (m, IH), 1.94-1.85 (m, IH).

LC / MS (Method 6, ESIpos): R _t = 1.42 min, m / z = 491 [M + H] ⁺ .

Example 60A

Methyl 3 - {[3- (3 - {4- [1- (methoxymethyl) cyclopentyl] phenyl} -1,2,4-oxadiazol-5-yl) -5-methyl-1H-pyrazol-1-yl ] methyl} benzoate

Analogously to the process described under Example 57A, from 350 mg (1.03 mmol) of the compound from Example 33A and methyl 3-bromomethylbenzoate 174 mg (35% of theory) of the title compound were obtained. In this case, the product was not isolated by MPLC but by preparative HPLC (Method 11).

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.12 (d, 2H), 7.99 (d, IH), 7.90 (s, IH), 7:45 (d, 2H), 7:42 (t, IH) , 7.33 (d, IH), 6.83 (s, IH), 5.50 (s, 2H), 3.91 (s, 3H), 3.41 (s, 2H), 3.23 (s, 3H), 2.28 (s, 3H), 2.07-2.00 (m, 2H), 1.96-1.88 (m, 2H), 1.79-1.70 (m, 4H).

LC / MS (Method 6, ESIpos): R _t = 1.43 min, m / z = 487 [M + H] ⁺ . Example 61A

Methyl 3- {[3- (3- {4- [1- (ethoxymethyl) cyclobutyl] phenyl} -1,2,4-oxadiazol-5-yl) -5-methyl-1H-pyrazol-1-yl] methyl} benzoate

Analogously to the process described under Example 56A, from 150 mg (0.443 mmol) of the compound from Example 32A and methyl 3-bromomethylbenzoate, 43 mg (19% of theory) of the title compound were obtained. In addition, 85 mg (41% of theory) of the corresponding benzoic acid were isolated. 'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.13 (d, 2H), 7.98 (d, IH), 7.90 (s, IH), 7:43 (t, IH), 7:33 (d, IH) , 7.30 (d, 2H), 6.83 (s, IH), 5.50 (s, 2H), 3.91 (s, 3H), 3.57 (s, 2H), 3.38 (quart, 2H), 2.40-2.30 (m, 4H ), 2.27 (s, 3H), 2.15-2.03 (m, IH), 1.92-1.83 (m, IH), 1.09 (t, 3H).

LC / MS (Method 6, ESlpos): R _t = 1.45 min, m / z = 487 [M + H] ⁺ .

Example 62A Methyl 3 - {[5-methyl-3 - (3 - {4- [(trifluoromethyl) sulfanyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazol-1-yl] methyl} benzoate

A solution of 250 mg (0.766 mmol) of the compound of Example 36A and 211 mg (0.919 mmol) of methyl 3-bromomethylbenzoate in 7.5 ml of anhydrous 1,4-dioxane was treated at 0 ° C. with 112 mg (0.996 mmol) of solid potassium hydroxide. feri. butyl acetate and then stirred for 15 h at RT. Thereafter, about 25 ml of water were added, and it was extracted three times with about 20 ml of ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally freed from the solvent on a rotary evaporator. From the crude product, 268 mg (74% of theory) of the title compound were obtained by MPLC (silica gel, eluent: cyclohexane / ethyl acetate 10: 1 → 5: 1).

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.27 (d, 2H), 7.99 (d, IH), 7.89 (s, IH), 7.78 (d, 2H), 7:43 (t, IH) , 7.34 (d, IH), 6.83 (s, IH), 5.51 (s, 2H), 3.91 (s, 3H), 2.29 (s, 3H). LC / MS (Method 6, ESIpos): R _t = 1.39 min, m / z = 475 [M + H] ⁺ . Example 63A

Methyl 3 - [(3 - {3 - [4- (4-fluorotetrahydro-2H-pyran-4-yl) -phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl-1H-pyrazole - 1-yl) methyl] benzoate

Analogously to the process described under Example 62A, from 500 mg (1.52 mmol) of the compound from Example 43A and methyl 3-bromomethylbenzoate, 434 mg (60% of theory) of the title compound were obtained. In this case, the product was not isolated by MPLC but by preparative HPLC (Method 11). Ή NMR (400 MHz, CDC1 ₃ , δ / ρρηι): 8.12 (d, 2H), 7.99 (d, 1H), 7.90 (s, 1H), 7.52 (d, 2H), 7.42 (t, 1H) , 7.34 (d, 1H), 6.84 (s, 1H), 5.51 (s, 2H), 4.00-3.87 (m, 4H), 3.91 (s, 3H), 2.29 (s, 3H), 2.29- 2.12 ( m, 2H), 1.98-1.92 (m, 2H).

LC / MS (Method 6, ESIpos): R _t = 1.23 min, m / z = 477 [M + H] ⁺ . Example 64A Methyl 3 - [(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,4,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl benzoate

Analogously to the process described under Example 54A (Method A), 300 mg (0.97 mmol) of the compound from Example 22A and methyl 3-bromomethylbenzoate gave 430 mg (89% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.20 (d, 2H), 7.91 (d, 1H), 7.84 (s, 1H), 7.59 (d, 2H), 7.55 (t, 1H ), 7.48 (d, 1H), 6.96 (s, 1H), 5.61 (s, 2H), 3.85 (s, 3H), 2.34 (s, 3H).

LC / MS (Method 4, ESIpos): R _t = 1.54 min, m / z = 459 [M + H] ⁺ .

Example 65A Methyl 3 - [(3 - {3 - [4- (1-fluorocyclobutyl) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl-1H-pyrazol-1-yl) - methyljbenzoat

Analogously to the process described under Example 54A (Method A), 200 mg (0.67 mmol) of the compound from Example 44A and methyl 3-bromomethylbenzoate gave 210 mg (68% of theory) of the title compound. The product was isolated in this case by preparative HPLC (Method 17).

¹ H-NMR (400 MHz, DMSO-de, δ / ppm): 8.12 (d, 2H), 7.91 (d, 1H), 7.84 (s, 1H), 7.70 (d, 2H), 7.55 (t, 1H ), 7.47 (d, 1H), 6.96 (s, 1H), 5.61 (s, 2H), 3.85 (s, 3H), 2.64 (t, 2H), 2.59 (t, 2H), 2.35 (s, 3H ), 2.07 (m, 1H), 1.77 (m, 1H). LC / MS (Method 6, ESIpos): R _t = 1.37 min, m / z = 447 [M + H] ⁺ .

Example 66A

1 - [3- ({3- [3- {A-tert-butylphenyl) -1, 2,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) -phenyl] - cyclopropyl acetate

To a solution of 200 mg (0.71 mmol) of the compound from Example 42A and 232 mg (0.78 mmol, purity 95%) of the compound from Example 47A in 5 ml of THF at 0 ° C were added 103 mg (0.92 mmol) of potassium ieri. given butylate. Subsequently, the reaction mixture was stirred for 1 h at RT. After dilution with ethyl acetate, it was washed once with water and the aqueous phase was back-extracted once with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 350 mg (80% purity, 84% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 ₃ , δ / ρρτη): 8.13 (d, 2H), 7.51 (d, 2H), 7.30-7.24 (m, 1H), 7.18 (d, 1H), 7.10 (s, 1H), 7.01 (d, 1H), 6.81 (s, 1H), 5.44 (s, 2H), 2.26 (s, 3H), 2.01 (s, 3H), 1.36 (s, 9H), 1.31 - 1.24 (m , 2H), 1.21-1.15 (m, 2H).

LC / MS (Method 4, ESIpos): R, = 1.64 min, m / z = 471 [M + H] ⁺ .

Example 67A

1 - {3 - [(5-Methyl-3- {3- [4- (tetrahydro-2H-pyran-4-yl) -phenyl] -l, 2,4-oxadiazol-5-yl} -lH-pyrazole 1-yl) methyl] phenyl} cyclopropylacetate

To a solution of 139 mg (0.45 mmol) of the compound from Example 28A and 147 mg (0.49 mmol, purity 95%) of the compound from Example 47A in 3.5 ml of THF at 0 ° C were 65 mg (0.58 mmol) alium-teri. given butylate. The mixture was stirred for a further hour at RT after heating to RT. After dilution with ethyl acetate, it was washed once with water and the aqueous phase was back-extracted once with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluent: cyclohexane / ethyl acetate 7: 3). After removal of the solvent, 164 mg (79% purity, 58% of theory) of the title compound were obtained. LC / MS (Method 6, ESIpos): R _t = 1.27 min, m / z = 499 [M + H] ⁺ . Example 68A

1 - {3 - [(5-Methyl-3- {3- [4- (trimethylsilyl) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] -phenyl } cyclopropylacetate

Analogously to the process described in Example 67A, from 211 mg (0.71 mmol) of the compound from Example 26A and 232 mg (0.78 mmol, purity 95%) of the compound from Example 47A, 231 mg (90% pure, 60% of theory) were obtained. ) of the title compound. The chromatographic purification of the product was carried out here with cyclohexane / ethyl acetate 4: 1 as the eluent.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.17 (d, 2H), 7.64 (d, 2H), 7:30 to 7:26 (m, 1H), 7.18 (d, 1H), 7.10 (s, 1H), 7.01 (d, 1H), 6.81 (s, 1H), 5.44 (s, 2H), 2.26 (s, 3H), 2.01 (s, 3H), 1.31 -1.15 (m, 4H), 0.31 (s , 9H).

LC / MS (Method 6, ESIpos): R _t = 1.49 min, m / z = 487 [M + H] ⁺ . Example 69A

1 - {3 - [(5-Methyl-3- {3- [4- (1,1,2-trifluoro-2-methylpropan-2-yl) -phenyl] -l, 2,4-oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl] phenyl} cyclopropylacetate

Analogously to the process described under Example 67A, from 238 mg (0.71 mmol) of the compound from Example 23A and 232 mg (0.78 mmol, purity 95%) of the compound from Example 47A, 286 mg (88% purity, 68% of theory). ) of the title compound. The chromatographic purification of the product was carried out here with cyclohexane / ethyl acetate 3: 1 as the eluent. 'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.20 (d, 2H), 7.62 (d, 2H), 7:30 to 7:26 (m, 1H), 7:21 to 7:17 (d, 1H), 7.10 ( s, 1H), 7.01 (d, 1H), 6.82 (s, 1H), 5.44 (s, 2H), 2.27 (s, 3H), 2.01 (s, 3H), 1.62 (s, 6H), 1.33- 1.15 (m, 4H).

LC / MS (Method 6, ESIpos): R _t = 1.40 min, m / z = 525 [M + H] ⁺ . Example 70A

1 - [3- ({3- [3- (4-Isopropylphenyl) -1,2,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) -phenyl] -cyclopropylacetate

Analogously to the process described under Example 66A, from 190 mg (0.71 mmol) of the compound from Example 41A and 232 mg (0.78 mmol, purity 95%) of the compound from Example 47A 359 mg (69% purity, 76% of theory) .) Of the title compound.

LC / MS (Method 6, ESIpos): R, = 1.41 min, m / z = 457 [M + H] ⁺ .

Example 71A

1 - [3- ({3- [3- (4-isobutylphenyl) -1,2,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) -phenyl] -cyclopropylacetate

Analogously to the process described under Example 66A, from 200 mg (0.71 mmol) of the compound from Example 39A and 232 mg (0.78 mmol, purity 95%) of the compound from Example 47A, 381 mg (72% purity, 82% of theory). ) of the title compound. LC / MS (Method 6, ESIpos): R, = 1.47 min, m / z = 471 [M + H] ⁺ . Example 72A 1- (3- {[5-Methyl-3- (3- {4- [1- (trifluoromethyl) cyc]

1 -yl] methyl} phenyl) cyclopropylacetate

Analogously to the method described under Example 66A, from 237 mg (0.71 mmol) of the compound from Example 30A and 232 mg (0.78 mmol, purity 95%) of the compound from Example 47A, 408 mg (70% purity, 77% of theory). ) of the title compound.

LC / MS (Method 6, ESIpos): R _t = 1.40 min, m / z = 523 [M + H] ⁺ .

Example 73A 1- {3 - [(5-Methyl-3- {3- [4- (pentafluoro- ^6- sulfanyl) phenyl], 2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) - methyl] phenyl} cyclopropylacetate

Analogously to the process described under Example 66A, from 275 mg (0.71 mmol) of the compound from Example 38A and 232 mg (0.78 mmol, purity 95%) of the compound from Example 47A, 423 mg (75% purity, 75% of theory) were obtained. ) of the title compound. The reaction time in this case was 4 h at RT.

LC / MS (Method 6, ESIpos): R, = 1.39 min, m / z = 541 [M + H] ⁺ .

Example 74A

1 - {3 - [(3- {3- [4- (2-fluoropropan-2-yl) -phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl-1H-pyrazole-1 L - yl) - methyl] phenyl} cyclopropylacetate H ₃ C CH ₃

Analogously to the process described under Example 66A, from 223 mg (0.78 mmol) of the compound from Example 24A and 255 mg (0.86 mmol, purity 95%) of the compound from Example 47A, 406 mg (75% purity, 82% of theory) were obtained. ) of the title compound. The reaction time in this case was 4 h at RT.

LC / MS (Method 6, ESIpos): R _t = 1.34 min, m / z = 475 [M + H] ⁺ .

Example 75A

1 - {3 - [(5-Methyl-3- {3- [4- (α-fluoromethyl) phenyl] -1,3,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] - phenyl} cyclopropyl acetate

Analogously to the process described under Example 66A, from 230 mg (0.78 mmol) of the compound from Example 27A and 255 mg (0.86 mmol, purity 95%) of the compound from Example 47A, 375 mg (74% purity, 74% of theory) were obtained. ) of the title compound. The reaction time in this case was 16 h at RT. LC / MS (Method 6, ESIpos): R _t = 1.55 min, m / z = 483 [M + H] ⁺ .

Example 76A 1- {3 - [(3- {3- [4- (4-fluorotetrahydro-2H-pyran-4-yl) -phenyl] -l, 2,4-oxadiazol-5-yl} -5-methyl- 1H-pyrazol-1-yl) methyl] phenyl 1} cyclopropylacetate

Analogously to the method described under Example 66A, from 256 mg (0.78 mmol) of the compound from Example 27A and 255 mg (0.86 mmol, purity 95%) of the compound from Example 47A 415 mg (65% purity, 67% of theory) of th .) Of the title compound. The reaction time in this case was 16 h at RT.

LC / MS (Method 4, ESIpos): R _t = 1.44 min, m / z = 517 [M + H] ⁺ .

Example 77A

1 - [3 - ({3 - [3 - (4-Cyclohexylphenyl) -1,2,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) -phenyl] -cyclopropylacetate

Analogously to the process described under Example 66A, from 195 mg (0.63 mmol) of the compound from Example 37A and 207 mg (0.70 mmol, purity 95%) of the compound from Example 47A 318 mg (42% _> purity, 43% _> d Th.) Of the title compound. The reaction time in this case was 4 h at RT. LC / MS (Method 6, ESIpos): R _t = 1.59 min, m / z = 497 [M + H] ⁺ .

Example 78A

1 - (3 - {[5-Methyl-3- (3 - {4- [(trifluoromethyl) sulfanyl] phenyl} -1,2,4-oxadiazol-5-yl) -H-pyrazole-1-yl] - methyl} phenyl) cyclopropylacetate

Analogously to the process described under Example 66A, from 254 mg (0.78 mmol) of the compound from Example 36A and 255 mg (0.86 mmol, purity 95%) of the compound from Example 47A 396 mg (72% purity, 70% of theory) were obtained. ) of the title compound. The reaction time in this case was 4 h at RT.

LC / MS (Method 6, ESIpos): R, = 1.25 min, m / z = 441 [M + H] ⁺ .

Example 79A

1 - {3 - [(3 - {3 - [4- (1-fluorocyclobutyl) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl-1H-pyrazol-1-yl) methyl) - phenyl} cyclopropyl acetate

To a solution of 233 mg (0.78 mmol) of the compound from Example 36A and 255 mg (0.86 mmol, purity 95%) of the compound from Example 47A in 5.5 ml of THF at 0 ° C 113 mg (1.01 mmol) of potassium tert , given butylate. The mixture was stirred for a further 4 h at RT after heating to RT. After dilution with ethyl acetate, it was washed once with water and the aqueous phase was back-extracted once with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Method 15). The clean product-containing fractions were combined, mixed with saturated aqueous sodium bicarbonate solution and concentrated again to a residual volume of aqueous phase. It was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. There were obtained 187 mg (62%> purity, 30% of theory) of the title compound.

LC / MS (Method 6, ESIpos): R _t = 1.37 min, m / z = 487 [M + H] Example 80A

1 - {3 - [(3- {3- [3-Fluoro-4- (1,1,2-trifluoro-2-methylpropan-2-yl) -phenyl] -1,2,4-oxadiazol-5-yl } -5-methyl-1H-pyrazol-1-yl) methyl] phenyl} cyclopropylacetate

Analogously to the process described under Example 66A, from 200 mg (0.54 mmol, purity 95%) of the compound from Example 45A and 176 mg (0.59 mmol, purity 96%) of the compound from Example I 47A, 192 mg (69% purity, 46% of theory) of the title compound. The reaction time in this case was 4 h at RT. The crude product was purified by preparative HPLC according to Method 15. LC / MS (Method 6, ESIpos): R _t = 1.45 min, m / z = 543 [M + H] ⁺ .

Example 81A

5- [1- (3-iodobenzyl) -5-methyl-1H-pyrazol-3-yl] -3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazole

Analogously to the process described under Example 54A (Method A), 500 mg (1.61 mmol) of the compound from Example 22A and 570 mg (1.93 mmol) of 3-iodobenzyl bromide were converted to 690 mg (78% of theory) of the title compound. The product was isolated here by preparative HPLC (Method 17).

'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 8.20 (d, 2H), 7.69 (m, 1H), 7.63 (s, 1H), 7.59 (d, 2H), 7.18 (i.e. , 2H), 6.94 (s, 1H), 5.49 (s, 2H), 2.35 (s, 3H). LC / MS (Method 2, ESIpos): R _t = 3.05 min, m / z = 527 [M + H] ⁺ . Example 82A

Ethyl {3 - [(5-methy 1 - 3 -

pyrazol-1-yl) methyl] phenyl} acetate

Analogously to the process described under Example 54A (Method A), 0.50 g (1.49 mmol) of the compound from Example 23A and 0.50 g (1.93 mmol) of ethyl [3- (bromomethyl) phenyl] acetate [Lit .: SR Kasibhatla et al, J. Med. Chem. 2000, 43 (8), 1508-1518] to 0.47 g (62% of theory) of the title compound. The product was isolated here by preparative HPLC (Method 17). 'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.09 (d, 2H), 7.77 (d, 2H), 7.33 (t, 1H), 7.21 (d, 1H), 7.10 (d, 2H), 6.94 (s, 1H), 5.50 (s, 2H), 4.04 (quart, 2H), 3.65 (s, 2H), 2.33 (s, 3H), 1.61 (s, 6H), 1.14 (t, 3H ).

LC / MS (Method 6, ESIpos): R _t = 1.43 min, m / z = 513 [M + H] ⁺ . Example 83A Ethyl {3 - [(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,4,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) -methyl ] phenyl} acetate

To a solution of 39.0 g (126 mmol) of the compound from Example 22A in 1 liter of anhydrous THF was added 15.5 g (138 mmol) of potassium tert-butoxide. Subsequently, at about 5 ° C. (ice / water bath), a solution of 38.8 g (151 mmol) of ethyl [3- (bromomethyl) phenyl] acetate [Lit: SR Kasibhatla et al., J. Med. Chem. 2000 43 (8), 1508-1518] in 700 ml of anhydrous THF. After the reaction mixture was stirred at RT for 40 h, the mixture was diluted with 1 liter of ethyl acetate. There were added about 100 g of anhydrous magnesium sulfate, and the heterogeneous mixture was stirred vigorously. It was then filtered and the filtrate was freed from the solvent on a rotary evaporator. The crude product was purified by suction filtration over about 2 kg of silica gel (0.06-0.2 mm particle size) with a cyclohexane / ethyl acetate gradient [9: 1 (5 liter) - ^"■ 8: 2 (4 liters) -> · 7: (3 4 liters) -> · 6: 4 (4 liters) -> 1: 1 (4 liters)] as eluent. There were obtained 33.8 g (48% of T, 87% purity) of the title compound.

