HK1164858A

HK1164858A - Heterocyclically substituted aryl compounds as hif inhibitors

Info

Publication number: HK1164858A
Application number: HK12105511.5A
Authority: HK
Inventors: Michael Härter; Hartmut Beck; Peter Ellinghaus; Kerstin Berhoerster; Susanne Greschat; Karl-Heinz Thierauch; Frank SÜSSMEIER
Original assignee: Bayer Schering Pharma Aktiengesellschaft
Priority date: 2008-11-14
Filing date: 2009-10-31
Publication date: 2012-09-28

Description

Aryl compounds with heterocyclic substituents and their use

The present application relates to novel aryl compounds having heterocyclic substituents, to processes for their preparation, to their use for the treatment and/or prophylaxis of diseases and to their use for the preparation of medicaments for the treatment and/or prophylaxis of diseases, in particular of hyperproliferative and angiogenic diseases and of those diseases which are caused by metabolic resilience to hypoxic conditions. Such treatment may be carried out as monotherapy or in combination with other drugs or further therapeutic measures.

Cancer diseases are the result of uncontrolled cell growth of most different tissues. In many cases, new cells infiltrate into living tissue (invasive growth), or they migrate into distant organs. Cancer diseases are present in most different organs and often have tissue-specific processes of the disease. The term cancer, as a general term, thus describes a large group of defined diseases of various organ, tissue and cell types.

In 2002, 4.4 million people worldwide have diagnosed breast, bowel, ovarian, lung or prostate tumor diseases. In the same year, approximately 2.5 million deaths were hypothesized to be the result of these diseases (Globocan 2002 Report). In the united states alone, over 1.25 million new cases and over 500,000 deaths for 2005 were predicted to be from cancer disease. Most of these new cases involve tumor diseases of the intestine (-100,000), lung (-170,000), breast (-210,000) and prostate (-230,000). An approximately further 15% increase in Cancer disease is envisaged relative to the next 10 years (American Cancer Society, Cancer Facts and regulations 2005).

Early stage tumors may be removed by surgery and radiotherapy measures. Metastatic tumors can usually only be treated palliatively by chemotherapeutic drugs. The goal here is to achieve an optimal combination of improvements in quality of life and life extension.

Chemotherapy often consists of a combination of cytotoxic drugs. Most of these substances have a mechanism of binding to tubulin as their action, or they are compounds that interact with the formation and processing of nucleic acids. These also include in recent years enzyme inhibitors which interfere with exogenous DNA modification or cell cycle progression (e.g. histone deacetylase inhibitors, aurora kinase inhibitors). Because this therapy is toxic, focus has been increasingly focused in recent years on targeted therapies where the characteristic processes in the cell are blocked without a high toxic load. These include, in particular, inhibitors of kinases that inhibit phosphorylation of receptors and signaling molecules. An example of these is imatinib, which is very successfully used for the treatment of Chronic Myelogenous Leukemia (CML) and gastrointestinal stromal tumors (GIST). Further examples are agents that block EGFR kinase and HER2, such as erlotinib, and VEGFR kinase inhibitors, such as sorafenib and sunitinib, which are useful in renal cell malignancies, liver cancer and advanced stages of GIST.

The life expectancy of colon cancer patients has been successfully extended with antibodies directed against VEGF. Bevacizumab inhibits the growth of blood vessels, which hinders the rapid spreading of tumors, since it requires a connection to the vascular system for constant functioning of supply and treatment.

One stimulus for angiogenesis is oxygen deficiency, which occurs in tandem with solid tumors because blood supply is inadequate due to unregulated growth. If oxygen is absent, the cells switch their metabolism from oxidative phosphorylation to glycolysis, so that ATP levels in the cells are stable. The process is controlled by transcription factors, which are up-regulated depending on the oxygen content in the cell. This transcription factor, known as "hypoxia-inducible factor" (HIF), is usually removed post-translationally by rapid degradation and prevents transport into the nucleus. This is influenced by hydroxylation of two proline units in the oxygen degradable range (ODD) and an asparagine unit near the C-terminus by the enzymes prolyl dehydrogenase and FIH ("factor inhibiting HIF"). After modification of the proline unit, HIF can be degraded by regulation by the proteasome unit (Maxwell, Wiesener et al, 1999) with von Hippel-Lindline (partial ubiquitin-E3-ligase complex). If hypoxia occurs, degradation does not occur and the protein upregulates and produces transcription or blocks transcription of a large number (over 100) of other proteins (Semenza and Wang, 1992; Wang and Semenza, 1995).

The transcription factor HIF is formed from a regulated α -subunit and constitutively provides a β -subunit (ARNT, an aromatic receptor nuclear translocation molecule). There are three different classes of α -subunits, 1 α, 2 α and 3 α, the last one being postulated to be an inhibitor (Makino, Cao et al, 2001). HIF subunits are bHLH (basic helical loop helix) proteins that polymerize through their HLH and PAS (Per-Arnt-Sim) domains into dimers, which initiate their transactivation activity (Jiang, Rue et al, 1996).

In the most important tumor tissues, overexpression of the HIF1 α protein was associated with increased density of blood vessels and enhanced VEGF expression (Hirota and Semenza, 2006). At the same time, glucose metabolism is converted into sugar decomposition, and the Krebs cycle is reduced, which is favorable for cell unit generation. This also suggests alterations in fat metabolism. This change appears to ensure the survival of the tumor. On the other hand, if HIF activity is now inhibited, tumor progression may be inhibited accordingly. This has been observed in various 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). Inhibitors specific to HIF-controlled metabolism should therefore be suitable as tumor therapy.

It is therefore an object of the present invention to provide novel compounds which act as inhibitors of the trans-activation of the transcription factor HIF and can be used as such for the treatment and/or prophylaxis of diseases, in particular of hyperproliferative and angiogenic diseases, for example cancer diseases.

Having pyrrole, pyrazole and/orSubstituted polycyclic heteroaryl compounds of the oxadiazole moiety structure and the use of these compounds for the treatment of various diseases are described in the patent literature in a number of forms and are therefore described, inter alia, in EP 0908456-A1, WO 97/36881-A1, WO 01/12627-A1, WO 01/85723-A1, WO 02/100826-A2, WO 2004/014370-A2, WO 2004/014881-A2, WO 2004/014902-A2, WO 2004/035566-A1, WO 2004/058176-A2, WO 2004/089303-A2, WO 2004/089308-A2, WO 2005/070925-A1, WO 2006/114313-A1, WO 2007/002559-A1, WO 2007/034279-A2, WO 2008/004096-A1, WO 2008/024390-A2 and WO 2008/114157-A1. WO 2005/030121-A2 and WO 2007/065010-A2 claim the use of certain pyrazole derivatives for inhibiting the expression of HIF and HIF-regulated genes in tumor cells. WO 2008/141731-A2 describes heteroaryl-substituted derivatives as inhibitors of the HIF regulatory pathway for the treatment of cancer diseases N-benzylpyrazole. Heteroaryl-substituted 5- (1) as cannabinoid receptor modulators for the treatment of various diseases is disclosed in US 2008/0255211-a1H-pyrazol-3-yl) -1,2,4-Diazole. Diaryl-substituted isoxazoles as inhibitors of monoamine oxidase B for the treatment of psychotic disorders are further described in WO 2009/029632-A1Oxazole and 1,2,4-Oxadiazole derivatives.

The invention provides a compound of the following general formula (I)

(I),

Wherein

Ring (C)Represents a phenyl or pyridyl ring,

having substituent R³Ring ofRepresents a heteroaryl ring of formula

Therein is provided with

# denotes the adjacent CH₂Attachment point of group

And

# denotes and RingThe connection point of (a) is,

ring (C)Represents a heteroaryl ring of formula

Therein is provided with

Denotes and ringsIs connected to

And

indicates and ringsThe connection point of (a) is,

ring (C)Represents a phenyl or pyridyl ring,

ring (C)Represents a saturated 4-to 10-membered aza-heterocycle comprising at least one N atom as a ring member and in addition may comprise one or two further substituents from the group consisting of N, O, S and/or S (O)₂The heterocyclic ring member of (a),

x represents a bond or represents [. diamond.. sup. -. sup.₂）_q-N（R⁶）-◆◆，◆-N（R⁶）-（CH₂）q-◆◆，-O-，-S-，-C（=O）-，-S（=O）₂-，◆-C（=O）-N（R⁶) -. diamond solid or diamond solid-N (R)⁶) -C (= O) -. diamond-solid, in which

Represent and ringsIs connected to

And

diamond-solid denotes a ringThe connection point of (a) is,

q represents the number 0, 1 or 2

And

R⁶represents hydrogen, (C)₁-C₆) -alkyl or (C)₃-C₆) -a cycloalkyl group,

in which (C)₁-C₆) -alkyl and (C)₃-C₆) Cycloalkyl groups may each be substituted by hydroxy or (C)₁-C₄) -an alkoxy group substitution,

R¹represents and ringIs selected from fluorine, cyano and (C)₁-C₆) Alkyl, hydroxy, (C)₁-C₆) -alkoxy, oxo, amino, mono- (C)₁-C₆) -alkylamino, di- (C)₁-C₆) -alkylamino and (C)₃-C₆) -a cycloalkyl group,

in which (C)₁-C₆) The alkyl radical may itself be substituted up to three times by fluorine and is selected from hydroxyl in the same or different manner, (C)₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) Alkylamino and di- (C)₁-C₄) Up to two substitutions of the radical of an alkylamino group

And

（C₃-C₆) Cycloalkyl groups themselves may be selected, in the same or different ways, from fluorine, (C)₁-C₄) Alkyl, hydroxy, (C)₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) Alkylamino and di- (C)₁-C₄) -the radical of alkylamino is substituted up to two times,

m represents the number 0, 1, 2, 3 or 4,

in which in the substituent R¹There are a number of times, the meaning of which can be the same or different,

R²Represents and ringIs selected from (C)₁-C₆) -alkyl, (C)₁-C₆) -alkylcarbonyl group, (C)₁-C₆) -alkoxycarbonyl, (C)₁-C₆) -alkylsulfonyl and (C)₃-C₆) -a cycloalkyl group,

in which is at (C)₁-C₆) -alkyl, (C)₁-C₆) -alkylcarbonyl group, (C)₁-C₆) -alkoxycarbonyl and (C)₁-C₆) The alkyl radical in alkylsulfonyl can itself be substituted up to three times by fluorine and selected in the same or different manner from hydroxy, (C)₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) -alkylamino, di- (C)₁-C₄) -alkylamino, (C)₃-C₆) Up to two substitutions of the radicals of-cycloalkyl and 4-to 6-membered heterocyclyl

And

（C₃-C₆) Cycloalkyl groups themselves may be selected, in the same or different ways, from fluorine, (C)₁-C₄) Alkyl, hydroxy, (C)₁-C₄) -alkoxy radicalRadical, amino radical, mono- (C)₁-C₄) Alkylamino and di- (C)₁-C₄) -the radical of alkylamino is substituted up to two times,

n represents the number 0 or 1, or if aza-heterocycleAlso contains an N atom as a ring member, representing the number 2,

in which in the substituent R²Where there are two, its meaning may be the same or different,

R³represents a methyl group, an ethyl group or a trifluoromethyl group,

R⁴represents hydrogen or is selected from halogen, cyano, pentafluorothio, (C) ₁-C₆) Alkyl, tri- (C)₁-C₄) -alkylsilyl, -OR⁷，-NR⁷R⁸，-N（R⁷）-C（=O）-R⁸，-N（R⁷）-C（=O）-OR⁸，-N（R⁷）-S（=O）₂-R⁸，-C（=O）-OR⁷，-C（=O）-NR⁷R⁸，-SR⁷，-S（=O）-R⁷，-S（=O）₂-R⁷，-S（=O）₂-NR⁷R⁸，-S（=O）（=NH）-R⁷，-S（=O）（=NCH₃）-R⁷，（C₃-C₆) -substituents of cycloalkyl, 4-to 6-membered heterocyclyl and 5-or 6-membered heteroaryl,

in which (C)₁-C₆) The alkyl radical may itself be substituted up to three times by fluorine and is selected from-OR in the same OR different manner⁷，-NR⁷R⁸，-N（R⁷）-C（=O）-R⁸，-N（R⁷）-C（=O）-OR⁸，-C（=O）-OR⁷，-C（=O）-NR⁷R⁸，（C₃-C₆) Cycloalkyl, 4-to 6-membered heterocyclyl and 5-orUp to two substitutions of the radical of a 6-membered heteroaryl group

And therein

The cycloalkyl and heterocyclyl radicals mentioned may themselves be selected, in the same or different ways, from fluorine, (C)₁-C₄) Alkyl, hydroxy, (C)₁-C₄) -alkoxy, trifluoromethoxy, oxo, amino, mono- (C)₁-C₄) -alkylamino, di- (C)₁-C₄) -alkylamino, (C)₁-C₄) -alkylcarbonylamino, (C)₁-C₄) -alkoxycarbonylamino group, (C)₁-C₄) -alkylcarbonyl and (C)₁-C₄) Up to two substitutions of the radical of alkoxycarbonyl

And

the heteroaryl groups mentioned may themselves be selected, in the same or different ways, from fluorine, chlorine, cyano, (C)₁-C₄) -alkyl, (C)₁-C₄) Up to two substitutions of the groups alkoxy and trifluoromethoxy

Wherein (C) is mentioned herein₁-C₄) The alkyl substituents may themselves be substituted by hydroxy, (C)₁-C₄) -alkoxy, trifluoromethoxy, (C) ₁-C₄) -alkylcarbonyloxy, carboxamido, mono- (C)₁-C₄) -alkylaminocarbonyl or di- (C)₁-C₄) -alkylaminocarbonyl or up to three times by fluorine,

and therein

R⁷And R⁸Representing hydrogen independently of one another for each individual occurrence, (C)₁-C₆) -alkyl, (C)₃-C₆) -cycloalkyl or 4-to 6-membered heterocyclyl,

in which (C)₁-C₆) Alkyl may be substituted up to fluorineThree times and selected in the same or different manner from the hydroxyl group, (C)₁-C₄) -alkoxy, trifluoromethoxy, amino, mono- (C)₁-C₄) -alkylamino, di- (C)₁-C₄) -alkylamino, (C)₁-C₄) -alkoxycarbonyl, (C)₃-C₆) Up to two substitutions of the radicals of-cycloalkyl and 4-to 6-membered heterocyclyl

And

the cycloalkyl and heterocyclyl radicals mentioned may be selected in the same or different manner from fluorine, (C)₁-C₄) -alkyl, trifluoromethyl, hydroxy, (C)₁-C₄) -alkoxy, trifluoromethoxy, oxo, amino, mono- (C)₁-C₄) -alkylamino, di- (C)₁-C₄) -alkylamino, (C)₁-C₄) -alkylcarbonyl and (C)₁-C₄) The radical of alkoxycarbonyl is substituted up to two times,

or

R⁷And R⁸In which both are attached to the nitrogen atom, together with the nitrogen atom form a 4-to 6-membered heterocyclic ring which may contain further substituents from the group consisting of N, O, S or S (O) ₂And which may be selected in the same or different manner from fluorine, (C)₁-C₄) -alkyl, trifluoromethyl, hydroxy, (C)₁-C₄) -alkoxy, oxo, amino, mono- (C)₁-C₄) -alkylamino, di- (C)₁-C₄) -alkylamino, (C)₁-C₄) -alkylcarbonyl and (C)₁-C₄) The radical of alkoxycarbonyl is substituted up to two times,

R⁵represents a substituent selected from fluorine, chlorine, cyano, methyl, trifluoromethyl and hydroxy

And

p represents the number 0, 1 or 2,

in which in the substituent R⁵Where there are two, its meaning may be the same or different,

and salts, solvates and solvates of salts thereof.

Alternative embodiments within the subject matter of the invention described above include compounds of formula (I), wherein

R¹Represents and ringIs selected from fluorine, (C)₁-C₆) Alkyl, hydroxy, (C)₁-C₆) -alkoxy, oxo, amino, mono- (C)₁-C₆) -alkylamino, di- (C)₁-C₆) -alkylamino and (C)₃-C₆) -a cycloalkyl group,

in which (C)₁-C₆) The alkyl radical may itself be substituted up to three times by fluorine and is selected from hydroxyl in the same or different manner, (C)₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) Alkylamino and di- (C) ₁-C₄) Up to two substitutions of the radical of an alkylamino group

And

m represents the number 0, 1, 2, 3 or 4,

in which in the substituent R¹In the case where there are a plurality of times,its meaning may be the same or different,

and

R⁴represents hydrogen or is selected from halogen, cyano, pentafluorothio, (C)₁-C₆) Alkyl, tri- (C)₁-C₄) -alkylsilyl, -OR⁷，-NR⁷R⁸，-N（R⁷）-C（=O）-R⁸，-N（R⁷）-C（=O）-OR⁸，-N（R⁷）S（=O）₂-R⁸，-C（=O）-OR⁷，-C（=O）-NR⁷R⁸，-SR⁷，-S（=O）-R⁷，-S（=O）₂-R⁷，-S（=O）₂-NR⁷R⁸，（C₃-C₆) -substituents of cycloalkyl, 4-to 6-membered heterocyclyl and 5-or 6-membered heteroaryl,

in which (C)₁-C₆) The alkyl radical may itself be substituted up to three times by fluorine and is selected from-OR in the same OR different manner⁷，-NR⁷R⁸，-N（R⁷）-C（=O）-R⁸，-N（R⁷）-C（=O）-OR⁸，-C（=O）-OR⁷，-C（=O）-NR⁷R⁸，（C₃-C₆) Up to two substitutions of the radicals of-cycloalkyl, 4-to 6-membered heterocyclyl and 5-or 6-membered heteroaryl

And therein

The cycloalkyl and heterocyclyl radicals mentioned may themselves be selected, in the same or different ways, from fluorine, (C)₁-C₄) -alkyl, trifluoromethyl, hydroxy, (C)₁-C₄) -alkoxy, trifluoromethoxy, oxo, amino, mono- (C) ₁-C₄) -alkylamino, di- (C)₁-C₄) -alkylamino, (C)₁-C₄) -alkylcarbonylamino, (C)₁-C₄) -alkoxycarbonylamino group, (C)₁-C₄) -alkylcarbonyl and (C)₁-C₄) Up to two substitutions of the radical of alkoxycarbonyl

And

the heteroaryl groups mentioned may themselves be selected, in the same or different ways, from fluorine, chlorine, cyano, (C)₁-C₄) -alkyl, trifluoromethyl, (C)₁-C₄) Up to two substitutions of the groups alkoxy and trifluoromethoxy

And in which R is⁷And R⁸Have the meanings given above

And salts, solvates and solvates of salts thereof.

The compounds according to the invention are compounds of the formula (I) and their salts, solvates and solvates of the salts, the compounds encompassed by the formula (I) and their salts, solvates and solvates of the salts mentioned in the following formulae, and the compounds encompassed by the formula (I) and their salts, solvates and solvates of the salts mentioned in the following as examples of embodiment, as long as the compounds encompassed by the formula (I) mentioned in the following are not also salts, solvates and solvates of the salts.

The compounds according to the invention may exist in stereoisomeric forms (among enantiomers, diastereomers), depending on their structure. The present invention therefore includes enantiomers or diastereomers and their respective mixtures. The stereoisomerically homogeneous components can be separated from such mixtures of enantiomers and/or diastereomers in a known manner; preference is given to using chromatography, in particular HPLC chromatography on the achiral or chiral phase.

If the compounds according to the invention can exist in tautomeric forms, the invention encompasses all tautomeric forms.

In the context of the present invention, preference is given toSalt (salt)Are physiologically acceptable salts of the compounds according to the invention. Also includes the use of compounds which are not suitable for pharmaceutical use but which are not suitable for pharmaceutical use per seAre salts which can be used, for example, for isolating or purifying the compounds according to the invention.

Physiologically acceptable salts of the compounds according to the invention include the acid addition salts of inorganic acids, carboxylic and sulfonic acids, for example the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenedisulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, benzoic acid and 4-sulfamoylbenzoic acid.

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

In the context of the present invention it is,solvatesRefers to those forms of the compounds according to the invention which form complexes in the solid or liquid state by coordination with solvent molecules. Hydrates are a particular form of solvates in which the coordination takes place with water. Hydrates are preferred solvates in the context of the present invention.

Of pyridyl rings and tertiary cyclic amine groups contained in the compounds according to the inventionNOxides are also included in the invention.

The invention furthermore comprises prodrugs of the compounds according to the invention. The term "prodrug" here denotes compounds which may be biologically active or inactive per se, but which are converted (e.g. metabolized or hydrated) during the residence time in the body to the compounds according to the invention.

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

in the context of the present invention it is,（ ₁ ₆C-C ） - alkyl radicalAnd（ ₁ ₄C-C ） - alkyl radicalRepresents a straight or branched alkyl group having 1 to 6 or 1 to 4 carbon atoms, respectively. Straight or branched alkyl groups having 1 to 4 carbon atoms are preferred. For example and preferably, mention may be made of: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl and 3-hexyl.

In the context of the present invention it is,（ ₁ ₆C-C ） - alkyl carbonylAnd（ ₁ ₄C-C ） - alkyl carbonylRepresents a straight-chain or branched alkyl group having 1 to 6 or 1 to 4 carbon atoms, respectively, via a carbonyl group [ -C (= O) -]And (4) connecting. Preference is given to straight-chain or branched alkylcarbonyl groups having 1 to 4 carbon atoms in the alkyl radical. For example and preferably, mention may be made of: acetyl, propionyl, N-butyryl, iso-butyryl, N-pentanoyl, pivaloyl, N-hexanoyl and N-heptanoyl.

In the context of the present invention it is,（ ₁ ₆C-C ） - alkyl sulfonyl radicalAnd（ ₁ ₄C-C ） - alkyl sulfonyl radicalRepresents a sulfonyl group having 1 to 6 or 1 to 4 carbon atoms respectively [ -S (= O)₂-]A linked linear or branched alkyl group. Linear or branched alkylsulfonyl groups having from 1 to 4 carbon atoms in the alkyl group are preferred. For example and preferably, mention may be made of: methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl.

In the context of the present invention it is,III - （ ₁ ₄C-C ） - Alkyl radicalSilyl radicalRepresents a silyl group having three identical or different linear or branched alkyl substituents containing from 1 to 4 carbon atoms. For example and preferably, mention may be made of: trimethylsilyl, tert-butyl-dimethylsilyl and triisopropylsilyl.

In the context of the present invention it is,（ ₁ ₆C-C ） - alkoxy radicalAnd（ ₁ ₄C-C ） - alkoxy radicalRepresents a linear or branched alkoxy group having 1 to 6 or 1 to 4 carbon atoms, respectively. Linear or branched alkoxy groups having 1 to 4 carbon atoms are preferred. For example and preferably, mention may be made of: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, 2-pentyloxy, 3-pentyloxy, neopentyloxy, n-hexyloxy, 2-hexyloxy and 3-hexyloxy.