Ή-NMR (400 MHz, DMSO-ds, δ / ppm): 8.20 (d, 2H), 7.60 (d, 2H), 7.33 (t, 1H), 7.21 (d, 1H), 7.11 (s, 1H) , 7.10 (d, 1H), 6.93 (s, 1H), 5.49 (s, 2H), 4.05 (quart, 2H), 3.65 (s, 2H), 2.34 (s, 3H), 1.14 (t, 3H) ,

LC / MS (Method 6, ESIpos): R _t = 1.37 min, m / z = 487 [M + H] ⁺ . Example 84A 1- {3 - [(5-Methyl-3- {3- [4- (trifluoropethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] - phenylacetone

A solution of 33.5 g (68.9 mmol) of the compound from Example 83A in 700 ml of anhydrous THF was added dropwise at 0 ° C with 50.5 ml (152 mmol) of methylmagnesium bromide solution (3 M in diethyl ether). Upon completion of the addition, the ice / water bath was removed and stirring continued at RT. After 2 h, the reaction was quenched by careful addition of 50 mL of saturated aqueous ammonium chloride solution. It was diluted with 700 ml of ethyl acetate and treated with 100 g of anhydrous magnesium sulfate. After brief stirring, the mixture was filtered and the filtrate was freed from the solvent on a rotary evaporator. The resulting residue was purified by suction filtration over 770 g of silica gel (0.06-0.2 mm particle size) with a cyclohexane / ethyl acetate gradient [8: 2 (8 liters) -> ■ 7: 3 (8 liters) -> ■ 6: 4 (8 liters) -> 1: 1 (4 liters)] as eluant. After evaporation of the solvent, 22.5 g of a crude product were obtained, which in addition to the title compound mainly the compound 2-methyl-l - {3 - [(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] - 1, 2 , 4-oxadiazol-5-yl} - lH-pyrazol-1-yl) methyl] phenyl} propan-2-o 1 (see Example 43).

7.6 g of this crude product were recrystallized from 61 ml of boiling diisopropyl ether. The crystals obtained at RT were filtered off and washed twice with 5 ml of cold diisopropyl ether. The material thus obtained consisted of pure 2-methyl-l- {3 - [(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,4,4-oxadiazol-5-yl} -lH-pyrazol-1-yl) methyl] phenyl} propan-2-ol (see Example 43). The mother liquor was freed from the solvent on a rotary evaporator, and the residue was separated into its components by preparative HPLC (Method 12). There were 540 mg of the title compound and an additional 2.85 g of 2-methyl-l- {3 - [(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5 -yl} - IH-pyrazol-1-yl) methyl] phenyl} propan-2-ol (see Example 43). The 540 mg of the title compound were finally crystallized from 5 ml of diisopropyl ether. After drying under high vacuum, 373 mg of the title compound were obtained in pure form (3.5% of theory, based on 7.6 g of further processed crude product). Ή-NMR (400 MHz, CDCl ₃ , δ / ppm): 8.25 (d, 2H), 7.33 (d, 2H), 7.31 (t, 1H), 7.14 (d, 1H), 7.07 (d, 1H), 7.01 (s, 1H), 6.82 (s, 1H), 5.43 (s, 2H), 3.69 (s, 2H), 2.29 (s, 3H), 2.14 (s, 3H).

LC / MS (Method 6, ESIpos): R, = 1.31 min, m / z = 457 [M + H] ⁺ .

Example 85A

Ethyl 2-methyl-2- (3- {[5-methyl-3- (3- {4- [1- (trifluoromethyl) cyclopropyl] phenyl} -1,4,4-oxadiazol-5-yl) -H -pyrazol-1-yl] methyl} phenyl) propanoate

To a solution of 227 mg (0.68 mmol) of the compound from Example 30A and 300 mg (0.75 mmol, purity 71%) of the compound from Example 49A in 5 ml of THF at 0 ° C 99 mg (0.88 mmol) of potassium ferric. given butylate. The mixture was allowed to come to RT and then stirred at RT overnight. After adding ethyl acetate and water, the aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Method 15). The clean product-containing fractions were combined and concentrated to a residual volume of aqueous phase. After adding saturated aqueous sodium bicarbonate solution, it was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. After drying the residue in vacuo, 264 mg (71> d.th.) of the title compound were obtained. 'H-NMR (400 MHz, CDC1 ₃ , δ / ρρηι): 8.19 (d, 2H), 7.59 (d, 2H), 7.29-7.26 (m, 2H), 7.16 (s, 1H), 7.03-6.98 ( m, 1H), 6.81 (s, 1H), 5.44 (s, 2H), 4.09 (quart, 2H), 2.26 (s, 3H), 1.52 (s, 6H), 1.42- 1.39 (m, 2H), 1.12 (t, 3H), 1.01 -1.08 (m, 2H).

LC / MS (Method 6, ESIpos): R, = 1.49 min, m / z = 539 [M + H] ⁺ . Example 86A

Ethyl 2-methyl-2- {3 - [(5-methyl-3- {3- [4- (tetrahydro-2H-pyran-4-yl) -phenyl] -l, 2,4-oxadiazol-5-yl } - lH-pyrazol-1-yl) methyl] phenyl} propanoate

A solution of 145 mg (0.467 mmol) of the compound from Example 28A and 173 mg (0.607 mmol) of the compound from Example 49A in 5 mL of anhydrous THF was added at 0 ° C with 58 mg (0.513 mmol) of solid alumina-tert-butoxide added. After removal of the ice / water bath, the reaction mixture was stirred at RT for 16 h. Then 1 ml of methanol was added and the reaction mixture was separated directly into its components by preparative HPLC (Method 11). In this way 198 mg (77% of theory, 93% purity) of the title compound were obtained. 'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.15 (d, 2H), 7:35 (d, 2H), 7:29 to 7:24 (m, 2H), 7.15 (s, 1 H) 7.00 (d , 1H), 6.80 (s, 1H), 5.44 (s, 2H), 4.12-4.06 (m, 2H), 4.09 (quart, 2H), 3.55 (dt, 2H), 2.87-2.80 (m, 1H) , 2.27 (s, 3H), 1.91-1.78 (m, 4H), 1.53 (s, 6H), 1.14 (t, 3H).

LC / MS (Method 4, ESIpos): R _t = 1.52 min, m / z = 515 [M + H]

Example 87A Ethyl 2-methyl-2- {3 - [(5-methyl-3- {3- [4- (1,1,2-trifluoro-2-methylpropan-2-yl) -phenyl] -l, 2 , 4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] phenyl} propanoate

Analogously to the procedure described under Example 85A, 0.50 g (1.49 mmol) of the compound from Example 23A and 0.55 g (1.93 mmol) of the compound from Example 49A were reacted to give 0.49 g (59% of theory) of the title compound. The product was purified by preparative HPLC according to Method 17.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.09 (d, 2H), 7.77 (d, 2H), 7.34 (t, IH), 7.27 (d, IH), 7.14 (s, IH ), 7.06 (d, IH), 6.93 (s, IH), 5.51 (s, 2H), 4.00 (quart, 2H), 2.32 (s, 3H), 1.61 (s, 6H), 1.47 (s, 6H) , 1.03 (t, 3H).

LC / MS (Method 6, ESIpos): R _t = 1.50 min, m / z = 541 [M + H] ⁺ . Example 88A

Ethyl 2-methyl-2-i3 - [(5-methyl-3- {3 ^

pyrazol-1-yl) methyl] phenyl} propanoate

Analogously to the process described under Example 85 A, 0.14 g (0.44 mmol) of the compound from Example 22A and 0.15 g (0.53 mmol) of the compound from Example 49A were reacted to give 0.14 g (60% of theory) of the title compound. The product was purified by preparative HPLC according to Method 17.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.20 (d, 2H), 7.60 (d, 2H), 7.34 (t, IH), 7.27 (d, IH), 7.14 (s, IH ), 7.06 (d, IH), 6.93 (s, IH), 5.51 (s, 2H), 4.00 (quart, 2H), 2.32 (s, 3H), 1.46 (s, 6H), 1.04 (t, 3H) ,

LC / MS (Method 6, ESIpos): R, = 1.44 min, m / z = 515 [M + H] Example 89A

Ethyl difluoro {3 - [(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] phenyl } acetate

To a solution of 546 mg (1.76 mmol) of the compound from Example 22A in 20 ml of THF was added at RT 814 mg (2.11 mmol, purity 76%) of the compound from Example 53 A. Subsequently, 257 mg (2.29 mmol) of potassium tert-butoxide were added at 0 ° C., and the mixture was stirred at RT for 20 h. Thereafter, another 150 mg (1.34 mmol) of potassium tert-butoxide was added, and the mixture was again stirred at RT for 6 h. After dilution with ethyl acetate, the mixture was extracted once with water and the aqueous wash phase was back-extracted once with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was taken up in methanol and purified by column chromatography (silica gel, eluent: cyclohexane / ethyl acetate 7: 3). After removal of the solvent and drying in vacuo, 125 mg of a product were obtained which according to Ή-NMR contained the title compound and the corresponding methyl ester in a total proportion of about 60% and was used as such in subsequent reactions.

LC / MS (Method 6, ESIpos): R _t = 1.43 min, m / z = 523 [M + H] ⁺ . Example 90A Diethyl {3 - [(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,4,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) -methyl ] phenyl} malonate

0.23 g (1.23 mmol) of sodium hydride (60% dispersion in mineral oil) and 0.20 ml (1.64 mmol) of diethyl carbonate were dissolved in 5.6 ml of abs. THF submitted. With ice bath cooling, a solution of 0.40 g (0.82 mmol) of the compound from Example 83A in 1 .6 ml abs. Dried THF and the mixture then heated for 2 h to reflux. It was then poured into 50 ml of ice-water and extracted twice with 50 ml of ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was freed from the solvent on a rotary evaporator and the residue was purified by preparative HPLC (Method 17). 0.29 g (63% of theory) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.20 (d, 2H), 7.59 (d, 2H), 7.38 (t, 1H), 7.32 (d, 1H), 7.19 (d, 2H) , 6.93 (s, 1H), 5.52 (s, 2H), 4.97 (s, 1H), 4.11 (m, 4H), 2.33 (s, 3H), 1.13 (t, 6H).

LC / MS (Method 6, ESIpos): R, = 1.38 min, m / z = 559 [M + H] ⁺ .

Example 91A

Diethyl-methyl {3 - [(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] phenyl } malonate

To 0.28 g (0.50 mmol) of the compound from Example 90A in 5.0 ml abs. DMF was added under ice-bath cooling 22 mg (0.55 mmol) of sodium hydride (60% dispersion in mineral oil), stirred for 5 min and then added with 34 .mu.ΐ (0.55 mmol) of methyl iodide. The mixture was stirred for 3 h at RT, then treated with a little 1 N hydrochloric acid and purified directly by preparative HPLC (Method 17). 0.25 g (86%) of theory was obtained. Th.) Of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.20 (d, 2H), 7.59 (d, 2H), 7.38 (t, 1H), 7.29 (d, 1H), 7.17 (d, 1 H), 7.12 (s, 1H), 6.93 (s, 1H), 5.52 (s, 2H), 4.1 1 (m, 4H), 2.32 (s, 3H), 1.73 (s, 3H), 1.1 1 (t, 6H). LC / MS (Method 6, ESIpos): R _t = 1.45 min, m / z = 573 [M + H] Example 92A

5- [5-methyl-1- (3-{2-methyl-2 - [(3-oxido-1, 5-dihyc ^

benzyl) -1 H -pyrazol-3-yl] -3 - [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazole

A solution of 300 mg (0.635 mmol) of the compound from Example 43 in 10 ml of dichloromethane was added at RT with 684 mg (2.86 mmol) of 3-diethylamino-1,5-dihydro-2,4,3-benzodioxaphosphepin and 31 mg ( 4.45 mmol) tetrazole added. After the mixture had been stirred for 10 min at RT, first 40 μΐ water and then, at -40 ° C, 1.1 g (4.45 mmol) of 70% wefa-chloroperbenzoic acid (mCPBA) were added. The mixture was first stirred at -40 ° C for a further 10 minutes before the cold bath was removed and stirring was continued for 16 hours at RT. Then 50 ml of water were added and the mixture was extracted three times with approx. 25 ml of ethyl acetate each time. The combined organic extracts were washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally freed from the solvent on a rotary evaporator. The residue was purified by MPLC (silica gel, eluent: cyclohexane / ethyl acetate 5: 1 → 1: 1). After evaporation of the appropriate fractions, the product was redissolved in ethyl acetate and washed with saturated sodium bicarbonate solution to remove the last traces of meta-chlorobenzoic acid. After renewed drying over anhydrous magnesium sulfate, filtration and evaporation, 255 mg (59% of theory) of the title compound were obtained. 'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.25 (d, 2H), 7:37 to 7:31 (m, 4H), 7:29 to 7:23 (m, 3H), 7.19 (d, 1H), 7:08 ( s, 1H), 7.05 (d, 1H), 6.77 (s, 1H), 5.41 (s, 2H), 5.18-4.98 (m, 4H), 3.04 (s, 2H), 2.23 (s, 3H), 1.53 (s, 6H).

LC / MS (Method 4, ESIpos): R _t = 1.55 min, m / z = 455 [MC ₈ H ₉ O ₄ P + H] ⁺ , 655 [M + H] ⁺ . Example 93A

Dibenzyl 2-methyl-2- {3 - [(5-methyl-3- {3- [4- (1,1,3-trifluoro-2-methylpropa

oxadiazol-5-yl} - lH-pyrazol-1-yl) methyl] phenyl} propyl phosphate

To 0.20 g (0.40 mmol) of the compound from Example 60 in 8 ml abs. THF was added under ice-bath cooling 18 mg (0.44 mmol) of sodium hydride (60% dispersion in mineral oil) and stirred for 5 min at this temperature. Subsequently, 0.24 g (0.44 mmol) of tetrabenzyl pyrophosphate were added and the mixture was stirred without further cooling for about 4 hours. The mixture was then diluted with ethyl acetate, washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was freed from the solvent on a rotary evaporator and the residue was purified by preparative HPLC (Method 17). 0.15 g (49% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.08 (d, 2H), 7.76 (d, 2H), 7.37-7.26 (m, 13H), 6.97 (d, 1H), 6.88 (s , 1H), 5.46 (s, 2H), 4.85 (d, 4H), 3.97 (d, 2H), 2.29 (s, 3H), 1.61 (s, 6H), 1.24 (s, 6H). LC / MS (Method 6, ESIpos): R _t = 1.56 min, m / z = 759 [M + H] ⁺ .

Example 94A

Dibenzyl-2-methyl-2- {3 - [(5-methyl-3- {3- [4- (trifluoromethoxy) -phenyl] -l, 2,4-oxadiazol-5-yl} -lH-pyrazole-1 - yl) methyl] phenyl} propylphosphat

Analogously to the process described under Example 93 A, starting from 0.10 g (0.21 mmol) of the compound from Example 61, 92 mg (59% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.18 (d, 2H), 7.58 (d, 2H), 7.35-7.25 (m, 13H), 6.98 (d, 1H), 6.88 (s , 1H), 5.46 (s, 2H), 4.85 (d, 4H), 3.96 (d, 2H), 2.30 (s, 3H), 1.24 (s, 6H). LC / MS (Method 6, ESIpos): R _t = 1.54 min, m / z = 733 [M + H] ⁺ .

Example 95A 1- {3 - [(3- {3- [3-Fluoro-4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl-1H-pyrazole-1 yl) methyl] phenyl} cyclopropylacetate

Analogously to the process described under Example 66A, 250 mg (0.762 mmol) of the compound from Example 29A and 249 mg (0.838 mmol, purity 96%) of the compound from Example 47A 41 were admixed with 1 mg (72% purity, 75% of theory) .) Of the title compound. The reaction time in this case was 16 h at RT.

LC / MS (Method 6, ESIpos): R _t = 1.39 min, m / z = 517 [M + H] ⁺ . Example 96A

5- [5-Methyl-1- (3-{2-methyl-2 - [(3-oxido-1, 5-dihydro-2,4,3-benzodioxaphosphepin-3-yl) oxy] -propyl} benzyl) -lH-pyrazol-3-yl] -3- {4 - [(trifluoromethyl) sulfanyl] phenyl} -1,4,4-oxadiazole

A solution of 500 mg (1.02 mmol) of the compound of Example 53 in 16 ml of dichloromethane was added at RT with 1.10 g (4.61 mmol) of 3-diethylamino-1,5-dihydro-2,4,3-benzodioxaphosphepin and 502 mg (7.16 mmol) of tetrazole. After the mixture had been stirred at RT for 10 min., First 65 .mu.ΐ water and then, at -40.degree. C., 1.77 g (7.16 mmol) of 70% meta-chloroperbenzoic acid (mCPBA) were added. The mixture was first roasted at -40 ° C for an additional 10 minutes before the cold bath was removed and stirring was continued for 16 hours at RT. Then 100 ml of water were added and the mixture was extracted three times with approx. 50 ml of ethyl acetate each time. The combined organic extracts were washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally freed from the solvent on a rotary evaporator. The residue was purified by MPLC (silica gel, eluent: cyclohexane / ethyl acetate 5: 1 → 1: 1). Evaporation of the appropriate fractions and drying of the residue under high vacuum gave 618 mg (85% of theory, 94% purity) of the title compound.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.27 (d, 2H), 7.79 (d, 2H), 7:35 to 7:31 (m, 3H), 7:29 to 7:23 (m, 2H, partially masked by CHCL signal), 7.20 (d, 1H), 7.08 (s, 1H), 7.05 (d, 1H), 6.78 (s, 1H), 5.41 (s, 2H), 5.17-4.99 (m, 4H), 3.03 (s, 2H), 2.23 (s, 3H), 1.53 (s, 6H).

LC / MS (Method 6, ESIpos): R _t = 1.42 min, m / z = 471 [MC ₈ H ₉ O ₄ P + H] ⁺ , 671 [M + H] ⁺ .

EXAMPLES

example 1

{3 - [(5-Methyl-3- {3- [4- (1,1,3-trifluoro-2-methylpropan-2-yl) -phenyl] -l, 2,4-oxadiazol-5-yl} -lH-pyrazol-1-yl) methyl] phenyl} methanol

100 mg (0.21 mmol) of the compound from Example 54A in 2 ml abs. THF at 0 ° C with 7.83 mg (0.21 mmol) of lithium aluminum hydride were added, and the mixture was stirred for 15 min under ice bath cooling. Thereafter, saturated aqueous ammonium chloride solution, anhydrous magnesium sulfate and ethyl acetate were added sequentially. The mixture was then filtered and the filtrate was evaporated on a rotary evaporator. The residue was purified by preparative HPLC. This gave 60 mg (64% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-ds, δ / ρρηι): 8.09 (d, 2H), 7.77 (d, 2H), 7.32 (t, 1H), 7.24 (d, 1H), 7.18 (s, 1H ), 7.06 (d, 1H), 6.93 (s, 1H), 5.50 (s, 2H), 5.20 (t, 1H), 4.47 (d, 2H), 2.34 (s, 3H), 1.61 (s, 6H ). LC / MS (Method 6, ESIpos): R _t = 1.25 min, m / z = 457 [M + H] ⁺ . Example 2

2,2,2-Trifluoro-1- {3 - [(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,4,4-oxadiazol-5-yl} -1H-pyrazole, 1 -yl) methyl] phenyl} ethanol (racemate)

A solution of 200 mg (0.383 mmol) of the compound from Example 55A in a mixture of 10 ml of 1,4-dioxane and 1 ml of water was mixed with 9.5 mg (0.249 mmol) of solid sodium borohydride. puts. After the reaction mixture had been stirred at RT for 1 h, first 2 ml of 1 M hydrochloric acid and then about 60 ml of water were added. It was extracted three times with approximately 60 ml of ethyl acetate each time. The combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally freed from the solvent on a rotary evaporator. The crude product thus obtained was stirred in a mixture of 25 ml of pentane and 1 ml of dichloromethane. After suctioning off and drying the residue in a high vacuum, 185 mg (94% of theory, 97% purity) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.24 (d, 2H), 7:43 (d, 1H), 7:39 (t, 1H), 7:34 (s, 1H), 7:32 (d, 2H) , 7.19 (d, 1H), 6.82 (s, 1H), 5.48 (s, 2H), 5.02 (s, 1H), 2.99 (s, broad, 1H), 2.27 (s, 3H).

LC / MS (Method 6, ESIpos): R _t = 1.29 min, m / z = 499 [M + H] ⁺ .

Example 3

1,1,1-trifluoro-2- {3 - [(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -l, 2,4-oxadiazol-5-yl} -1H-pyrazole 1 -yl) methyl] phenyl} propan-2-ol (racemate)

A solution of 250 mg (0.475 mmol) of the compound from Example 81 A in 10 ml of anhydrous THF was treated at -30 ° C. rapidly with 731 .mu.l (0.950 mmol) of a 1.3 M solution of isopropylmagnesium chloride lithium chloride complex in THF. After 30 minutes at -30 ° C, 266 mg (2.37 mmol) of 1,1,1-trifluoroacetone were added and the cold bath was removed. After the reaction mixture had reached RT, about 1 ml of methanol was added. Subsequently, the reaction mixture was dried over anhydrous magnesium sulfate, filtered and finally freed from the solvent on a rotary evaporator. The residue obtained was first freed from nonpolar impurities by means of MPLC (about 50 g of silica gel, eluent: cyclohexane / ethyl acetate 4: 1). The further purification of the product was then carried out by preparative HPLC (Method 13). 49 mg (11% of theory) of the title compound were thus obtained.

'H-NMR (400 MHz, CDCI _3, δ / ppm): 8.25 (d, 2H), 7:51 (d, 1H), 7:47 (s, 1H), 7:37 (t, 1H), 7:33 (d, 2H) , 7.14 (d, 1H), 6.83 (s, 1H), 5.49 (s, 2H), 2.70 (s, broad, 1H), 2.28 (s, 3H), 1.77 (s, 3H). LC / MS (Method 6, ESIpos): R, = 1.31 min, m / z = 513 [M + H] ⁺ .

Example 4

2- {3 - [(5-Methyl-3- {3- [4- (teu-ahydro-2H-pyran-4-yl) -phenyl] -l, 2,4-oxadiazol-5-yl} -lH- pyrazol-1-yl) methyl] phenyl} propan-2-ol

A solution of 100 mg (0.218 mmol) of the compound from Example 56A in 2.2 ml of anhydrous THF was treated dropwise at 0 ° C. with 153 μl (0.459 mmol) of methylmagnesium chloride solution (3M in THF). Subsequently, the ice / water bath was removed and stirring continued at RT. After 3 h, about 5 drops of saturated aqueous ammonium chloride solution were added. It was diluted with about 10 ml of ethyl acetate and then added as much anhydrous magnesium sulfate that the aqueous phase was completely absorbed. It was then filtered and the filtrate was freed from the solvent on a rotary evaporator. From the residue, 36 mg of the title compound were obtained by preparative HPLC (method 11) (66% of theory, based on the conversion) and 45 mg of the starting material were recovered. 'H-NMR (400 MHz, DMSO-ds, δ / ppm): 8.01 (d, 2H), 7.48 (d, 2H), 7.41 (s, 1H), 7.38 (d, 1H), 7.28 (t, 1H ), 6.97 (d, 1H), 6.91 (s, 1H), 5.49 (s, 2H), 5.01 (s, 1H), 3.99-3.94 (m, 2H), 3.46 (dt, 2H), 2.91-2.83 (m, 1H), 2.34 (s, 3H), 1.78-1.65 (m, 4H), 1.40 (s, 6H).

LC / MS (Method 6, ESIpos): R _t = 1.19 min, mz = 459 [M + H]

Example 5 2- [3- ({3- [3- (tert-Butyl-phenyl) -1,4,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) -phenyl ] - propan-2-ol

Analogously to the process described under Example 4, from 100 mg (0.232 mmol) of the compound from Example 57A and methylmagnesium chloride, 66 mg (66% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.13 (d, 2H), 7:51 (d, 2H), 7:41 (d, 1H), 7:37 (s, 1H), 7.30 (t, 1H) , 7.01 (d, 1H), 6.81 (s, 1H), 5.47 (s, 2H), 2.29 (s, 3H), 1.73 (s, 1H), 1.55 (s, 6H), 1.37 (s, 9H).

LC / MS (Method 4, ESIpos): R _t = 1.54 min, m / z = 413 [MH ₂ O + H] ⁺ .

Example 6

2- (3- {[3- (3- {4- [1- (methoxymethyl) cyclobutyl] phenyl} -1, 2,4-oxadiazol-5-yl) -5-methyl-1H-pyrazol-1-ylmethyl } phenyl) propan-2-ol

Analogously to the process described under Example 4, 150 mg (0.317 mmol) of the compound from Example 58A and methylmagnesium chloride 1 gave 14 mg (75% of theory) of the title compound. The reaction was stopped here after 3 h at RT by addition of 100 μΐ acetic acid. Subsequently, the reaction mixture was concentrated on a rotary evaporator to dryness. From the obtained residue, the title compound was isolated by MPLC (silica gel, eluent: cyclohexane / ethyl acetate 5: 1-> 3: 1).

'H-NMR (400 MHz, CDCI _3, δ / ppm): 8.13 (d, 2H), 7:40 (d, 1H), 7:36 (s, 1H), 7.30 (t, 1H), 7.29 (d, 2H) , 7.01 (d, 1H), 6.80 (s, 1H), 5.47 (s, 2H), 3.56 (s, 2H), 3.28 (s, 3H), 2.43-2.28 (m, 4H), 2.29 (s, 3H ), 2.15-2.03 (m, 1H), 1.93-1.83 (m, 1H), 1.74 (s, 1H), 1.56 (s, 6H). LC / MS (Method 4, ESIpos): R _t = 1.49 min, m / z = 455 [MH ₂ O + H] ⁺ .

Example 7

2- (3 - {[3- (3 - {3-Fluoro-4- [1 - (methoxymethyl) cyclobutyl] phenyl} -1,2,4-oxadiazol-5-yl) -5-methyl-1H-pyrazole -l-yl] methyl} phenyl) propan-2-ol

Analogously to the process described under Example 4, from 150 mg (0.306 mmol) of the compound from Example 59A and methylmagnesium chloride, 120 mg (80% of theory) of the title compound were obtained. Ή-NMR (400 MHz, CDCl ₃ , δ / ppm): 7.93 (dd, 1H), 7.82 (dd, 1H), 7.40 (d, 1H), 7.37 (s, 1H), 7.30 (t, 1H), 7.22 (d, 1H), 7.00 (d, 1H), 6.81 (s, 1H), 5.47 (s, 2H), 3.66 (s, 2H), 3.28 (s, 3H), 2.48-2.40 (m, 2H ), 2.37-2.30 (m, 2H), 2.29 (s, 3H), 2.19-2.07 (m, 1H), 1.94-1.85 (m, 1H), 1.73 (s, 1H), 1.55 (s, 6H).

LC / MS (Method 6, ESIpos): R _t = 1.36 min, m / z = 473 [MH ₂ O + H] ⁺ , 491 [M + H] ⁺ . Example 8

2- (3- {[3- (3- {4- [1- (methoxymethyl) -cyclopentyl] -phenyl} -l, 2,4-oxadiazol-5-yl) -5-methyl-1H-pyrazol-1-yl ] methyl} phenyl) propan-2-ol

Analogously to the process described under Example 4, from 145 mg (0.298 mmol) of the compound from Example 60A and methylmagnesium chloride 1, 19 mg (82% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.12 (d, 2H), 7.96 (d, 2H), 7:40 (d, 1H), 7:37 (s, 1H), 7.30 (t, 1H) , 7.01 (d, 1H), 6.81 (s, 1H), 5.47 (s, 2H), 3.41 (s, 2H), 3.22 (s, 3H), 2.29 (s, 3H), 2.07-2.00 (m, 2H ), 1.96-1.88 (m, 2H), 1.82 (s, 1H), 1.78-1.70 (m, 4H), 1.55 (s, 6H). LC / MS (Method 6, ESIpos): R _t = 1.37 min, m / z = 469 [MH ₂ O + H] ⁺ , 487 [M + H] ⁺ . Example 9

2- (3- {[3- (3- {4- [1- (ethoxymethyl) cyclobutyl] phenyl} -1,2,4-oxadiazol-5-yl) -5-methyl-1H-pyrazol-1-yl ] methyl} phenyl) propan-2-ol

Analogously to the process described in Example 4, from 36.5 mg (0.075 mmol) of the compound from Example 61A and methylmagnesium chloride, 30.8 mg (84% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.13 (d, 2H), 7:41 (d, 1H), 7:36 (s, 1H), 7.30 (t, 1H), 7.29 (d, 2H) , 7.01 (d, 1H), 6.81 (s, 1H), 5.47 (s, 2H), 3.57 (s, 2H), 3.38 (quart, 2H), 2.41 -2.30 (m, 4H), 2.28 (s, 3H), 2.15-2.03 (m, 1H), 1.92-1.82 (m, 1H), 1.76 (s, 1H), 1.55 (s, 6H), 1.10 (t, 3H).

LC / MS (Method 2, ESIpos): R _t = 2.83 min, m / z = 469 [MH ₂ O + H] ⁺ , 487 [M + H]

Example 10

2- (3 - {[5-Methyl-3- (3 - (4- [(trifluoromethyl) sulfanyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazol-1-yl] - methyl} phenyl) propan-2-ol

Analogously to the process described under Example 4, from 100 mg (0.211 mmol) of the compound from Example 62A and methylmagnesium chloride, 76 mg (77% of theory) of the title compound were obtained. The reaction time at RT was 1.5 h in this case.

'H-NMR (400 MHz, CDCI _3, δ / ppm): 8.27 (d, 2H), 7.78 (d, 2H), 7:41 (d, 1H), 7:37 (s, 1H), 7.30 (t, 1H) , 7.01 (d, 1H), 6.82 (s, 1H), 5.47 (s, 2H), 2.29 (s, 3H), 1.74 (s, 1H), 1.55 (s, 6H).

LC / MS (Method 4, ESIpos): R _t = 1.53 min, m / z = 457 [MH ₂ O + H] ⁺ . Example 11

2- {3 - [(3- {3- [4- (4-fluorotetrahydro-2H-pyran-4-yl) -phenyl] -l, 2,4-oxadiazol-5-yl} -5-methyl-1H- pyrazol-1-yl) methyl] phenyl} propan-2-ol

Analogously to the process described under Example 4, from 100 mg (0.210 mmol) of the compound from Example 63A and methylmagnesium chloride, 83 mg (83% of theory) of the title compound were obtained. The reaction time at RT was 1.5 h in this case.

Ή-NMR (400 MHz, COC, δ / ppm): 8.23 (d, 2H), 7.52 (d, 2H), 7.41 (d, 1H), 7.37 (s, 1H), 7.30 (t, 1H), 7.01 (d, 1H), 6.82 (s, 1H), 5.47 (s, 2H), 4.00-3.87 (m, 4H), 2.29 (s, 3H), 2.29-2.21 (m, 2H), 1.98-1.91 (m , 2H), 1.76 (s, 1H), 1.55 (s, 6H).

LC / MS (Method 6, ESIpos): R _t = 1.16 min, m / z = 459 [MH ₂ O + H] ⁺ , 477 [M + H] ⁺ .

Example 12

2- {3 - [(3- {3- [3-Fluoro-4- (trifluoropethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl-1H-pyrazol-1-yl) - methyl] phenyl} propan-2-ol

To a solution of 131 mg (0.40 mmol) of the compound from Example 29A in 2 ml of THF at RT 58 mg (0.52 mmol) of potassium / eri. butylate, followed by a solution of 147 mg (0.60 mmol) of the compound of Example 46A in 1.5 ml of THF. The mixture was stirred at RT for 1 h. Subsequently, the mixture was mixed with 30 ml of water and extracted three times with 30 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Method 14). The clean product fractions were pooled, except for a residual volume of aqueous phase concentrated. By adding saturated aqueous sodium bicarbonate solution, a pH of 7 was set and the aqueous phase was then extracted twice with 30 ml of ethyl acetate each time. The combined organic phases were then dried over sodium sulfate, filtered and concentrated. There were thus obtained 191 mg (53% of theory) of the title compound. Ή-NMR (400 MHz, CDCl ₃ , δ / ppm): 8.08 (dd, 1H), 8.06-8.01 (m, 1H), 7.46-7.39 (m, 2H), 7.37 (s, 1H), 7.30 ( t, 1H), 7.01 (d, 1H), 6.82 (s, 1H), 5.47 (s, 2H), 2.29 (s, 3H), 1.56 (s, 6H).

LC / MS (Method 6, ESIpos): R _t = 1.33 min, m / z = 477 [M + H] ⁺ .

Example 13

2- {3 - [(3- {3- [4- (2-fluoropropan-2-yl) -phenyl] -l, 2,4-oxadiazol-5-yl} -5-methyl-1H-pyrazole-1-one yl) - methyl] phenyl} propan-2-ol

Analogously to the process described under Example 12, from 1 to 14 mg (0.40 mmol) of the compound from Example 24A and 147 mg (0.60 mmol) of the compound from Example 46A 81 mg (43%) d. Th.) Of the title compound. Purification by preparative HPLC was carried out here according to Method 15.

Ή NMR (400 MHz, CDCl ₃ , δ / ppm): 8.20 (d, 2H), 7.50 (d, 2H), 7.43-7.38 (d, 1H), 7.36 (s, 1H), 7.30 (t , 1H), 7.03-6.98 (d, 1H), 6.82 (s, 1H), 5.47 (s, 2H), 2.29 (s, 3H), 1.75 (s, 3H), 1.70 (s, 3H), 1.55 ( s, 6H).

LC / MS (Method 2, ESIpos): R _t = 2.59 min, m / z = 417 [MH ₂ O + H] ⁺ . Example 14

2- (3- {[5-Methyl-3- (3- {4 - [(trifluoromethyl) sulfonyl] phenyl} -1, 2,4-oxadiazol-5-yl) -1H-pyrazol-1-yl] - methyl} phenyl) propan-2-ol

Analogously to the process described under Example 12, from 143 mg (0.40 mmol) of the compound from Example 25A and 147 mg (0.60 mmol) of the compound from Example 46A, 78 mg (37% of theory, purity 95%) of the title compound were obtained , Purification by preparative HPLC was carried out here according to Method 15.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8:52 (d, 2H), 8.18 (d, 2H), 7:43 to 7:36 (m, 2H), 7.31 (t, 1H), 7:01 (d, 1H), 6.84 (s, 1H), 5.48 (s, 2H), 2.31 (s, 3H), 1.56 (s, 6H).

LC / MS (Method 2, ESIpos): R _t = 2.63 min, m / z = 489 [MH ₂ O + H] ⁺ .

Example 15 2- (3- {[5-Methyl-3- (3- {4- [1- (trifluoromethyl) cyclopropyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazole-1 -yl] methyl} phenyl) propan-2-ol

Analogously to the process described in Example 12, from 134 mg (0.40 mmol) of the compound from Example 30A and 147 mg (0.60 mmol) of the compound from Example 46A 103 mg (50%) of theory. Th., Purity 95%) of the title compound. Purification by preparative HPLC was carried out here according to Method 15.

'H-NMR (400 MHz, CDCI _3, δ / ppm): 8.18 (d, 2H), 7:58 (d, 2H), 7:39 (d, 1H), 7:36 (s, 1H), 7.30 (t, 1H) , 7.01 (d, 1H), 6.81 (s, 1H), 5.46 (s, 2H), 2.29 (s, 3H), 1.55 (s, 6H), 1.43-1.37 (m, 2H), 1.12- 1.05 (m , 2H). LC / MS (Method 2, ESIpos): R _t = 2.74 min, m / z = 463 [MH ₂ O + H] ⁺ . Example 16

2- {3 - [(5-methyl-3- {3- [4- (tri methyl)}

phenyl} propan-2-ol

Analogously to the process described under Example 12, from 120 mg (0.40 mmol) of the compound from Example 26A and 147 mg (0.60 mmol) of the compound from Example 46A, 89 mg (46% of theory, purity 92%) of the title compound were obtained , Purification by preparative HPLC was carried out here according to Method 15.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.17 (d, 2H), 7.64 (d, 2H), 7:40 (d, 1H), 7:36 (s, 1H), 7.30 (t, 1H) , 7.00 (d, 1H), 6.82 (s, 1H), 5.47 (s, 2H), 2.28 (s, 3H), 1.55 (s, 6H), 0.31 (s, 9H).

LC / MS (Method 2, ESIpos): R _t = 2.94 min, m / z = 447 [M + H] ⁺ .

Example 17

2- {3 - [(5-Methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,4,4-oxadiazol-5-yl} -1H-pyrazol-1-yl> phenyl} propane 2-ol

Analogously to the method described in Example 4 were from 150 mg (0.33 mmol) of the compound from Example 64A and methyl magnesium bromide solution (1.4 M in THF / toluene) 51 mg (34%) d. Th.) Of the title compound. The reaction time at RT was in this case 1 h, and the purification of the crude product by preparative HPLC was carried out according to Method 17. 'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.20 (d, 2H), 7.59 ( d, 2H), 7.41 (s, 1H), 7.38 (d, 1H), 7.28 (t, 1H), 6.97 (d, 1H), 6.93 (s, 1H), 5.49 (s, 2H), 5.01 (s , 1H), 2.34 (s, 3H), 1.40 (s, 6H).

LC / MS (Method 6, ESIpos): R _t = 1.31 min, m / z = 459 [M + H] ⁺ . Example 18

2- {3 - [(5-Methyl-3- {3- [4- (1,1-trifluoro-2-methylpropan-2-yl) -phenyl] -1,2,4-oxadiazol-5-yl } - 1H-pyrazol-1-yl) methyl] phenyl} propan-2-ol

A solution of 1.0 g (22.7 mmol) of the compound from Example 54A in 220 ml of anhydrous THF was treated dropwise at 0.degree. C. with 15.9 ml (47.7 mmol) of methylmagnesium chloride solution (3M in THF). Subsequently, the ice / water bath was removed and stirring continued at RT. After 1 h, about 100 ml of saturated aqueous ammonium chloride solution and 1.5 liters of water were added. It was extracted three times with about 500 ml of ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally freed from the solvent on a rotary evaporator. The crude product obtained was purified by suction filtration over about 330 g of silica gel with cyclohexane / ethyl acetate 4: 1 → 1: 1 as eluent. After the solvent was removed from the pooled product fractions, the product was crystallized from 120 ml of ethanol / water (2: 1) (boiling heat- »■ RT). Filtration and drying under high vacuum gave 5.79 g (53% of theory) of the title compound.

Melting point: 167 ° C

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.20 (d, 2H), 7.62 (d, 2H), 7:41 (d, 1 H), 7:37 (s, 1H), 7.31 (t, 1H ), 7.01 (d, 1H), 6.83 (s, 1H), 5.47 (s, 2H), 2.29 (s, 3H), 1.75 (s, 1H), 1.62 (s, 6H), 1.55 (s, 6H) ,

LC / MS (Method 6, ESIpos): R _t = 1.32 min, m / z = 467 [MH ₂ O + H] ⁺ , 485 [M + H] ⁺ .

Example 19

2- {3 - [(3- {3- [4- (1-fluorocyclobutyl) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl-1H-pyrazol-1-yl) methyl] - phenyl} propan-2-ol

Analogously to the process described under Example 4, from 180 mg (0.40 mmol) of the compound from Example 65A and methylmagnesium chloride, 70 mg (40% of theory) of the title compound were obtained. The reaction time at RT was in this case 1 h, and the purification of the crude product by preparative HPLC was carried out according to method 17.

Ή-NMR (400 MHz, DMSO-k, δ / ppm): 8.12 (d, 2H), 7.70 (d, 2H), 7.41 (s, 1H), 7.38 (d, 1H), 7.28 (t, 1H) , 6.96 (d, 1H), 6.94 (s, 1H), 5.49 (s, 2H), 5.03 (s, 1H), 2.64 (t, 2H), 2.59 (t, 2H), 2.35 (s, 3H) , 2.07 (m, 1H), 1.77 (m, 1H), 1.40 (s, 6H).

LC / MS (Method 6, ESIpos): R _t = 1.29 min, m / z = 447 [M + H] ⁺ . Example 20

1 - [3- (\ 3- [3- (4-tert-butylphenyl) -1,4,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) -phenyl] - cyclopropanol

250 mg (0.532 mmol) of the compound from Example 66A were dissolved in 5 ml of anhydrous THF and treated dropwise at RT with a total of 2.2 ml of ethyl magnesium chloride solution (2 M in THF). The progress of the reaction was monitored by means of analytical HPLC and only as much of the Grignard reagent was added, as was necessary for complete conversion. Subsequently, 2 ml of water were added. After most of the solvent and water had been removed on a rotary evaporator, the resulting residue was purified by preparative HPLC (Method 15). The clean product fractions were combined and concentrated to a residual volume of aqueous phase. After addition of saturated aqueous sodium bicarbonate solution, the aqueous phase was washed twice with 30 ml of ethyl acetate each time extracted. The combined organic phases were then dried over magnesium sulfate, filtered and concentrated. 97 mg (32% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.13 (d, 2H), 7.50 (d, 2H), 7.29 (d, 1H), 7:21 to 7:14 (m, 2H), 6.98 (d, 1 H), 6.80 (s, 1H), 5.44 (s, 2H), 2.27 (s, 3H), 1.36 (s, 9H), 1.29-1.23 (m, 3H), 1.01 (dd, 2H).

LC / MS (Method 4, ESIpos): R _t = 1.53 min, m / z = 429 [M + H] ⁺ . Example 21 1 - {3 - [(5-Methyl-3- {3- [4- (tetrahydro-2H-pyran-4-yl) -phenyl] -l, 2,4-oxadiazol-5-yl} -LH- pyrazol-1-yl) methyl] phenyl} cyclopropanol

To a solution of 160 mg (0.25 mmol, 79% purity) of the compound from Example 67A in 5 ml of THF at 0 ° C 1.6 ml (3.21 mmol) of ethyl magnesium chloride solution (2 M in THF) was added slowly. The mixture was then allowed to come to RT and stirred at RT for 30 min. After removal of the solvent, the residue was purified by column chromatography (silica gel, eluent: cyclohexane / ethyl acetate 6: 4). The combined product fractions were concentrated and the residue was purified again by preparative thin-layer chromatography (silica gel, eluent: cyclohexane / ethyl acetate 1: 1). The product zone was extracted with dichloromethane / methanol (95: 5). After removal of the solvent, 15 mg (12% of theory, purity 94%) of the title compound were obtained. 'H-NMR (400 MHz, CDCl ₃ , δ / ppm): 8.15 (d, 2H), 7.35 (d, 2H), 7.31-7.26 (m, 1H), 7.21-7.14 (m, 2H), 6.99 ( d, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 4.13-4.06 (m, 2H), 3.55 (td, 2H), 2.89-2.78 (m, 1H), 2.28 (s, 3H) , 1.92-1.77 (m, 4H), 1.29-1.24 (m, 2H), 1.04-0.99 (m, 2H).