In the context of the present invention it is,（ ₁ ₆C-C ） - alkoxycarbonyl radicalAnd（ ₁ ₄C-C ） - alkoxycarbonyl radicalRepresents a carbonyl group [ -C (= O) -]A linked linear or branched alkoxy group. Preference is given to straight-chain or branched alkoxycarbonyl groups having from 1 to 4 carbon atoms in the alkoxy radical. For example and preferably, mention may be made of: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

In the context of the present invention it is,a - （ ₁ ₆C-C ） - Alkylamino radicalAnda - （ ₁ ₄C-C ） - Alkylamino radical Represents an amino group having a linear or branched alkyl substituent containing 1 to 6 or 1 to 4 carbon atoms, respectively. Preferably a linear or branched monoalkylamino group having 1 to 4 carbon atoms. For example and preferably, mention may be made of: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, tert-butylamino, n-pentylamino and n-hexylamino.

In the context of the present invention it is,II - （ ₁ ₆C-C ） - Alkylamino radicalAndII - （ ₁ ₄C-C ） - Alkylamino radicalRepresents an amino group having two identical or different straight-chain or branched alkyl substituents, each substituent containing 1 to 6 or 1 to 4 carbon atoms, respectively. Preference is given to straight-chain or branched dialkylamino groups having in each case 1 to 4 carbon atoms. For example and preferably, mention may be made of:N,N-a dimethylamino group,N,N-a diethylamino group,N-an ethyl-N-methylamino group,N-methyl-N-a n-propylamino group,N-isopropyl-N-a methylamino group, which is a cyclic amino group,N-isopropyl-N-a n-propylamino group,N,N-a diisopropylamino group,N-n-butyl-N-a methylamino group, which is a cyclic amino group,N-tert-butyl-N-a methylamino group, which is a cyclic amino group,N-methyl-N-n-pentylamino andN-n-hexyl-N-methylamino.

In the context of the present invention, a- Or two - （ ₁ ₄C-C ） - Alkyl amino carbonylRepresents a group represented by the formula [ -C (= O) - ]Amino groups which are linked and each have a linear or branched chain or two identical or different linear or branched alkyl substituents each having 1 to 4 carbon atoms. For example and preferably, mention may be made of: methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, tert-butylaminocarbonyl,N,N-a dimethylaminocarbonyl group,N,N-a diethylaminocarbonyl group,N-ethyl-N-a methyl-amino-carbonyl group,N-methyl-N-n-propylaminocarbonyl group,N-isopropyl-N-a methyl-amino-carbonyl group,N,N-a diisopropylaminocarbonyl group,N-n-butyl-N-methylaminocarbonyl andN-tert-butyl-N-methylaminocarbonyl.

In the context of the present invention it is,（ ₁ ₄C-C ） - alkylcarbonylamino groupRepresents an amino group having a linear or branched alkylcarbonyl substituent containing from 1 to 4 carbon atoms in the alkyl group and attached to the N atom via a carbonyl group. For example and preferably, mention may be made of: acetylamino, propionylamino, n-butyrylamino, iso-butyrylamino, n-pentanoylamino and pivaloylamino.

In the context of the present invention it is,（ ₁ ₄C-C ） - alkyl carbonyl oxygen radicalRepresents an oxy group having a straight or branched alkyl carbonyl substituent containing from 1 to 4 carbon atoms in the alkyl group and attached to the O atom through the carbonyl group. For example and preferably, mention may be made of: acetoxy, propionyloxy, n-butyryloxy, iso-butyryloxy, n-valeryloxy and pivaloyloxy.

In the context of the present invention it is,（ ₁ ₄C-C ） - alkoxycarbonyl amino groupRepresents an amino group having a linear or branched alkoxycarbonyl substituent which contains from 1 to 4 carbon atoms in the alkoxy group and is linked to the N atom via a carbonyl group. For example and preferably, mention may be made of: methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, n-butoxycarbonylamino and tert-butoxycarbonylamino.

In the context of the present invention it is,（ ₃ ₆C-C ） - cycloalkyl radicalsAnd（ ₃ ₅C-C ） - cycloalkyl radicalsRepresent monocyclic, saturated cycloalkyl radicals having in each case 3 to 6 or 3 to 5 ring carbon atoms. For example and preferably, mention may be made of: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the context of the present invention it is,4- to 6- Heterocyclic radicalAnd4- or 5- Heterocyclic radicalRepresents a monocyclic, saturated heterocycle having a total of 4 to 6 or 4 or 5 ring atoms, respectively, which contains one or two ring atoms from the group consisting of N, O, S and/or S (O)₂And are attached through a ring carbon atom or optionally through a ring nitrogen atom. Preference is given to 4-or 5-membered heterocyclic groups having ring heteroatoms from N, O or S and 6-membered heterocyclic groups having one or two ring heteroatoms from N, O and/or S. Mention may be made, for example, of: azetidinyl, oxetanyl, Thietanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, thioalkylthio (thiolanyl), 1, 1-dioxothioalkylthio (dioxidothiolan), 1,3- Oxazolidinyl, 1, 3-thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1, 3-diAlkyl, 1, 4-diAlkyl, morpholinyl, thiomorpholinyl and 1, 1-dioxothiomorpholinyl. Preference is given to azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl and thiomorpholinyl.

In the context of the present invention it is,4- to 10- Meta-aza ring - Heterocyclic ringsRepresents a mono-or optionally bicyclic, saturated heterocycle having a total of 4 to 10 ring atoms, comprising at least one ring nitrogen atom and which may additionally comprise one or two further substituents from the group N, O, S and/or S (O)₂And are attached through a ring carbon atom or optionally through a ring nitrogen atom. Preferably at least one ring nitrogen atom and may additionally comprise further nitrogen atoms from the group N, O, S or S (O)₂4-to 10-membered aza-heterocycles of the ring heteroatoms of (a). For example and preferably, mention may be made of: azetidinyl, pyrrolidinyl, pyrazolidinyl, 1,3-Oxazolidinyl, 1, 3-thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1, 1-dioxothiomorpholinyl, hexahydroazepinyl, hexahydro-1, 4-diazepinyl, octahydroazepinyl (octahydrocinninyl), octahydropyrrolo [3,4-b ] pyrrolo ]Pyrrolyl, octahydroisoindolyl, octahydropyrrolo [3,2-b ]]Pyridyl, octahydropyrrolo [3,4-b ] s]Pyridyl, octahydropyrrolo [3, 4-c)]Pyridinyl, octahydropyrrolo [1,2-a ]]Pyrazinyl, decahydroisoquinolinyl, octahydropyrido [1,2-a ]]Pyrazinyl, 7-azabicyclo [2.2.1]Heptyl, 3-azabicyclo [3.2.0]Heptyl, 2-oxa-6-aza-spiro [3.3]Heptyl, 3-azabicyclo [3.2.1]Octyl, 8-azabicyclo [3.2.1]Octyl, 8-oxa-3-azabicyclo [3.2.1]Octyl and 9-aza-bicyclo [3.3.1]Nonyl radical.

In the context of the present invention it is,5- or 6- Membered heteroarylRepresents an aromatic heterocyclic radical (heteroaromatic) having in each case a total of 5 or 6 ring atoms, which contains up to three identical or different ring heteroatoms from N, O and/or S and is bonded via a ring carbon atom or optionally via a ring nitrogen atom. Mention may be made, for example, of: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl,azolyl radical, isoAn azole group, an isothiazolyl group, a triazolyl group,oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl. Preferably 5-or 6-membered heteroaryl groups having up to two ring heteroatoms from N, O and/or S, for example, furyl, pyrrolyl, thienyl, thiazolyl, Azolyl, isothiazolyl, iso-thiazolylOxazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl.

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

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

In the compounds according to the invention, if a group is substituted, the group may be mono-or polysubstituted, unless stated otherwise. In the context of the present invention, for all radicals present several times, their meanings are independent of one another. Preferably by one or by two or three identical or different substituents. Particular preference is given to substitution by one or by two identical or different substituents.

The invention provides, inter alia, those compounds of the general formula (I) in which the ring isX and CH, representing phenyl or pyridyl rings and adjacent radicals₂Andare linked to one another in a 1,3 or 1,4 relationship

And

ring (C)With a substituent R⁴And R⁵Represents a phenyl ring of formula

Therein of which

Indicates and ringThe connection point of (a) is,

and salts, solvates and solvates of salts thereof.

In the context of the present invention, preferred compounds of the formula (I) are those in which

Ring (C)Represents a pyridyl ring and the adjacent radicals X and CH₂To the ring carbon atoms of the pyridyl ring in a 1,3 or 1,4 relationship to each other

And

ring (C)With a substituent R⁴And R⁵Represents a phenyl ring of the formula

Therein of which

Indicates and ringThe connection point of (a) is,

and salts, solvates and solvates of salts thereof.

Preferred compounds of the formula (I) are also those in which

Ring (C)The radicals X and CH representing a phenyl ring and being adjacent₂To the phenyl ring in a 1,3 or 1,4 relationshipIn this connection, the connection between the first and second terminals,

ring (C)With a substituent R³Represents a heteroaryl ring of formula

Therein is provided with

# denotes the adjacent CH₂Attachment point of group

And

# denotes and RingThe connection point of (a) is,

and

ring (C)With a substituent R⁴And R⁵Represents a phenyl ring of formula

Therein of which

Indicates and ringThe connection point of (a) is,

and salts, solvates and solvates of salts thereof.

Also preferred compounds of the formula (I) are those in which

Ring (C)The radicals X and CH representing a phenyl ring and being adjacent₂Are linked to each other in a 1,3 or 1,4 relationship to the phenyl ring,

ring (C)With a substituent R³Represents a heteroaryl ring of formula

Therein of which

# denotes the adjacent CH₂Attachment point of group

And

# denotes and RingThe connection point of (a) is,

ring (C)With a substituent R⁴And R⁵Represents a phenyl ring of formula

Therein of which

Indicates and ringThe connection point of (a) is,

R¹represents and ringIs selected from cyano, (C)₁-C₆) -alkyl, oxo and (C)₃-C₆) -a cycloalkyl group,

And

in which is at (C)₁-C₆) -alkyl, (C)₁-C₆) -alkylcarbonyl group, (C)₁-C₆) -alkoxycarbonyl and (C)₁-C₆) The alkyl radical in alkylsulfonyl can itself be substituted up to three times by fluorine and selected in the same or different manner from hydroxy, (C) ₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) -alkylamino, di- (C)₁-C₄) -alkylamino, (C)₃-C₆) Up to two substitutions of the radicals of-cycloalkyl and 4-to 6-membered heterocyclyl

And

m represents the number 0, 1, 2, 3 or 4,

in the case where the substituent R1 is present a plurality of times, its meaning may be identical or different,

and

in which the sum of m and n is not equal to the number 0,

and salts, solvates and solvates of salts thereof.

An alternative embodiment within the last-described embodiment includes compounds of formula (I), wherein

R¹Represents and ringIs selected from (C)₁-C₆) -alkyl, oxo and (C) ₃-C₆) -a cycloalkyl group,

in which (C)₁-C₆) Alkyl groups themselves being optionally substituted by fluorineUp to three times and selected from hydroxyl groups, (C) in the same or different manner₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) Alkylamino and di- (C)₁-C₄) Up to two substitutions of the radical of an alkylamino group

And

m represents the number 0, 1, 2, 3 or 4,

and

n represents the number 0 or 1 or, if aza-heterocycleAlso contains an N atom as a ring member, representing the number 2,

in which the sum of m and n is not equal to the number 0,

and salts, solvates and solvates of salts thereof.

Particularly preferred compounds of the formula (I) in the context of the present invention are those in which

Ring (C)Represents a pyridyl ring and the adjacent radicals X and CH ₂To the ring carbon atoms of the pyridyl ring in a 1,3 or 1,4 relationship to each other,

ring (C)With a substituent R³Represents a heteroaryl ring of formula

Therein is provided with

# denotes the adjacent CH₂Attachment point of group

And

# denotes and RingThe connection point of (a) is,

ring (C)Represents a heteroaryl ring of formula

Therein is provided with

Denotes and ringsIs connected to

And

indicates and ringsThe connection point of (a) is,

ring (C)With a substituent R⁴And R⁵Represents a phenyl ring of formula

Therein of which

Indicates and ringThe connection point of (a) is,

ring (C)Represents a saturated 4-to 10-membered aza-heterocycle comprising at least one N atom as a ring member and may additionally comprise further substituents from the group consisting of N, O, S or S (O)₂The heterocyclic ring member of (a),

x represents a bond or represents [. diamond.. sup. -. sup.₂）_q-N（R⁶）-◆◆，-O-，-S-，-C（=O）-，-S（=O）₂-or-N (R)⁶) -C (= O) -. diamond-solid, in which

Represent and ringsIs connected to

And

diamond-solid denotes a ringThe connection point of (a) is,

q represents the number 0, 1 or 2

And

R⁶represents hydrogen, (C)₁-C₄) -alkyl or (C)₃-C₆) -a cycloalkyl group,

R¹represents and ringIs selected from fluorine, cyano and (C)₁-C₄) Alkyl, hydroxy, (C)₁-C₄) -alkoxy, oxo, amino, mono- (C) ₁-C₄) -alkylamino, di- (C)₁-C₄) -alkylamino and (C)₃-C₆) -a cycloalkyl group,

in which (C)₁-C₄) The alkyl radical may itself be chosen from hydroxyl, (C)₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) Alkylamino and di- (C)₁-C₄) -alkylamino is substituted and up to three times by fluorine,

and

m represents the number 0, 1 or 2,

in which in the substituent R¹Where there are two, its meaning may be the same or different,

R²represents and ringIs selected from (C)₁-C₄) -alkyl, (C)₁-C₄) -alkylcarbonyl group, (C)₁-C₄) -alkoxycarbonyl, (C)₁-C₄) -alkylsulfonyl and (C)₃-C₆) -a cycloalkyl group,

in which is at (C)₁-C₄) -alkyl, (C)₁-C₄) -alkylcarbonyl group, (C)₁-C₄) -alkoxycarbonyl and (C)₁-C₄) The alkyl group in the alkylsulfonyl radical may itself be chosen from hydroxyl, (C)₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) -alkylamino, di- (C)₁-C₄) -alkylamino, (C) ₃-C₆) Up to three times with substituents of cycloalkyl and 4-to 6-membered heterocyclyl and with fluorine

And

n represents the number 0 or 1,

R³represents a methyl group, an ethyl group or a trifluoromethyl group,

R⁴represents a group selected from fluorine, chlorine, cyano, pentafluorothio, (C)₁-C₆) Alkyl, tri- (C)₁-C₄) -alkylsilyl, -OR⁷，-NR⁷R⁸，-SR⁷，-S（=O）-R⁷，-S（=O）₂-R⁷，-S（=O）（=NH）-R⁷，-S（=O）（=NCH₃）-R⁷，（C₃-C₆) -cycloalkyl and 4-to 6-membered heterocyclyl,

in which (C)₁-C₆) The alkyl radical may itself be substituted up to three times by fluorine and is selected from-OR in the same OR different manner⁷，-NR⁷R⁸，-N（R⁷）-C（=O）-R⁸，-C（=O）-NR⁷R⁸，（C₃-C₆) Up to two substitutions of the radicals of-cycloalkyl, 4-to 6-membered heterocyclyl and 5-or 6-membered heteroaryl

And therein

The cycloalkyl and heterocyclyl radicals mentioned may themselves be selected, in the same or different ways, from fluorine, (C)₁-C₄) Alkyl, hydroxy, (C)₁-C₄) -alkoxy, trifluoromethoxy, oxo and (C)₁-C₄) Up to two substitutions of the radical-alkylcarbonyl

And

the heteroaryl groups mentioned may themselves be selected, in the same or different ways, from fluorine, chlorine, cyano, (C) ₁-C₄) -alkyl, (C)₁-C₄) Up to two substitutions of the groups alkoxy and trifluoromethoxy

Wherein (C) is mentioned herein₁-C₄) The alkyl substituents may themselves be substituted by hydroxy, methoxy, trifluoromethoxy, ethoxy, acetoxy, aminocarbonyl, methylaminocarbonyl or dimethylaminocarbonyl or up to three times by fluorine,

and therein

R⁷And R⁸Representing hydrogen independently of one another for each individual occurrence, (C)₁-C₄) -alkyl, (C)₃-C₆) -cycloalkyl or 4-to 6-membered heterocyclyl,

in which (C)₁-C₄) Alkyl may be substituted up to fluorineThree times and selected in the same or different manner from the hydroxyl group, (C)₁-C₄) -alkoxy, trifluoromethoxy, (C)₃-C₆) Up to two substitutions of the radicals of-cycloalkyl and 4-to 6-membered heterocyclyl

And

the cycloalkyl and heterocyclyl radicals mentioned may be selected in the same or different manner from fluorine, (C)₁-C₄) -alkyl, trifluoromethyl, hydroxy, (C)₁-C₄) -alkoxy, trifluoromethoxy, oxo and (C)₁-C₄) Up to two substitutions of the radical-alkylcarbonyl

Or

R⁷And R⁸In which both are attached to the nitrogen atom, together with the nitrogen atom form a 4-to 6-membered heterocyclic ring which may contain further substituents from the group consisting of N, O, S or S (O) ₂And which may be selected in the same or different manner from fluorine, (C)₁-C₄) -alkyl, trifluoromethyl, hydroxy, (C)₁-C₄) -alkoxy, oxo and (C)₁-C₄) -the radical of alkylcarbonyl is substituted up to two times,

R⁵represents a substituent selected from fluorine, chlorine and methyl

And

p represents the number 0 or 1,

and salts, solvates and solvates of salts thereof.

R¹Represents and ringIs selected from fluorine, (C)₁-C₄) Alkyl, hydroxy, (C)₁-C₄) -alkoxy, oxo, amino, mono- (C)₁-C₄) -alkylamino, di- (C)₁-C₄) -alkylamino and (C)₃-C₆) -a cycloalkyl group,

and

m represents the number 0, 1 or 2

and

R⁴represents a group selected from fluorine, chlorine, cyano, pentafluorothio, (C)₁-C₆) Alkyl, tri- (C)₁-C₄) -alkylsilyl, -OR⁷，-NR⁷R⁸，-SR⁷，-S（=O）-R⁷，-S（=O）₂-R⁷，（C₃-C₆) -cycloalkyl and 4-to 6-membered heterocyclyl,

And therein

The cycloalkyl and heterocyclyl radicals mentioned may themselves be selected, in the same or different ways, from fluorine, (C)₁-C₄) -alkyl, trifluoromethyl, hydroxy, (C)₁-C₄) -alkoxy, trifluoromethoxy, oxo and (C)₁-C₄) Up to two substitutions of the radical-alkylcarbonyl

And

And in which R is⁷And R⁸Having the meaning given in the last described embodiment,

And salts, solvates and solvates of salts thereof.

Also particularly preferred compounds of the formula (I) are those in which

ring (C)With a substituent R³Represents a heteroaryl ring of formula

Therein is provided with

# denotes the adjacent CH₂Attachment point of group

And

# denotes and RingThe connection point of (a) is,

ring (C)Represents a heteroaryl ring of formula

Therein is provided with

Denotes and ringsIs connected to

And

indicates and ringsThe connection point of (a) is,

ring (C)With a substituent R⁴And R⁵Represents a phenyl ring of formula

Therein of which

Indicates and ringThe connection point of (a) is,

Represent and ringsIs connected to

And

diamond-solid denotes a ringThe connection point of (a) is,

q represents the number 0, 1 or 2

And

R¹represents and ringIs selected from fluorine, cyano and (C) ₁-C₄) -alkyl radicalHydroxy, (C)₁-C₄) -alkoxy, oxo, amino, mono- (C)₁-C₄) -alkylamino, di- (C)₁-C₄) -alkylamino and (C)₃-C₆) -a cycloalkyl group,

and

m represents the number 0, 1 or 2

in which is at (C)₁-C₄) -alkyl, (C)₁-C₄) -alkylcarbonyl group, (C)₁-C₄) -alkoxycarbonyl and (C)₁-C₄) The alkyl group in the alkylsulfonyl radical may itself be chosen from hydroxyl, (C)₁-C₄) Alkoxy, amino, mono- (C) ₁-C₄) -alkylamino, di- (C)₁-C₄) -alkylamino, (C)₃-C₆) Up to three times with substituents of cycloalkyl and 4-to 6-membered heterocyclyl and with fluorine

And

n represents the number 0 or 1,

R³represents a methyl group, an ethyl group or a trifluoromethyl group,

And therein

And

and therein

in which (C)₁-C₄) Alkyl may be substituted up to three times by fluorine and is selected from hydroxy in the same or different manner, (C)₁-C₄) -alkoxy, trifluoromethoxy, (C)₃-C₆) Up to two substitutions of the radicals of-cycloalkyl and 4-to 6-membered heterocyclyl

And

Or

R⁷And R⁸In which both are attached to the nitrogen atom, together with the nitrogen atom form a 4-to 6-membered heterocyclic ring which may contain further substituents from the group consisting of N, O, S or S (O)₂And which may be selected in the same or different manner from fluorine, (C)₁-C₄) -alkyl, trifluoromethyl, hydroxy, (C)₁-C₄) -alkoxy, oxo and (C)₁-C₄) -the radical of alkylcarbonyl is substituted up to two times,

R⁵represents a substituent selected from fluorine, chlorine and methyl

And

p represents the number 0 or 1,

and salts, solvates and solvates of salts thereof.

and

（C₃-C₆) Cycloalkyl groups themselves may be selected, in the same or different ways, from fluorine, (C) ₁-C₄) Alkyl, hydroxy, (C)₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) Alkylamino and di- (C)₁-C₄) -the radical of alkylamino is substituted up to two times,

m represents the number 0, 1 or 2,

and

in which (C)₁-C₆) The alkyl radical may itself be substituted up to three times by fluorine and selected from-OR in the same OR different manner⁷，-NR⁷R⁸，-N（R⁷）-C（=O）-R⁸，-C（=O）-NR⁷R⁸，（C₃-C₆) Up to two substitutions of the radicals of-cycloalkyl, 4-to 6-membered heterocyclyl and 5-or 6-membered heteroaryl

And therein

And

the heteroaryl groups mentioned may themselves be selected, in the same or different ways, from fluorine, chlorine, cyano, (C)₁-C₄) -alkyl, trifluoromethyl, (C) ₁-C₄) Up to two substitutions of the groups alkoxy and trifluoromethoxy

And in which R is⁷And R⁸Having the meaning given in this last described embodiment,

and salts, solvates and solvates of salts thereof.

Likewise particularly preferred compounds of the formula (I) are those in which

ring (C)With a substituent R³Represents a heteroaryl ring of formula

Therein of which

# denotes the adjacent CH₂Attachment point of group

And

# denotes and RingThe connection point of (a) is,

ring (C)Represents a heteroaryl ring of formula

Therein is provided with

Denotes and ringsIs connected to

And

indicates and ringsThe connection point of (a) is,

ring (C)With a substituent R⁴And R⁵Represents a phenyl ring of formula

Therein of which

Indicates and ringThe connection point of (a) is,

ring (C)Represents a saturated 4-to 10-membered aza-heterocycle which contains at least one N atom as a ring member and may additionally contain furtherFrom N, O, S or S (O)₂The heterocyclic ring member of (a),

Represent and ringsIs connected to

And

diamond-solid denotes a ring The connection point of (a) is,

q represents the number 0, 1 or 2

And

R¹represents and ringIs selected from cyano, (C)₁-C₄) -alkyl, oxo and (C)₃-C₆) -a cycloalkyl group,

and

in which is at (C)₁-C₄) -alkyl, (C)₁-C₄) -alkylcarbonyl group, (C)₁-C₄) -alkoxycarbonyl and (C)₁-C₄) The alkyl group in the alkylsulfonyl radical may itself be chosen from hydroxyl, (C)₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) -alkylamino, di- (C) ₁-C₄) -alkylamino (C)₃-C₆) Up to three times with substituents of cycloalkyl and 4-to 6-membered heterocyclyl and with fluorine

And

m represents the number 0, 1 or 2

n represents the number 0 or 1,

in which the sum of m and n is equal to the number 1, 2 or 3,

R³represents a methyl group, an ethyl group or a trifluoromethyl group,

R⁴represents a group selected from fluorine, chlorine, cyano, pentafluorothio, (C)₁-C₆) Alkyl, tri- (C)₁-C₄) -alkylsilyl, -OR⁷，-NR⁷R⁸，-SR⁷，-S（=O）R⁷，-S（=O）₂-R⁷，-S（=O）（=NH）-R⁷，-S（=O）（=NCH₃）-R⁷，（C₃-C₆) -cycloalkyl and 4-to 6-membered heterocyclyl,

And therein

The cycloalkyl and heterocyclyl radicals mentioned may themselves be selected, in the same or different ways, from fluorine, (C) ₁-C₄) Alkyl, hydroxy, (C)₁-C₄) -alkoxy, trifluoromethoxy, oxo and (C)₁-C₄) Up to two substitutions of the radical-alkylcarbonyl

And

the heteroaryl groups mentioned may themselves be the sameOr in a different manner by a group selected from fluorine, chlorine, cyano, (C)₁-C₄) -alkyl, (C)₁-C₄) Up to two substitutions of the groups alkoxy and trifluoromethoxy

and therein

And

the cycloalkyl and heterocyclyl radicals mentioned may be selected in the same or different manner from fluorine, (C) ₁-C₄) -alkyl, trifluoromethyl, hydroxy, (C)₁-C₄) -alkoxy, trifluoromethoxy, oxo and (C)₁-C₄) Up to two substitutions of the radical-alkylcarbonyl

Or

R⁵represents a substituent selected from fluorine, chlorine and methyl

And

p represents the number 0 or 1,

and salts, solvates and solvates of salts thereof.

R¹Represents and ringIs selected from (C)₁-C₄) -alkyl, oxo and (C)₃-C₆) -a cycloalkyl group,

in which (C)₁-C₄) The alkyl radical may itself be chosen from hydroxyl, (C)₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) Alkylamino and di- (C)₁-C₄) -alkylamino radical substituted and up to three times substituted by fluorine

And

m represents the number 0, 1 or 2,

therein is provided withAt the substituent R¹Where there are two, its meaning may be the same or different,

n represents the number 0 or 1,

in which the sum of m and n is equal to the number 1, 2 or 3,

and

And therein

And

the heteroaryl groups mentioned may themselves be selected, in the same or different ways, from fluorine, chlorine, cyano, (C) ₁-C₄) -alkyl, trifluoromethyl, (C)₁-C₄) -alkoxy and trisUp to two substitutions of the fluoromethoxy group

and salts, solvates and solvates of salts thereof.

Very particularly preferred compounds of the formula (I) in the context of the present invention are those in which

Ring (C)Represents a pyridyl ring of the formula

Therein of which

Denotes the point of attachment to the adjacent radical X

And

indicating neighboring CH₂The point of attachment of the group,

ring (C)With a substituent R³Represents a heteroaryl ring of formula

Therein of which

# denotes the adjacent CH₂Attachment point of group

And

# denotes and RingThe connection point of (a) is,

ring (C)Represents a heteroaryl ring of formula

Therein of which

Denotes and ringsIs connected to

And

indicates and ringsThe connection point of (a) is,

ring (C)With a substituent R⁴And R⁵Represents a phenyl ring of formula

Therein of which

Indicates and ringThe connection point of (a) is,

x represents a bond or represents [. diamond.. sup. -. sup.₂）_q-N（R⁶) -. diamond-solid, -C (= O) -or-N (R) ⁶) -C (= O) -. diamond-solid, in which

Represent and ringsIs connected to

And

diamond-solid denotes a ringThe connection point of (a) is,

q represents the number 0, 1 or 2

And

R⁶represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl,

R¹represents and ringIs selected from fluorine, cyano and (C)₁-C₄) Alkyl, hydroxy, (C)₁-C₄) -alkoxy, oxo, amino, mono- (C)₁-C₄) -alkylamino, di- (C)₁-C₄) Alkylamino, cyclopropyl and cyclobutyl,

m represents the number 0 or 1,

R²represents and ringIs selected from (C)₁-C₄) -alkyl, (C)₁-C₄) -alkylcarbonyl group, (C)₁-C₄) -alkoxycarbonyl, (C)₁-C₄) -alkylsulfonyl, cyclopropyl and cyclobutyl,

in which is at (C)₁-C₄) -alkyl, (C)₁-C₄) -alkylcarbonyl group, (C)₁-C₄) -alkoxycarbonyl and (C)₁-C₄) The alkyl group in the alkylsulfonyl radical may itself be chosen from hydroxyl, (C)₁-C₄) Alkoxy, amino, mono- (C) ₁-C₄) -alkylamino, di- (C)₁-C₄) -alkylamino, (C)₃-C₅) -cycloalkyl and 4-or 5-membered heterocyclyl are substituted and up to three times by fluorine,

n represents the number 0 or 1,

R³represents a methyl group, and a salt thereof,

R⁴represents a compound selected from chlorine, pentafluorothio, (C)₁-C₆) -alkyl, trimethylsilyl, -OR⁷，-SR⁷，-S（=O）-R⁷，-S（=O）₂-R⁷，-S（=O）（=NCH₃）-CF₃，（C₃-C₆) -cycloalkyl and 4-to 6-membered heterocyclyl,

in which (C)₁-C₆) The alkyl radical may itself be chosen from-OR⁷，-NR⁷R⁸，-C（=O）-NR⁷R⁸，（C₃-C₆) Up to three times with substituents of cycloalkyl and 4-to 6-membered heterocyclyl and with fluorine

And

the cycloalkyl and heterocyclyl radicals mentioned may themselves be identical orIn different ways from fluorine, (C)₁-C₄) -alkyl, trifluoromethyl, (C)₁-C₄) Up to two substitutions of the radicals alkoxy, trifluoromethoxy and oxo,

(C) mentioned therein₁-C₄) The alkyl substituents may themselves be substituted by methoxy, trifluoromethoxy or ethoxy,

and therein

R⁷And R⁸Representing hydrogen independently of one another for each individual occurrence, (C)₁-C₄) -alkyl or (C)₃-C₆) -a cycloalkyl group,

in which (C)₁-C₄) Alkyl groups may be chosen from hydroxyl, (C)₁-C₄) -alkoxy, trifluoromethoxy and (C)₃-C₆) -radical substitution of cycloalkyl and up to three times by fluorine

And

the cycloalkyl radicals mentioned may be chosen, in the same or different ways, from fluorine, (C)₁-C₄) -alkyl, trifluoromethyl, hydroxy, (C)₁-C₄) Up to two substitutions of the groups alkoxy and trifluoromethoxy,

or

R⁵represents fluorine and is selected from the group consisting of,

and

p represents the number 0 or 1,

and salts, solvates and solvates of salts thereof.

R¹Represents and ringIs selected from fluorine, (C)₁-C₄) Alkyl, hydroxy, (C)₁-C₄) -alkoxy, oxo, amino, mono- (C)₁-C₄) -alkylamino, di- (C)₁-C₄) Alkylamino, cyclopropyl and cyclobutyl,

in which (C)₁-C₄) The alkyl radical may itself be chosen from hydroxyl, (C) ₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) Alkylamino and di- (C)₁-C₄) -alkylamino is substituted and up to three times by fluorine,

m represents the number 0 or 1,

and

R⁴represents a compound selected from chlorine, pentafluorothio, (C)₁-C₆) -alkyl, trimethylsilyl, -OR⁷，-SR⁷，-S（=O）-R⁷，-S（=O）₂-R⁷，（C₃-C₆) -cycloalkyl and 4-to 6-membered heterocyclyl,

in which (C)₁-C₆) The alkyl radical may itself be chosen from-OR⁷，-NR⁷R⁸，-C（=O）-NR⁷R⁸，（C₃-C₆) The radicals of-cycloalkyl and 4-to 6-membered heterocyclylSubstituted and up to three times substituted by fluorine

And

the cycloalkyl and heterocyclyl radicals mentioned may themselves be selected, in the same or different ways, from fluorine, (C)₁-C₄) -alkyl, trifluoromethyl, (C)₁-C₄) Up to two substitutions of the radicals alkoxy, trifluoromethoxy and oxo,

and salts, solvates and solvates of salts thereof.

Also very particularly preferred compounds of the formula (I) are those in which

ring (C)With a substituent R³Represents a heteroaryl ring of formula

Therein of which

# denotes the adjacent CH₂Attachment point of group

And

# denotes and RingThe connection point of (a) is,

ring (C)Represents a heteroaryl ring of formula

Therein of which

Denotes and ringsIs connected to

And

indicates and ringsThe connection point of (a) is,

ring (C)With a substituent R⁴And R⁵Represents a phenyl ring of formula

Therein of which

Indicates and ringThe connection point of (a) is,

x represents a bond or represents [. diamond.. sup. -. sup.₂）_q-N（R⁶) -. diamond solid, -C (= O) -or-N（R⁶) -C (= O) -. diamond-solid, in which

Represent and ringsIs connected to

And

diamond-solid denotes a ringThe connection point of (a) is,

q represents the number 0, 1 or 2

And

R⁶represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl,

in which (C)₁-C₄) The alkyl radical may itself be chosen from hydroxyl, (C)₁-C₄) Alkoxy, amino, mono- (C) ₁-C₄) Alkylamino and di- (C)₁-C₄) -alkylamino is substituted and up to three times by fluorine,

m represents the number 0 or 1,

in which is at (C)₁-C₄) -alkyl, (C)₁-C₄) -alkylcarbonyl group, (C)₁-C₄) -alkoxycarbonyl and (C)₁-C₄) The alkyl group in the alkylsulfonyl radical may itself be chosen from hydroxyl, (C)₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) -alkylamino, di- (C)₁-C₄) -alkylamino (C)₃-C₅) -cycloalkyl and 4-or 5-membered heterocyclyl are substituted and up to three times by fluorine,

n represents the number 0 or 1,

R³represents a methyl group, and a salt thereof,

And

the cycloalkyl and heterocyclyl radicals mentioned may themselves be selected, in the same or different ways, from fluorine, (C) ₁-C₄) -alkyl, trifluoromethyl, (C)₁-C₄) Up to two substitutions of the radicals alkoxy, trifluoromethoxy and oxo,

and therein

And

or

R⁵Represents fluorine and is selected from the group consisting of,

and

p represents the number 0 or 1,

and salts, solvates and solvates of salts thereof.

m represents the number 0 or 1,

and

And

the cycloalkyl and heterocyclyl radicals mentioned may themselves be selected, in the same or different ways, from fluorine, (C)₁-C₄) -alkyl, trifluoromethyl, (C) ₁-C₄) Up to two substitutions of the radicals alkoxy, trifluoromethoxy and oxo,

and salts, solvates and solvates of salts thereof.

Very particularly preferred compounds of the formula (I) are those in which

ring (C)With a substituent R³Represents a heteroaryl ring of formula

Therein of which

# denotes the adjacent CH₂Attachment point of group

And

# denotes and RingThe connection point of (a) is,

ring (C)Represents a heteroaryl ring of formula

Therein of which

Denotes and ringsIs connected to

And

indicates and ringsThe connection point of (a) is,

ring (C)With a substituent R⁴And R⁵Represents a phenyl ring of formula

Therein of which

Is represented byThe point of attachment of the loop or loops,

x represents a bond or represents [. diamond.. sup. -. sup.₂）_q-N（R⁶) -. diamond-solid, -C (= O) -or-N (R)⁶）-C（=O）-◆◆，

Therein is provided with

Represent and ringsIs connected to

And

Diamond-solid denotes a ringThe connection point of (a) is,

q represents the number 0, 1 or 2

And

R⁶represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl,

R¹represents and ringIs selected from cyano, (C)₁-C₄) Alkyl, oxo, cyclopropyl and cyclobutyl,

m represents the number 0 or 1,

n represents the number 0 or 1,

In which the sum of m and n is equal to the number 1 or 2,

R³represents a methyl group, and a salt thereof,

And

and therein

And

the cycloalkyl radicals mentioned may be chosen, in the same or different ways, from fluorine, (C) ₁-C₄) -alkyl, trifluoromethyl, hydroxy, (C)₁-C₄) Up to two substitutions of the groups alkoxy and trifluoromethoxy,

or

R⁵represents fluorine and is selected from the group consisting of,

and

p represents the number 0 or 1,

and salts, solvates and solvates of salts thereof.

R¹Represents and ringIs selected from (C)₁-C₄) Alkyl, oxo, cyclopropyl and cyclobutyl,

m represents the number 0 or 1,

n represents the number 0 or 1,

in which the sum of m and n is equal to the number 1 or 2,

And

and salts, solvates and solvates of salts thereof.

A particular embodiment of the invention relates to compounds of the formula (I) in which, in the definition of the radical X,

q represents the number 0 or 1,

and salts, solvates and solvates of salts thereof.

More particularly preferred compounds of the formula (I) in the context of the present invention are those in which

Ring (C)Represents a pyridyl ring of the formula

Therein of which

Denotes the point of attachment to the adjacent radical X

And

indicating neighboring CH₂The point of attachment of the group,

Ring (C)With a substituent R³Represents a heteroaryl ring of formula

Therein of which

# denotes the adjacent CH₂Attachment point of group

And

# denotes and RingThe connection point of (a) is,

ring (C)Represents a heteroaryl ring of formula

Therein of which

Denotes and ringsIs connected to

And

indicates and ringsThe connection point of (a) is,

ring (C)With a substituent R⁴And R⁵Represents a phenyl ring of formula

Therein of which

Indicates and ringThe connection point of (a) is,

Therein is provided with

Represent and ringsIs connected to

And

diamond-solid denotes a ringThe connection point of (a) is,

q represents the number 0 or 1

And

R⁶represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl,

m represents the number 0 or 1,

in which is at (C)₁-C₄) -alkyl, (C)₁-C₄) -alkylcarbonyl group, (C)₁-C₄) -alkoxycarbonyl and (C)₁-C₄) The alkyl group in the alkylsulfonyl radical may itself be chosen from hydroxyl, (C)₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) -alkylamino, di- (C)₁-C₄) -alkylamino, (C)₃-C₅) -cycloalkyl and 4-or 5-membered heterocyclyl are substituted and up to three times by fluorine,

n represents the number 0 or 1,

R³represents a methyl group, and a salt thereof,

And

and therein

And

the cycloalkyl radicals mentioned may be chosen, in the same or different ways, from fluorine, (C)₁-C₄) -alkyl, trifluoromethyl, hydroxy, (C)₁-C₄) -alkoxy and trifluoromethoxy radicalsThe substitution is carried out up to two times,

or

R⁷And R⁸In which both are attached to the nitrogen atom, together with the nitrogen atom form a 4-to 6-membered heterocyclic ring which may contain further substituents from the group consisting of N, O, S or S (O)₂And which may be selected in the same or different manner from fluorine, (C) ₁-C₄) -alkyl, trifluoromethyl, hydroxy, (C)₁-C₄) -alkoxy, oxo and (C)₁-C₄) -the radical of alkylcarbonyl is substituted up to two times,

R⁵represents fluorine and is selected from the group consisting of,

and

p represents the number 0 or 1,

and salts, solvates and solvates of salts thereof.

Also particularly preferred compounds of the formula (I) are those in which

ring (C)With a substituent R³Represents a heteroaryl ring of formula

Therein of which

# denotes the adjacent CH₂Attachment point of group

And

# denotes and RingThe connection point of (a) is,

ring (C)Represents a heteroaryl ring of formula

Therein of which

Denotes and ringsIs connected to

And

indicates and ringsThe connection point of (a) is,

ring (C)With a substituent R⁴And R⁵Represents a phenyl ring of formula

Therein of which

Indicates and ringThe connection point of (a) is,

ring (C)Represents a saturated 4-to 10-membered aza-heterocycle which contains at least one N atom as a ring member and may additionally be contained inOne step from N, O, S or S (O)₂The heterocyclic ring member of (a),

Therein is provided with

Represent and ringsIs connected to

And

diamond-solid denotes a ringThe connection point of (a) is,

q represents the number 0 or 1

And

R⁶represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl,

in which (C)₁-C₄) The alkyl radical may itself be chosen from hydroxyl, (C)₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) Alkylamino and di- (C)₁-C₄) Substituted by radicals of alkylamino radicals and by fluorineThe generation time is up to three times,

m represents the number 0 or 1,

in which is at (C)₁-C₄) -alkyl, (C)₁-C₄) -alkylcarbonyl group, (C)₁-C₄) -alkoxycarbonyl and (C)₁-C₄) The alkyl group in the alkylsulfonyl radical may itself be chosen from hydroxyl, (C)₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) -alkylamino, di- (C)₁-C₄) -alkylamino (C) ₃-C₅) -cycloalkyl and 4-or 5-membered heterocyclyl are substituted and up to three times by fluorine,

n represents the number 0 or 1,

R³represents a methyl group, and a salt thereof,

And

and therein

And

or

R⁵represents fluorine and is selected from the group consisting of,

and

p represents the number 0 or 1,

and salts, solvates and solvates of salts thereof.

Also particularly preferred compounds of the formula (I) are those in which

ring (C)With a substituent R³Represents a heteroaryl ring of formula

Therein of which

# denotes the adjacent CH₂Attachment point of group

And

# denotes and RingThe connection point of (a) is,

ring (C)Represents a heteroaryl ring of formula

Therein of which

Denotes and ringsIs connected to

And

indicates and ringsThe connection point of (a) is,

ring (C)With a substituent R⁴And R⁵Represents a phenyl ring of formula

Therein of which

Indicates and ringThe connection point of (a) is,

Therein is provided with

Represent andring (C)Is connected to

And

diamond-solid denotes a ringThe connection point of (a) is,

q represents the number 0 or 1

And

R⁶represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl,

in which is at (C)₁-C₄) -alkyl, (C) ₁-C₄) -alkylcarbonyl group, (C)₁-C₄) -alkoxycarbonyl and (C)₁-C₄) The alkyl group in the alkylsulfonyl radical may itself be chosen from hydroxyl, (C)₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) -alkylamino, di- (C)₁-C₄) -alkylamino (C)₃-C₅) Up to three times by radical substitution of cycloalkyl and 4-or 5-membered heterocyclyl and by fluorine

m represents the number 0 or 1,

n represents the number 0 or 1,

in which the sum of m and n is equal to the number 1 or 2,

R³represents a methyl group, and a salt thereof,

And

as mentioned therein（C₁-C₄) The alkyl substituents may themselves be substituted by methoxy, trifluoromethoxy or ethoxy,

and therein

R⁷And R ⁸Representing hydrogen independently of one another for each individual occurrence, (C)₁-C₄) -alkyl or (C)₃-C₆) -a cycloalkyl group,

And

or

R⁵represents fluorine and is selected from the group consisting of,

and

p represents the number 0 or 1,

and salts, solvates and solvates of salts thereof.

The radical definitions specified in detail in a particular radical combination or preferred radical combination are also optionally replaced by radical definitions of other combinations, independently of the particular combination of radicals specified.

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

The compounds according to the invention can be prepared in a number of ways. The principle methods which are referred to below as methods a, B, C and D and which can be carried out in various transformation methods are used in particular here.

For all the methods and method variants of the methods described hereinafter, if the radical R is attached to the nitrogen atom N of the ring²Represents hydrogen (i.e. n = 0), which, depending on the type of reaction, is replaced by an amino-protecting group, and is isolated again when the reaction has been carried out or at the end of the reaction sequence in order to obtain the target compound of formula (I). This is always the case if the hydrogen atom attached to the nitrogen atom is not compatible with the reaction conditions used. This step, including the knowledge when the corresponding reaction conditions are incompatible, and the methods for the suitable amino-protecting groups for this, including their introduction and isolation, are known and familiar per se to the person skilled in the art. Examples of such amino-protecting groups are tert-butoxycarbonyl and benzyloxycarbonyl. A detailed description of this protecting group manipulation is found in the experimental teaching for the preparation of starting materials and intermediates and in the embodiment examples of the experimental section. For easier understanding, this type of protecting group and protecting group manipulation is not further referred to in the following description of the preparation process.

Process A (by means of variants A.1, A.2 and A.3; cf. schemes 1 to 3) is characterized by compounds of the formula (V) in which B, D, E, R³，R⁴，R⁵And p has the meaning described above and in which the hydrogen atom shown is attached to the nitrogen atom of the ring B, with compounds of the formula (II), (III) or (IV) in which A, N, X, R¹，R²M and n have the meanings described above and wherein Y usually represents an atom in its entiretyOr a group by which the linking group X can form a ring N (including the substituent R thereof)¹And R²) May be attached, and wherein Z represents a leaving group. Examples of Y are chlorine, bromine, iodine, cyano, nitro, hydroxy, formyl, carboxy and alkoxycarbonyl; examples of Z are chlorine, bromine, iodine, methanesulfonate (methanesulfonate), trifluoromethanesulfonate (trifluoromethanesulfonate) and 4-methylbenzenesulfonate (toluenesulfonate).

Scheme(s) 1 ：Method A.1

Scheme(s) 2 ：Method A.2

Scheme(s) 3 ：Method A.3

。

The reaction of the compound of formula (II), (III) or (IV) with the compound of formula (V) is carried out in the presence of a strong base, such as and preferably potassium tert-butoxide, in a suitable solvent, such as and preferably tetrahydrofuran, at a temperature in the range of from-10 ℃ to +50 ℃, preferably from 0 ℃ to room temperature. The subsequent reaction of the intermediates of formulae (VI) and (VIII) to give the product of formula (I) varies and depends inter alia on the nature of the group X and of the ring A. These subsequent reactions are described below.