LC / MS (Method 6, ESIpos): R, = 1.15 min, m / z = 457 [M + H] ⁺ . Example 22 1- {3 - [(5-Methyl-3- {3- [4- (trimethylsilyl) phenyl] -1,4,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) -mhenyl } cyclopropanol

To a solution of 230 mg (0.43 mmol, 90% purity) of the compound from Example 68A in 7.5 ml of THF at 0 ° C 2.4 ml (4.73 mmol) of ethyl magnesium chloride solution (2 M in THF) was added slowly. The mixture was then allowed to come to RT and stirred at RT for 30 min. Thereafter, it was cooled again to 0 ° C, and the mixture was added dropwise with 5 ml of water, followed by 5 ml of 1 M hydrochloric acid. It was further diluted with water and extracted twice with ethyl acetate. The combined ethyl acetate phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Method 15). The clean product fractions were combined and concentrated to a residual volume of aqueous phase. After addition of saturated aqueous sodium bicarbonate solution was extracted twice with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. Drying of the residue in vacuo gave 121 mg (58% of theory) of the title compound.

Ή-NMR (400 MHz, CDCl ₃ , δ / ppm): 8.17 (d, 2H), 7.64 (d, 2H), 7.30-7.26 (m, 1H), 7.20 (s, 1H), 7.16 (d, 1H ), 6.98 (d, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 2.28 (s, 3H), 1.29-1.24 (m, 2H), 1.03-0.99 (m, 2H), 0.31 ( s, 9H).

LC / MS (Method 4, ESIpos): R _t = 1.59 min, m / z = 445 [M + H] ⁺ .

Example 23

1 - {3 - [(5-Methyl-3- {3- [4- (1,1,2-trifluoro-2-methylpropan-2-yl) -phenyl] -l, 2,4-oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl] phenyl} cyclopropanol

Analogously to the process described under Example 22, from 285 mg (0.48 mmol, 88% purity) of the compound from Example 69A and ethylmagnesium chloride solution, 120 mg (52% of theory) of the title compound were obtained. 'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.19 (d, 2H), 7.62 (d, 2H), 7.28 (t, 1H), 7.20 (s, 1H), 7.16 (d, 1H) , 6.99 (d, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 2.28 (s, 3H), 1.62 (s, 6H), 1.27 (dd, 2H), 1.01 (dd, 2H).

LC / MS (Method 4, ESIpos): R _t = 1.49 min, m / z = 483 [M + H] ⁺ . Example 24 1- [3- ({3- [3- (4-Isopropylphenyl) -1,2,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) phenyl] - -cyclopropanol

Analogously to the process described under Example 22, from 359 mg (0.55 mmol, 69% purity) of the compound from Example 70A and ethyl magnesium chloride solution, 126 mg (55% of theory) of the title compound were obtained.

¹ H-NMR (400 MHz, CDCl ₃ , δ / ppm): 8.12 (d, 2H), 7.34 (d, 2H), 7.29 (d, 1H), 7.21-7.13 (m, 2H), 6.99 (i.e. , 1H), 6.80 (s, 1H), 5.44 (s, 2H), 2.97 (sept, 1H), 2.49 (s, 1H), 2.27 (s, 3H), 1.31-1.24 (m, 8H), 1.01 (dd, 2H).

LC / MS (Method 6, ESIpos): R _t = 1.30 min, m / z = 415 [M + H] ⁺ . Example 25 1- [3 - ({3- [3- (4-Isobutylphenyl) -1,2,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) phenyl] - -cyclopropanol

Analogously to the process described under Example 22, from 380 mg (0.57 mmol, 72% purity) of the compound from Example 71A and ethyl magnesium chloride solution, 132 mg (54% of theory) of the title compound were obtained.

Ή NMR (400 MHz, CDCl ₃ , δ / ppm): 8.10 (d, 2H), 7.31-7.24 (m, 3H), 7.20 (s, 1H), 7.16 (d, 1H), 6.99 (d, 1H), 6.80 (s, 1H), 5.44 (s, 2H), 2.54 (d, 2H), 2.51 (s, 1H), 2.27 (s, 3H), 1.98-1.85 (m, 1H), 1.26 (dd , 2H), 1.01 (dd, 2H), 0.93 (d, 6H).

LC / MS (Method 6, ESIpos): R _t = 1.37 min, m / z = 429 [M + H] ⁺ .

Example 26

1 - (3- {[5-Methyl-3- (3- {4- [1- (trifluoromethyl) cyclopropyl] phenyl} -1, 2,4-oxadiazol-5-yl) -1H-pyrazol-1-ylmethyl } phenyl) cyclopropanol

Analogously to the process described under Example 22, from 400 mg (0.54 mmol, 70% purity) of the compound from Example 72A and ethyl magnesium chloride solution, 118 mg (46% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.18 (d, 2H), 7:58 (d, 2H), 7:31 to 7:27 (m, 1H), 7.20 (s, 1 H), 7.16 (d , 1H), 6.99 (d, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 2.42 (s, 1H), 2.28 (s, 3H), 1.40 (dd, 2H), 1.27 (dd, 2H), 1.12-1.05 (m, 2H), 1.01 (dd, 2H).

LC / MS (Method 6, ESIpos): R _t = 1.29 min, m / z = 481 [M + H] ⁺ . Example 27

1- {3 - [(5-methyl-3- {3- [4- (pentafluoro ^

methyl] phenyl} cyclopropanol

Analogously to the process described under Example 22, from 422 mg (0.59 mmol, 75% purity) of the compound from Example 73A and ethylmagnesium chloride solution, 107 mg (35% of theory, purity 94%) of the title compound were obtained.

Ή NMR (400 MHz, CDCl ₃ , δ / ppm): 8.31 (d, 2H), 7.89 (d, 2H), 7.32-7.27 (m, 1H), 7.20 (s, 1H), 7.16 (d, 1H), 6.99 (d, 1H), 6.82 (s, 1H), 5.46 (s, 2H), 2.39 (s, broad, 1H), 2.29 (s, 3H), 1.27 (dd, 2H), 1.02 (dd, 2H).

LC / MS (Method 6, ESIpos): R _t = 1.27 min, m / z = 499 [M + H] ⁺ .

Example 28

1 - {3 - [(3- {3- [4- (2-fluoropropan-2-yl) -phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl-1H-pyrazole-1 - yl) - methylphenyl} cyclopropanol

Analogously to the process described under Example 22, from 405 mg (0.64 mmol, 75% purity) of the compound from Example 74A and ethyl magnesium chloride solution, 145 mg (52% of theory) of the title compound were obtained.

Ή NMR (400 MHz, CDCl ₃ , δ / ppm): 8.19 (d, 2H), 7.50 (d, 2H), 7.29 (d, 1H), 7.20 (s, 1H), 7.16 (d, 1H), 6.99 (d, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 2.42 (s, 1H), 2.28 (s, 3H), 1.75 (s, 3H), 1.69 (s, 3H), 1.26 (dd, 2H), 1.01 (dd, 2H). LC / MS (Method 6, ESIpos): R _t = min, m / z = 433 [M + H]

Example 29

1 - {3 - [(5-Methyl-3- {3- [4- (trifluoromethyl) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] -phenyl } cyclopropanol

Analogously to the process described under Example 22, from 375 mg (0.58 mmol, 75% purity) of the compound from Example 75A and ethyl magnesium chloride solution, 148 mg (58% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8:34 (d, 2H), 7.76 (d, 2H), 7:31 to 7:27 (m, 1H), 7.21 (s, 1H), 7.16 (d, 1H), 6.99 (d, 1H), 6.82 (s, 1H), 5.45 (s, 2H), 2.39 (s, 1H), 2.29 (s, 3H), 1.27 (dd, 2H), 1.02 (dd, 2H ).

LC / MS (Method 6, ESIpos): R _t = 1.25 min, m / z = 441 [M + H] ⁺ . Example 30

1 - {3 - [(3- {3- [4- (4-fluorotetrahydro-2H-pyran-4-yl) -phenyl] -1,4,4-oxadiazol-5-yl} -5-methyl-1H- pyrazol-1-yl) methyl] phenyl} cyclopropanol

Analogously to the process described in Example 22, 141 mg (49% of theory) of the title compound were obtained from 415 mg (0.60 mmol, 75% purity) of the compound from Example 76A and ethyl magnesium chloride solution. For preparative HPLC method 14 was used here. 'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.22 (d, 2H), 7:52 (d, 2H), 7:31 to 7:27 (m, 1H), 7.20 (s, 1 H), 7.16 (d , 1H), 6.99 (d, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 4.00-3.94 (m, 2H), 3.94-3.85 (m, 2H), 2.47 (s, 1H), 2.28 (s, 3H), 2.28-2.10 (m, 2H), 1.99-1.89 (m, 2H), 1.27 (dd, 2H), 1.01 (dd, 2H).

LC / MS (Method 6, ESIpos): R _t = 1.15 min, m / z = 475 [M + H] ⁺ . Example 31 1- [3 - ({3- [3- (4-Cyclohexylphenyl) -1,2,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) phenyl] - -cyclopropanol

Analogously to the process described under Example 22, from 318 mg (0.24 mmol, 42% purity) of the compound from Example 77A and ethyl magnesium chloride solution, 50 mg (37% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDCl ₃ , δ / ppm): 8.1 1 (d, 2H), 7.33 (d, 2H), 7.30-7.26 (m, 1H), 7.19 (s, 1H), 7.16 ( d, 1H), 6.99 (d, 1H), 6.80 (s, 1H), 5.44 (s, 2H), 2.60-2.51 (m, 1H), 2.43 (s, 1H), 2.27 (s, 3H), 1.95 -1.82 (m, 4H), 1.77 (d, 1H), 1.52-1.34 (m, 4H), 1.32-1.22 (m, 3H), 1.01 (dd, 2H). LC / MS (Method 6, ESIpos): R _t = 1.45 min, m / z = 455 [M + H] ⁺ .

Example 32

1 - (3 - {[5-Methyl-3- (3 - {4- [(trifluoromethyl) sulfanyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazol-1-yl] - methyl} phenyl) cyclopropanol

Analogously to the process described under Example 22, 395 mg (0.55 mmol, 72% purity) of the compound from Example 78 A and ethyl magnesium chloride solution gave 125 mg (46% of theory) of the title compound. For preparative HPLC method 14 was used here.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.26 (d, 2H), 7.78 (d, 2H), 7.29 (t, 1H), 7.20 (s, 1H), 7.17 (d, 1 H ), 6.99 (d, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 2.31 (s, 1H), 2.28 (s, 3H), 1.27 (dd, 2H), 1.02 (dd, 2H ).

LC / MS (Method 6, ESIpos): R _t = 1.32 min, m / z = 473 [M + H] ⁺ . Example 33

1- {3 - [(3- {3- [4- (1-fluorocyclobutyl) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl-1H-pyrazol-1-yl) methyl] - phenyl} cyclopropanol

Analogously to the process described under Example 22, 185 mg (0.24 mmol, 62% purity) of the compound from Example 79A and ethyl magnesium chloride solution gave 86 mg (76% of theory) of the title compound. For preparative HPLC method 14 was used here. Ή-NMR (400 MHz, CDCl ₃ , δ / ppm): 8.23 (d, 2H), 7.59 (d, 2H), 7.31-7.27 (m, 1H), 7.20 (s, 1H), 7.16 (d, 1H), 6.99 (d, 1H), 6.82 (s, 1H), 5.45 (s, 2H), 2.78-2.54 (m, 4H), 2.49 (s, 1H), 2.28 (s, 3H), 2.19-2.07 (m, 1H), 1.87-1.74 (m, 1H), 1.27 (dd, 2H), 1.01 (dd, 2H).

LC / MS (Method 6, ESIpos): R _t = 1.25 min, m / z = 445 [M + H]

Example 34

1 - {3 - [(5-Methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,4,4-oxadiazol-5-yl} -1H-pyrazol-1-yl):

phenyl} cyclopropanol

Analogously to the process described in Example 66A and Example 22, 70 mg (0.23 mmol) of the compound from Example 22A, 102 mg (0.345 mmol) of the compound from Example 47A and ethylmagnesium chloride solution 12 mg (12% of theory) were added in two steps. Th.) Of the title compound. For preparative HPLC, method 18 was used here.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.20 (d, 2H), 7.60 (d, 2H), 7.27 (t, 1H), 7.22 (s, 1H), 7.08 (d, 1H) , 6.96 (d, 1H), 6.93 (s, 1H), 5.93 (s, 1H), 5.48 (s, 2H), 2.34 (s, 3H), 1.09 (dd, 2H), 0.92 (dd, 2H) ,

LC / MS (Method 7, ESIpos): R _t = 2.68 min, m / z = 457 [M + H] ⁺ . Example 35

1 - {3 - [(3- {3- [3-Fluoro-4- (1,1,2-trifluoro-2-methylpropan-2-yl) -phenyl] -l, 2,4-oxadiazol-5-yl } -5-methyl-1H-pyrazol-1-yl) methyl] phenyl} cyclopropanol

Analogously to the process described under Example 22, from 192 mg (0.25 mmol, purity 69%) of the compound from Example 80A and ethyl magnesium chloride solution, 70 mg (57% of theory) of the title compound were obtained. To purify the crude product, a preparative thin-layer chromatography was first carried out here (silica gel, mobile phase: cyclohexane / ethyl acetate 1: 1). The product zone was extracted with dichloromethane / methanol 95: 5. Further purification was carried out by preparative HPLC (Method 15). Concentration of the product fractions treated with saturated aqueous sodium bicarbonate solution gave the title compound as a solid, which was filtered off, washed twice with water and dried in vacuo. 'H-NMR (400 MHz, CDC1 _3, δ / ppm): 7.96 (dd, 1H), 7.91 (dd, 1H), 7:55 (t, 1H), 7:32 to 7:26 (m, 2H), 7.20 (s, 1H), 7.16 (d, 1H), 6.99 (d, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 2.47 (s, 1H), 2.28 (s, 3H), 1.69 (s, 6H ), 1.27 (dd, 2H), 1.02 (dd, 2H).

LC / MS (Method 4, ESIpos): R _t = 1.58 min, m / z = 501 [M + H] ⁺ . Example 36 1 - {3 - [(5-Methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,3,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] - phenyl} cyclobutanol

0.10 g (0.19 mmol) of the compound from Example 81A were dissolved in 3.8 ml of abs. Dissolved THF and treated at -40 ° C dropwise with 0.22 g of isopropyl magnesium chloride-lithium chloride (14% strength in THF, 0.21 mmol). The mixture was then stirred for 1 h at about -40 ° C to -30 ° C. Then 16 μΐ (0.21 mmol) of cyclobutanone were added and the mixture was stirred for 1 h without further cooling. The mixture was then concentrated on a rotary evaporator, the residue was suspended in ethyl acetate and treated with anhydrous magnesium sulfate. It was filtered and the filtrate was concentrated on a rotary evaporator. The residue was purified by preparative HPLC (Method 17). This gave 18 mg (20% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.20 (d, 2H), 7.59 (d, 2H), 7.42 (d, 1H), 7.39 (s, 1H), 7.33 (t, 1H ), 7.02 (d, 1H), 6.93 (s, 1H), 5.51 (s, 2H), 5.50 (s, 1H), 2.35 (s, 3H), 2.35 (m, 2H), 2.25 (m, 2H) , 1.90 (m, 1H), 1.62 (m, 1H). LC / MS (Method 6, ESIpos): R _t = 1.31 min, m / z = 471 [M + H] ⁺ .

Example 37

4- {3 - [(5-Methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] -phenyl } tetrahydro-2H-pyran-4-ol

100 mg (0.19 mmol) of the compound from Example 81 A were in 3.8 ml abs. Dissolved THF and treated at -40 ° C dropwise with 220 mg of isopropyl magnesium chloride-lithium chloride (14% strength in THF, 0.21 mmol). The mixture was then stirred for 0.5 h at about -40 ° C to -30 ° C. A solution of 21 .mu.l (0.21 mmol) of tetrahydro-2H-pyran-4-one in 0.2 ml of abs. THF added and stirred for 0.5 h without further cooling. Then, saturated aqueous ammonium chloride solution and ethyl acetate were added, and the organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated on a rotary evaporator and the residue was purified by preparative HPLC (Method 17). This gave 66 mg (66% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.20 (d, 2H), 7.59 (d, 2H), 7.42 (d, 2H), 7.33 (t, 1H), 7.02 (d, 1H ), 6.93 (s, 1H), 5.51 (s, 2H), 5.05 (s, 1H), 3.76 (t, 2H), 3.70 (dd, 2H), 2.35 (s, 3H), 1.93 (td, 2H) , 1.50 (d, 2H).

LC / MS (Method 4, ESIpos): R _t = 1.38 min, m / z = 501 [M + H] ⁺ . Example 38

2- {3 - [(5-Methyl-3- {3- [4- (1,1,2-trifluoro-2-methylpropan-2-yl) -phenyl] -l, 2,4-oxadiazol-5-yl } - 1H-pyrazol-1-yl) methyl] phenyl} ethanol

0.10 g (0.20 mmol) of the compound from Example 82A were dissolved in 2.0 ml of abs. Dissolved THF and mixed at 0 ° C with 0.20 ml (0.20 mmol) of a 1 M solution of lithium aluminum hydride in THF. It was stirred for 5 min under ice bath cooling. Subsequently, saturated aqueous ammonium chloride solution, anhydrous magnesium sulfate and ethyl acetate were added successively. It was filtered from the solid, and the filtrate was evaporated on a rotary evaporator. This gave 72 mg (77% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.09 (d, 2H), 7.77 (d, 2H), 7.27 (t, 1H), 7.16 (d, 1H), 7.09 (s, 1H ), 6.99 (d, 1H), 6.93 (s, 1H), 5.47 (s, 2H), 4.62 (t, 1H), 3.58 (quart, 2H), 2.70 (t, 2H), 2.34 (s, 3H) , 1.61 (s, 6H).

LC / MS (Method 6, ESIpos): R _t = 1.27 min, m / z = 471 [M + H] ⁺ .

Example 39

1, 1, 1-trifluoro-3- {3 - [(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -l, 2,4-oxadiazol-5-yl} -1H-pyrazole 1 -yl) methyl] phenyl} propan-2-ol (racemate)

A solution of 250 mg (0.475 mmol) of the compound from Example 81 A in 10 ml of anhydrous THF was added rapidly at -20 ° C with 1.1 ml (1.43 mmol) of a 1.3 M solution of isopropylmagnesium chloride / lithium chloride complex in THF. After 2 minutes, 1 .8 mg (0.01 mmol) of copper (I) iodide was added and after a further minute 205 μΐ (2.37 mmol) of trifluoromethyl-oxirane was added. Subsequently, the reaction mixture was warmed to RT. After 20 min at RT, 100 ml of 25% aqueous ammonia solution were added and the mixture was extracted three times with approximately 100 ml of ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally freed from the solvent on a rotary evaporator. The residue obtained was first freed from nonpolar impurities by means of MPLC (about 50 g of silica gel, eluent: cyclohexane / ethyl acetate 4: 1). The further purification of the product was then carried out by preparative HPLC (Method 13). This gave 17 mg (7% of theory) of the title compound.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.24 (d, 2H), 7:33 (d, 2H), 7:32 (t, 1H), 7.22 (d, 1H), 7.12 (s, 1H) , 7.08 (d, 1H), 6.82 (s, 1H), 5.43 (s, 2H), 4.13 (m, 1H), 3.02 (dd, 1H), 2.84 (dd, 1H), 2.31 (d, 1H), 2.29 (s, 3H).

LC / MS (Method 6, ESIpos): R _t = 1.33 min, m / z = 513 [M + H] ⁺ . Example 40

1 - {3 - [(5-Methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,4,4-oxadiazol-5-yl} -1H-pyrazol-1-yl):

phenyl} propan-2-ol (racemate)

To a solution of 150 mg (0.329 mmol) of the compound from Example 84A in 7.5 ml of anhydrous THF was added at 0 ° C with 164 μΐ lithium aluminum hydride solution (1 M in THF). After the reaction mixture was stirred for 1 h at 0 ° C, the reaction was terminated by addition of 20 μΐ glacial acetic acid. The solvent was removed on a rotary evaporator and the crude product was purified by MPLC (silica gel, eluent: cyclohexane / ethyl acetate 2: 1 - ^■ 1: 2). 122 mg (81% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 ₃ , δ / ρρηι): 8.26 (d, 2H), 7.33 (d, 2H), 7.29 (t, 1H), 7.16 (d, 1H), 7.03 (d and s, 2H), 6.81 (s, 1H), 5.44 (s, 2H), 4.03-3.97 (m, 1H), 2.77 (dd, 1H), 2.67 (dd, 1H), 2.29 (s, 3H), 1.48 (d, 1H), 1.22 (d, 3H).