In process B, ring D is formed, where ring D represents 1,2,4-Diazole. Method B was applied with various modifications. Taking into account the raw materials used and the followingPartial reaction of the oxadiazole ring closure, the transformation methods of method B (transformation methods b.1, b.2 and b.3) are similar to the various transformation methods of method a. Only transformation method b.1 is therefore described in detail below (scheme 4). A compound of formula (VIII), wherein A, B, N, X, R¹，R²，R³M and n have the meanings indicated above, are reacted here with hydroxyamidines of the formula (IX), in which E, R⁴，R⁵And p has the meaning given above, to give a product of formula (I-A).

Scheme(s) 4 ：Method B.1

In coupling agents, e.g. 1H-benzotriazol-1-ols andN- [3- (dimethylamino) propyl group]-N'Ethyl carbodiimide hydrochloride in the presence of a tertiary amine base, e.g. triethylamine, in a suitable solvent, e.g.,N,N-dimethylformamide, the reaction of the compound of formula (VIII) with the compound of formula (IX). The reaction partners (Reaktionpartner) first react with one another at room temperature for a certain period of time before the mixture is heated to a temperature in the range from +80 ℃ to +140 ℃. Alternatively, the compound of formula (VIII) may be first converted to the corresponding acid chloride. A chlorinating agent, e.g., oxalyl chloride or thionyl chloride, in an inert solvent, e.g., dichloromethane or chloroform, is used for the reaction. The reaction is preferably carried out at room temperature and in catalytic amounts N,N-dimethylformamide is carried out. The acid chloride obtained in this way is then reacted with a compound of the formula (IX). The product of the reaction is then dissolved in an inert solvent, for example, dimethyl sulfoxide orN,N-twoThe methylformamide is heated to a temperature in the range from +80 ℃ to +140 ℃.

In the remaining conversion process of Process B, instead of the compound of the formula (VIII), use is made of a carboxylic acid of the formula (X) (process B.2) or (XI) (process B.3), in which A, B, X, Y and R³Each having the meaning described above.

If ring D represents 1,3-Oxazole, can be used in process C, which can be carried out in various permutations c.1, c.2 and c.3 similar to processes a and B. As in the case of method B, only transformation method c.1 (scheme 5) is explained in more detail below. In process C.1, a compound of formula (VIII) is reacted with a compound of formula (XII) to give an intermediate of formula (XIII), which is cyclized and oxidized to the product of formula (I-B). A, B, E, N, X, R¹，R²，R³，R⁴，R⁵M, n and p each have the meaning described above.

Scheme(s) 5 ：Method C.1

The coupling agent may be added to the reaction mixture in the presence of, for example,O- (7-azabenzotriazol-1-yl) -N,N,N',N'-tetramethylurea  hexafluorophosphate, reacting the compound of formula (VIII) with (XII) aminoalcohol. The reaction is carried out at room temperature in the presence of a tertiary amine base, e.g., triethylamine, in a polar aprotic solvent, e.g., N,N-dimethylformamide. Subsequent cyclisation to give the compound of formula (XIV) is effected with the aid of cyclising reagents, e.g. and preferably, with primary aminesGiss reagent (Burgess reagent) (carbonyl methoxysulfamoyl-triethylammonium hydroxide). The reaction is carried out in a suitable solvent, for example, tetrahydrofuran, at the boiling point of the solvent, and the final oxidation can be carried out with various oxidizing agents. Preferably in tetrahydrofuran, at the boiling point of the solvent, with activated manganese dioxide.

1,3-The azole ring is formed in the same manner. Here, instead of the compounds of the formula (VIII), use is made of carboxylic acids of the formula (X) (method C.2) or (XI) (method C.3), in which A, B, X, Y and R³Have the meaning described above.

Process D describes the preparation of compounds of the formula (I) in which ring D represents 1,2,4-Oxadiazoles, their preparation and their use as fungicidesOxadiazole derivatives, in contrast, are attached to adjacent groups in a manner in which the side is converted. Similar to methods a, B and C, method D can be performed in various transformation methods d.1, d.2 and d.3; just as in the case of methods B and C, the transformation method d.1 (scheme 6) is explained in more detail below. The carboxylic acids of the formula (VIII) are here first converted into primary amines of the formula (XV) and the nitriles of the formula (XVI) are then prepared therefrom. These are converted into hydroxyamidines of the formula (XVII) by reaction with hydroxylamines, from which the products of the formula (I-C) are obtained by coupling with acid chlorides of the formula (XVIII) and subsequent cyclization. A, B, E, N, X, R ¹，R²，R³，R⁴，R⁵M, n and p each have the meaning described above.

Scheme(s) 6 ：Method D.1

The reaction of carboxylic acids of formula (VIII) to give amides of formula (XV) is carried out in two steps: by first reacting with a chlorinating agent, for example oxalyl chloride or thionyl chloride, in an inert solvent, for example dichloromethane or chloroform, and then by reacting in a suitable co-solvent, for example tetrahydrofuran or 1, 4-bisReaction of the acid chloride obtained in this way with an ammonia solution in methanol or water in an alkane. Dehydration of the Primary amine of formula (XV) to give the nitrile of formula (XVI) by reaction with an anhydride or chloride of a strong acid, for example and preferably, trifluoromethanesulfonic acid or trifluoroacetic acid, in an excess of a base, for example, triethylamine orN,NIn the presence of diisopropylethylamine in an inert solvent, for example dichloromethane. The reaction is preferably carried out at a temperature ranging from 0 ℃ to room temperature. The subsequent reaction with hydroxylamine is preferably carried out in an alcoholic solvent, e.g. ethanol, at the boiling point of the solvent. The hydroxyamidines of the formula (XVII) obtained in this way are reacted with an acid chloride of the formula (XVIII) in the presence of a base, for example triethylamine orN,NIn the presence of diisopropylethylamine in an inert solvent, for example dichloromethane or ethyl acetate, at temperatures from-10 ℃ to room temperature. The intermediate thus obtained is in an inert solvent, e.g. dimethyl sulfoxide or N,NCyclizing in dimethylformamide at a temperature of from +80 ℃ to +160 ℃ to form the product of the formula (I-C).

The reaction to produce the product of formula (I) from the intermediate of formula (VI) (method a.2, scheme 2) depends on the nature of the group X and ring a, described below. These reactions are also used correspondingly in processes B.2, C.2 and D.2.

a)If X represents [. diamond-solid. ] - (CH)₂）_q-NR⁶-. diamond solid, O or S, in which R is⁶Q,. diamond-solid and. diamond-solid have the meanings described above, and Ring A represents a pyridine ring, and groups Y andthe carbon atom of the pyridine ring directly adjacent to the pyridine nitrogen atom is attached, and Y represents halogen or sulfonate, and the compound of formula (VI) is reacted with the corresponding compound of formula (XIX) according to scheme 7. The reaction is carried out in the presence of an excess of the compound of formula (XIX) and, if X represents O or S, additionally in the presence of a base, for example sodium hydride. The reaction is carried out in a solvent, such as diglyme or N-methylpyrrolidone, or, if X represents-₂）_q-NR⁶-. diamond-solid in a tertiary amine base, e.g.N,N-diisopropylethylamine, or the compound of formula (XIX) itself as a solvent. The reaction is carried out at elevated temperatures, preferably in the temperature range from +80 ℃ to +200 ℃. Preferably, the reaction is carried out in a microwave apparatus in a closed pressure vessel in the upper region of the temperature interval mentioned.

Scheme(s) 7 ：Second part of Process A.2

[X=◆-（CH₂）_q-NR⁶-. diamond solid, O or S; y = chloro, bromo, iodo, methanesulfonate or toluenesulfonate]

b)If X represents [. diamond-solid. ] - (CH)₂）_q-NR⁶-, O or S and the group Y represent a halogen or a sulfonate and are attached to the carbon atom of the pyridine ring a at any desired position relative to the pyridine nitrogen atom, or ring a is a benzene ring, and the compound of formula (VI) and the compound of formula (XIX) are reacted with each other in the presence of a palladium catalyst according to scheme 7. Suitable palladium sources are, for example, palladium (II) acetate or tris (dibenzylidene-acetone) dipalladium (0). Ligands which may be used are, for example, 2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl, 1- [2- (dicyclohexylphosphino) ferrocenyl]Ethyl di-tert-butylphosphine or bis (diphenylphosphino) ferrocene. In the presence of a base, e.g. triethylamine or sodium tert-butoxideThe reaction is carried out. Suitable solvents are, for example, toluene,N-methyl pyrrolidone or 1, 2-dimethoxyethane. The reaction is generally carried out at respective boiling temperature intervals of +60 ℃ to the solvent.

c)If X represents. diamond-solid. -NR⁶-C (= O) -. diamond-solid, in which R is⁶Diamond-solid-has the meaning described above, compounds of formula (VI), wherein Y represents an alkoxycarbonyl group or a cyano group, are first converted to the corresponding carboxylic acids by treatment with aqueous base, and these are then reacted with compounds of formula (XX) to give products of formula (I) (see scheme 8). The reaction being either directly from the carboxylic acid at the coupling agent, e.g. 1 H-benzotriazol-1-ols andN- [3- (dimethylamino) propyl group]-N'-ethylcarbodiimide hydrochloride, in the presence of it, or by converting the carboxylic acid into the corresponding acid chloride, for example by means of thionyl chloride or oxalyl chloride, and then reacting it with the amine component (XX).

Scheme(s) 8 ：Second part of Process A.2

[X=◆-NR⁶-C (= O) -. diamond solid; y = alkoxycarbonyl, cyano, carboxyl or chlorocarbonyl]

Ester (VI) [ Y = alkoxycarbonyl group]The hydrolysis is preferably carried out with an aqueous solution of lithium hydroxide, sodium hydroxide or potassium hydroxide in the presence of a water-miscible inert solvent, for example methanol, ethanol or tetrahydrofuran. The reaction is generally carried out at a temperature interval of from room temperature to +60 ℃, preferably at room temperature. Nitrile (VI) [ Y = cyano]The hydrolysis of (a) is likewise carried out with aqueous base, preferably with aqueous potassium hydroxide, in ethanol at the boiling point of the solvent. The carboxylic acid obtained in this way is subsequently converted into the corresponding acid chloride with a chlorinating agent, such as and preferably oxalyl chloride or thionyl chloride, in an inert solvent, such as, for example, dichloroIn methane. The reaction is carried out at a temperature ranging from 0 ℃ to the boiling point of the solvent, preferably at room temperature. An amine of formula (XX) with formula (VI) [ Y = chlorocarbonyl [ ] ]The final reaction of the acid chloride is carried out in the presence of a base, for example triethylamine,N,Nin the presence of diisopropylethylamine or potassium carbonate in an inert solvent, for example dichloromethane or ethyl acetate. The reaction is carried out at a temperature ranging from 0 ℃ to room temperature. Amine of formula (XX) with formula (VI) [ Y = carboxy]Reaction of carboxylic acids by means of conventional coupling agents, e.g. 1H-benzotriazol-1-ols andN- [3- (dimethylamino) propyl group]-N'Ethyl carbodiimide hydrochloride, in a suitable solvent, for example,N,Ndimethylformamide and in the presence of a tertiary amine base, for example triethylamine. The reaction is preferably carried out at room temperature.

d)If X represents-C (= O) -and the ring N is attached to X via a nitrogen atom, a compound of formula (VI) wherein Y represents carboxy or chlorocarbonyl (see scheme 8) is reacted with a compound of formula (XXI) wherein the hydrogen atom shown is attached to the nitrogen atom of the ring N to give a product of formula (I).

The reaction conditions for this are completely analogous to those described under section c).

e)If X represents-C (= O) -NH-. diamond solid, in which the solid and the solid have the meanings described above, a compound of the formula (VI), in which Y represents a nitro group, is first reduced to the corresponding amine [ Y = NH ] ₂]And these are then reacted with compounds of formula (XXII) or (XXIII) to give the products of formula (I) (see scheme 9). The reaction is carried out in conventional coupling agents, e.g. 1H-benzotriazol-1-ols andN- [3- (dimethylamino) propyl group]-N'In the presence of ethylcarbodiimide hydrochloride, in the case of carboxylic acids (XXII) and in the case of acid chlorides (XXIII), directly in a tertiary amine base, for example triethylamine orN,NIn the presence of diisopropylethylamine.

Scheme(s) 9 ：Second part of Process A.2

[ X = -C (= O) -NH- ] diamond solid; y = nitro or amino group ]

The reduction of the nitro group is effected, for example, by catalytic hydrogenation with the aid of a noble metal catalyst, for example palladium on charcoal, in an inert solvent, for example ethanol, in the presence of hydrogen at a pressure of from 1 to 50 bar, preferably from 1 to 5 bar. The reaction is generally carried out at room temperature. The subsequent reaction with the carboxylic acid (XXII) or acid chloride (XXIII) is carried out either with the aid of a coupling agent or directly in the presence of a tertiary amine base, as already described above.

f)If X represents oxygen, optionally compounds of the formula (XXIV) in which Z represents a leaving group, for example chlorine, bromine or methane sulphonate, and compounds of the formula (VI) in which Y represents hydroxy, may also be reacted with one another. The latter, for example, can be obtained by the corresponding silyl ethers (see scheme 10).

Scheme(s) 10 ：Second part of Process A.2

[ X = O; y = hydroxy ]

The compound of formula (VI) wherein Y represents a silyl ether yields free compound of formula (VI) [ Y = OH]Reaction of the hydroxy compound, for example, by treatment with a fluoride source, such as tetra-n-butylammonium fluoride, in a solvent, such as tetrahydrofuran, at a temperature preferably between 0 ℃ and room temperatureThe process is carried out. The subsequent reaction with a compound of the formula (XXIV) is carried out in an inert solvent, for example and preferably,N,Ndimethylformamide in the presence of a base, for example sodium hydride or cesium carbonate, at temperatures ranging from room temperature to +140 ℃.

g)If X represents NH, a method analogous to that described under f) can be used. Wherein Y represents NH shown in scheme 9₂Is first converted into the corresponding carbamate, e.g. with di-tert-butyl dicarbonate or with benzyloxycarbonyl chloride, which is then reacted with a compound of formula (XXIV) (see scheme 10), wherein Z represents a leaving group, e.g. chloro, bromo or methanesulfonate. In the last reaction, the carbamate protecting group is removed again for the product of formula (I) obtained in this way, in which X represents NH. Methods for introducing and removing carbamate protecting groups are described in the chemical literature known to those skilled in the art. A compound of formula (XXIV) and a compound derived from formula (VI) [ Y = NH ] ₂]The reaction of the carbamate of the compound is carried out under reaction conditions analogous to those described under f).

h)If X represents a bond, ring N is linked to ring A via a ring nitrogen atom, A represents a pyridine ring and the group Y is linked to the carbon atom of the pyridine ring directly adjacent to the pyridine nitrogen atom, and Y represents halogen or a sulfonate, a compound of formula (VI) is reacted with a compound of formula (XXI) in which the hydrogen atom shown is linked to the nitrogen atom of ring N (cf. scheme 11). The reaction is carried out in the presence of an excess of a compound of formula (XXI) and optionally in the presence of a tertiary amine base, for example,N,Nin the presence of diisopropylethylamine. In solvents, e.g. diglyme orN-methylpyrrolidone, or tertiary amine base or the compound of formula (XXI) itself as solvent. The reaction is carried out at elevated temperatures, preferably in the temperature range from +80 ℃ to +200 ℃. Preferably, the reaction is carried out in a microwave device in a closed pressure vessel in the upper region of the temperature interval mentioned.

Scheme(s) 11 ：MethodSecond part of step A.2

[ X = bond; y = chloro, bromo, iodo, mesylate or tosylate; ring N bound via a nitrogen atom ]

i)If X represents a bond, ring N is linked to ring A via a ring nitrogen atom and the radical Y represents halogen or sulfonate and is linked to a carbon atom of the pyridine ring A in any desired position relative to the pyridine nitrogen atom, or ring A is a benzene ring, the compounds of the formula (VI) and of the formula (XXI) are reacted with one another according to scheme 11 in the presence of a palladium catalyst. Suitable palladium sources are, for example, palladium (II) acetate or tris (dibenzylidene-acetone) dipalladium (0). Ligands which may be used are, for example, 2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl, 1- [2- (dicyclohexylphosphino) ferrocenyl ]Ethyl di-tert-butylphosphine or bis (diphenylphosphino) ferrocene. The reaction is carried out in the presence of a base, for example, triethylamine or sodium tert-butoxide. Suitable solvents are, for example, toluene,N-methyl pyrrolidone or 1, 2-dimethoxyethane. The reaction is generally carried out at a temperature interval of +60 ℃ to the respective boiling points of the solvents.

The reaction to produce the product of formula (I) from intermediates of the type of formula (VII) (method a.3, scheme 3) depends on the nature of the groups Y and Z, described below. These reactions are also used correspondingly in processes B.3, C.3 and D.3.

j)The compound of formula (XXV) in which Y represents a hydroxyl group is first converted to a compound of formula (XXVI) in which Z represents a leaving group, for example, chlorine, bromine or methane sulfonate, and these are then reacted with an amine of formula (XX) to give a compound of formula (XX) in which X represents a group-NR⁶-CH₂-. The product of formula (I) was prepared (. diamond. sup.12).

Scheme(s) 12 ：Method A.3 ofLast partial step

[X=◆-NR⁶-CH₂-. diamond solid; x = hydroxy; z = leaving group]

The conversion of a compound of formula (XXV) wherein Y represents hydroxy into a compound of formula (XXVI) is carried out as follows: they are converted to compounds of formula (XXVI) by reaction with, for example, bromine in the presence of triphenylphosphine in a suitable solvent, for example, tetrahydrofuran, at room temperature to give the corresponding bromide (XXVI) [ Z = Br ]. The conversion can also be carried out, for example and preferably, with the aid of trifluoromethanesulfonic anhydride or methanesulfonic anhydride in the presence of a base, for example triethylamine or 2, 6-lutidine. These reactions are preferably carried out in dichloromethane or tetrahydrofuran at low temperatures of about-78 ℃. In this way, a compound of formula (XXVI) is obtained in which Z represents trifluoromethanesulfonate (triflate) or methanesulfonate (methanesulfonate). The compound of formula (XXVI) is then reacted with an amine of formula (XX) to produce the product of formula (I) by reaction of the reactants, for example, in dichloromethane or tetrahydrofuran, in the presence of a tertiary amine base, for example triethylamine or 2, 6-lutidine, at a temperature of-78 ℃ to room temperature. If Z represents trifluoromethanesulphonate or methanesulphonate, the reaction sequence can also be carried out as a one-pot process (Eintopfverfahren) starting from compounds of the formula (XXV) [ Y = OH ].

The compounds of the formulae (II), (III), (IV), (V), (VIII), (IX), (X), (XI), (XII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII) and (XXIV) are commercially available or are described in the literature as such, or they can be prepared by routes which are analogous to the methods published in the literature and which are obvious to the person skilled in the art. Thus, for example, wherein ring D represents 1,2,4-Oxadiazole or 1,3-The compounds of formula (V) of oxazoles can be prepared analogously to process methods B, C and D described above, and the compounds of formulae (II), (VIII), (X) and (XI) can be obtained analogously to transformation methods a.1, a.2 and a.3 using part of the procedures described in schemes 7 to 12.

For example, the compounds of the formula (I-D) according to the invention

(I-D),

Wherein rings A and E and R¹，R²，R³，R⁴，R⁵M, n and p each have the meanings given above,

and

ring N represents ring N connected to ring a via a ring nitrogen atom, as defined above,

prepared by the following steps, wherein the formula (IX)N'Hydroxy amidines

(IX)

Wherein rings E and R⁴，R⁵And p has the meaning given above,

firstly, can

[A] By condensation with pyrazolecarboxylic acids of the formula (XXVII)

(XXVII)

Wherein R is³Having the meaning given above, the use of,

to give the following formula (XXVIII) 1,2,4-Oxadiazole derivatives

(XXVIII)

Wherein rings E and R³，R⁴，R⁵And p has the meaning given above,

and which is then alkylated with a compound of formula (III) below in the presence of a base

(III),

Wherein ring a has the meaning given above,

y represents chlorine, bromine or iodine

And

z represents chlorine, bromine, iodine, methanesulfonate, trifluoromethanesulfonate or toluenesulfonate,

to give a compound of the formula (XXIX)

(XXIX)

Wherein rings A and E and R³，R⁴，R⁵P and Y have the meanings given above,

or

[B] By condensation with pyrazolecarboxylic acids of the formula (XXX)

(XXX)

Wherein rings A and R³Having the meaning given above, the use of,

and

y represents chlorine, bromine or iodine,

to give a compound of the formula (XXIX)

(XXIX)

Wherein rings A and E and R³，R⁴，R⁵P and Y have the abovementioned meanings,

and the compound of the formula (XXIX) obtained in this way is then reacted with a compound of the formula (XXXI), optionally in the presence of a palladium catalyst and/or a base

(XXXI)

Wherein rings N and R¹，R²M and N have the meanings given above and the hydrogen atoms shown are linked to the nitrogen atom of the ring N

(in this connection reference is made to method A.2 described above, in combination with the transformation method of the second partial step shown in scheme 11, and methods B.1 and B.2 with the respective reaction parameters are described there).

A large body of detailed teaching and literature information on the preparation of starting materials is also found in the experimental section in the preparation of the starting compounds and intermediates sections.

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

The compounds according to the invention are very potent inhibitors of the HIF regulatory pathway and have good bioavailability according to oral administration.

Based on their action profile, the compounds according to the invention are generally particularly suitable for the treatment of hyperproliferative diseases in humans and mammals. The compounds can inhibit, hinder, reduce or reduce cell proliferation and cell division and on the other hand increase apoptosis.

Hyperproliferative diseases which can be treated using the compounds according to the invention include, in particular, psoriasis, keloids, scars and other skin proliferative diseases, benign diseases, for example Benign Prostatic Hyperplasia (BPH), and in particular tumor disease types. In the context of the present invention, these are to be understood as meaning, in particular but not limited to, the following diseases: breast and mammary tumors (ductal and lobular forms, also in situ), respiratory tumors (small-and non-small-cell malignancies, bronchopulmonary carcinoma), cerebromas (e.g. brainstem and hypothalamus, astrocytomas, medulloblastoma, ependymoma and neuroectodermal and pineal tumors), digestive organ (oesophagus, stomach, gall bladder, small intestine, large intestine, rectum) tumors, liver tumors (especially hepatocellular carcinoma, hepato-and mixed hepato-and-bilial cancers), head and neck (larynx, hypopharynx, nasopharynx, oropharynx, lips and oral cavity) tumors, skin tumors (squamous epithelial carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer and nonmelatomatosus skin cancer), soft tissue tumors (especially soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma and rhabdomyosarcoma), tumors of the eye (especially intraocular melanomas and retinoblastomas), tumors of the endocrine and exocrine glands (such as thyroid and parathyroid glands, pancreas and salivary glands), tumors of the urinary tract (tumors of the bladder, penis, kidney, renal pelvis and ureter) and of the reproductive organs (female endometrial, cervical, ovarian, vaginal, vulval and uterine malignancies and male prostate and testicular malignancies). These also include proliferative blood diseases in solid form and as circulating blood cells, such as lymphomas, leukemias and myeloproliferative and extramyeloproliferative diseases, such as acute myeloid, acute lymphoblastic, chronic lymphocytic, chronic myelogenous and hairy cell leukemia, and aids-related lymphomas, hodgkin's lymphoma, non-hodgkin's lymphoma, cutaneous T-cell lymphoma, burkitt's tumor and lymphoma in the central nervous system.

These well-described human diseases may also arise due to comparable etiologies associated with other mammals and where the compounds of the present invention may be used to treat.

The term "treatment" is used in the context of the present invention in the conventional sense and means the care, care and care of a patient with the aim of combating, reducing, alleviating or alleviating a disease or health abnormality and improving the state of life impaired by the disease, for example, due to a cancerous disease.

The compounds according to the invention act as modulators of the HIF regulatory pathway and are therefore also suitable for the treatment of diseases which are associated with the unwanted expression of HIF transcription factors. This applies in particular to the transcription factors HIF-1. alpha. and HIF-2. alpha. The term "detrimental expression of HIF" as used herein means an abnormal physiological presence of HIF protein. This can be attributed to over-synthesis (mRNA-or translation-related), reduced degeneration or insufficient anti-regulation of the protein in the functioning of transcription factors.

HIF-1 α and HIF-2 α regulate more than 100 genes. This applies to proteins that play a role in angiogenesis and are therefore directly associated with tumors, and those that affect glucose, amino acid and lipid metabolism and cell migration, metastasis and DNA repair, or improve the survival of tumor cells by inhibiting apoptosis. Others act more indirectly by suppressing the immune response and up-regulating angiogenic factors in inflammatory cells. HIF also plays an important role in stem cells, and here in particular tumor stem cells, which are reported to have elevated HIF levels. By inhibiting the HIF regulatory pathway by the compounds of the invention, tumor stem cells (which do not have a high proliferation rate and are therefore only insufficiently affected by cytotoxic substances) are therefore also therapeutically affected (see Semenza, 2007; Weidemann and Johnson, 2008).

For tumors, cellular metabolism is not altered by HIF alone, and occurs with other pathophysiological processes of hypoxia, whether chronic or transient. HIF inhibitors-such as the compounds of the invention-are therapeutically beneficial at those points where, for example, additional damage results from adaptation of the cells to hypoxic conditions, as damaged cells may cause further damage if they do not act as intended. An example of this is the formation of epileptic foci in partially destroyed tissue following stroke. Similar conditions are found with cardiovascular disease if ischemic processes occur in the heart or in the brain due to thromboembolic events, inflammation, wounds, poisoning, or other causes. These may produce damage, such as a delay in the local mobility potential, which in turn may cause arrhythmia or chronic heart failure. In a temporary form, for example due to asphyxiation, essential hypertension may occur in certain cases, which may lead to known secondary diseases, for example stroke and myocardial infarction.

Inhibition of the HIF regulatory pathway is for example accomplished by compounds according to the invention and may therefore also be beneficial for diseases such as cardiac insufficiency, arrhythmia, myocardial infarction, asphyxia-induced hypertension, pulmonary hypertension, graft ischemia, reperfusion injury, stroke and macular degeneration, and for recovery of neurological functions after traumatic injury or severance.

Since HIF is one of the factors controlling the transition from epithelial to mesenchymal cell types, which is important in particular for the lung and kidney, the compounds according to the invention can also be used to prevent or control HIF-related fibrosis of the lung and kidney.

Further diseases for which the compounds according to the invention can be used for the treatment are inflammatory joint diseases, such as various forms of arthritis, and inflammatory bowel diseases, such as crohn's disease.

During erythropoiesis, in particular in the spleen, Chugwash polycythemia is regulated by HIF-2 α activity. The compounds according to the invention, as inhibitors of the HIF regulatory pathways, are therefore also suitable here for inhibiting excessive erythropoiesis and thus for alleviating the effects of the disease.

The compounds of the invention may furthermore be useful in the treatment of diseases associated with excessive or abnormal angiogenesis. These include, inter alia, diabetic retinopathy, ischemic retinal vein occlusion and retinopathy in preterm infants (see Aiello et al, 1994; Peer et al, 1995), age-related macular degeneration (AMD; see Lopex et al, 1996), neovascular glaucoma, psoriasis, retrolental fibroplasia, angiofibroma, inflammation, Rheumatoid Arthritis (RA), restenosis, in-stent restenosis following vascular grafts.

The increased blood supply is furthermore associated with the neogenetic tissue of the patient suffering from cancer and here leads to an increased tumor growth. The growth of new blood and lymph vessels furthermore facilitates the formation of secondary tumors and thus the spread of the tumor. New lymphatic and blood vessels are also detrimental to immune-privileged (immunoprivileged) tissues, such as allografts in the eye, which, for example, increase sensitivity to rejection. The compounds of the invention may therefore also be used for the treatment of one of the above-mentioned diseases, for example by inhibition of growth or reduction of the number of blood vessels. This can be accomplished by inhibiting endothelial cell proliferation or other mechanisms that prevent or reduce angiogenesis and by cytoreduction of apoptotic neoplastic cells.

The invention furthermore provides the use of the compounds according to the invention for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases.

The invention furthermore provides the use of the compounds according to the invention for the preparation of medicaments for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases.

The invention furthermore provides the use of the compounds according to the invention in a method for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases.

The invention furthermore provides a method for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases, in which an active amount of at least one compound according to the invention is used.

The compounds according to the invention can be used alone or, if desired, in combination with one or more other pharmacologically active substances, as long as the combination does not produce undesired and unacceptable side effects. The present invention therefore furthermore provides medicaments comprising at least one compound according to the invention and one or more further active substances, in particular for the treatment and/or prophylaxis of the abovementioned diseases.

For example, the compounds of the present invention may be used in combination with known anti-hyperproliferative, cytostatic or cytotoxic substances for the treatment of cancer diseases. The combination of the compounds according to the invention with other substances customary for cancer therapy or with radiotherapy is therefore specified in particular, since hypoxic regions of tumors respond only weakly to the conventional therapy mentioned, where the compounds of the invention exhibit in particular their activity.

Suitable active substances in the combinations which may be mentioned are, for example:

aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, alopirm, aloxi (trade name of palonosetron), altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole, anzmet, alfa bepotin, arglabin, arsenic trioxide, arnosine, 5-azacytidine, azathioprine, BCG or tide-BCG, betadine, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, 5-deoxyuridine, bortezomib, busulfan, hemoclin, campath (trade name of alemtuzumab), capecitabine, carboplatin, custard, cefesone, simox interleukin, erythromycin, chlorambucil, cisplatin, clorplatin, clodronic acid, cyclophosphamide, alexan, dacarbazine, dexamethasone, doxycycline phosphate, estradiol valerate, dinil interleukin-toxin linker, methylprednisolone, dessertraline, dexrazoxane, diethylstilbestrol, tolbutan, docetaxel, doxifluridine, doxorubicin, dronabinol, DW-166HC, erigeron, erigerot, epirubicin hydrochloride, emend, epirubicin, alfapentin, erythropoietin formulation (epo), eptaplatin, levamisole hydrochloride, micronized estradiol formulation, estradiol, estramustine sodium phosphate, ethinylestradiol, amifostine, etidronic acid, etoposide, fadrozole, farstone, filgrastim, finasteride, legumine, fluorouracil deoxynucleoside, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluorohydroxymethyltestosterone, flutamide, formestane, fosetabine, fotemustine, fulvestrant, immunophilin, gemcitabine, gemumab, gleevec, carmustine wafer, goserelin, granisetron hydrochloride, histrelin, topotecan, hydrocortisone, erythro-hydroxynonyladenine, hydroxyurea, temozolomide, idarubicin, ifosfamide, interferon- α -2 α, interferon- α -2 β, interferon- α -n1, interferon- α -n3, interferon- β, interferon- γ -1 α, interferon-2, ganlexan, iressa, irinotecan, ketrey, lentinan, letrozole, leucovorin, leuprorelin, leuprolide, levotetramisoxaglitazone, levotretinoid, levothyroxine sodium, levothyroxine sodium preparations, lomustine, lonidamine, dronabinol, methyldichloroethylamine, methylcobalamin, megestrol, melphalan, esterified estrol tablets, 6-mercaptopurine, sodium mercaptoethanesulfonate, methotrexate, metivol, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, trilostane, myocet (doxorubicin citrate liposome injection), nedaplatin, neurasta (trade name of pegylated filgrastim), neugega, neupogen, nilutamide, nonvadex (tamoxifen), NSC-631570, OCT-43, octreotide, ondansetron hydrochloride, orapred (prednisolone oral tablets), oxaliplatin, paclitaxel, dispidipered (prednisone preparations), peruvine, pexin, penfluxin, pentostatin, streptococcus (paraquat), L-arginine hydrochloride), pirarubicin, plicamycin, porfimer sodium, prednimustine, dehydroepinol, prednisone, pramlinone, procarbazine, procrit (alfa ebert injection), raltitrexed, rilobine, rhenium-186 etidronate, rituximab, wikstrom, lomustine, sulindac, octreotide, sargramostim, methylcyclohexylnitrosourea, cefurazone, sobuzosin, methylprednisolone, streptozotocin, strontium-89 chloride, synthid (trade name for the left thyroid), tamoxifen, tamsulosin, tasol, testolactone, taxotere, temozolomide, epidophyllotoxin thiophene glycoside, testosterone propionate, testified (mesterone capsule), thioguanine, tepa, thyrotropin, temustine, topotecan, toremifene, tolyturvee, tolyturveol, totivol, tretinomycin, tretinoin, trexal (methotrexate), trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, desacetylvinblastine, vinorelbine, vitamins such as ritin (virulizin), zinecard (dexrazoxane powder injection), neat stastin polymer (zinostatin stimamer), pinosyl; ABI-007, acobiprofen, actimmune (interferon gamma-1 b), affinitak (PKC-alpha inhibitor), pteridine amine, azoxifene, axolitinib, atamestane, atrasentan, avastin, BAY 43-9006 (sorafenib), CCI-779, CDC-501, celebrex, cetuximab, clinatot, cyproterone acetate, decitabine, DN-101, Adeliamycin-MTC, SLIDM, dutasteride, Elecarine, Ifluornithine, irinotecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implants, holmium-166 DOTMP, Illinophosphonic acid, interferon gamma, intron-PEG, salpilone, keyhole limpet hemocyanin, L-1582, lanreotide, lasioxifene, loxifene, clofenamide, minoxifene, phosphominoxifene, disodium phosphate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, neovastat, nolatrexed, orlamexane, onko-TCS, osidem, docetaxel, pamidronate disodium, PN-401, QS-21, quazepam, R-1549, raloxifene, ranpirnase, 13-cis-rotic acid, satraplatin, seocalcitol, T-138067, it's Savaw, taxotere (docosahexanoic acid and paclitaxel), conjugates-alpha-1, thifluzaline, tipifarnib, tirapazamine, TLK-286, toremifene, transMID-107R, valproma, vapreotide, valtartalarone, verteporipofen, vinflunine, Z-100, zoledronic acid and combinations of these.

In a preferred embodiment, the compounds of the invention may be combined with an anti-hyperproliferative agent, which may be, for example (this list is not definitive):

aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, bleomycin, busulfan, camptothecin, carboplatin, nitrosourea mustard, chlorambucil, cisplatin, levo-asparaginase, cyclophosphamide, cytarabine, dacarbazine, actinomycin, daunorubicin, diethylstilbestrol, 2',2' -difluorodeoxycytidine, docetaxel, doxorubicin (doxorubicin), epirubicin, epothilone and its derivatives, erythro-hydroxynonyladenine, ethinyl estradiol, etoposide, fludarabine phosphate, 5-fluorodeoxyuridine, 5-fluorouracil monophosphate, fluoromethyltestosterone, flutamide, hexamethylmelamine, hydroxyurea, hydroxyprogesterone caproate, idarubicin, ifosfamide, interferon, irinotecan, folinic acid, lomustine, mechlorethamine, megestrol, melphalan, 6-mercaptopurine, mercaptoethanesulfonic acid sodium, methotrexate, mitomycin C, mitotane, mitoxantrone, paclitaxel, pentostatin, N-phosphonoacetyl L-aspartic acid (PALA), plicamycin, dehydrocortisol, prednisone, procarbazine, raloxifene, methylcyclohexylnitrosurea, streptozotocin, tamoxifen, epipodophyllotoxin thiophenoside, testosterone propionate, 2-aminopurine-6-thiol, thiotepa, topotecan, trimethylmelamine, uracilPyridine nucleosides, vinblastine, vincristine, desacetylvinblastide and vinorelbine.

The compounds according to the invention can also be combined in a very promising manner with biological therapies, such as antibodies (e.g. avastin, rituximab, erbitux, herceptin) and recombinant proteins, which additionally or synergistically enhance the effect of HIF signaling pathway transmission inhibition.

Inhibitors of the HIF regulatory pathway, such as compounds according to the invention, may also be combined with other anti-angiogenesis therapies, e.g., avastin, axitinib, DAST, cediranib, sorafenib, or sunitinib. Combinations with inhibitors of the proteasome and mTOR and with inhibitors of the anti-hormonal drugs and enzymes of the steroid metabolism are particularly suitable because of their favorable side-effect profile.

In general, the following objectives can be pursued with the compounds of the present invention in combination with other agents having cytostatic or cytotoxic effects:

● improved activity in respect of slowing down the growth of the tumor, in respect of reducing its size or even in respect of its complete elimination compared to treatment with the active compound alone,

● the possibility of using chemotherapeutic drugs at lower doses than monotherapy;

● the possibility of a more tolerable treatment with fewer side effects than the administration alone;

● possibility of treating a broad spectrum of neoplastic diseases;

● achieve a more rapid response to treatment;

● longer survival time of the patient compared to modern standard treatments.

The compounds according to the invention can furthermore be used in combination with radiotherapy and/or surgery.

The invention also provides medicaments comprising at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable auxiliary substances, and the use thereof for the purposes mentioned above.

The compounds according to the invention may act systemically and/or locally. They can be administered for this purpose in a suitable manner, for example orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as implants or stents.

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

Acting according to the prior art, administration forms which release the compounds according to the invention rapidly and/or in a modified manner and which comprise the compounds according to the invention in crystalline and/or amorphous and/or dissolved form are suitable for oral administration, for example tablets (uncoated or sugar-coated tablets, for example barriers which are resistant to gastric juices or dissolve or are insoluble in a delayed manner and control the release of the compounds according to the invention), tablets or film/starch films, films/lyophilisates or capsules which disintegrate rapidly in the oral cavity (for example hard or soft capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be carried out by bypassing the absorption step (e.g., intravenous, intra-arterial, intracardiac, intraspinal or intralumbar) or by including absorption at the same time (e.g., intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal). Administration forms suitable for parenteral administration are, in particular, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For further administration routes such as inhalation dosage forms (in particular inhalants and nebulisers), nasal drops, solutions or sprays, tablets, films/starch films or capsules for lingual, sublingual or buccal administration, suppositories, otic or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal dosage forms (e.g. patches), emulsions, pastes, foams, dusting powders, implants or stents are suitable.

Oral and parenteral administration, in particular oral and intravenous administration, are preferred.

The compounds according to the invention can be converted into the administration forms mentioned. This can be carried out in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable auxiliary substances. These include, in particular, carrier substances (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium lauryl sulfate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (for example antioxidants, for example ascorbic acid), colorants (for example inorganic pigments, for example iron oxide) and flavor and/or odor improvers.

In general, it has proven advantageous in the case of parenteral administration to administer amounts of from about 0.001 to 1mg/kg, preferably from about 0.01 to 0.5mg/kg, of body weight in order to achieve effective results. In the case of oral administration, the dosage is about 0.01 to 100mg/kg, preferably about 0.01 to 20mg/kg and very particularly preferably 0.1 to 10mg/kg of body weight.

However, it may be necessary to deviate from the amounts mentioned and, in particular, depend on the body weight, the route of administration, the individual behaviour towards the active substance, the nature of the preparation and the point or interval at which administration takes place. It may therefore sometimes be sufficient to administer less than the minimum amount mentioned above, while in other cases the upper limit mentioned must be exceeded. In the case of relatively large amounts, it may be appropriate to divide these into several individual doses throughout the day.

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

The percentage data in the following tests and examples are weight percentages unless otherwise indicated; parts are parts by weight. The solvent ratio, dilution ratio and concentration data for the liquid/liquid solution in all cases relate to volume.

A. Examples of the embodiments

Abbreviations and acronyms:

abs

aq. containing water

Boc Tertiary amine-butoxycarbonyl group

Ex. examples

Bu butyl

approx. In the approximation that the difference between the first and second values,about

CI chemical ionization (in MS)

d doublet (in NMR)

d days

TLC thin layer chromatography

DCI direct chemical ionization (in MS)

Bimodal peak dd (in NMR)

DMAP 4-N,N-dimethylaminopyridine

DME 1, 2-dimethoxyethane

DMF dimethyl formamide

DMSO dimethyl sulfoxide

double peaks of dt Tri-peaks (in NMR)

of th. theory (chemical yield)

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

ee enantiomeric excess

EI Electron impact ionization (in MS)

eq. equivalent

ESI electrospray ionization (in MS)

Et Ethyl group

GC gas chromatography

h hours

HOBt 1-hydroxy-1H-benzotriazole hydrate

HPLC high pressure, high performance liquid chromatography

ⁱPr isopropyl group

LC-MS liquid chromatography-mass spectrometry combination

m multiplet (in NMR)

min for

MPLC Medium pressure liquid chromatography (by silica gel; also known as "flash chromatography")

MS Mass Spectrometry

NMP N-methyl-2-pyrrolidone

NMR nuclear magnetic resonance spectrum

Pd/C on activated carbon

PEG polyethylene glycol

Pr propyl group

quartert quartet (in NMR)

quint quintet (in NMR)

R_fRetention index (in TLC)

RT Room temperature

R_tResidence time (in HPLC)

s singlet (in NMR)

sept heptads (in NMR)

t triplet (in NMR)

^tBu Tertiary amine-butyl radical

TFA trifluoroacetic acid

THF tetrahydrofuran

UV ultraviolet spectrum

v/v (of solution) volume to volume ratio

tog.

HPLC Method：

Method A

The instrument comprises the following steps: HP 1100 with DAD detection; column: kromasil 100 RP-18, 60mm × 2.1mm, 3.5 μm; eluent A: 5ml perchloric acid (70% strength)/l water, eluent B: acetonitrile; gradient: 0min 2% B → 0.5min 2% B → 4.5min 90% B → 6.5min 90% B → 6.7min 2% B → 7.5min 2% B; flow rate: 0.75 ml/min; column temperature: 30 ℃; and (4) UV detection: 210 nm.

Method B

The instrument comprises the following steps: HP 1100 with DAD detection; column: kromasil 100 RP-18, 60mm × 2.1mm, 3.5 μm; eluent A: 5ml perchloric acid (70% strength)/l water, eluent B: acetonitrile; gradient: 0min 2% B → 0.5min 2% B → 4.5min 90% B → 9min 90% B → 9.2min 2% B → 10min 2% B; flow rate: 0.75 ml/min; column temperature: 30 ℃; and (4) UV detection: 210 nm.

LC/MS The method comprises the following steps:

Method C

device type MS: micromass ZQ; device type HPLC: HP 1100 Series; UV DAD; column: phenomenex Gemini 3 mu, 30mm multiplied by 3.00 mm; eluent A: 1 l of water +0.5ml of 50% strength formic acid, eluent B: 1 l acetonitrile +0.5ml 50% strength formic acid; gradient: 0.0min 90% A → 2.5min 30% A → 3.0min 5% A → 4.5min 5% A; flow rate: 0.0min 1ml/min → 2.5min/3.0min/4.5min 2 ml/min; oven: 50 ℃; and (4) UV detection: 210 nm.

Method D

Device type MS: waters Micromass Quattro Micro; device type HPLC: agilent 1100 Series; column: thermo Hypersil GOLD 3 μ, 20mm × 4 mm; eluent A: 1 l of water +0.5ml of 50% strength formic acid, eluent B: 1 l acetonitrile +0.5ml 50% strength formic acid; gradient: 0.0min 100% A → 3.0min 10% A → 4.0min 10% A → 4.01min 100% A → 5.00min 100% A; oven: 50 ℃; flow rate: 2 ml/min; and (4) UV detection: 210 nm.

Method E

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

Method F

The instrument comprises the following steps: micromass Quattro Premier with Waters UPLC Acquity; column: thermo Hypersil GOLD 1.9 μ, 50mm × 1 mm; eluent A: 1 l of water +0.5ml of 50% strength formic acid, eluent B: 1 l acetonitrile +0.5ml 50% strength formic acid; gradient: 0.0min 90% A → 0.1min 90% A → 1.5min 10% A → 2.2min 10% A; flow rate: 0.33 ml/min; oven: 50 ℃; and (4) UV detection: 210 nm.

Method G

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

Method H

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

Method I

The instrument comprises the following steps: waters Acquity SQD UPLC System; column: waters Acquity UPLC HSS T31.8 μm, 50mm × 1 mm; eluent A: 1 l of water +0.25ml of 99% strength formic acid, eluent B: 1 l acetonitrile +0.25ml 99% strength formic acid; gradient: 0.0min 90% A → 1.2min 5% A → 2.0min 5% A; flow rate: 0.40 ml/min; oven: 50 ℃; and (4) UV detection: 210-400 nm.

Method J

And (4) an instrument MS: waters ZQ 2000; HPLC (high Performance liquid chromatography) of an instrument: agilent 1100, 2-column cycle; an automatic sampler: HTC PAL; column: YMC-ODS-AQ, 50 mm. times.4.6 mm, 3.0 μm; eluent A: water +0.1% formic acid, eluent B: acetonitrile +0.1% formic acid; gradient: 0.0min 100% A → 0.2min 95% A → 1.8min 25% A → 1.9min 10% A → 2.0min 5% A → 3.2min 5% A → 3.21min 100% A → 3.35min 100% A; oven: 40 ℃; flow rate: 3.0 ml/min; and (4) UV detection: 210 nm.

Method K

And (4) an instrument MS: waters SQD; HPLC (high Performance liquid chromatography) of an instrument: waters UPLC; column: zorbax SB-Aq (Agilent), 50 mm. times.2.1 mm, 1.8 μm; eluent A: water +0.025% formic acid, eluent B: acetonitrile +0.025% formic acid; gradient: 0.0min 98% A → 0.9min 25% A → 1.0min 5% A → 1.4min 5% A → 1.41min 98% A → 1.5min 98% A; oven: 40 ℃; flow rate: 0.60 ml/min; and (4) UV detection: DAD, 210 nm.