LC / MS (Method 2, ESIpos): R _t = 2.68 min, m / z = 459 [M + H] ⁺ . Example 41 and Example 42

1 - {3 - [(5-methyl-3 - {3 - [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1 H -pyrazol-1-yl) methyl] - phenyl} propan-2-ol (enantiomer 1 and 2)

100 mg of the racemic compound from Example 40 were dissolved in 6 ml of isopropanol and separated into the enantiomers in 15 portions by preparative HPLC on a chiral phase [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Eluent: isohexane / isopropanol 1: 1 (0-10 min); Flow: 15 ml min; Temperature: 30 ° C; UV detection: 220 nm]: Example 41 (Enantiomer 1):

Yield: 33 mg

R _t = 6.63 min, 99% ee [analytical chiral HPLC: column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4.6 mm; Eluent: isohexane / isopropanol / diethylamine 50: 49.8: 0.2 (0-10 min); Flow: 1.0 ml / min; Temperature: 30 ° C; UV detection: 220 nm],

Example 42 (Enantiomer 2):

Yield: 30 mg

R _t = 7.75 min, 98% ee [analytical chiral HPLC: column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4.6 mm; Eluent: isohexane / isopropanol / diethylamine 50: 49.8: 0.2 (0-10 min); Flow: 1.0 ml / min; Temperature: 30 ° C; UV detection: 220 nm].

'H-NMR (400 MHz, CDC1 ₃ , δ / ρρηι): 8.25 (d, 2H), 7.33 (d, 2H), 7.29 (t, 1H), 7.16 (d, 1H), 7.03 (d and s, 2H), 6.82 (s, 1H), 5.44 (s, 2H), 4.03-3.96 (m, 1H), 2.77 (dd, 1H), 2.68 (dd, 1H), 2.29 (s, 3H), 1.57 (d, 1H), 1.22 (d, 3H).

LC / MS (Method 6, ESIpos): R _t = 1.28 min, m / z = 459 [M + H] ⁺ . Example 43

2-Methyl-1- {3 - [(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) - methyl] phenyl} propan-2-ol

A solution of 33.5 g (68.9 mmol) of the compound from Example 83A in 700 ml of anhydrous THF was added dropwise at 0 ° C with 50.5 ml (152 mmol) of methylmagnesium bromide solution (3 M in diethyl ether). Upon completion of the addition, the ice / water bath was removed and stirring continued at RT. After 2 h, the reaction was quenched by careful addition of 50 mL of saturated aqueous ammonium chloride solution. It was diluted with 700 ml of ethyl acetate and treated with 100 g of anhydrous magnesium sulfate. After brief stirring, the mixture was filtered and the filtrate was freed from the solvent on a rotary evaporator. The resulting residue was purified by suction filtration over 770 g of silica gel (0.06-0.2 mm grain size) with a cyclohexane ethyl acetate gradient [8: 2 (8 liters) -> 7: 3 (8 liters) -> 6: 4 (8 liters) -> 1: 1 (4 liters)] as eluent. After evaporating off the solvent, 22.5 g of a crude product were obtained which mainly contained the title compound and, in addition, the compound 1- {3 - [(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,4,4 -oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] -phenyl} acetone (see Example 84A). 7.6 g of this crude product were recrystallized from 61 ml of boiling diisopropyl ether. The crystals obtained at RT were filtered off, washed twice with 5 ml of cold diisopropyl ether and dried under high vacuum. This gave 5.19 g (73% of theory) of the pure title compound.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.25 (d, 2H), 7:33 (d, 2H), 7.29 (t, 1H), 7.17 (d, 1H), 7:05 (d, 1H) , 7.03 (s, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 2.73 (s, 2H), 2.29 (s, 3H), 1.31 (s, 1H), 1.20 (s, 6H).

LC / MS (Method 6, ESIpos): R, = 1.33 min, m / z = 473 [M + H] ⁺ .

Example 44

1 - [3- (3- [3- (4-tert-butylphenyl) -1,4,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) -phenyl] - 2-methylpropan-2-ol

A solution of 200 mg (0.708 mmol) of the compound of Example 42A and 366 mg (1.42 mmol) of the compound from Example 48A in 8 mL of anhydrous THF was added at 0 ° C with 119 mg (1.06 mmol) of solid potassium hydroxide. butylate added. Subsequently, the reaction mixture was stirred at RT for 30 min. After addition of about 1 ml of methanol, the mixture was separated directly into its components by preparative HPLC (Method 13). There were thus isolated 242 mg (77% of theory) of the title compound.

'H-NMR (400 MHz, CDCl ₃ , δ / ppm): 8.13 (d, 2H), 7.50 (d, 2H), 7.28 (t, 1H), 7.16 (d, 1H), 7.05 (d, 1H) , 7.02 (s, 1H), 6.80 (s, 1H), 5.45 (s, 2H), 2.73 (s, 2H), 2.28 (s, 3H), 1.36 (s, 9H), 1.29 (s, 1H), 1.19 (s, 6H). LC / MS (Method 6, ESIpos): R, = 1.41 min, m / z = 445 [M + H] ⁺ . Example 45 1- (3- {[3- (3- {4- [1- (Metoxymethyl) cyclobutyl] phenyl}, 2,4-oxadiazol-5-yl) -5-methyl-H-pyrazole 1-yl ] methyl} phenyl) -2-methylpropan-2-ol

Analogously to the process described under Example 44, from 105 mg (0.324 mmol) of the compound from Example 40A and 167 mg (0.647 mmol) of the compound from Example 48A, 130 mg (83% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.13 (d, 2H), 7.29 (d, 2H), 7.28 (t, 1H), 7.16 (d, 1H), 7:04 (d, 1H) , 7.02 (s, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 3.55 (s, 2H), 3.28 (s, 3H), 2.73 (s, 2H), 2.41-2.29 (m, 4H ), 2.27 (s, 3H), 2.15-2.03 (m, 1H), 1.93-1.83 (m, 1H), 1.29 (s, broad, 1H), 1.19 (s, 6H).

LC / MS (Method 6, ESIpos): R _t = 1.37 min, m / z = 487 [M + H] ⁺ .

Example 46

2-Methyl-1- {3 - [(5-methyl-3- {3- [4- (trimethylsilyl) phenyl] -1,3,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) - methyl] phenyl} propan-2-ol

Analogously to the process described under Example 44, from 100 mg (0.335 mmol) of the compound from Example 26A and 173 mg (0.670 mmol) of the compound from Example 48A, 112 mg (73% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDCl ₃ , δ / ρρηι): 8.17 (d, 2H), 7.64 (d, 2H), 7.28 (t, 1H), 7.17 (d, 1H), 7.05 (d, 1H) , 7.03 (s, 1H), 6.81 (s, 1H), 5.46 (s, 2H), 2.73 (s, 2H), 2.28 (s, 3H), 1.30 (s, 1H), 1.19 (s, 6H), 0.31 (s, 9H). LC / MS (Method 6, ESIpos): R _t = 1.46 min, m / z = 461 [M + H] ⁺ . Example 47

2-Methyl-1- (3 - {[5-methyl-3- (3 - {4- [1- (trifluoromethyl) cyclopropyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazole - 1 -yl] methyl} phenyl) propan-2-ol

Analogously to the process described under Example 44, from 100 mg (0.285 mmol) of the compound from Example 30A and 147 mg (0.571 mmol) of the compound from Example 48A, 116 mg (82% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.18 (d, 2H), 7:58 (d, 2H), 7.28 (t, 1H), 7.17 (d, 1H), 7:04 (d, 1H) , 7.03 (s, 1H), 6.80 (s, 1H), 5.45 (s, 2H), 2.74 (s, 2H), 2.28 (s, 3H), 1.42-1.39 (m, 2H), 1.31 (s, 1H ), 1.19 (s, 6H), 1.11-1.07 (m, 2H).

LC / MS (Method 6, ESIpos): R _t = 1.35 min, m / z = 497 [M + H] ⁺ . Example 48 1 - {3 - [(3- {3- [3-Fluoro-4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl-1H-pyrazole-1 yl) - methylphenyl} -2-methylpropan-2-ol

Analogously to the process described under Example 44, from 100 mg (0.305 mmol) of the compound from Example 29A and 157 mg (0.609 mmol) of the compound from Example 48A, 110 mg (74% of theory) of the title compound were obtained. Ή NMR (400 MHz, CDCl ₃ , δ / ppm): 8.08 (dd, 1H), 8.03 (ddd, 1H), 7.43 (dd, 1H), 7.29 (t, 1H), 7.17 (d, 1H), 7.04 (d, 1H), 7.03 (s, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 2.73 (s, 2H), 2.29 (s, 3H), 1.31 (s, 1H), 1.20 (s, 6H). LC / MS (Method 6, ESIpos): R _t = 1.35 min, m / z = 491 [M + H]. Example 49

2-methylm {3 - [(5-methyl-3-yl]

methyl] phenyl} propan-2-ol

Analogously to the process described under Example 44, from 100 mg (0.340 mmol) of the compound from Example 27A and 175 mg (0.680 mmol) of the compound from Example 48A, 126 mg (81% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8:33 (d, 2H), 7.76 (d, 2H), 7.29 (t, 1H), 7.17 (d, 1H), 7:05 (d, 1H) , 7.03 (s, 1H), 6.82 (s, 1H), 5.45 (s, 2H), 2.73 (s, 2H), 2.29 (s, 3H), 1.31 (s, 1H), 1.20 (s, 6H).

LC / MS (Method 6, ESIpos): R _t = 1.31 min, m / z = 457 [M + H] ⁺ .

Example 50 1 - {3 - [(3- {3- [4- (4-Fluorotetrahydro-2H-pyran-4-yl) -phenyl] -l, 2,4-oxadiazol-5-yl} -5-methyl- 1H-pyrazol-1-yl) methyl] phenyl} -2-methylpropan-2-ol

Analogously to the process described under Example 44, 58 mg (0.177 mmol) of the compound from Example 43A and 91 mg (0.353 mmol) of the compound from Example 48A gave 64 mg (74% of theory) of the title compound. 'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.22 (d, 2H), 7:52 (d, 2H), 7.29 (t, 1H), 7.17 (d, 1H), 7:05 (d, 1H) , 7.03 (s, 1H), 6.82 (s, 1H), 5.45 (s, 2H), 4.00-3.88 (m, 4H), 2.73 (s, 2H), 2.28 (s, 3H), 2.30- 2.11 (m , 2H), 1.98-1.91 (m, 2H), 1.32 (s, broad, 1H), 1.20 (s, 6H).

LC / MS (Method 6, ESIpos): R _t = 1.22 min, m / z = 491 [M + H] ⁺ . Example 51

2-Methyl-1- {3 - [(5-methyl-3- {3- [4- (tetrahydro-2H-pyran-4-yl) -phenyl] -l, 2,4-oxadiazol-5-yl} - 1H-pyrazol-1-yl) methyl] phenyl} propan-2-ol

Analogously to the process described under Example 44, from 75 mg (0.242 mmol) of the compound from Example 28A and 94 mg (0.362 mmol) of the compound from Example 48A, 98 mg (86% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDCl ₃ , δ / ppm): 8.15 (d, 2H), 7.35 (d, 2H), 7.29 (t, 1H), 7.16 (d, 1H), 7.05 (d, 1H) , 7.03 (s, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 4.13-4.08 (m, 2H), 3.55 (dt, 2H), 2.88-2.80 (m, 1H), 2.73 (s , 2H), 2.28 (s, 3H), 1.92-1.78 (m, 4H), 1.22 (s, 1H), 1.20 (s, 6H). LC / MS (Method 6, ESIpos): R _t = 1.22 min, m / z = 473 [M + H] ⁺ .

Example 52 1 - {3 - [(3- {3- [4- (3-Fluorooxetan-3-yl) phenyl] -1,3,4-oxadiazol-5-yl} -5-methyl-1H-pyrazole 1-yl) - methyl] phenyl} -2-methylpropan-2-ol

Analogously to the process described under Example 44, from 70 mg (0.233 mmol) of the compound from Example 35A and 90 mg (0.350 mmol) of the compound from Example 48A, 76 mg (70% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.29 (d, 2H), 7.71 (d, 2H), 7.29 (t, IH), 7.17 (d, IH), 7:05 (d, IH) , 7.03 (s, IH), 6.82 (s, IH), 5.46 (s, 2H), 5.06 (dd, 2H), 5.00 (dd, 2H), 2.73 (s, 2H), 2.29 (s, 3H), 1.31 (s, wide, IH), 1.20 (s, 6H).

LC / MS (Method 6, ESIpos): R _t = 1.17 min, m / z = 463 [M + H] ⁺ . Example 53

2-Methyl-1- (3 - {[5-methyl-3- (3 - {4- [(trifluoromethyl) sulfanyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazole-1 -yl] methyl} phenyl) propan-2-ol

Analogously to the process described under Example 44, 87 mg (73% of theory) of the title compound were obtained from 80 mg (0.245 mmol) of the compound from Example 36A and 95 mg (0.368 mmol) of the compound from Example 48A. 'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.27 (d, 2H), 7.78 (d, 2H), 7.29 (t, IH), 7.17 (d, IH), 7:05 (d, IH) , 7.03 (s, IH), 6.82 (s, IH), 5.45 (s, 2H), 2.73 (s, 2H), 2.29 (s, 3H), 1.29 (s, wide, IH), 1.20 (s, 6H ).

LC / MS (Method 6, ESIpos): R _t = 1.38 min, m / z = 489 [M + H] ⁺ .

Example 54 1 - (3 - {[3 - (3 - (3-Fluoro-4- [1 - (methoxymethyl) cyclobutyl] phenyl} -1,2,4-oxadiazol-5-yl) -5-methyl-1H - pyrazol-1-yl] methyl} phenyl) -2-methylpropan-2-ol

Analogously to the process described under Example 44, from 100 mg (0.292 mmol) of the compound from Example 31A and 151 mg (0.584 mmol) of the compound from Example 48A, 58 mg (39% of theory) of the title compound were obtained. ¹ H-NMR (400 MHz, CDCl ₃ , δ / ρρηι): 7.93 (dd, 1H), 7.82 (dd, 1H), 7.29 (t, 1H), 7.24 (t, 1H), 7.16 (d, 1H) , 7.05 (d, 1H), 7.02 (s, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 3.67 (s, 2H), 3.28 (s, 3H), 2.73 (s, 2H), 2.48-2.40 (m, 2H), 2.37-2.30 (m, 2H), 2.27 (s, 3H), 2.19-2.06 (m, 1H), 1.94-1.84 (m, 1H), 1.29 (s, 1H), 1.19 (s, 6H).

LC / MS (Method 6, ESIpos): R _t = 1.39 min, m / z = 505 [M + H] ⁺ . Example 55

1 - (3 - {[3- (3 - {4- [1- (methoxymethyl) cyclopentyl] phenyl} -1,2,4-oxadiazol-5-yl) -5-methyl-1H-pyrazol-1-ylmethyl } phenyl) -2-methylpropan-2-ol

Analogously to the process described under Example 44, from 100 mg (0.295 mmol) of the compound from Example 33A and 153 mg (0.591 mmol) of the compound from Example 48A, 66 mg (45% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.12 (d, 2H), 7:45 (d, 2H), 7.29 (t, 1H), 7.17 (d, 1H), 7:04 (d, 1H) , 7.03 (s, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 3.41 (s, 2H), 3.23 (s, 3H), 2.73 (s, 2H), 2.28 (s, 3H), 2.07-2.00 (m, 2H), 1.96-1.88 (m, 2H), 1.79-1.71 (m, 4H), 1.30 (s, 1H), 1.19 (s, 6H). LC / MS (Method 2, ESIpos): R _t = 2.82 min, m / z = 501 [M + H] ⁺ . Example 56

2-methyl-1- {3 - [(5-methyl-3- {3- [3-m]

 pyrazol-1-yl) methyl] phenyl} propan-2-ol

Analogously to the process described under Example 44, from 125 mg (0.385 mmol) of the compound from Example 34A and 149 mg (0.577 mmol) of the compound from Example 48A, 60 mg (32% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.14 (d, 1H), 8:06 (dd, 1H), 7:32 (d, 1H), 7.29 (t, 1H), 7.17 (d, 1H) , 7.05 (d, 1H), 7.03 (s, 1H), 6.81 (s, 1H), 5.46 (s, 2H), 2.73 (s, 2H), 2.39 (s, 3H), 2.28 (s, 3H), 1.30 (s, 1H), 1.19 (s, 6H).

LC / MS (Method 6, ESIpos): R _t = 1.37 min, m / z = 487 [M + H] ⁺ .

Example 57

2-Methyl-1- {3 - [(5-methyl-3- {3- [4- (1,1,2-trifluoro-2-methylpropan-2-yl) -phenyl] -l, 2,4-oxadiazole -5-yl} - lH-pyrazol-1-yl) methyl] phenyl} propan-2-ol

A solution of 155 mg (0.302 mmol) of the compound from Example 82A in 3 ml of anhydrous THF was added at 0 ° C with 212 .mu.M methylmagnesium chloride solution (3 M in diethyl ether). The ice / water bath was then removed and stirring continued at RT. After 1.5 h, the reaction was terminated by addition of 0.5 ml of saturated aqueous ammonium chloride solution. It was diluted with about 9 ml of ethyl acetate and treated with anhydrous magnesium sulfate. After brief stirring, the mixture was filtered and the filtrate was freed from the solvent on a rotary evaporator. The residue obtained was stirred with 5 ml of pentane. The solid was filtered off and dried under high vacuum. 125 mg (83% of theory) of the title compound were obtained. Ή NMR (400 MHz, CDCl ₃ , δ / ppm): 8.20 (d, 2H), 7.63 (d, 2H), 7.29 (t, 1H), 7.16 (d, 1H), 7.05 (d, 1H), 7.03 (s, 1H), 6.81 (s, 1H), 5.46 (s, 2H), 2.73 (s, 2H), 2.27 (s, 3H), 1.63 (s, 6H), 1.30 (s, 1H), 1.19 (s, 6H).

LC / MS (Method 6, ESIpos): R _t = 1.34 min, m / z = 499 [M + H] ⁺ . Example 58

2-Methyl-2- (3- {[5-methyl-3- (3- {4- [1- (trifluoromethyl) cyclopropyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazole - 1 -yl] methyl} phenyl) propane-1-ol

0.37 ml (0.37 mmol) of lithium aluminum hydride solution (1 M in THF) were added dropwise under argon at 0 ° C. to a solution of 200 mg (0.37 mmol) of the compound from Example 85A in 3.5 ml of THF. The mixture was stirred for 1 h at 0 ° C and then added 1 ml of water dropwise. After warming to RT, it was diluted with ethyl acetate and the resulting solid was filtered off. The solid was washed twice with ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Method 14). After removal of the solvent and drying of the residue in vacuo, 17 mg (9% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.18 (d, 2H), 7:58 (d, 2H), 7:35 to 7:27 (m, 3H), 7.22 (s, 1H), 6.99 (d, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 3.59 (s, 2H), 2.29 (s, 3H), 1.40 (dd, 2H), 1.30 (s, 6H), 1.25 (s, 1H ), 1.11-1.05 (m, 2H). LC / MS (Method 6, ESIpos): R _t = 1.37 min, m / z = 497 [M + H] ⁺ .

Example 59

2-Methyl-2- {3 - [(5-methyl-3- {3- [4- (tetrahydro-2H-pyran-4-yl) -phenyl] -l, 2,4-oxadiazol-5-yl} - 1H-pyrazol-1-yl) methyl] phenyl} propan-1-ol

A solution of 74 mg (0.129 mmol) of the compound from Example 86A in 3 ml of anhydrous THF was added at -78 ° C with 130 μΐ (0.130 mmol) of lithium aluminum hydride solution (1 M in THF). Subsequently, the reaction mixture was first stirred for 1 h at -78 ° C and then at 0 ° C for a further 30 min. Thereafter, about 9 ml of 1 M sodium hydroxide solution were added and the mixture was extracted three times with about 10 ml of ethyl acetate each time. The combined organic extracts were washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally freed from the solvent on a rotary evaporator. From the residue obtained, 42 mg (69% of theory) of the title compound were isolated by preparative HPLC (Method 11).

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.14 (d, 2H), 7:36 to 7:28 (m, 4H), 7.22 (s, 1 H), 6.99 (d, 1H), 6.81 (s , 1H), 5.45 (s, 2H), 4.10 (dd, 2H), 3.59 (d, 2H), 3.54 (dt, 2H), 2.88-2.78 (m, 1H), 2.29 (s, 3H), 1.91 -1.78 (m, 4H), 1.30 (s, 6H), 1.24 (t, 1H).