GC/MS The method comprises the following steps:

Method L

the instrument comprises the following steps: micromass GCT, GC 6890; column: restek RTX-35, 15 m.times.200. mu.m.times.0.33. mu.m; constant helium flow rate: 0.88 ml/min; oven: 70 ℃; an inlet: 250 ℃; gradient: 70 ℃, 30 ℃/min → 310 ℃ (hold for 3 min).

Method M

The instrument comprises the following steps: micromass GCT, GC 6890; column: restek RTX-35, 15 m.times.200. mu.m.times.0.33. mu.m; constant helium flow rate: 0.88 ml/min; oven: 70 ℃; an inlet: 250 ℃; gradient: 70 ℃, 30 ℃/min → 310 ℃ (12 min hold).

Preparation of HPLC The method comprises the following steps:

Method N

column: GROM-SIL 120 ODS-4 HE, 10 μm, 250mm × 30 mm; mobile phase and gradient program: acetonitrile/0.1% aqueous formic acid 10: 90 (0-3 min), acetonitrile/0.1% aqueous formic acid 10: 90 → 95: 5 (3-27 min), acetonitrile/0.1% aqueous formic acid 95: 5 (27-34 min), acetonitrile/0.1% aqueous formic acid 10: 90 (34-38 min); flow rate: 50 ml/min; temperature: 22 ℃; and (4) UV detection: 254 nm.

Method O

Column: reprosil C18, 10 μm, 250mm × 30 mm; mobile phase and gradient program: acetonitrile/0.1% aqueous trifluoroacetic acid 10: 90 (0-2 min), acetonitrile/0.1% aqueous trifluoroacetic acid 10: 90 → 90: 10 (2-23 min), acetonitrile/0.1% aqueous trifluoroacetic acid 90: 10 (23-28 min), acetonitrile/0.1% aqueous trifluoroacetic acid 10: 90 (28-30 min); flow rate: 50 ml/min; temperature: 22 ℃; and (4) UV detection: 210 nm.

Method P

Column: reprosil C18, 10 μm, 250mm × 30 mm; mobile phase and gradient program: acetonitrile/0.1% aqueous ammonia 20: 80 (0-3 min), acetonitrile/0.1% aqueous ammonia 20: 80 → 98: 2 (3-35 min), acetonitrile/0.1% aqueous ammonia 98: 2 (35-40 min); flow rate: 50 ml/min; temperature: 22 ℃; and (4) UV detection: 210 nm.

LC/MS The method comprises the following steps:

Method Q

device type MS: waters ZQ; device type HPLC: agilent 1100 Series; UV DAD; column: thermo Hypersil GOLD 3 μ, 20mm × 4 mm; eluent A: 1 l of water +0.5ml of 50% strength formic acid, eluent B: 1 l acetonitrile +0.5ml 50% strength formic acid; gradient: 0.0min 100% A → 3.0min 10% A → 4.0min 10% A → 4.1min 100% A (flow rate 2.5 ml/min); oven: 55 ℃; flow rate: 2 ml/min; and (4) UV detection: 210 nm.

For all preparations there are no reactants or reagents explicitly described hereinafter which are commercially available from commonly available sources. For all other preparations also reactants or reagents which are not described below and are not commercially available or are obtained from generally not available sources, reference is made to the publications in which their preparation is described.

Initial compounds and intermediates:

examples 1A

N'-hydroxy-4- (1, 1, 1-trifluoro-2-methylpropan-2-yl) benzoylimine amide

Step (ii) of 1 ： 2- (4-bromophenyl) -1,1, 1-trifluoropropan-2-ol

First a suspension of (dimethyl) titanium dichloride in a heptane/dichloromethane mixture was prepared as follows: A1M solution of 100ml (100 mmol) of titanium tetrachloride in dichloromethane was cooled to-30 ℃, 100ml (100 mmol) of a 1M solution of dimethylzinc in heptane was added dropwise and the mixture was subsequently stirred at-30 ℃ for 30 min. After the suspension is cooledIt was cooled to-40 ℃ and a solution of 10g (39.5 mmol) of 1- (4-bromophenyl) -2,2, 2-trifluoroacetone in 50ml of dichloromethane was added. The mixture was then stirred at-40 ℃ for 5min, then the temperature was allowed to reach RT and the mixture was stirred at RT for a further 2 h. 50ml of water was slowly dropped while cooling with ice, and then further diluted with 300ml of water. Two extractions with dichloromethane were performed, the combined dichloromethane phases were washed once with water, dried over anhydrous magnesium sulfate and filtered and the solvent was removed on a rotary evaporator. The residue is purified by column chromatography over silica gel (mobile phase: cyclohexane/ethyl acetate 85: 15). 10.5g (100% of theory) of the title compound are obtained according to ¹H-NMR, still containing residues of solvent.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.52 (d, 2H), 7.47 (d, 2H), 1.76 (s, 3H).

LC/MS (method C, ESIpos) R_t = 2.27 min, m/z = 268 [M+H]⁺。

Step (ii) of 2 ： Methanesulfonic acid 2- (4-bromophenyl) -1,1, 1-trifluoropropan-2-yl ester

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

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.58 (d, 2H), 7.43 (d, 2H), 3.16 (s, 3H), 2.28 (s, 3H).

LC/MS (method D, ESIpos) R_t = 2.32 min, m/z = 364 [M+NH₄]⁺。

Step (ii) of 3 ： 1-bromo-4- (1, 1, 1-trifluoro-2-methylpropan-2-yl) benzene

12.4g (35.72 mmol) of the compound obtained in example 1A/step 2 are initially added to 250ml of dichloromethane and the mixture is cooled to 0 ℃. Then 35.7ml (71.44 mmol) of a solution of 2M trimethylaluminum are slowly added dropwise at 0 ℃ while stirring, and the mixture is then allowed to reach RT and subsequently stirred for a further 1.5h at RT. To the mixture was slowly added dropwise 120ml of a saturated aqueous sodium bicarbonate solution, followed by 40ml of a saturated aqueous sodium chloride solution. The mixture was filtered through celite and the celite was washed twice with dichloromethane. The combined dichloromethane phases were washed once with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and the solvent was removed on a rotary evaporator. 8.69g (87% of theory) of the title compound are obtained in 95% purity.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.49 (d, 2H), 7.33 (d, 2H), 1.55 (s, 6H).

LC/MS (method E, ESIpos) R_t= 2.54 min, no ionization.

GC/MS (method L, EI) R_t = 3.48 min, m/z = 266 [M]⁺。

Step (ii) of 4 ： 4- (1, 1, 1-trifluoro-2-methylpropan-2-yl) benzonitrile

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

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.68 (d, 2H), 7.62 (d, 2H), 1.60 (s, 6H).

GC/MS (method L, EI) R_t = 3.83 min, m/z = 213 [M]⁺。

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

A mixture of 2.40g (11.26 mmol) of the compound from example 1A/step 4, 1.72g (24.77 mmol) of hydroxylamine hydrochloride and 3.45ml (24.77 mmol) of triethylamine in 60ml of ethanol is stirred at reflux for 1 h. After cooling to RT, the solvent was removed on a rotary evaporator. Ethyl acetate was added to the residue and the solids present were filtered off. The ethyl acetate solution was washed with water and a saturated aqueous sodium chloride solution in this order, dried over anhydrous magnesium sulfate and filtered. After removal of the solvent, the oil obtained was triturated with petroleum ether. After the resulting solid has been filtered off with suction and dried under high vacuum, 2.65g (96% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.0 (s, width, 1H), 7.62 (d, 2H), 7.52 (d, 2H), 4.88 (s, width, 2H), 1.60 (s, 6H).

LC/MS (method D, ESIpos) R_t = 1.34 min, m/z = 247 [M+H]⁺。

Examples 2A

4- (2-Fluoropropan-2-yl) -N' -hydroxybenzoylimide amides

Step (ii) of 1 ： 4- (2-Fluoropropan-2-yl) benzonitrile

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

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.57 (d, 2H), 7.48 (d, 2H), 1.72 (s, 3H), 1.68 (s, 3H).

LC/MS (method D, ESIpos) R_t = 2.12 min, m/z = 163 [M+H]⁺。

Step (ii) of 2 ： 4- (2-Fluoropropan-2-yl) -N' -hydroxybenzoylimide amides

756mg (93% of theory) of the title compound are obtained from 675mg (4.14 mmol) of the compound from example 2A/step 1 by the method described under example 1A/step 5.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 7.62 (d, 2H), 7.41 (d, 2H), 4.89 (s, width, 2H), 1.72 (s, 3H), 1.68 (s, 3H).

LC/MS (method D, ESIpos) R_t = 1.04 min, m/z = 197 [M+H]⁺。

Examples 3A

N'-hydroxy radical4- [ (trifluoromethyl) sulfonyl ] -group]Benzoylimide amides

By the method described under example 1A/step 5, starting from 4.60g (19.56 mmol) of 4- [ (trifluoromethyl) sulfonyl group]Benzonitrile [ w, Su,Tetrahedron. Lett. 1994，35 （ 28 ），4955-4958]5.08g (97% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 10.26 (s, 1H), 8.13 (dd, 4H), 6.12 (s, 2H).

LC/MS (method D, ESIpos) R_t = 1.57 min, m/z = 269 [M+H]⁺。

Examples 4A

N'-hydroxy-4- (3-methyloxetan-3-yl) benzoylimine amide

Step (ii) of 1 ： [4- (dibenzylamino) phenyl group]Boric acid

Under inert conditions, 60g (17.03 mmol) of anhydrous THF are initially added to a mixture of 75ml of anhydrous diethyl ether and 75ml of anhydrous THFN,N-dibenzyl-4-bromobenzeneAmines [ t, Saitoh, et al,J. Am. Chem. Soc. 2005，127 （ 27 ），9696-9697]the solution of (1). To this solution was added dropwise a 1.6 molar solution of 13.9ml (22.14 mmol) of n-butyllithium in hexane at-78 ℃. When the addition had ended, the mixture was stirred at-78 ℃ for 60min before 6.3ml (27.25 mmol) of triisopropyl borate were added dropwise at-78 ℃. The reaction mixture was allowed to reach RT for a further 15min at-78 ℃. After stirring for 3h at RT, 18ml of 2M hydrochloric acid are added and the resulting mixture is stirred vigorously for 20min at RT. After dilution with about 200ml of water, the mixture was extracted three times with about 200ml of ethyl acetate each time. The combined organic extracts were washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and the solvent was removed on a rotary evaporator. The oily residue obtained is triturated with a mixture of 50ml of tert-butyl methyl ether and 50ml of pentane. After having filtered off the solid produced with suction and dried under high vacuum, 3.91g (72% of theory, purity 90%) of the title compound are obtained, which are used in the next stage without further purification.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 7.58 (d, 2H), 7.32-7.30 (m, 4H), 7.27-7.23 (m, 6H), 6.66 (d, 2H), 4.70 (s, 4H).

HPLC (method A) R_t = 4.35 min.

MS (ESIpos): m/z = 318 [M+H]⁺。

Step (ii) of 2 ： {3- [4- (dibenzylamino) phenyl]Oxetazedin-3-yl } acetic acid ethyl ester

To a solution of 304mg (0.616 mmol) of (1, 5-cyclooctadiene) rhodium (I) chloride dimer in 30ml of 1, 4-bisTo the solution in alkane was added 10.7ml (16.0 mmol) of 1.5M potassium hydroxide solution. Then 1.75g (12.31 mmol) of oxetan-3-alkylideneacetic acid ethyl ester [ G. Wuitschik et al, Angew. chem. int. Ed. Engl. 2006, 45 (46), 7736-7739-]In 1ml of 1, 4-bisSolution in an alkane and in 60ml of 1, 4-bis3.91g (12.31 mmol) of the compound from example 4A/step 1 in an alkane. The reaction mixture was stirred at RT for 6 h. It is then diluted with about 200ml of water and extracted three times with about 200ml of ethyl acetate each time. The combined organic extracts were washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and the solvent was removed on a rotary evaporator. The crude product obtained is purified by MPLC (silica gel, mobile phase: cyclohexane/ethyl acetate 20: 1, (5: 1.) 3.51g (67% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.33-7.30 (m, 4H), 7.27-7.23 (m, 6H), 6.97 (d, 2H), 6.69 (d, 2H), 4.94 (d, 2H), 4.81 (d, 2H), 4.62 (s, 4H), 4.00 (quart, 2H), 3.04 (s, 2H), 1.11 (t, 3H).

LC/MS (method E, ESIpos) R_t = 2.57 min, m/z = 416 [M+H]⁺。

Step (ii) of 3 ： 2- {3- [4- (dibenzylamino) phenyl]Oxetazedin-3-yl } ethanol

To a solution of 2.90g (6.98 mmol) of the compound from example 4A/step 2 in 145ml of anhydrous THF are added dropwise, under inert conditions and at a temperature of 0 deg.C, 4.9ml (4.88 mmol) of a 1M solution of lithium aluminum hydride in THF. When the dropwise addition had ended, the reaction mixture was stirred at 0 ℃ for 1.5 h. Then 2g of diatomaceous earth and 2ml of water are carefully added. The heterogeneous mixture was suction filtered through a paper filter. The filtrate was diluted with about 250ml of water and extracted three times with about 250ml of ethyl acetate each time. The combined organic extracts were washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and the solvent was removed on a rotary evaporator. The crude product obtained is purified by MPLC (silica gel, mobile phase: cyclohexane/ethyl acetate 4: 1). 2.34g (87% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.36-7.31 (m, 4H), 7.27-7.22 (m, 6H), 6.88 (d, 2H), 6.71 (d, 2H), 4.93 (d, 2H), 4.71 (d, 2H), 4.63 (s, 4H), 3.55 (quart, 2H), 2.29 (t, 2H), 1.12 (t, 1H).

HPLC (method B) R_t = 3.98 min.

MS (DCI, NH₃): m/z = 374 [M+H]⁺.

LC/MS (E, ESIpos): R_t = 2.15 min, m/z = 374 [M+H]⁺。

Step (ii) of 4 ： {3- [4- (dibenzylamino) phenyl]Oxetadin-3-yl) acetaldehyde

807. mu.l of anhydrous DMSO is added dropwise to a solution of 496. mu.l (5.68 mmol) of oxalyl chloride in 5ml of anhydrous dichloromethane at-78 ℃ under inert conditions. After 20min, 1.93g (5.17 mmol) of the compound from example 4A/step 3 in 5ml of anhydrous dichloromethane are slowly added dropwise at the same temperature, after stirring for 60 min at-78 ℃ 3.7ml (26.87 mmol) of anhydrous triethylamine are added dropwise. After a further 10min at this temperature, the reaction mixture was warmed to RT. The mixture was then added to a suction filter filled with silica gel and filtered first with cyclohexane and then with cyclohexane/ethyl acetate 7: 1 → 1: 1 elution is carried out. The product fractions were combined and evaporated to dryness and the residue was taken up in ethyl acetate. The washing was carried out successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and the solvent was removed on a rotary evaporator. 1.81g (92% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 9.69 (t, 1H), 7.34-7.31 (m, 4H), 7.28-7.23 (m, 6H), 6.97 (d, 2H), 6.70 (d, 2H), 5.00 (d, 2H), 4.72 (d, 2H), 4.63 (s, 4H), 3.18 (d, 2H).

HPLC (method B) R_t = 4.61 min.

MS (DCI, NH₃): m/z = 372 [M+H]⁺.

LC/MS (method F, ESIpos) R_t = 1.43 min, m/z = 372 [M+H]⁺。

Step (ii) of 5 ： N,N-dibenzyl-4- (3-methyloxetan-3-yl) aniline

A solution of 1.81g (4.87 mmol) of the compound from example 4A/step 4 and 13.57g (14.62 mmol) of tris (triphenylphosphine) rhodium (I) chloride in 240ml of toluene is heated for one hour under reflux under inert conditions. After cooling to RT, the insoluble constituents were filtered off. The solvent was removed on a rotary evaporator and the residue was purified by MPLC (silica gel, cyclohexane/ethyl acetate 20: 1 → 5: 1). 1.36g (73% of theory, purity approx. 90%) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.35-7.31 (m, 4H), 7.27-7.24 (m, 6H), 7.07 (d, 2H), 6.72 (d, 2H), 4.90 (d, 2H), 4.64 (s, 4H), 4.55 (d, 2H), 1.96 (s, 3H).

LC/MS (method F, ESIpos) R_t = 1.55 min, m/z = 344 [M+H]⁺。

Step (ii) of 6 ： 4- (3-Methyloxyoxetan-3-yl) anilines

In a flow-through hydrogenation unit ("H-Cube" from Thales Nano, Budapest, Hungary) (condition: 10% Pd/C catalyst, "full H₂"mode, 1ml/min, 50 ℃) A solution of 1.35g (3.93 mmol) of the compound from example 4A/step 5 in 135ml of ethanol was hydrogenated. After removal of the solvent on a rotary evaporator, the crude product is purified by MPLC (silica gel, cyclohexane/ethyl acetate 4: 1 → 2: 1). 386mg (60% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 7.03 (d, 2H), 6.69 (d, 2H), 4.92 (d, 2H), 4.58 (d, 2H), 3.63 (s, Width, 2H), 1.69 (s, 3H).

LC/MS (method D, ESIpos) R_t = 0.77 min, m/z = 164 [M+H]⁺。

Step (ii) of 7 ： 4- (3-Methyloxyoxetan-3-yl) benzonitrile

To a solution of 375mg (2.30 mmol) of the compound from example 4A/step 6 in 17ml of water at 0 ℃ are first added 1.7ml (20.7 mmol) of concentrated hydrochloric acid and then a solution of 159mg (2.30 mmol) of sodium nitrite in 5ml of water is added dropwise. The mixture is stirred for 30min at 0 ℃ before 1.1g (10.3 mmol) of solid sodium carbonate are added in portions. The solution obtained in this way is added dropwise at 0 ℃ to a solution of 257mg (2.87 mmol) of copper (I) cyanide and 464mg (7.12 mmol) of potassium cyanide in 16ml of toluene/water (2: 1). The reaction mixture was stirred at 0 ℃ for 1 h. The mixture was then warmed to RT. The organic phase is then separated off and washed successively with water and saturated sodium chloride solution. After the solvent had been separated off on a rotary evaporator, the crude product was purified by MPLC (silica gel, cyclohexane/ethyl acetate 10: 1 → 2: 1). 390mg (83% of theory, purity approx. 84%) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.66 (d, 2H), 7.31 (d, 2H), 4.92 (d, 2H), 4.68 (d, 2H), 1.73 (s, 3H).

GC/MS (method L, EIpos) R_t = 5.45 min, m/z = 173 (M)⁺。

Step (ii) of 8 ： N'-hydroxy-4- (3-methyloxetan-3-yl) benzoylimine amide

297mg (74% of theory) of the title compound are obtained from 375mg (1.83 mmol) of the compound from example 4A/step 7 by the method described under example 1A/step 5.

¹H-NMR (400 MHz, DMSO-d₆δ/ppm) 9.59 (s, 1H), 7.64 (d, 2H), 7.23 (d, 2H), 5.79 (s, width, 2H), 4.80 (d, 2H), 4.53 (d, 2H), 1.62 (s, 3H).

HPLC (method A) R_t = 2.74 min.

MS (DCI, NH₃): m/z = 207 [M+H]⁺。

Example 5A

4- (3-Fluorooxetan-3-yl) -N' -hydroxybenzenecarboximidamides

Step (ii) of 1 ： 4- (3-hydroxyoxetan-3-yl) benzonitrile

To a solution of 5.0g (21.8 mmol) of 4-iodobenzonitrile in 100ml of anhydrous THF at-40 ℃ are added dropwise, under inert conditions, 11ml (21.8 mmol) of a 2M solution of isopropylmagnesium chloride in diethyl ether. After the mixture had been stirred at the same temperature for 1.5h, cooled to-78 ℃ and slowly added with the aid of a cannula (Kan ü le) to 2.95g (32.7 mmol, 80% in dichloromethane) of 3-oxoepoxybutane [ G. Wuitschik ] which had likewise been cooled to-78 ℃Etc. of，Angew. Chem. Int. Ed. Engl. 2006，45 （ 46 ），7736-7739]Dissolution in 100ml of anhydrous THFIn the liquid. When the addition had ended, the reaction mixture was first stirred at-78 ℃ for 10min, then at 0 ℃ for 2h and finally at RT for 30 min. Then a few ml of saturated aqueous ammonium chloride solution are added. Most of the solvent was then removed on a rotary evaporator. The residue obtained is diluted with 200ml of water and extracted three times with approximately 200ml of ethyl acetate each time. The combined organic extracts were washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and the solvent was removed on a rotary evaporator. The crude product obtained was purified by purification from cyclohexane/ethyl acetate 10: and (1) crystallizing and purifying. 2.42g (63% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 7.88 (d, 2H), 7.80 (d, 2H), 6.63 (s, 1H), 4.79 (d, 2H), 4.65 (d, 2H).

HPLC (method A) R_t = 3.09 min.

MS (DCI, NH₃): m/z = 193 [M+NH₄]⁺。

Step (ii) of 2 ： 4- (3-Fluorooxetan-3-yl) benzonitrile

To a suspension of 600mg (3.43 mmol) of the compound from example 5A/step 1 in 55ml of dichloromethane are added dropwise, under inert conditions, at-78 ℃ a solution of 662mg (4.11 mmol) of diethylaminosulfur trifluoride (DAST) in 5ml of dichloromethane. After 30min at-78 ℃, the reaction mixture was very rapidly warmed to-20 ℃ with the aid of an ice/water bath. After about 30 seconds, 20ml of 1M sodium hydroxide solution were added and the mixture allowed to warm to RT. After dilution with 150ml of water, the mixture is extracted three times with approximately 50ml of diethyl ether each time. 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, cyclohexane/ethyl acetate 8: 1). 495mg (82% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.76 (d, 2H), 7.73 (d, 2H), 5.15 (dd, 2H), 4.81 (dd, 2H).

LC/MS (method D, ESIpos) R_t = 1.59 min, m/z = 178 [M+H]⁺。

Step (ii) of 3 ： 4- (3-fluorooxetan-3-yl) -N'-hydroxybenzoylimidic amides

470mg (86% of theory) of the title compound are obtained from 450mg (2.54 mmol) of the compound from example 5A/step 2 by the method described under example 1A/step 5.

¹H-NMR (400 MHz, DMSO-d₆δ/ppm) 9.71 (s, 1H), 7.77 (d, 2H), 7.54 (d, 2H), 5.87 (width s, 2H), 4.97 (dd, 2H), 4.91 (dd, 2H).

HPLC (method A) R_t = 2.64 min.

MS (DCI, NH₃): m/z = 211 [M+H]⁺.

LC/MS (method D, ESIpos) R_t = 0.80 min, m/z = 211 [M+H]⁺。

Examples 6A

N'-hydroxy-4- (3-methoxyoxetan-3-yl) benzoylimine amide

Step (ii) of 1 ： 4- (3-Methyloxyoxetan-3-yl) benzonitrile

To a solution of 600mg (3.43 mmol) of the compound from example 5A/step 1 in 12.5ml of anhydrous DMF at 5 ℃ are added 151mg (3.77 mmol) of a 60% strength dispersion of sodium hydride in mineral oil. The mixture was stirred at 5 ℃ for 1h, then 256. mu.l (4.11 mmol) of methyl iodide were added. The reaction mixture is then brought to RT, 15 minutes later 150ml of water are added and the mixture is extracted twice with approximately 150ml of diethyl ether each time. The combined organic extracts were dried over anhydrous magnesium sulfate. After filtration and removal of the solvent on a rotary evaporator, the residue obtained is purified by MPLC (silica gel, cyclohexane/ethyl acetate 20: 1 → 4: 1). 566mg (87% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 7.92 (d, 2H), 7.68 (d, 2H), 4.81 (d, 2H), 4.74 (d, 2H), 3.07 (s, 3H).

HPLC (method A) R_t = 3.63 min.

MS (DCI, NH₃): m/z = 207 [M+NH₄]⁺.

LC/MS (method D, ESIpos) R_t = 1.50 min, m/z = 190 [M+H]⁺。

Step (ii) of 2 ： N'-hydroxy-4- (3-methoxyoxetan-3-yl) benzoylimine amide

520mg (89% of theory) of the title compound are obtained from 500mg (2.64 mmol) of the compound from example 6A/step 1 by the method described under example 1A/step 5.

¹H-NMR (400 MHz, DMSO-d₆δ/ppm) 9.67 (s, 1H), 7.73 (d, 2H), 7.43 (d, 2H), 5.83 (s, 2H) wide, 4.77 (m, 4H), 3.03 (s, 3H).

HPLC (method A) R_t = 2.54 min.

MS (DCI, NH₃): m/z = 223 [M+H]⁺。

Examples 7A

4- (4-Fluorotetrahydro-2H-pyran-4-yl) -N'-hydroxybenzoylimidic amides

Step (ii) of 1 ： 4- (4-Hydroxytetrahydro-2)H-pyran-4-yl) benzonitrile

By following the procedure in example 5A/step 1The procedure described, 25.0g (109 mmol) of 4-iodobenzonitrile and 16.4g (164 mmol) of tetrahydro-4HPyran-4-one to give 7.56g (34% of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆, 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 A) R_t = 3.35 min.

MS (DCI, NH₃): m/z = 204 [M+H]⁺, 221 [M+NH₄]⁺。

Step (ii) of 2 ： 4- (4-Fluorotetrahydro-2)H-pyran-4-yl) benzamides

By the method described under example 5A/step 2, 6.5g (31.98 mmol) of the compound from example 7A/step 1 were reacted to yield 3.73g (57% of theory) of the title compound.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.68 (d, 2H), 7.50 (d, 2H), 3.98-3.83 (m, 4H), 2.23-2.05 (m, 2H), 1.91-1.85 (m, 2H).

HPLC (method A) R_t = 4.04 min.

MS (DCI, NH₃): m/z = 223 [M+NH₄]⁺。

Step (ii) of 3 ： 4- (4-Fluorotetrahydro-2)H-pyran-4-yl) -N'-hydroxybenzoylimidic amides

By the method described under example 1A/step 5, 3.57g (88% of theory) of the title compound are obtained from 3.5g (17.05 mmol) of the compound from example 7A/step 2.

¹H-NMR (500 MHz, DMSO-d₆, 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 A) R_t = 3.06 min.

MS (DCI, NH₃): m/z = 239 [M+H]⁺.

LC/MS (method F, ESIpos) R_t = 0.40 min, m/z = 239 [M+H]⁺。

Examples 8A

N'-hydroxy-4- (4-methoxytetrahydro-2)H-pyran-4-yl) benzoylimine amide

Step (ii) of 1 ： 4- (4-methoxytetrahydro-2)H-pyran-4-yl) benzonitrile

238mg (74% of theory) of the title compound are obtained by the method described under example 6A/step 1 from 300mg (1.48 mmol) of the compound from example 7A/step 1 and 111. mu.l (1.77 mmol) of methyl iodide.

¹H-NMR (500 MHz, CDCl₃, δ/ppm): 7.68 (d, 2H), 7.51 (d, 2H), 3.89-3.82 (m, 4H), 2.99 (s, 3H), 2.03-1.98 (m, 2H), 1.94-1.91 (m, 2H).

HPLC (method A) R_t = 3.99 min.

MS (DCI, NH₃): m/z = 235 [M+NH₄]⁺.

GC/MS (method L, EIpos) R_t = 6.57 min, m/z = 217 (M)⁺。

Step (ii) of 2 ： N'-hydroxy-4- (4-methoxytetrahydro-2)H-pyran-4-yl) benzoylimine amide

229mg (99% of theory) of the title compound are obtained from 200mg (0.921 mmol) of the compound from example 8A/step 1 by the method described under example 1A/step 5.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 9.63 (s, 1H), 7.68 (d, 2H), 7.39 (d, 2H), 5.80 (s, 2H), 3.71-3.67 (m, 4H), 2.88 (m, 2H), 1.93-1.89 (m, 4H).

HPLC (method B) R_t = 2.95 min.

MS (DCI, NH₃): m/z = 251 [M+H]⁺.

LC/MS (method D, ESIpos) R_t = 0.93 min, m/z = 251 [M+H]⁺。

Analogously to the method described under example 1A/step 5, listed in the following TableN'The hydroxybenzeneimides were prepared from the corresponding commercially available benzonitrile. Benzonitrile which is not commercially available is prepared according to the following teaching in the literature: 4-cyclohexylbenzonitrile [ E, Riguet et al,J. Organomet. Chem. 2001，624 （ 1-2 ），376-379]4- (piperidin-1-yl) benzonitrile [ A. -H. Kuthier et al,J. Org. Chem. 1987，52 （ 9 ），1710-1713]4- (pentafluoro- λ)⁶Thio) benzonitrile [ P.J. Crowley et al,Chimia 2004，58 （ 3 ），138-142]。

examples 24A

N'-hydroxy-4- (1-hydroxycyclobutyl) benzoylimine amide

Step (ii) of 1 ： 4- (1-hydroxycyclobutyl) benzonitrile

In analogy to the procedure described under example 5A/step 1, 9.47g (83% of theory) of the title compound are obtained from 15.0g (65.5 mmol) of 4-iodobenzonitrile, 34.4ml (68.8 mmol) of a solution of isopropylmagnesium chloride (2M in diethyl ether) and 7.4ml (98.2 mmol) of cyclobutanone. Purification of the product was performed by MPLC (silica gel, mobile phase: cyclohexane/ethyl acetate 10: 1 → 4: 1).

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.67 (d, 2H), 7.62 (d, 2H), 2.58-2.51 (m, 2H), 2.44-2.37 (m, 2H), 2.23-2.04 (m, 2H), 1.83-1.72 (m, 1H).

HPLC (method A) R_t = 3.47 min.

MS (DCI, NH₃): m/z = 191 [M+NH₄]⁺。

Step (ii) of 2 ： N' -hydroxy-4- (1-hydroxycyclobutyl) benzamide

In analogy to the procedure described under example 1A/step 5, starting from 1.0g (5.77 mmol) of the compound from example 24A/step 1, 1.1g of the title compound are obtained (92% of theory). However, in contrast to what is described under example 1A/step 5, about 50ml of water are added to the residue after removal of the solvent and the mixture is extracted three times with about 50ml of ethyl acetate each time. The combined organic extracts were washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the solvent is removed on a rotary evaporator and the residue obtained is purified by MPLC (silica gel, mobile phase: dichloromethane/methanol 50: 1 → 10: 1).

¹H-NMR (400 MHz, DMSO-d₆Delta/ppm) 9.57 (s, 1H), 7.63 (d, 2H), 7.47 (d, 2H), 5.79 (s, width, 2H), 5.50 (s, 1H), 2.42-2.33 (m, 2H), 2.30-2.22 (m, 2H), 1.97-1.60 (m, 1H), 1.70-1.59 (m, 1H).

HPLC (method A) R_t = 2.26 min.

MS (EIpos): m/z = 207 [M+H]⁺.

LC/MS (method I, ESIpos) R_t = 0.25 min, m/z = 207 [M+H]⁺。

Examples 25A

N'-hydroxy-4- (1-methoxycyclobutyl) benzoylimine amide

Step (ii) of 1 ： 4- (1-methoxycyclobutyl) benzonitrile

In analogy to the procedure described under example 6A/step 1, from 2.0g (11.5 mmol) of the compound from example 24A/step 1, 508mg (12.7 mmol) of a 60% strength dispersion of sodium hydride in mineral oil and 863. mu.l (13.9 mmol) of methyl iodide there are obtained 1.27g (59% of theory) of the title compound. The product was purified by MPLC (silica gel; mobile phase: cyclohexane/ethyl acetate 20: 1 → 4: 1).

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.68 (d, 2H), 7.54 (d, 2H), 2.95 (s, 3H), 2.46-2.32 (m, 4H), 2.03-1.93 (m, 1H), 1.76-1.63 (m, 1H).

MS (DCI, NH₃): m/z = 205 [M+NH₄]⁺。

Step (ii) of 2 ： N'-hydroxy-4- (1-methoxycyclobutyl) benzoylimine amide

In analogy to the procedure described under example 1A/step 5, starting from 1.1g (5.87 mmol) of the compound from example 25A/step 1, 1.28g (98% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆Delta/ppm) 9.62 (s, 1H), 7.68 (d, 2H), 7.40 (d, 2H), 5.80 (s, width, 2H), 2.83 (s, 3H), 2.37-2.24 (m, 4H), 1.91-1.81 (m, 1H), 1.65-1.53 (m, 1H).

HPLC (method A) R_t = 3.02 min.

MS (DCI, NH₃): m/z = 221 [M+H]⁺。

Examples 26A

4- (1-fluorocyclobutyl) -N'-hydroxybenzoylimidic amides

Step (ii) of 1 ： 4- (1-fluorocyclobutyl) benzonitrile

In analogy to the procedure described under example 5A/step 2, from 2.0g (11.5 mmol) of the compound from example 24A/step 1 and 1.8ml (13.9 mmol) of diethylaminosulfur trifluoride (DAST) 1.39g (69% of theory) of the title compound are obtained. Purification of the product was performed by MPLC (silica gel, mobile phase: cyclohexane/ethyl acetate 10: 1 → 5: 1).

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 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 L, EIpos) R_t = 4.71 min, m/z = 155 [M–HF]⁺。

Step (ii) of 2 ： 4- (1-fluorocyclobutyl) -N'-hydroxybenzoylimidic amides

By the method described under example 1A/step 5, 1.16g (78% of theory) of the title compound are obtained starting from 1.25g (7.13 mmol) of the compound from example 26A/step 1.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 7.67 (d, 2H), 7.50 (d, 2H), 4.87 (s, width, 2H), 2.72-2.52 (m, 5H), 2.16-2.05 (m, 1H), 1.82-1.71 (m, 1H).

HPLC (method A) R_t = 3.17 min.

MS (DCI, NH₃): m/z = 209 [M+H]⁺。

Examples 27A

2-amino-2- [4- (trifluoromethoxy) phenyl ] ethanol

834mg (38.3 mmol) of lithium borohydride and 1ml (19.1 mmol) of concentrated sulfuric acid are dissolved in 1ml of THF and added in succession to a solution of 3.0g (12.8 mmol) of racemic 4- (trifluoromethoxy) phenylglycine in 20ml of THF. The reaction mixture was stirred at RT for 24 h. Then 15ml of methanol was added and the mixture was stirred until a clear solution formed. To this solution was then added dropwise 20ml of 4M sodium hydroxide solution. Whereupon a precipitate precipitates out and is filtered off with suction and discarded. The filtrate was freed of organic solvent on a rotary evaporator. The residue was extracted three times with approximately 20ml of toluene each time. The combined organic extracts were concentrated on a rotary evaporator. 2.25g (80% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆δ/ppm) 7.48 (d, 2H), 7.31 (d, 2H), 5.63 und 5.51 (each wide, tog. 2H), 4.91 (wide, 1H), 3.71-3.67 (m, 1H), 3.66-3.59 (m, 2H).

MS (DCI, NH₃): m/z = 222 [M+H]⁺。

Examples 28A

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

At RT, 23.3g (0.121 mol) EDC, 16.4g (0.121 mol) HOBt and 26.7g (0.121 mol)N'-hydroxy-4- (trifluoromethoxy) benzoylimine amide was added in sequence to 15.3g (0.121 mol) of 5-methyl-1H-pyrazole-3-carboxylic acid in 600ml anhydrous DMF. The mixture was first stirred at RT for 2h and then at 140 ℃ for 5 h. After cooling, the mixture was diluted with 2 l of water and extracted three times with 1 l of ethyl acetate each time. The combined organic extracts were washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and the solvent was removed on a rotary evaporator. The crude product obtained is purified by suction filtration through a suction filter filled with silica gel (eluent: cyclohexane/ethyl acetate 5: 1 → 1: 1). The product fractions were combined and the solvent was removed on a rotary evaporator to such an extent that the product just started to precipitate out. Precipitation was completed at RT. By filtration and further concentration of the mother liquor, two solid fractions were obtained, which were combined and dried under high vacuum. In this way a total of 19.7g (52% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃Delta/ppm) 10.75 (width, 1H), 8.24 (d, 2H), 7.34 (d, 2H), 6.81 (s, 1H), 2.46 (s, 3H).

HPLC (method A) R_t = 4.72 min.

MS (DCI, NH₃): m/z = 311 [M+H]⁺.

LC/MS (method F, ESIpos) R_t = 1.27 min, m/z = 311 [M+H]⁺。

The compounds listed in the following table were prepared from 5-methyl-1 by the method described in example 28AH-pyrazole-3-carboxylic acid, 5- (trifluoromethyl) -1H-pyrazole-3-carboxylic acid, 5-nitro-1H-pyrazole-3-carboxylic acid or 2-methyl-1H-imidazole-4-carboxylic acid hydrate and correspondingN'-hydroxybenzoylimide amide preparation. The reaction time, which is first carried out at RT, is from 0.5 to 4h, depending on the size of the batch. The mixture was then heated at 140 ℃ for 1 to 15 h. Depending on the polarity of the product obtained, this already precipitates out on addition of water after the reaction has ended, and it is then washed and dried under high vacuum. Alternatively, the mixture is worked up by extraction as described above and the product is purified by chromatography on silica gel; the respective mobile phases were used for chromatography. It is sometimes possible to omit chromatography and to purify it directly by stirring in dichloromethane, ethyl acetate, acetonitrile or tert-butyl methyl ether. The compound in example 41A was purified by preparative HPLC (method N).

Examples 42A

3- {3- [4- (trifluoromethoxy) phenyl group ]-1,2,4-Oxadiazol-5-yl-1H-pyrazol-5-amines

A solution of 342mg (1.0 mmol) of the compound from example 39A in 43ml of ethyl acetate is hydrogenated in a flow-through hydrogenation apparatus ("H-Cube" from Thales Nano, Budapest, Hungary) (conditions: 10% Pd/C catalyst, 1 bar H₂At 25 ℃ and 1 ml/min). After removal of the solvent on a rotary evaporator, the crude product is purified by MPLC (silica gel, cyclohexane/ethyl acetate 1: 1). 322mg (93% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 12.49 (s, 1H), 8.19 (d, 2H), 7.49 (d, 2H), 5.93 (s, 1H), 5.44 (s, 2H).

MS (DCI, NH₃): m/z = 312 [M+H]⁺.

LC/MS (method E, ESIpos) R_t = 1.76 min, m/z = 312 [M+H]⁺。

Examples 43A

2-chloro-4- (chloromethyl) pyridine

1.00g (6.97 mmol) (2-chloropyridin-4-yl) methanol was dissolved in 40ml dichloromethane, 10ml thionyl chloride was slowly added at RT and the mixture was stirred at RT overnight. The mixture was then concentrated on a rotary evaporator and the residue was stirred in a mixture of dichloromethane and aqueous sodium bicarbonate solution. The phases were separated and the dichloromethane phase was dried over anhydrous magnesium sulfate, filtered and concentrated on a rotary evaporator. 1.10g (97% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.49 (d, 1H), 7.38 (s, 1H), 7.27-7.22 (m, 1H), 4.52 (s, 2H).

LC/MS (method E, ESIpos) R_t = 1.43 min, m/z = 162 [M+H]⁺。

Examples 44A

2- (chloromethyl) -5-iodopyridine

Step (ii) of 1 ： 2- (hydroxymethyl) -5-iodopyridine

To a solution of 2.50g (7.56 mmol) of 2, 5-diiodopyridine in 90ml of toluene, 5.7ml (9.07 mmol) of a 1.6 molar solution of n-butyllithium in hexane are added dropwise under inert conditions and at a temperature of-78 ℃. The mixture was stirred at-78 ℃ for 2.5h and 756. mu.l of anhydrous DMF was added after the same temperature. After a further 60min at-78 ℃ the reaction mixture was allowed to warm to-10 ℃ and 572mg (15.11 mmol) of solid sodium borohydride were added and stirring continued at 0 ℃ for 30 min. After which 25ml of saturated aqueous ammonium chloride solution was added and the mixture was warmed to RT. The organic phase is separated off and the solvent is removed on a rotary evaporator. The residue was purified by preparative HPLC. 890mg (50% of theory) of the title compound (see below for analytical data) and 243mg (14% of theory) of the isomer 5- (hydroxymethyl) -2-iodopyridine are obtained [ preparative HPLC conditions: column: sunfire C18 OBD 5. mu.M, 19 mm. times.150 mm; temperature: 40 ℃; mobile phase: water/acetonitrile/1% strength aqueous TFA 76: 5: 19; flow rate: 25 ml/min; 1.3g of the crude product are dissolved in a mixture of 8ml of 1% strength aqueous TFA and 4ml of acetonitrile; injection volume: 1ml ].

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.87 (d, 1H), 8.30 (dd, 1H), 7.38 (d, 1H), 5.43 (Width, 1H), 4.85 (s, 2H).

HPLC (method A) R_t = 0.87 min.

MS (DCI, NH₃): m/z = 236 [M+H]⁺.

LC/MS (method E, ESIpos) R_t = 0.85 min, m/z = 236 [M+H]⁺。

Step (ii) of 2 ： 2- (chloromethyl) -5-iodopyridine

357 μ l (4.88 mmol) of thionyl chloride are added dropwise at 0 ℃ to a solution of 765mg (3.26 mmol) of the compound from example 44A/step 1 in 12ml of anhydrous dichloromethane. The reaction mixture was then stirred at RT for 15 h. After which about 50ml of saturated aqueous sodium bicarbonate solution are added and the mixture is extracted three times with about 50ml of dichloromethane each time. The combined organic extracts were washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed on a rotary evaporator. 541mg (66% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.79 (d, 1H), 8.03 (dd, 1H), 7.29 (d, 1H), 4.61 (s, 2H).

MS (ESIpos): m/z = 254/256 (³⁵Cl/³⁷Cl) [M+H]⁺.

LC/MS (method D, ESIpos) R_t = 1.87 min, m/z = 254/256 (³⁵Cl/³⁷Cl) [M+H]⁺。

Examples 45A

5- (chloromethyl) pyridine-2-carbonitrile hydrochloride

To 250mg (1.86 mmol) of 5- (hydroxymethyl) pyridine-2-carbonitrile [ A. Ashimori, etc. ], at 0 deg.C,Chem. Pharm. Bull. 1990，38 （ 9 ），2446-2458]to a solution in 5ml of anhydrous dichloromethane 272. mu.l (3.73 mmol) of thionyl chloride was added. The reaction mixture was then stirred at RT for 6 h. All volatile components are then removed on a rotary evaporator and the residue obtained is dried under high vacuum. 263mg (75% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.73 (d, 1H), 7.90 (dd, 1H), 7.72 (d, 1H), 4.63 (s, 2H).

MS (ESIpos): m/z = 153/155 (³⁵Cl/³⁷Cl) [M+H]⁺.

LC/MS (method F, ESIpos) R_t = 0.75 min, m/z = 153/155 (³⁵Cl/³⁷Cl) [M+H]⁺。

Examples 46A

Methanesulfonic acid (6-cyanopyridin-3-yl) methyl ester

3.51ml (27.14 mmol) at 0 deg.CN,NDiisopropylethylamine and 2.87ml (25.05 mmol) methanesulfonyl chloride were sequentially added to 2.8g (20.87 mmol) of 5- (hydroxymethyl) pyridine-2-carbonitrile [ A. Ashimori, etc.,Chem. Pharm. Bull. 1990，38 （ 9 ），2446-2458]in a solution in 50ml of anhydrous dichloromethane. The reaction mixture was then stirred at RT for 1 h. 10ml of water are then added, the phases are separated and the aqueous phase is extracted twice with approximately 10ml of dichloromethane each time. The combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and the solvent removed on a rotary evaporator. The residue obtained was separated into its components by MPLC (silica gel, cyclohexane/ethyl acetate 1: 1). 2.12g (48% of theory) of the title compound (see below for analytical data) and 1.51g (47% of theory) of the compound described in example 45A were obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.76 (d, 1H), 7.93 (dd, 1H), 7.78 (d, 1H), 5.32 (s, 2H), 3.10 (s, 3H).

MS (DCI, NH₃): m/z = 213 [M+H]⁺, 230 [M+NH₄]⁺.

LC/MS (method F, ESIpos) R_t = 0.57 min, m/z = 213 [M+H]⁺。

Examples 47A

[3- (bromomethyl) phenoxy ] (tripropyl-2-yl) silane

Step (ii) of 1 ： 3- [ (tripropyl-2-ylsilyl) oxy group]Benzoic acid ethyl ester

5.98g (30.99 mmol) of triisopropylsilyl chloride are added dropwise at 0 ℃ to a solution of 5.0g (30.09 mmol) of ethyl 3-hydroxybenzoate and 2.41g (35.35 mmol) of imidazole in 20ml of anhydrous DMF. After the reaction mixture has been stirred at RT for 15h, about 100ml of water are added and the mixture is extracted three times with about 100ml of diethyl ether each time. The combined organic extracts were washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate and filtration, the solvent was removed on a rotary evaporator. The residue obtained is filtered by suction through silica gel with cyclohexane/ethyl acetate 10 as mobile phase: 1 → 1: 1, purifying. 9.70g (100% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.62 (dd, 1H), 7.53 (m, 1H), 7.28 (dd, 1H), 7.06 (dd, 1H), 4.37 (quart, 2H), 1.39 (t, 3H), 1.28 (sept, 3H), 1.10 (d, 18H).