LC / MS (Method 6, ESIpos): R _t = 1.21 min, m / z = 473 [M + H] ⁺ . Example 60

2-Methyl-2- {3 - [(5-methyl-3- {3- [4- (1,1,2-trifluoro-2-methylpropan-2-yl) -phenyl] -l, 2,4-oxadiazole -5-yl} - lH-pyrazol-1-yl) methyl] phenyl} propan-1-ol

Analogously to the process described in Example 59, 80 mg (0.15 mmol) of the compound from Example 87A were converted to 50 mg (68% of theory) of the title compound. The preparative HPLC purification was carried out here according to Method 17. 'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.09 (d, 2H), 7.77 (d, 2H), 7.32-7.25 (m, 3H), 6.92 (d, 2H), 5.49 (s , 2H), 4.67 (s, broad, 1H), 3.39 (d, 2H), 2.34 (s, 3H), 1.61 (s, 6H), 1.20 (s, 6H).

LC / MS (Method 6, ESIpos): R _t = 1.36 min, m / z = 499 [M + H] ⁺ .

Example 61 2-Methyl-2- {3 - [(5-methyl-3- {3- [4- (trifluoromiethoxy) -phenyl] -l, 2,4-oxadiazol-5-yl} -H-pyrazole-1-one yl) - methylphenyl} propan-1-ol

Analogously to the process described in Example 59, 80 mg (0.16 mmol) of the compound from Example 88A were converted to 40 mg (54% of theory) of the title compound. The preparative HPLC purification was carried out here according to Method 17.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.20 (d, 2H), 7.59 (d, 2H), 7.32-7.25 (m, 3H), 6.92 (d, 2H), 5.49 (s, 2H), 4.67 (t, 1H), 3.39 (d, 2H), 2.34 (s, 3H), 1.20 (s, 6H).

LC / MS (Method 4, ESIpos): R _t = 1.48 min, m / z = 473 [M + H] ⁺ .

Example 62 1,1-Dideutero-2-methyl-2- {3 - [(5-methyl-3- {3- [4- (1,1,2-trifluoro-2-methylpropan-2-yl) -phenyl] -l, 2,4-oxadiazol-5-yl} - lH-pyrazol-1-yl) methyl] phenyl} propan-1-ol

Analogously to the method described under Example 59, 300 mg (0.555 mmol) of the compound from Example 87A were reacted with 555 μΐ (0.555 mmol) lithium aluminum deuteride solution (1 M in THF) to give 166 mg (60% of theory) of the title compound , The preparative HPLC purification was carried out here according to Method 13. Ή NMR (400 MHz, CDCl ₃ , δ / ppm): 8.20 (d, 2H), 7.62 (d, 2H), 7.32 (d, 1H), 7.31 (t, 1H), 7.22 (s, 1H), 7.00 (d, 1H), 6.82 (s, 1H), 5.45 (s, 2H), 2.29 (s, 3H), 1.61 (s, 6H), 1.30 (s, 6H), 1.24 (s, wide,

1H).

LC / MS (Method 6, ESIpos): R _t = 1.35 min, m / z = 501 [M + H]. Example 63

(1 - {3 - [(5-Methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) phenyl} cyclopropyl ) methanol

A solution of 125 mg (0.403 mmol) of the compound of Example 22A and 249 mg (0.604 mmol) of the compound from Example 50A in 5 mL of anhydrous THF was solidified at 0 ° C with 68 mg (0.604 mmol) of solid potassium. butylate added. The reaction mixture was stirred at RT for 6 days and then at 40 ° C. for a further 2 h. Then, it was mixed with about 50 ml of water and extracted three times with about 50 ml of ethyl acetate. The combined organic extracts were washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally freed from the solvent on a rotary evaporator. The residue obtained was redissolved in 5 ml of THF and admixed with 483 μΐ (0.483 mmol) of tetra-n-butylammonium fluoride solution (1 M in THF). After 1 h at RT, the reaction mixture was diluted with 2 ml of methanol and then separated directly into its components by preparative HPLC (Method 13). In this way 85 mg (45% of theory) of the title compound were obtained. Ή NMR (400 MHz, CDC1 ₃ , δ / ppm): 8.26 (d, 2H), 7.33 (d, 2H), 7.32-7.25 (m, 2H), 7.22 (s, 1H), 7.00 (d, 1H), 6.81 (s, 1H), 5.44 (s, 2H), 3.66 (s, 2H), 2.30 (s, 3H), 1.39 (broad, 1H), 0.85 (s, 4H).

LC / MS (Method 6, ESIpos): R _t = 1.29 min, m / z = 471 [M + H]

Example 64

(1 - {3 - [(5-Methyl-3- {3- [4- (1,1,2-trifluoro-2-methylpropan-2-yl) -phenyl] -l, 2,4-oxadiazol-5 yl} -1H-pyrazol-1-yl) methyl] phenyl} cyclopropyl) methanol

Analogously to the process described in Example 63, 124 mg (77% of theory) of the title compound were obtained in two steps from 109 mg (0.323 mmol) of the compound from Example 23A and 200 mg (0.485 mmol) of the compound from Example 50A. The reaction mixture was stirred for 16 h at RT in the first part of the step; subsequent heating to 40 ° C. was omitted.

Ή-NMR (400 MHz, CDC1 ₃ , δ / ρρηι): 8.20 (d, 2H), 7.62 (d, 2H), 7.32-7.25 (m, 2H), 7.22 (s, IH), 7.00 (d, IH ), 6.82 (s, IH), 5.43 (s, 2H), 3.66 (d, 2H), 2.29 (s, 3H), 1.62 (s, 6H), 1.43 (t, wide, IH), 0.86 (s, 4H). LC / MS (Method 4, ESIpos): R _t = 1.51 min, m / z = 497 [M + H] ⁺ . Example 65

[1 - (3- {[5-Methyl-3- (3- {4- [1- (trifluoromethyl) cyclopropyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazole-1 - yl] methyl} phenyl) cyclopropyl] methanol

Analogously to the process described under Example 63, 141 mg (89% of theory) of the title compound were obtained in two steps from 108 mg (0.323 mmol) of the compound from Example 30A and 200 mg (0.485 mmol) of the compound from Example 50A. The reaction mixture was stirred for 16 h at RT in the first part of the step; subsequent heating to 40 ° C. was omitted.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.19 (d, 2H), 7:59 (d, 2H), 7:31 to 7:25 (m, 2H), 7.22 (s, IH) 7.00 (d, IH), 6.82 (s, IH), 5.43 (s, 2H), 3.66 (s, 2H), 2.29 (s, 3H), 1.46-1.39 (m, 3H), 1.10-1.07 (m, 2H), 0.85 (s, 4H). LC / MS (Method 4, ESIpos): R _t = 1.50 min, m / z = 495 [M + H] ⁺ . Example 66

[1 - (3 - {[5-Methyl-3- (3 - {4- [(trifluoromethyl) sulfanyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazol-1-yl] - methyl} phenyl) cyclopropyl] methanol

Analogously to the process described under Example 63, 130 mg (83% of theory) of the title compound were obtained from 105 mg (0.323 mmol) of the compound from Example 36A and 200 mg (0.485 mmol) of the compound from Example 50A in two substeps. The reaction mixture was stirred for 16 h at RT in the first part of the step; subsequent heating to 40 ° C was withdrawn.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.27 (d, 2H), 7.78 (d, 2H), 7:31 to 7:26 (m, 2H), 7.22 (s, 1H) 7.00 (d, 1H), 6.82 (s, 1H), 5.46 (s, 2H), 3.66 (s, 2H), 2.30 (s, 3H), 1.43 (broad, 1H), 0.86 (s, 4H).

LC / MS (Method 4, ESIpos): R _t = 1.53 min, m / z = 487 [M + H] ⁺ .

Example 67 [1 - (3 - {[5-Methyl-3- (3 - {4- [(trifluoromethyl) sulfonyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazole-1 - yl] - methyl} phenyl) cyclopropyl] methanol

Analogously to the process described under Example 63, 74 mg (44% of theory) of the title compound were obtained from 1,16 mg (0.323 mmol) of the compound from Example 25A and 200 mg (0.485 mmol) of the compound from Example 50A in two substeps , The reaction mixture was stirred for 16 h at RT in the first part of the step; subsequent heating to 40 ° C. was omitted. ^: H-NMR (400 MHz, CDCl ₃ , δ / ρρηι): 8.52 (d, 2H), 8.18 (d, 2H), 7.32-7.27 (m, 2H), 7.23 (s, 1H), 7.00 (d, 1H), 6.84 (s, 1H), 5.45 (s, 2H), 3.66 (d, 2H), 2.31 (s, 3H), 1.41 (t, 1H), 0.86 (s, 4H).

LC / MS (method MHZ-QP-GO-1, ESIpos): R _t = 1.43 min, m / z = 519 [M + H] ⁺ .

Example 68 Dideutero (1- {3 - [(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] phenyl} cyclopropyl) methanol

A solution of 115 mg (0.371 mmol) of the compound from Example 22A and 231 mg (0.556 mmol) of the compound from Example 51A in 5 ml of anhydrous THF was treated at 0 ° C. with 62 mg (0.556 mmol) of solid potassium tert. butoxide added. After removal of the ice / water bath, the reaction mixture was stirred at RT for 16 h. Thereafter, it was mixed with about 50 ml of water and extracted three times with about 50 ml of ethyl acetate. The combined organic extracts were washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally freed from the solvent on a rotary evaporator. The residue obtained was redissolved in 5 ml of THF and combined with 445 μΐ (0.445 mmol) of tetra-n-butylammonium fluoride solution (1 M in THF). After 1 h at RT, the reaction mixture was diluted with 2 ml of methanol and then separated directly into its components by preparative HPLC (Method 13). In this way, 105 mg (60% of theory) of the title compound were obtained. Ή NMR (400 MHz, CDCl ₃ , δ / ppm): 8.25 (d, 2H), 7.33 (d, 2H), 7.30-7.24 (m, 2H), 7.21 (s, 1H), 7.00 (d, 1H ), 6.82 (s, 1H), 5.43 (s, 2H), 2.30 (s, 3H), 1.39 (broad, 1H), 0.85 (s, 4H).

LC / MS (Method 6, ESIpos): R _t = 1.28 min, m / z = 473 [M + H] ⁺ .

Example 69

Dideutero (1 - {3 - [(5-methyl-3- {3- [4- (1,1,2-trifluoro-2-methylpropan-2-yl) -phenyl] -l, 2,4-oxadiazole-5 - yl} - lH-pyrazol-1-yl) methyl] phenyl} cyclopropyl) methanol H ₃ C CH ₃

Analogously to the process described under Example 68, 57 mg (35% of theory) of the title compound were obtained in two steps from 108 mg (0.322 mmol) of the compound from Example 23A and 200 mg (0.482 mmol) of the compound from Example 51A , The reaction mixture was stirred here in the second partial step for 2 h at RT.

'H-NMR (400 MHz, CDC1 ₃ , δ / ppm): 8.20 (d, 2H), 7.62 (d, 2H), 7.31-7.27 (m, 2H), 7.22 (s, 1H), 7.00 (d, 1H), 6.82 (s, 1H), 5.43 (s, 2H), 2.29 (s, 3H), 1.63 (s, 6H), 1.43 (broad, 1H), 0.83 (s, 4H).

LC / MS (Method 4, ESIpos): R _t = 1.51 min, m / z = 499 [M + H] ⁺ .

Example 70 Dideutero [1- (3 - {[5-Methyl-3- (3 - {4- [1- (trifluoromethyl) cyclopropyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazole -l-yl] methyl} phenyl) cyclopropyl] methanol

Analogously to the process described under Example 68, 73 mg (45% of theory) of the title compound were obtained from 107 mg (0.322 mmol) of the compound from Example 30A and 200 mg (0.482 mmol) of the compound from Example 51A in two substeps.

'H-NMR (400 MHz, CDCl ₃ , δ / ppm): 8.19 (d, 2H), 7.59 (d, 2H), 7.31-7.25 (m, 2H), 7.22 (s, 1H), 7.00 (d, 1H), 6.82 (s, 1H), 5.43 (s, 2H), 2.29 (s, 3H), 1.43-1.39 (m, 3H), 1.11-1.07 (m, 2H), 0.85 (s, 4H).

LC / MS (Method 6, ESIpos): R _t = 1.31 min, m / z = 497 [M + H] ⁺ . Example 71

Dideutero [1- (3- {[5-methyl-3- (3- {4 - [(trifluoromethyl) sulfanyl] phenyl} -1, 2,4-o

pyrazol-1-yl] methyl} phenyl) cyclopropyl] methanol

Analogously to the process described under Example 68, 81 mg (52% of theory) of the title compound were obtained from 105 mg (0.322 mmol) of the compound from Example 36A and 200 mg (0.482 mmol) of the compound from Example 51A in two substeps ,

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.28 (d, 2H), 7.79 (d, 2H), 7:31 to 7:27 (m, 2H), 7.22 (s, 1H) 7.00 (d, 1H), 6.83 (s, 1H), 5.44 (s, 2H), 2.29 (s, 3H), 1.45 (broad, 1H), 0.84 (s, 4H). LC / MS (Method 6, ESIpos): R _t = 1.34 min, m / z = 489 [M + H] ⁺ .

Example 72

Dideutero [1- (3- {[5-methyl-3- (3- {4 - [(trifluoromethyl) sulfonyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazole-1-ylmethyl } phenyl) cyclopropyl] methanol

Analogously to the process described under Example 68, 41 mg (25% of theory) of the title compound were obtained from 15 mg (0.322 mmol) of the compound from Example 25A and 200 mg (0.482 mmol) of the compound from Example 51A in two substeps ,

'H-NMR (400 MHz, CDCl ₃ , δ / ppm): 8.52 (d, 2H), 8.18 (d, 2H), 7.32-7.27 (m, 2H), 7.23 (s, 1H), 7.00 (d, 1H), 6.83 (s, 1H), 5.45 (s, 2H), 2.31 (s, 3H), 1.41 (t, 1H), 0.84 (s, 4H). LC / MS (Method 6, ESIpos): R _t = 1.25 min, m / z = 521 [M + H] ⁺ . Example 73

Dideutero (1- {3 - [(3- {3- [4- (4-fluorotetrahydro-2H-pyran-4-yl) -phenyl], 2,4-oxadiazole-5

1H-pyrazol-1-yl) methyl] phenyl} cyclopropyl) methanol

Analogously to the process described under Example 68, 60 mg (61% of theory) of the title compound were obtained in two steps from 65 mg (0.198 mmol) of the compound from Example 43A and 123 mg (0.297 mmol) of the compound from Example 51A.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.23 (d, 2H), 7:52 (d, 2H), 7:31 to 7:26 (m, 2H), 7.21 (s, 1H) 7.00 (d, 1H), 6.82 (s, 1H), 5.43 (s, 2H), 4.00-3.87 (m, 4H), 2.29 (s, 3H), 2.30-2.1 1 (m, 2H), 1.98- 1.91 (m, 2H ), 1.41 (s, broad, 1H), 0.84 (s, 4H).

LC / MS (Method 6, ESIpos): R _t = 1.18 min, m / z = 491 [M + H] ⁺ .

Example 74

2,2-Difluoro-2- {3 - [(5-methyl-3- {3- [4- (trimethylsilyl) phenyl] -l, 2,4-oxadiazol-5-yl} -1H-pyrazole-1-one yl) - methylphenyl} ethanol

To a solution of 155 mg (0.52 mmol) of the compound from Example 26A in 4 ml of THF under argon at 0 ° C 85 mg (0.75 mmol) of potassium tert. given butylate. After stirring for 30 minutes at 0 ° C, 392 mg (1.56 mmol) of the compound from Example 52A in 2 ml of THF were added and the mixture was stirred at RT for 16 h. Thereafter, an additional 58 mg (0.52 mmol) of potassium tert. - Butylate was added, and the mixture was stirred again for 2 h at RT. Then, the mixture was added with 30 ml of water and 30 ml of ethyl acetate. After phase separation, the aqueous phase extracted once with 30 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluent: cyclohexane / ethyl acetate 7: 3). After removal of the solvent, the product fraction was purified again by preparative thin-layer chromatography (silica gel, eluent: dichloromethane / methanol 97: 3). Removal of the solvent and drying of the residue in vacuo gave 47 mg (19% of theory) of the title compound.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.17 (d, 2H), 7.64 (d, 2H), 7:47 (d, 1 H), 7:42 (t, 1H), 7:36 (s, 1H ), 7.23 (d, 1H), 6.84 (s, 1H), 5.49 (s, 2H), 3.95 (t, 2H), 2.29 (s, 3H), 0.31 (s, 9H).

LC / MS (Method 6, ESIpos): R _t = 1.37 min, m / z = 469 [M + H] ⁺ . Example 75

2- [3- ({3- [3- (4-tert-butylphenyl) -1, 2,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) -phenyl] - 2,2-difluoroethanol

To a solution of 155 mg (0.55 mmol) of the compound from Example 42A in 3 ml of THF under argon at 0 ° C 89 mg (0.80 mmol) of potassium tert. given butylate. After stirring at 0 ° C for 30 min, 414 mg (1.65 mmol) of the compound of Example 52A was added. The mixture was allowed to come to RT and then stirred at RT for 16 h. Then 30 ml of water and 30 ml of ethyl acetate were added and the phases were separated. The aqueous phase was extracted once more with 30 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluent: cyclohexane / ethyl acetate 4: 1). After removing the solvent and drying the residue in vacuo, 93 mg (36% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDCI _3, δ / ppm): 8.13 (d, 2H), 7:51 (d, 2H), 7:47 (d, 1H), 7:42 (t, 1H), 7:36 (s, 1H) , 7.23 (d, 1H), 6.83 (s, 1H), 5.49 (s, 2H), 3.95 (dt, 2H), 2.29 (s, 3H), 2.10 (t, 1H), 1.36 (s, 9H). LC / MS (Method 4, ESIpos): R _t = 1.53 min, m / z = 453 [M + H] ⁺ . Example 76

2,2-Difluoro-2- {3 - [(5-methyl-3- {3- [4- (1,1,3-trifluoro-2-methyl-propan-2-yl) -phen]

yl} - lH-pyrazol-1-yl) methyl] phenyl} ethanol

Analogously to the process described under Example 75, from 168 mg (0.50 mmol) of the compound from Example 23A and 377 mg (1.50 mmol) of the compound from Example 52A, 66 mg (26% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.19 (d, 2H), 7.62 (d, 2H), 7:47 (d, IH), 7:43 (t, IH), 7:36 (s, IH) , 7.24 (d, IH), 6.83 (s, IH), 5.49 (s, 2H), 3.95 (dt, 2H), 2.29 (s, 3H), 2.10 (t, IH), 1.62 (s, 6H). LC / MS (Method 6, ESIpos): R _t = 1.30 min, m / z = 507 [M + H] ⁺ .

Example 77

2,2-Difluoro-2- {3 - [(3- {3- [4- (3-fluoro-oxetan-3-yl) -phenyl] -l, 2,4-oxadiazol-5-yl} -5-methyl- 1H-pyrazol-1-yl) methyl] phenyl} ethanol

Analogously to the process described under Example 75, from 126 mg (0.42 mmol) of the compound from Example 35A and 317 mg (1.26 mmol) of the compound from Example 52A, 38 mg (19% of theory) of the title compound were obtained. The product was here after the chromatography over silica again after preparative HPLC (Method 16).

'H-NMR (400 MHz, CDCI _3, δ / ppm): 8.28 (d, 2H), 7.71 (d, 2H), 7:46 (d, IH), 7:44 (t, IH), 7:36 (s, IH) , 7.24 (d, IH), 6.84 (s, IH), 5.50 (s, 2H), 5.15 (dd, 2H), 4.90 (d, 2H), 3.95 (t, 2H), 2.30 (s, 3H). LC / MS (Method 4, ESIpos): R _t = 1.25 min, m / z = 471 [M + H] ⁺ . Example 78

2,2-Difluoro-2- (3- {[5-methyl-3- (3- {4- [1- (trifluoromethyl) cyclopropyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H -pyrazol-l-yl] methyl} phenyl) ethanol

Analogously to the process described under Example 75, from 167 mg (0.50 mmol) of the compound from Example 30A and 377 mg (1.50 mmol) of the compound from Example 52A, 93 mg (36% of theory) of the title compound were obtained. Silica gel chromatography was carried out here with cyclohexane / ethyl acetate 3: 1 as the eluent. 'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.18 (d, 2H), 7:59 (d, 2H), 7:46 (d, 1H), 7:44 (t, 1H), 7:36 (s, 1H) , 7.24 (d, 1H), 6.83 (s, 1H), 5.49 (s, 2H), 3.95 (td, 2H), 2.29 (s, 3H), 2.07 (t, 1H), 1.42-1.38 (m, 2H ), 1.11-1.06 (m, 2H).

LC / MS (Method 6, ESIpos): R _t = 1.32 min, m / z = 505 [M + H] ⁺ . Example 79 2,2-Difluoro-2- {3 - [(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazole 1 -yl) methyl] phenyl} ethanol

To a solution of 1.33 g (1.02 mmol, purity 40%) of the compound from Example 89A in 20 ml of ethanol were added at RT 38 mg (1.02 mmol) of sodium borohydride. After 1 h of stirring at RT and re-addition of 38 mg (1.02 mmol) of sodium borohydride and 5 ml of methanol, the solvent was removed. The residue was triturated with ethyl acetate, solid was filtered off and the filtrate was concentrated. Since the residue obtained according to LC / MS mainly from the carboxylic acid corresponding to Example 89A, this residue was taken up in 20 ml of methanol and treated dropwise at 0 ° C with 2 ml (27 mmol) of thionyl chloride. The mixture was then stirred for 1 h at 0 ° C. Thereafter, the mixture was concentrated and the residue was dried in vacuo. This residue was dissolved in 20 ml of ethanol and again treated with 38 mg (1.02 mmol) of sodium borohydride. After rinsing for 30 min at RT, the mixture was concentrated. The residue was taken up in ethyl acetate and water and acidified with 10% citric acid. After separation of the phases, the aqueous phase was back-extracted once with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Method 15). Subsequent column chromatography over silica gel (eluent: dichloromethane / methanol 98.5: 1.5) provided, after removal of the solvent and drying of the residue in vacuo, 248 mg (51% of theory) of the title compound.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.25 (d, 2H), 7:47 (d, 1H), 7:43 (t, 1H), 7:36 (s, 1H), 7:33 (d, 2H) , 7.24 (d, 1H), 6.83 (s, 1H), 5.49 (s, 2H), 3.95 (td, 2H), 2.30 (s, 3H), 2.19 (t, 1H). LC / MS (Method 6, ESIpos): R _t = 1.25 min, m / z = 481 [M + H] ⁺ .

Example 80

2-methyl-2- {3 - [(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,3,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) - methyl] phenyl} propane-1,3-diol

To a solution of 0.12 g (0.21 mmol) of the compound from Example 91 A in 4 ml abs. THF and 4 ml of methanol were added under ice-bath cooling 79 mg (2.10 mmol) of sodium borohydride and stirred overnight at 40 ° C. Thereafter, a further 79 mg of sodium borohydride were added and stirring was continued for another hour at 40.degree. This was followed by two more additions of 79 mg of sodium borohydride, wherein the reaction mixture was stirred for 1 h at 40 ° C in each case. The reaction was then treated with saturated aqueous ammonium chloride solution and with water and extracted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was on a rotary evaporator freed from the solvent and the residue purified by preparative HPLC (Method 17). This gave 60 mg (59% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-d _ö , δ / ppm): 8.20 (d, 2H), 7.59 (d, 2H), 7.32 (d, 2H), 7.26 (t, 1H), 6.93 (d, 2H), 5.48 (s, 2H), 3.54 (s, 4H), 2.35 (s, 3H), 1.17 (s, 3H). LC / MS (Method 2, ESIpos): R, = 2.46 min, m / z = 489 [M + H] ⁺ .

Example 81

2-methyl-1 - {3 - [(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,3,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) - methyl] phenyl} propan-2-yl dihydrogen phosphate

In a flow hydrogenation apparatus ("H-Cube" from ThalesNano, Budapest, Hungary), a solution of 197 mg (0.301 mmol) of the compound from Example 92A in 6 ml of methanol / water 10: 1 was hydrogenated (conditions: 10% Pd / C catalyst, 1 bar, 1 ml / min, 22 ° C). After removal of the solvent on a rotary evaporator, the crude product was purified by preparative HPLC (Method 1 1). 91 mg (54% of theory) of the title compound were obtained. 'H-NMR (400 MHz, CDC1 ₃ , δ / ρριη): 8.19 (d, 2H), 7.30 (d, 2H), 7.20 (t, 1H), 7.19 (s, 1H), 7.09 (d, 1H) , 6.96 (d, 1H), 6.78 (s, 1H), 5.43 (s, 2H), 2.89 (s, 2H), 2.26 (s, 3H), 1.41 (s, 6H).

LC / MS (Method 4, ESIpos): R, = 1.29 min, m / z = 455 [MH ₃ P 0 ₄ + H] ⁺ , 553 [M + H] ⁺ .

Example 82

2-Methyl-2- {3 - [(5-methyl-3- {3- [4- (1,1,3-trifluoro-2-methylpropan-2-yl) -phenyl] -l, 2,4-oxadiazole -5-yl} -lH-pyrazol-1-yl) methyl] phenyl} propyl dihydrogen phosphate

A solution of 136 mg (0.18 mmol) of the compound from Example 93A in 3.6 ml of dichloromethane was admixed with 52 μΐ (0.39 mmol) of bromotrimethylsilane while cooling with an ice bath and stirred at RT overnight. Then 1 N hydrochloric acid was added and the mixture was diluted with more dichloromethane. The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The filtrate was finally freed from the solvent on a rotary evaporator. This gave 104 mg (95% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-cL, δ / ppm): 8.08 (d, 2H), 7.76 (d, 2H), 7.35-7.24 (m, 3H), 6.92 (d, 2H), 5.49 (s, 2H), 3.83 (d, 2H), 2.33 (s, 3H), 1.60 (s, 6H), 1.25 (s, 6H).

LC / MS (Method 6, ESIpos): R, = 1.13 min, m / z = 579 [M + H] ⁺ .

Example 83

2-methyl-2- {3 - [(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,4,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) - methyl] phenyl} propyl dihydrogen phosphate

Analogously to the process described under Example 82, from 90 mg (0.12 mmol) of the compound from Example 94A, 58 mg (81% of theory) of the title compound were obtained.

Tl NMR (400 MHz, DMSO-cL, δ / ppm): 8.20 (d, 2H), 7.59 (d, 2H), 7.35-7.28 (m, 3H), 6.94 (d, 1H), 6.93 (s, 1H), 5.50 (s, 2H), 3.84 (d, 2H), 2.35 (s, 3H), 1.26 (s, 6H).

LC / MS (Method 6, ESIpos): R _t = 1.09 min, m / z = 553 [M + H] ⁺ . Example 84

2-Methyl-2- {3 - [(5-methyl-3- {3- [4- (1,1-trifluoro-2-methylpropan-2-yl) -phenyl] -1,2,4-oxadiazole -5-yl} - lH-pyrazol-1-yl) methyl] phenyl} propyl-N, N-dimethylglycinate

60 mg (0.12 mmol) of the compound from Example 60 and 21 mg (0.13 mmol) of N, N-dimethylglycyl chloride hydrochloride were initially charged in 2.4 ml of dichloromethane, treated with 18 .mu.l (0.13 mmol) of triethylamine and overnight at RT touched. After renewed addition of 21 mg (0.13 mmol) of N, N-dimethylglycyl chloride hydrochloride and 18 .mu.ΐ triethylamine was added again for 1 h at RT. It was then diluted with ethyl acetate and washed successively with water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was finally freed from the solvent on a rotary evaporator. 65 mg (86% of theory) of the title compound were thus obtained.

Ή-NMR (400 MHz, DMSO-dg, δ / ppm): 8.09 (d, 2H), 7.77 (d, 2H), 7.36-7.29 (m, 3H), 6.98 (d, 1H), 6.93 (s, 1H), 5.50 (s, 2H), 4.1 1 (s, 2H), 3.05 (s, 2H), 2.34 (s, 3H), 2.10 (s, 6H), 1.61 (s, 6H), 1.29 (s, 6H).

LC / MS (Method 6, ESIpos): R _t = 1.12 min, m / z = 584 [M + H] ⁺ . Example 85

(S) -2-Methyl-2- {3 - [(5-methyl-3- {3- [4- (1,1,2-trifluoro-2-methylpropan-2-yl) -phenyl] -l, 2 , 4-oxadiazol-5-yl} - lH-pyrazol-1-yl) methyl] phenyl} propyl-L-valinate

100 mg (0.20 mmol) of the compound from Example 60 were initially charged in 4 ml of dichloromethane, with 73 mg (0.30 mmol) of tert-butyl (4S) -4-isopropyl-2,5-dioxo-1,3-oxazolidine 3-carboxylate and 25 mg (0.20 mmol) of 4-N, N-dimethylaminopyridine and stirred overnight at RT. Thereafter, it was diluted with ethyl acetate and the mixture was washed successively with saturated ammonium chloride solution, water, half-concentrated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was freed from the solvent on a rotary evaporator. The residue was stirred in 2 ml of a 4 M solution of hydrogen chloride gas in dioxane at RT for 30 min. Subsequently, the mixture was freed from the solvent on a rotary evaporator. After preparative HPLC purification of the residue (Method 17), 48 mg (40% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 8.09 (d, 2H), 7.77 (d, 2H), 7.37-7.28 (m, 3H), 6.97 (d, 1H), 6.93 (s, 1H), 5.49 (s, 2H), 4.16 (d, 1H), 4.01 (d, 1H), 2.98 (d, 1H), 2.33 (s, 3H), 1.64 (m, 1H), 1.61 (s, 6H ), 1.30 (d, 6H), 0.70 (d, 3H), 0.63 (d, 3H). LC / MS (Method 6, ESIpos): R _t = 1.16 min, m / z = 598 [M + H] ⁺ .

Example 86 and Example 87

2,2,2-trifluoro-1- {3 - [(5-methyl-3- {3- [4- (trifluoro-methoxy) -phenyl] -l, 2,4-oxadiazol-5-yl} -H-pyrazole -yl) methyl] phenyl} ethanol (enantiomer 1 and 2)

The racemate of Example 2 was chromatographically split into its optical isomers. For this purpose, 157 mg (0.316 mmol) of the racemate from Example 2 were dissolved in a mixture of 20 ml each of isopropanol and isohexane. In portions of 0.5 ml each, this solution was separated by HPLC on a chiral stationary phase [column material: Daicel Chiralpak AS-H, 5 μm, 250 mm × 20 mm; Mobile phase: isohexane / isopropanol 90:10; Flow: 20 ml / min; Temperature: 25 ° C; UV detection: 230 nm]. The target fractions of the separated enantiomers were each freed from the solvent on a rotary evaporator and then with a mixture of 5 ml of pentane and 1 ml Diethyl ether stirred at RT. After aspirating and drying the solid in a high vacuum, the enantiomers were obtained in pure form.

Example 86 (Enantiomer 1):

Yield: 48 mg (61% of theory) R _t = 4.32 min,> 99% ee [analytical chiral HPLC: column: Daicel AS-H, 5 μm, 250 mm × 4 mm; Mobile phase: isohexane / isopropanol 60:40; Flow: 1 ml min; Temperature: 25 ° C; UV detection: 230 μm].

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.24 (d, 2H), 7:43 (d, 1H), 7:39 (t, 1H), 7:34 (s, 1H), 7:32 (d, 2H) , 7.19 (d, 1H), 6.82 (s, 1H), 5.48 (s, 2H), 5.02 (m, 1H), 2.74 (s, broad, 1H), 2.27 (s, 3H). LC / MS (Method 6, ESIpos): R _t = 1.27 min, mz = 499 [M + H] ⁺ .

Example 87 (Enantiomer 2):

Yield: 41 mg (52% of theory)

R _t = 4.62 min, 99% ee [analytical chiral HPLC: column: Daicel AS-H, 5 μm, 250 mm × 4 mm; Mobile phase: isohexane / isopropanol 60:40; Flow: 1 ml / min; Temperature: 25 ° C; UV detection: 230 nm].

'H-NMR (400 MHz, CDCI _3, δ / ppm): 8.24 (d, 2H), 7:43 (d, 1H), 7:39 (t, 1H), 7:35 (s, 1H), 7:32 (d, 2H) , 7.19 (d, 1H), 6.82 (s, 1H), 5.48 (s, 2H), 5.02 (m, 1H), 2.77 (s, broad, 1H), 2.27 (s, 3H).

LC / MS (Method 6, ESIpos): R _t = 1.27 min, m / z = 499 [M + H] ⁺ .

Example 88 and Example 89 1,1,1-Trifluoro-2- {3 - [(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,3,4-oxadiazol-5-yl} -lH-pyrazol-1-yl) methyl] phenyl} propan-2-ol (enantiomer 1 and 2)

The racemate of Example 3 was chromatographically split into its optical isomers. 191 mg (0.373 mmol) of the racemate from Example 3 were dissolved in a mixture of 20 ml of isopropanol and isohexane. In portions of 1.0 ml each, this solution was separated by HPLC on a chiral stationary phase [column material: Daicel Chiralpak AS-H, 5 μm, 250 mm × 20 mm; Mobile phase: isohexane / isopropanol 85:15; Flow: 20 ml / min; Temperature: 25 ° C; UV detection: 230 μm]. The target fractions of the separated enantiomers were freed of solvent on a rotary evaporator and then stirred with a mixture of 5 ml of pentane and 1 ml of diethyl ether at RT. After aspirating and drying the solid in a high vacuum, the enantiomers were obtained in pure form. Example 88 (Enzyme 1):

Yield: 54 mg (56% of theory)

R _t = 5.65 min,> 99% ee [analytical chiral HPLC: column: Daicel AS-H, 5 μm, 250 mm × 4 mm; Mobile phase: isohexane / isopropanol 60:40; Flow: 1 ml / min; Temperature: 25 ° C; UV detection: 230 nm]. 'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.25 (d, 2H), 7:51 (d, 1H), 7:47 (s, 1H), 7:38 (t, 1H), 7:33 (d, 2H) , 7.14 (d, 1H), 6.83 (s, 1H), 5.49 (s, 2H), 2.58 (s, broad, 1H), 2.28 (s, 3H), 1.77 (s, 3H).

LC / MS (Method 6, ESIpos): R _t = 1.32 min, m / z = 513 [M + H] ⁺ .

Example 89 (Enzyme 2):

Yield: 73 mg (76% of theory) R _t = 6.44 min,> 99% ee [analytical chiral HPLC: column: Daicel AS-H, 5 μm, 250 mm × 4 mm; Mobile phase: isohexane / isopropanol 60:40; Flow: 1 ml / min; Temperature: 25 ° C; UV detection: 230 nm].

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.25 (d, 2H), 7:51 (d, 1H), 7:47 (s, 1H), 7:38 (t, 1H), 7:33 (d, 2H) , 7.14 (d, 1H), 6.83 (s, 1H), 5.49 (s, 2H), 2.58 (s, broad, 1H), 2.28 (s, 3H), 1.77 (s, 3H). LC / MS (Method 6, ESIpos): R _t = 1.32 min, m / z = 513 [M + H] ⁺ .

Example 90 1- {3 - [(5-Methyl-3- {3- [3-fluoro-4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazole-1-one yl) - methylphenyl} cyclopropanol

Analogously to the process described under Example 22, from 410 mg (0.571 mmol, purity 72%) of the compound from Example 9A and ethyl magnesium chloride solution, 100 mg (37% of theory) of the title compound were obtained. The reaction time at RT was 2 h, and the preparative HPLC purification was carried out according to Method 14.

Ή NMR (400 MHz, CDCl ₃ , δ / ppm): 8.08 (dd, 1H), 8.03 (dd, 1H), 7.43 (t, 1H), 7.30 (d, 1H), 7.20 (s, 1H), 7.16 (d, 1H), 6.99 (d, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 2.47 (s, broad, 1H), 2.29 (s, 3H), 1.27 (m, 2H ), 1.02 (m, 2H).

LC / MS (Method 6, ESIpos): R _t = 1.29 min, m / z = 475 [M + H] ⁺ . Example 91

(1 - {3 - [(3- {3- [3-Fluoro-4- (1,1,2-trifluoro-2-methylpropan-2-yl) -phenyl] -l, 2,4-oxadiazol-5 yl} -5-methyl-1H-pyrazol-1-yl) methyl] phenyl} cyclopropyl) methanol

A solution of 197 mg (0.529 mmol) of the compound from Example 45A and 240 mg (0.582 mmol) of the compound from Example 50A in 4 mL of anhydrous THF was added at 0 ° C with 77 mg (0.687 mmol) of solid potassium tert-butoxide added. The reaction mixture was stirred at RT for 16 h. Subsequently, 793 μΐ (0.793 mmol) of tetra-n-butylammonium fluoride solution (1 M in THF) were added. After a further 30 min at RT, it was diluted with water and extracted with ethyl acetate. After drying the organic phase over anhydrous magnesium sulfate and filtration, the solvent was removed on a rotary evaporator. The resulting crude product was purified by preparative HPLC (Method 14). The product-containing fractions were combined and made alkaline with saturated sodium bicarbonate solution. Subsequently, all volatiles were removed on a rotary evaporator to a small residual volume of water. It was extracted with ethyl acetate. After drying the extract over anhydrous magnesium Sodium sulfate, filtration and evaporation to dryness gave 76 mg (28% of theory) of the title compound.

'H-NMR (400 MHz, CDC1 ₃ , δ / ρρηι): 7.97 (d, 1H), 7.92 (d, 1H), 7.32-7.25 (m, 3H, partially covered by the CHC1 ₃ signal), 7.22 (s , 1H), 7.00 (d, 1H), 6.81 (s, 1H), 5.44 (s, 2H), 3.66 (s, 2H), 2.29 (s, 3H), 1.69 (s, 6H), 1.57 (broad, 1H), 0.85 (s, 4H).

LC / MS (Method 6, ESIpos): R _t = 1.36 min, m / z = 515 [M + H] ⁺ .

Example 92

(1 - {3 - [(3- {3- [4- (4-fluorotetrahydro-2H-pyran-4-yl) -phenyl] -l, 2,4-oxadiazol-5-yl} -5-methyl-1H - pyrazol-1-yl) methyl] phenyl} cyclopropyl) methanol

Analogously to the process described under Example 63, 64 mg (66% of theory) of the title compound were obtained from 65 mg (0.198 mmol) of the compound from Example 43A and 122 mg (0.297 mmol) of the compound from Example 50A in two substeps , The reaction mixture was stirred for 16 h at RT in the first part of the step; subsequent heating to 40 ° C. was omitted. Ή-NMR (400 MHz, CDC1 ₃ , δ / ρρηι): 8.23 (d, 2H), 7.52 (d, 2H), 7.32-7.25 (m, 2H, partially covered by the CHC1 ₃ signal), 7.22 (s, 1H), 7.00 (d, 1H), 6.82 (s, 1H), 5.43 (s, 2H), 4.00-3.87 (m, 4H), 3.65 (s, 2H), 2.29 (s, 3H), 2.27-2.12 (m, 2H), 1.98-1.91 (m, 2H), 1.43 (s, broad, 1H), 0.85 (s, 4H).

LC / MS (Method 6, ESIpos): R _t = 1.18 min, mz = 489 [M + H]

Example 93 2,2-Difluoro-2- [3- (3,3- (4-isopropylphenyl) -1,4,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl } - methyl) phenyl] ethanol

Analogously to the process described under Example 75, from 134 mg (0.50 mmol) of the compound from Example 41A and 377 mg (1.50 mmol) of the compound from Example 52A, 95 mg (42% of theory) of the title compound were obtained. 'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8.12 (d, 2H), 7:47 (d, IH), 7:42 (t, IH), 7:36 (s, IH), 7:35 (d, 2H) , 7.23 (d, IH), 6.83 (s, IH), 5.48 (s, 2H), 3.95 (dt, 2H), 2.98 (sept, IH), 2.29 (s, 3H), 2.18 (t, IH), 1.29 (d, 6H).

LC / MS (Method 6, ESIpos): R _t = 1.29 min, m / z = 439 [M + H] ⁺ . Example 94 2,2-Difluoro-2- {3 - [(3- {3- [3-fluoro-4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl- 1H-pyrazol-1-yl) methyl] phenyl} ethanol

Analogously to the process described under Example 75, 101 mg (41% of theory) of the title compound were obtained from 164 mg (0.50 mmol) of the compound from Example 29A and 377 mg (1.50 mmol) of the compound from Example 52A. The chromatographic purification on silica gel was carried out here with cyclohexane / ethyl acetate 3: 1 as the eluent.

¹ H-NMR (400 MHz, CDCl ₃ , δ / ppm): 8.08 (dd, IH), 8.03 (d, IH), 7.49-7.41 (m, 3H), 7.36 (s, IH), 7.24 (d, IH), 6.83 (s, IH), 5.50 (s, 2H), 3.95 (dt, 2H), 2.30 (s, 3H), 2.10 (t, IH).

LC / MS (Method 6, ESIpos): R _t = 1.27 min, m / z = 499 [M + H] ⁺ . Example 95

2,2-Difluoro-2- (3- {[5-methyl-3- (3- {4 - [(trifluoromethyl) sulfonyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazole - 1 -yl] methyl} phenyl) ethanol

Analogously to the process described under Example 75, from 179 mg (0.50 mmol) of the compound from Example 25A and 377 mg (1.50 mmol) of the compound from Example 52A, 29 mg (10% of theory) of the title compound were obtained.

'H-NMR (400 MHz, CDC1 _3, δ / ppm): 8:52 (d, 2H), 8.18 (d, 2H), 7:48 (d, 1H), 7:44 (t, 1H), 7:36 (s, 1H) , 7.25 (d, 1H, partially covered by the CHC1 ₃ signal), 6.83 (s, 1H), 5.50 (s, 2H), 3.96 (t, 2H), 2.31 (s, 3H).

LC / MS (Method 6, ESIpos): R _t = 1.27 min, m / z = 529 [M + H] ⁺ .

Example 96

2-Methyl-1- (3 - [[5-methyl-3- (3- {4 - [(trifluoromethyl) sulfanyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazole-1 -ylmethyl} phenyl) propan-2-yl dihydrogen phosphate

A solution of 348 mg (0.519 mmol) of the compound from Example 96A was admixed with 28 mg (0.026 mmol) of palladium (10% on activated charcoal) and hydrogenated in a Parr apparatus at RT and a hydrogen pressure of 1 bar. The reaction time was 6 days in total. In the course of this time were added three times more each 28 mg of the palladium catalyst. After the reaction was filtered off a little diatomaceous earth from the catalyst and the filtrate was evaporated to dryness. The crude product obtained was purified by preparative HPLC [column: X-Bridge Shield, 5 μm, 100 mm × 19 mm; Eluent: acetonitrile / water / 1% aq. Trifluoroacetic acid 60: 35: 5 (0-6 min); Flow: 25 ml / min; Temperature: 25 ° C; UV detection: 210 nm]. 131 mg (44% of theory) of the title compound were thus obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.22 (d, 2H), 7.93 (d, 2H), 7.28 (t, 1H), 7.22 (d, 1H), 7.13 (s, 1H ), 7.03 (d, 1H), 6.93 (s, 1H), 5.48 (s, 2H), 2.92 (s, 2H), 2.33 (s, 3H), 1.31 (s, 6H). LC / MS (Method 6, ESIpos): R _t = 1.17 min, m / z = 471 [MH ₃ P 0 ₄ + H] ⁺ , 569 [M + H] ⁺ .

B. Evaluation of Pharmacological Activity

The pharmacological activity of the compounds of the invention can be demonstrated by in vitro and in vivo assays as known to those skilled in the art. The usefulness of the substances of the invention can be illustrated by way of example by in vitro (tumor) cell experiments and in vz ^'vo-tumor models, as listed below. The relationship between inhibition of HIF transcriptional activity and inhibition of tumor growth has been demonstrated by numerous studies described in the literature (see eg Warburg, 1956, Semenza, 2007).

Bl. HIF luciferase assay: HCT 116 cells were stably transfected with a plasmid containing a luciferase reporter under the control of an HIF-responsive sequence. These cells were seeded in microtiter plates [20,000 cells / well in RPMI 1640 medium with 10% fetal calf serum (FCS) and 100 μg / ml hygromycin]. It was incubated overnight under standard conditions (5% CO ₂ , 21% O ₂ , 37 ° C, humidified). The next morning the cells were incubated with different concentrations of the test substances (0-10 μηιοΙ / L) in a hypoxia chamber (1% O ₂ ). After 24 hours Bright Glo reagent (Promega, Wisconsin, USA) was added according to the manufacturer's instructions and after 5 minutes luminescence was measured. Cells incubated under nomioxia served as background controls.

The following table shows representative IC ₅ o values from this assay:

Example No. IC50 [nmol / L]

 5 0.5

 18 0.5

 22 0.5

 23 0.4

26 0.9

 27 0.5

 28 0.5

30 0.5 Example No. IC ₅₀ [nmol / L]

 32 0.6

 46 0.5

 53 1.5

 57 2.0

 60 2.0

 62 0.9

 72 2.0

 4.5

 4.0

 89 2.0

 90 1.0

 1.5

The compound described as Example 1 in WO 2008/141731-A2 5- [5-methyl-1- (4-methylbenzyl) -1H-pyrazol-3-yl] -3- [4- (trifluoromethoxy) phenyl] - l, 2,4-oxadiazole which, unlike the compounds of this invention does not have a hydroxyalkyl substituent on the benzyl group header, showing an IC ₅ o-value of 30 nmol / L in this assay.

B-2. Suppression of HIF target genes in vitro:

Human bronchial carcinoma cells (H460 and A549) were incubated for 16 h with variable concentrations of the test substances (1 nM to 10 μΜ) under normoxic conditions and under 1% oxygen partial pressure (see HIF luciferase assay). From the cells, the total RNA was isolated, transcribed into cDNA and analyzed in real-time PCR mRNA expression of HIF target genes. Already under normoxic conditions, but especially under hypoxic conditions, active test substances reduce the mRNA expression of the HIF target genes compared to untreated cells. B-3. Human Xenograft Tumor Models:

Human tumor xenograft models in immunodeficient mice were used for substance evaluation. For this purpose, tumor cells were cultured in vitro and implanted subcutaneously, or tumor xenograft fragments were subcutaneously transplanted. The treatment of the animals was carried out by oral, subcutaneous or intraperitoneal therapy after the establishment of the tumor. The efficacy of test substances was analyzed in monotherapy and in combination therapy with other pharmacological agents. In addition, the tumor-inhibitory potency of test substances on tumors of advanced size (about 100 mm ² ) was characterized. The state of health of the animals was checked daily and the treatments were carried out according to animal welfare regulations. The tumor area was measured with calipers (length L, width B = smaller extent). The tumor volume was calculated according to the formula (L x B ² ) / 2. The inhibition of tumor growth was determined at the end of the experiment as T / C ratio of the tumor areas or tumor weights and as TGI value (tumor growth inhibition, calculated according to the formula [1 - (T / C)] x 100) (T = Tumor size of the treated group; C = tumor size of the untreated control group).

The influence of test substances on tumor vasculature and blood flow within the tumor was identified by means of micro computed tomography and micro-ultrasound examinations on treated and untreated tumor-bearing mice.

C. Determination of the Solubility and Stability The solubility of the prodrug compounds according to the invention in aqueous systems and their stability to non-specific hydrolysis and in plasma can be determined in the tests described below:

C-l. Determination of solubility in aqueous buffer solution pH 6.5:

The test substance was dissolved in DMSO and then mixed with aqueous PBS buffer (pH 6.5) so that the final DMSO concentration was 1% by volume. The resulting suspension was shaken for 24 h at room temperature. After ultra-centrifugation at 224000g for 30 min, the supernatant was diluted with DMSO and analyzed by HPLC. Quantification was done by a two-point calibration curve of the respective test compound in DMSO. The solubilities thus determined are given below for some representative embodiments and their prodrug forms:

C-2. Determination of the pH-Dependent Hydrolysis Stability: 0.3 mg of the test substance (prodrug) were weighed into a 2 ml HPLC vial and admixed with 0.6 ml of acetonitrile or acetonitrile / DMSO mixture (with up to 20% by volume of DMSO). To dissolve the substance, the sample vessel was placed in an ultrasonic bath for about 10 seconds. Subsequently, 1.0 ml of the respective aqueous buffer solution was added (commercially available buffer solutions of pH 2.0, 7.0 and 10.0) and the sample was again treated in an ultrasonic bath. Over a period of 24 hours at 25.degree. C., 5 .mu.l of the sample solution were analyzed per hour by HPLC for their content of unchanged prodrug or active ingredient released therefrom by hydrolysis. The area percent of the corresponding HPLC peaks was quantified.

Below, the stability values at pH 7.0 (Examples 82 and 84) or pH 6.5 (Example 96) are listed for representative prodrug compounds:

% Prodrug% active ingredient% prodrug% active ingredient

Time [h]

 Example 82 Example 60 Example 84 Example 60

 0 100 0 98 2

2 100 0 97 3 % Prodrug% active ingredient% prodrug% active ingredient

Time [h]

 Example 82 Example 60 Example 84 Example 60

4 100 0 98 2

6 100 0 97 3

12 100 0 97 3

24 100 0 95 5

Depending on the pH, the following values were obtained after 24 h for these examples:

% Prodrug% active ingredient

 PH value

 Example 96 Example 53

 2 100 0

6.5 100 0 % Prodrug% active ingredient

 PH value

 Example 96 Example 53

 10 100 0

C-3. Determination of plasma stability in vitro:

1 mg of the test substance (prodrug) was weighed into a 2 ml HPLC vial and treated with 1.5 ml of DMSO and 1 ml of water. To dissolve the substance, the sample vessel was placed in an ultrasonic bath for about 10 seconds. To 0.5 ml of this solution was added 0.5 ml of 37 ° C warm rat or human plasma. The sample was shaken and taken for a first analysis about 10 μΐ (time t ₀ ). In the period up to 2 hours after incubation, 4-6 additional aliquots were taken for quantification. The sample was held at 37 ° C over the test time. Characterization and quantification were by HPLC. In the following, the stability values in rat plasma are listed for representative prodrug examples:

% Prodrug% active ingredient

 Time [h]

 Example 96 Example 53

 0 100 0

0.5 100 0

1 100 0 % Prodrug% active ingredient

 Time [h]

 Example 96 Example 53

 2 100 0

 4 100 0

In human plasma, the following values were obtained for these examples:

D. Determination of pharmacokinetic parameters

The pharmacokinetic parameters of the compounds according to the invention after intravenous or peroral administration can be determined as follows: The substance to be investigated was administered to animals (eg mice or rats) intravenously as a solution (eg in appropriate plasma with a small amount of DMSO or in a PEG / ethanol / water mixture), the peroral application was carried out as a solution (eg in Solutol / ethanol / Water or PEG / ethanol / water mixtures) or as a suspension (eg in Tylose) in each case via a gavage. After substance administration, the animals were bled at fixed times. This was heparinized, then plasma was recovered therefrom by centrifugation. The substance was analytically quantified in plasma via LC-MS / MS. The pharmacokinetic parameters were calculated from the plasma concentration-time curves determined using an internal standard and with the aid of a validated computer program, such as AUC (area under the concentration-time curve), C _max (maximum plasma concentration), Ι _υ2 (half-life ), Vss (distribution volume) and CL (clearance) as well as the absolute and the relative bioavailability F or F _re i (iv / po comparison or comparison of suspension to solution after po administration).

To determine the drug release from a prodrug compound, the prodrug was administered either intravenously or orally, as described above, and the levels of both the prodrug and the drug released were quantitated in the processed plasma.

D-l. Pharmacokinetic parameters after intravenous administration in the rat:

The substance to be investigated was administered intravenously to rats each in amounts of between 0.3 and 1.0 mg / kg as a solution in plasma containing up to 2% DMSO. The kinetic parameters determined in this way are shown below for some exemplary embodiments [CLpiasma = plasiiia clearance]:

Example No. tl / 2 [h] CL _{p asma} [L / h / kg] V _ss [L / kg]

 1 8 7.5 0.7 4.0

23 6.8 1 .2 6.6

32 5.5 0.8 4.3

53 6.7 1. 1 8. 1

57 8.0 1 .3 8.6

66 1 .4 3.5 4.8

79 7.5 0.9 8.5

90 7.2 0.7 4.7 The compound described as Example 1 in WO 2008/14173 1-A2 5- [5-methyl-1- (4-methylbenzyl) -1H-pyrazol-3-yl] -3- [4- (trifluoromethoxy) phenyl] 1-l, 2,4-oxadiazole, which, unlike the compounds according to the invention, has no hydroxyalkyl substituent on the benzyl head group, shows the following data with respect to these parameters after intravenous administration in the rat: t _1/2 = 30 h , CL ^ '= 0.4 L / h / kg, V _ss = 6.9 L / kg.

D-2. Pharmacokinetic parameters after oral administration in the rat:

The substance to be tested was administered orally to rats each in amounts between 1 and 3 mg / kg as a solution in solutol / ethanol / water (40:10:50 or 40:20:40). The kinetic parameters determined in this way are shown below for some exemplary embodiments [AUC _norm = dose-normalized exposure (area under the concentration-time curve)]:

The compound described as Example 1 in WO 2008/141731-A2 5- [5-methyl-1- (4-methylbenzyl) -1H-pyrazol-3-yl] -3- [4- (trifluoromethoxy) phenyl] - l, 2,4-oxadiazole, which, in contrast to the compounds according to the invention, does not have a hydroxyalkyl substituent on the benzyl head group, shows the following data with respect to these parameters after oral administration in the rat: t _1/2 = 29 h, AUC _norm = 1.9 kg-h L, F = 74%.

D-3. Release of active ingredient in vivo after intravenous prodrug application in the rat:

After intravenous administration of the prodrug of Example 81 (0.35 mg / kg, dissolved in plasma with 1% DMSO addition) in rats, a rapid and complete release of the corresponding active compound was carried out (Example 43): The half-life of the release was approx. for 2 minutes and the dose-normalized exposure (AUC _norm value) of free drug after prodrug administration was 3.1 kg-h / L and was therefore within the scope of the measurement accuracy identical to the value after direct drug administration (3.0 kg-h / L). E. Exemplary Embodiments of Pharmaceutical Compositions

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

Tablet: composition:

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

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

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

Orally administrable suspension:

Composition:

1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel ^® (xanthan gum of the firm FMC, Pennsylvania, USA) and 99 g of water. A single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.

production:

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

Composition:

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

The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention. iv solution: The compound according to the invention is dissolved in a concentration below the saturation solubility in a physiologically tolerated solvent (eg isotonic saline solution, glucose solution 5% and / or PEG 400 solution 30%). The solution is sterile filtered and filled into sterile and pyrogen-free Injektionsbehälmisse.

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Claims

claims

1. Compound of formula (I)

in which

A is a group of the formula

stands in which

* denotes the point of attachment to the hydroxy group,

** indicates the point of attachment to the phenyl ring,

R ^1A and R ^1B independently of one another are hydrogen, deuterium, methyl, hydroxymethyl or trifluoromethyl or are linked to one another and, together with the carbon atom to which they are bonded, form a cyclopropan-1, 1-diyl, cyclobutane-1, 1 -diyl, oxetane-3,3-diyl or tetrahydro-2H-pyran-4,4-diyl ring, R ^2A and R ^2B independently of one another represent hydrogen, deuterium, methyl or trifluoromethyl, and

R ^3A and R ^3B independently of one another denote hydrogen, fluorine, methyl, hydroxymethyl or trifluoromethyl or and together with the carbon atom to which they are attached, a cyclopropane-l, l-diyl, cyclobutane-l, l-diyl, oxetane-3,3-diyl or tetrahydro-2H-pyran-4 To form 4-diyl ring,

R ^{4 is} trifluoromethoxy, trifluoromethylsulfanyl, trifluoromethylsulfonyl, pentafluorosulfanyl, trimethylsilyl or a group of the formula in which

# denotes the point of attachment to the phenyl ring,

R ^5A and R ^5B independently of one another are hydrogen, fluorine, methyl, ethyl, n-propyl or isopropyl or are linked to one another and, together with the carbon atom to which they are bonded, are a cyclopropan-1, 1-diyl, cyclobutane-1 , l-diyl, cyclopentane-l, l-diyl, cyclohexane-l, l-diyl, oxetane-3,3-diyl or tetrahydro-2H-pyran-4,4-diyl ring, and

R ^{6 is} hydrogen, fluorine, methyl, trifluoromethyl, methoxymethyl or ethoxymethyl, and

R ^{7 is} hydrogen, fluorine or methyl, and their salts, solvates and solvates of the salts.

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

A is a group of the formula stands in which

* denotes the point of attachment to the hydroxy group, ** denotes the point of attachment to the phenyl ring, and

R ^2A and R ^{2B are} both hydrogen or deuterium, for trifluoromethyl, trifluoromethoxy, trifluoromethylsulfanyl, pentafluorosulfanyl, trimethylsilyl or a group of the formula stands in which

# denotes the point of attachment to the phenyl ring,

R ^5A and R ^{5B are} both methyl or linked together and together with the carbon atom to which they are attached form a cyclopropane-1,1-diyl or tetrahydro-2H-pyran-4,4-diyl ring, and

R ^{6 is} fluorine, methyl or trifluoromethyl, and

R ^{7 is} hydrogen or fluorine, and their salts, solvates and solvates of the salts.

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

 stands in which

 the linkage site with the hydroxy group and

 mark the point of attachment with the phenyl ring,

R ^{4 is} trifluoromethoxy, trifluoromethylsulfanyl or a group of the formula

Λ Λ Λ «the

CH CH C _g H _{g g g} H C CH, wherein

 # denotes the point of attachment to the phenyl ring, and

 stands for hydrogen,

and their salts, solvates and solvates of the salts.

Compound of the formula (I-PD)

in which A, R ⁴ and R ^{7 have} the meanings listed in claim 1, 2 or 3, and

R ^{PD is} a group of the formula

stands in which

## denotes the linkage point with the oxygen atom,

R ^{8 is} hydrogen or (C _r C ₄ ) -alkyl, and

R ^9A and R ^9B independently of one another denote hydrogen or methyl, and their salts, solvates and solvates of the salts. A compound of the formula (I-PD) according to claim 4, in which R ^{PD is} a group of the formula

stands in which

## denotes the point of attachment to the oxygen atom and

R ^{8 is} methyl, isopropyl, isobutyl or ec-butyl, and their salts, solvates and solvates of the salts.

6. Process for the preparation of compounds of the formulas (I) and (I-PD) as defined in claims 1 to 5, characterized in that first an N'-hydroxyamidine of the formula (II) in which R ⁴ and R ^{7 have} the meanings given in claims 1 to 3, with a pyrazolecarboxylic acid of the formula (III)

to a 1,2,4-oxadiazole derivative of the formula (IV)

in which R ⁴ and R ^{7 have} the meanings given above, then condensing the compound (IV) in the presence of a base with a compound of the formula (V)

in which A has the meaning given in claims 1 to 3,

X is a leaving group such as chlorine, bromine, iodine, mesylate, triflate or tosylate, and R is hydrogen or a conventional hydroxy protecting group such as acetyl, tetrahydropyranyl, trimethylsilyl, triisopropylsilyl, tert-butyl-dimethylsilyl or tert. Butyl (diphenyl) silyl, to give a compound of formula (VI)

, 10

in which A, R ⁴ , R ⁷ and R ^1U each have the meanings given above, then, if appropriate, the hydroxy protective group R is eliminated and the resulting compound of the formula (I)

in which A, R ⁴ and R ^{7 have} the meanings given above, finally, if desired, with a compound of formula (VII)

R ^PD - OH (VII) or an activated form of this compound in which R ^{PD has} the meaning given in claim 4 or 5, in the prodrug compound of the formula (I-PD)

in which A, R ^PD , R ⁴ and R ⁷ each have the meanings given above, optionally converted into its enantiomers and / or diastereomers and / or with the corresponding (i) solvents and / or (ii) bases or acids in their solvates, Salts and / or solvates of the salts überfuhrt.

A compound as defined in any one of claims 1 to 5 for the treatment and / or prevention of diseases.

A compound as defined in any one of claims 1 to 5 for use in a method for the treatment and / or prevention of cancer or tumor diseases.

A compound as defined in any one of claims 1 to 5 for use in a method for the treatment and / or prevention of ischemic cardiovascular diseases, cardiac insufficiency, myocardial infarction, arrhythmia, stroke, pulmonary hypertension, kidney fibrosis and lung, psoriasis, diabetic retinopathy, macular degeneration, rheumatoid arthritis and chugwash polycythemia.

10. Use of a compound as defined in any one of claims 1 to 5 for the manufacture of a medicament for the treatment and / or prevention of cancer or tumor diseases.

Use of a compound as defined in any one of claims 1 to 5 for the manufacture of a medicament for the treatment and / or prevention of ischemic cardiovascular diseases, cardiac insufficiency, myocardial infarction, arrhythmia, stroke, pulmonary hypertension, kidney fibrotic diseases and Lung, psoriasis, diabetic retinopathy, macular degeneration, rheumatoid arthritis and chugwash polycythemia.

12. A medicament containing a compound as defined in any one of claims 1 to 5, in combination with one or more inert, non-toxic, pharmaceutically suitable excipients.

13. A pharmaceutical composition containing a compound as defined in any one of claims 1 to 5, in combination with one or more further active ingredients.

14. Medicament according to claim 12 or 13 for the treatment and / or prevention of cancer or tumor diseases.

15. Medicament according to claim 12 or 13 for the treatment and / or prevention of ischemic cardiovascular diseases, cardiac insufficiency, myocardial infarction, arrhythmia, stroke, pulmonary hypertension, fibrotic diseases of kidney and lung, psoriasis, diabetic retinopathy, macular degeneration, rheumatoid arthritis and the Chugwash

Polycythemia.

16. A method for the treatment and / or prevention of cancer or tumor diseases in humans and animals using an effective amount of at least one compound as defined in any one of claims 1 to 5, or a drug as defined in any one of claims 12 to 14 , 17. A method for the treatment and / or prevention of ischemic cardiovascular diseases, cardiac insufficiency, myocardial infarction, arrhythmia, stroke, pulmonary hypertension, kidney and lung fibrotic diseases, psoriasis, diabetic retinopathy, macular degeneration, rheumatoid arthritis and chugwash Polycythaemia in humans and animals using an effective amount of at least one compound as defined in any one of claims 1 to 5 or a pharmaceutical composition as in any of the claims

12, 13 and 15 defined.