GC/MS (method L, EI) R_t = 6.62 min, m/z = 322 (M)⁺, 279 (M–C₃H₇)⁺。

Step (ii) of 2 ： {3- [ (tripropyl-2-ylsilyl) oxy group]Phenyl } carbinols

Under inert conditions, 50ml (49.61 mmol) of a 1M solution of lithium aluminium hydride in THF are diluted with 50ml of anhydrous ether and then a solution of 8.0g (24.80 mmol) of the compound from example 47A/step 1 in 50ml of anhydrous ether is added dropwise at 0 ℃. The reaction mixture was stirred at RT for 1 h. Then to solvate the excess hydride, a few ml of methanol are added first, and then about 150ml of 0.1M hydrochloric acid. The organic phase is separated off rapidly and the aqueous phase is extracted twice with approximately 50ml of diethyl ether each time. The combined organic extracts were washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate and subsequent filtration, the solvent was removed on a rotary evaporator. The residue obtained is filtered by suction through silica gel with the mobile phase cyclohexane/ethyl acetate 5: 1 → 1: 1, purifying. 6.69g (96% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.20 (dd, 1H), 6.93-6.90 (m, 2H), 6.80 (dd, 1H), 4.64 (d, 2H), 1.61 (t, 3H), 1.26 (sept, 3H), 1.09 (d, 18H).

GC/MS (method L, EI) R_t = 6.38 min, m/z = 280 (M)⁺, 237 (M–C₃H₇)⁺。

Step (ii) of 3 ： [3- (bromomethyl) phenoxy group](tripropyl-2-yl) silane

1.0g (3.57 mmol) of the compound from example 47A/step 2 are dissolved in 20ml of anhydrous THF and 1.12g (4.28 mmol) of triphenylphosphine are added. After this had dissolved, 1.42g (4.28 mmol) of tetrabromomethane were added. The mixture was then stirred at RT for 20 h. The precipitate which has precipitated out is then filtered off and the filtrate is freed of the solvent on a rotary evaporator. The crude product was purified by MPLC (silica gel, cyclohexane/ethyl acetate 50: 1). 1.10g (90% of theory, purity approx. 90%) of the title compound are obtained, which are used without further purification.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.18 (dd, 1H), 6.95 (dd, 1H), 6.91 (m, 1H), 6.80 (dd, 1H), 4.43 (s, 2H), 1.25 (sept, 3H), 1.10 (d, 18H).

HPLC (method B) R_t = 6.17 min.

GC/MS (method L, EI) R_t = 6.56 min, m/z = 342/344 (⁷⁹Br/⁸¹Br) (M)⁺。

Examples 48A

(4- { [ (methylsulfonyl) oxy ] methyl } phenyl) acetic acid ethyl ester

1.1g (5.66 mmol) of [4- (hydroxymethyl) phenyl ]]Ethyl acetate [ G, Biagi, etc.,Farmaco Ed. Sci.，1988，43 （ 7/8 ），597-612]and a solution of 1.03ml (7.36 mmol) triethylamine in 10ml dry THF was cooled to 0 deg.C. A solution of 526. mu.l (6.80 mmol) of methanesulfonyl chloride in 5ml of anhydrous THF is then added dropwise. After 15min at 0 ℃, the mixture was warmed to RT. After a further hour, about 60ml of water were added and the mixture was extracted twice with about 50ml of ethyl acetate each time. The combined organic extracts were washed with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate and filtration, the solvent was removed on a rotary evaporator. The crude product was purified by MPLC (silica gel, cyclohexane/ethyl acetate 7: 3). 1.19g (56% of theory, purity approx. 73%) of the title compound are obtained, which are used without further purification.

MS (DCI, NH₃): m/z = 290 [M+NH₄]⁺.

LC/MS (method C, ESIpos) R_t = 1.96 min, m/z = 177 (M–CH₃SO₂O)⁺。

Examples 49A

1- [ (6-Chloropyridin-3-yl) methyl group]-5-methyl-1H-pyrazole-3-carboxylic acid

Step (ii) of 1 ： 1- [ (6-Chloropyridin-3-yl) methyl group]-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester

At 0 deg.C, to a solution of 10.0g (64.9 mmol) of 3-methyl-1HTo a solution of ethyl-pyrazole-5-carboxylate and 13.66g (84.3 mmol) of 2-chloro-5- (chloromethyl) pyridine in 162ml of anhydrous THF was added 9.46g (84.3 mmol) of potassium tert-butoxide. The mixture was allowed to reach RT and stirred at RT for a further 18 h. It is then diluted with 200ml of ethyl acetate and 350ml of water, the phases are thoroughly mixed and the aqueous phase is separated off and extracted twice with 200ml of ethyl acetate each time. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator. The residue is purified by column chromatography over silica gel (mobile phase: cyclohexane/ethyl acetate 4: 1 → 2: 1). After drying in vacuo, 12.4g (65% of theory) of the title compound are obtained in 95% purity.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 8.30 (d, 1H), 7.58 (dd, 1H), 7.52 (d, 1H), 6.60 (s, 1H), 5.45 (s, 2H), 4.24 (quart, 2H), 2.28 (s, 3H), 1.27 (t, 3H).

LC/MS (method C, ESIpos) R_t = 1.88 min, m/z = 280 [M+H]⁺。

Step (ii) of 2 ： 1- [ (6-Chloropyridin-3-yl) methyl group]-5-methyl-1H-pyrazole-3-carboxylic acid

To a solution of 11.85g (42.36 mmol) of the compound from example 49A/step 1 in 100ml THF were added 3.39g (84.7 mmol) of sodium hydroxide dissolved in 100ml water and the mixture was stirred at RT for 5 h. The mixture was then diluted with 150ml of water and washed once with 100ml of ethyl acetate. The aqueous phase is adjusted to a pH of about 3 with 1N hydrochloric acid and extracted three times with 150ml of ethyl acetate each time. The latter ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator. After the residue has been dried in vacuo, 9.72g (91% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆δ/ppm) 12.60 (s, width, 1H), 8.31 (d, 1H), 7.60 (dd, 1H), 7.52 (d, 1H), 6.53 (s, 1H), 5.42 (s, 2H), 2.28 (s, 3H).

LC/MS (method F, ESIpos) R_t = 0.75 min, m/z = 252 [M+H]⁺。

Examples 50A

1- [ (6-Chloropyridin-3-yl) methyl group]-5-methyl-1H-pyrrole-3-carboxylic acid

Step (ii) of 1 ： 2- (hydroxymethyl) -4-oxopentanoic acid methyl ester

A suspension of 7.63g (190.7 mmol) of 60% strength sodium hydride in mineral oil was degreased with pentane under inert conditions. Then 150ml of anhydrous ether and, at 0 ℃, 138. mu.l (3.4 mmol) of methanol were added. After stirring for 10min at RT, the mixture is again cooled to 0 ℃ and a mixture of 12.6ml (204.3 mmol) of methyl formate and 30.0g (170.2 mmol) of methyl 4, 4-dimethoxyvalerate [ C. Meister et al, Liebigs Ann. chem. 1983 (6), 913-921] is slowly added. The reaction mixture was stirred at RT for 16 h. Approximately 60ml of ice-water were then added and the mixture was extracted with 100ml of diethyl ether. The organic extracts were discarded and the aqueous phase brought to pH 2-3 with 3M hydrochloric acid. It is extracted four times with approximately 50ml of tert-butyl methyl ether each time. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and the solvent was removed on a rotary evaporator. 4.2g (13% of theory, purity 85%) of the title compound are obtained, which are used without further purification.

GC/MS (method L, EI) R_t = 3.33 min, m/z = 158 (M)⁺, 140 (M–H₂O)⁺。

Step (ii) of 2 ： 1- [ (6-Chloropyridin-3-yl) methyl group]-5-methyl-1H-pyrrole-3-carboxylic acid methyl ester

A mixture of 4.20g (22.73 mmol, 85% purity) of the compound from example 50A/step 1 and 3.24g (22.73 mmol) of 5- (aminomethyl) -2-chloropyridine in 42ml of methanol is stirred at RT for three days. The solvent was then removed on a rotary evaporator and the crude product was purified by MPLC (silica gel, cyclohexane/ethyl acetate 2: 1). 3.37g (56% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.19 (d, 1H), 7.30-7.20 (m, 3H), 6.38 (d, 1H), 5.03 (s, 2H), 3.79 (s, 3H), 2.12 (s, 3H).

HPLC (method A) R_t = 4.10 min.

MS (DCI, NH₃): m/z = 265 [M+H]⁺。

Step (ii) of 3 ： 1- [ (6-Chloropyridin-3-yl) methyl group]-5-methyl-1H-pyrrole-3-carboxylic acid

To a solution of 1.93g (7.29 mmol) of the compound from example 50A/step 2 in 38ml of methanol 14.5ml (14.5 mmol) of 1M sodium hydroxide solution are added dropwise. The reaction mixture was heated at reflux for 15 h. After cooling to RT, methanol was largely removed on a rotary evaporator. The residue was first diluted with 100ml of water and then acidified with 2M hydrochloric acid. The precipitate which had precipitated out was filtered off, washed with water and dried under high vacuum. 1.41g (76% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 11.67 (s, 1H), 8.23 (s, 1H), 7.51 (d, 2H), 7.45 (d, 2H), 6.18 (d, 1H), 5.19 (s, 2H), 2.07 (s, 3H).

HPLC (method A) R_t = 3.59 min.

MS (ESIpos): m/z = 251 [M+H]⁺。

Examples 51A

2-chloro-5- [ (2-methyl-4- {3- [4- (trifluoromethoxy) phenyl) ]-1,2,4-Oxadiazol-5-yl } -1H-pyrrol-1-yl) methyl]Pyridine compound

To a solution of 400mg (1.60 mmol) of the compound from example 50A in 20ml of anhydrous dichloromethane are added 418. mu.l (4.79 mmol) of oxalyl chloride at 0 ℃ under inert conditions. The reaction mixture was stirred at RT for 2 h. All volatile constituents were then removed on a rotary evaporator and the residue obtained in this way was dried under high vacuum for 20 min. The residue was subsequently dissolved again in 4ml of dichloromethane and 527mg (2.39 mmol) of 4- (trifluoromethoxy) propanoic acid at 0 DEG.CN'-hydroxybenzoylimide amide and 445. mu.l (3.19 mmol) triethylamine in 16ml dichloromethane. After the reaction mixture had been stirred for 16h at RT, all volatile constituents were removed again on a rotary evaporator and the residue obtained was dissolved in 30ml DMSO. The solution was then heated in a microwave oven at 140 ℃ for 30min (CEM Discover, initial radiant power 250W). After cooling to RT, the reaction mixture is purified by preparative HPLC (method N). 196mg (28% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.24 (d, 1H), 8.17 (d, 2H), 7.47 (d, 1H), 7.32-7.27 (m, 4H), 6.60 (d, 1H), 5.10 (s, 2H), 2.20 (s, 3H).

LC/MS (method C, ESIpos) R_t = 3.01 min, m/z = 435 [M+H]⁺。

Examples 52A

2-chloro-5- [ (3- {3- [4- (2-fluoroprop-2-yl) phenyl) ]-1,2,4-Oxadiazol-5-yl } -5-methyl-1H-pyrazol-1-yl) methyl]Pyridine compound

To a solution of 667mg (2.65 mmol) of the compound from example 49A in 10ml of anhydrous DMF at RT are added 508mg (2.65 mmol) EDC and 358mg (2.65 mmol) HOBt. After 30min, 520mg (2.65 mmol) of the compound from example 2A dissolved in 5ml of DMF are added. The mixture was first stirred at RT for 1h and then at 140 ℃ for 1 h. After cooling, most of the solvent was removed on a rotary evaporator. 50ml of each of water and ethyl acetate were added. After phase separation, the organic phase is washed with 50ml of 10% strength aqueous citric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous sodium sulfate, the mixture was filtered and the solvent was removed on a rotary evaporator. The crude product obtained was purified by MPLC (silica gel, cyclohexane/ethyl acetate 2: 1). 418mg (36% of theory, purity 93%) of the title compound are obtained, which are used without further purification.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 8.39 (d, 1H), 8.08 (d, 2H), 7.68 (dd, 1H), 7.62 (d, 2H), 7.52 (d, 1H), 6.93 (s, 1H), 5.56 (s, 2H), 2.39 (s, 3H), 1.72 (s, 3H), 1.86 (s, 3H).

LC/MS (method F, ESIpos) R_t = 1.43 min, m/z = 412 [M+H]⁺。

The compounds in the table below were prepared from the corresponding precursors analogously to one of the methods described under examples 51A and 52A. The preparation of the N' -hydroxyformamidides (hydroxyamidines) most used has already been described above; a few are commercially available or their preparation is described in the literature.

Examples 75A

2-bromo-6- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridine compound

To a solution of 1.83g (5.90 mmol) of the compound from example 28A and 2.04g (7.67 mmol) of methyl (6-bromopyridin-2-yl) methanesulfonate [ T. Kawano et al, Bull. chem. Soc. Jpn. 2003, 76 (4), 709-720] in 50ml of anhydrous THF at 0 ℃ was added 0.73g (6.49 mmol) of solid potassium tert-butoxide. The reaction mixture was then brought to RT. After 1.5h, about 100ml of water were added and the mixture was extracted three times with about 100ml of ethyl acetate each time. The combined organic extracts were dried over anhydrous sodium sulfate and, after filtration, the solvent was removed on a rotary evaporator. The residue obtained is stirred with 30ml of dichloromethane. After filtration and drying of the residue on a filter, a first amount of 1.21g (43% of theory) of the title compound is obtained. The mother liquor was freed of solvent on a rotary evaporator and the residue was purified by MPLC (silica gel, cyclohexane/ethyl acetate 4: 1 → 1: 1). In this way 0.42g (16% of theory) of the title compound are further obtained.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 8.20 (d, 2H), 7.78 (t, 1H), 7.63-7.58 (m, 3H), 7.18 (d, 1H), 6.96 (s, 1H), 5.60 (s, 2H), 2.39 (s, 3H).

LC/MS (method F, ESIpos) R_t = 1.53 min, m/z = 480/482 (⁷⁹Br/⁸¹Br) [M+H]⁺。

Examples 76A

5-iodo-2- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl) ]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridine compound

To a solution of 504mg (1.62 mmol) of the compound from example 28A and 535mg (2.11 mmol) of the compound from example 44A in 20ml of anhydrous THF at 0 ℃ were added 219mg (1.95 mmol) of solid potassium tert-butoxide. The reaction mixture was then brought to RT. After 15h, about 100ml of water were added and the mixture was extracted three times with about 100ml of ethyl acetate each time. The combined organic extracts were washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed on a rotary evaporator. The title compound was isolated by preparative HPLC (method N). 657mg (77% of theory) are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.79 (d, 1H), 8.24 (d, 2H), 7.97 (dd, 1H), 7.33 (d, 2H), 6.86 (d, 1H), 6.83 (s, 1H), 5.50 (s, 2H), 2.36 (s, 3H).

HPLC (method B) R_t = 5.25 min.

MS (ESIpos): m/z = 528 [M+H]⁺。

The compounds in the table below were prepared analogously to the methods described in examples 75A and 76A from the corresponding starting materials. Depending on the polarity of the compounds, they are stirred with dichloromethane, ethyl acetate, acetonitrile or diethyl ether, separated by preparative HPLC with a cyclohexane/ethyl acetate mixture as mobile phase or by MPLC on silica gel. Arylmethyl chlorides, -bromides or-methanesulfonates used as starting materials are also commercially available, or they are prepared as described above or their preparation is described in the literature: methyl (6-chloropyridin-3-yl) methanesulfonate [ K.C. Iee et al, J. org. chem. 1999, 64 (23), 8576-8581 ].

Examples 91A

5- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridine-2-carbaldehyde

To a solution of 980mg (2.30 mmol) of the compound from example 77A in 30ml of anhydrous THF are added, under inert conditions and at-78 deg.C, 3.5ml (3.5 mmol) of a 1M solution of diisobutylaluminum hydride (DIBAL-H) in heptane. After the reaction mixture had been stirred at-78 ℃ for 3h, 22ml of 1M hydrochloric acid were added. The mixture was allowed to warm to RT while stirring. It was then extracted with ethyl acetate. The organic extract was washed with water followed by saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and the solvent was removed on a rotary evaporator. The crude product was purified by MPLC (silica gel, cyclohexane/ethyl acetate 1: 1). 300mg (30% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 10.07 (s, 1H), 8.67 (d, 1H), 8.25 (d, 2H), 7.95 (d, 1H), 7.67 (dd, 1H), 7.34 (d, 2H), 6.87 (s, 1H), 5.57 (s, 2H), 2.35 (s, 3H).

MS (DCI, NH₃): m/z = 430 [M+H]⁺.

LC/MS (method C, ESIpos) R_t = 2.66 min, m/z = 430 [M+H]⁺。

Examples 92A

5- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridine-2-carboxylic acid

To a solution of 500mg (1.17 mmol) of the compound from example 77A in 5ml of ethanol was added 5ml of 30% strength aqueous potassium hydroxide solution and the mixture was heated at reflux for 1 h. After cooling to RT, approximately 20ml of water were added and the product was precipitated out with concentrated hydrochloric acid. It is filtered off, washed to neutrality with water and dried under high vacuum. 448mg (86% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.52 (d, 1H), 8.24 (d, 2H), 8.22 (d, 1H), 7.75 (dd, 1H), 7.33 (d, 2H), 6.88 (s, 1H), 5.57 (s, 2H), 2.36 (s, 3H).

MS (DCI, NH₃): m/z = 446 [M+H]⁺.

LC/MS (method F, ESIpos) R_t = 1.22 min, m/z = 446 [M+H]⁺。

Examples 93A

3- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Benzoic acid

To a suspension of 8.13g (17.7 mmol) of the compound from example 82A in 120ml of methanol 89ml (88.7 mmol) of 1M sodium hydroxide solution are added and the mixture is heated at reflux for 1 h. Most of the methanol was then removed on a rotary evaporator. The remaining aqueous solution was acidified with 100ml of 1M hydrochloric acid while stirring. The product is thus precipitated out and filtered off with suction, washed with water and dried under high vacuum. 7.51g (95% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆δ/ppm) 13.07 (s, width, 1H), 8.20 (d, 2H), 7.40 (d, 1H), 7.78 (s, 1H), 7.59 (d, 2H), 7.51 (dd, 1H), 7.46 (d, 1H), 6.97 (s, 1H), 5.60 (s, 2H), 2.34 (s, 3H).

LC/MS (method C, ESIpos) R_t = 2.68 min, m/z = 445 [M+H]⁺。

In analogy to the procedure described in example 9A, the compounds in the following table were obtained by hydrolysis of the corresponding esters:

。

examples 95A

3- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]-phenol

To a solution of 500mg (1.61 mmol) of the compound from example 28A and 719mg (2.10 mmol) of the compound from example 47A in 10ml of anhydrous THF at 0 ℃ were added 199mg (1.77 mmol) of solid potassium tert-butoxide. The reaction mixture was then brought to RT. After 15h, about 100ml of water were added and the mixture was extracted three times with about 100ml of ethyl acetate each time. The combined organic extracts were washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed on a rotary evaporator. The residue obtained in this way was dissolved again in 20ml of THF and 3.2ml (3.2 mmol) of a 1M solution of tetra-n-butylammonium fluoride in THF were added at 0 ℃. After having been stirred for 1h at RT, the batch is diluted with a few ml of methanol and separated into its constituents directly by preparative HPLC (method N). 218mg (32% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.11 (d, 2H), 7.29 (d, 2H), 7.20 (t, 1H), 6.80 (d, 1H), 6.79 (s, 1H), 6.73 (d, 1H), 6.62 (s, 1H), 6.50 (s, 1H), 5.33 (s, 2H), 2.06 (s, 3H).

HPLC (method A) R_t = 4.81 min.

MS (DCI, NH₃): m/z = 417 [M+H]⁺.

LC/MS (method E, ESIpos) R_t = 2.34 min, m/z = 417 [M+H]⁺。

In analogy to the procedure described under example 95A, the compounds in the following table were obtained from the corresponding starting materials:

。

examples 97A

4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]-aniline

A solution of 400mg (0.898 mmol) of the compound from example 85A in a mixture of 25ml ethanol and 25ml ethyl acetate was hydrogenated in a flow-through hydrogenation unit ("H-Cube", Budapest, Hungary, from Thales Nano) (conditions: 10% Pd/C catalyst, "full H2" mode, 1ml/min, 25 ℃). After removal of the solvent, the residue is taken up in a few ml of ethanol and the insoluble material is filtered off. This insoluble material is the feedstock material which is subsequently hydrogenated again, as described above. The crude products obtained from the two hydrogenations were combined and purified by preparative HPLC (method N). 229mg (62% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.25 (d, 2H), 7.33 (d, 2H), 7.01 (d, 2H), 6.87 (s, 1H), 6.63 (d, 2H), 5.33 (s, 2H), 3.69 (Width, 2H), 2.27 (s, 3H).

LC/MS (method C, ESIpos) R_t = 2.57 min, m/z = 416 [M+H]⁺。

The compounds in the following table were prepared from the corresponding nitro compounds by hydrogenation in analogy to the procedure described under example 97A:

。

Examples 99A

{4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl ]]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl } carbamic acid tert-butyl ester

To a solution of 200mg (0.481 mmol) of the compound from example 97A in 10ml of anhydrous THF were added 134. mu.l (0.963 mmol) of triethylamine and 3mg (0.024 mmol) of DMAP. The reaction mixture was cooled to 0 ℃ and 132mg (0.602 mmol) of di-tert-butyl dicarbonate were added. The reaction mixture was stirred at 0 ℃ for 1h and then at RT for a further 16 h. Thereafter, it was diluted with 5ml of methanol and the product was separated into two fractions by preparative HPLC (method N). 74mg (30% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.26 (d, 2H), 7.33 (2 d, tog. 4H), 7.12 (d, 2H), 6.79 (s, 1H), 6.49 (s, width, 1H), 5.39 (s, 2H), 2.26 (s, 3H), 1.50 (s, 9H).

LC/MS (method E, ESIpos) R_t = 2.74 min, m/z = 516 [M+H]⁺。

Examples 100A

2-bromo-5- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridine compound

A mixture of 1.95g (4.47 mmol) of the compound from example 79A and 1.37g (8.95 mmol) of bromo (trimethyl) silane in 0.5ml of propionitrile is heated in a microwave apparatus at 120 ℃ for 70min while stirring (CEM Discover, initial radiation power 250W). A relatively significant increase in pressure and temperature was observed during the first 10min of operation. After cooling to RT, an additional 350mg (2.29 mmol) of bromo (trimethyl) silane are added and the mixture is heated in a microwave oven for a further 60min at 120 ℃. A relatively significant increase in pressure and temperature was again observed during the first 10min of operation. After cooling to RT, the mixture is diluted with 100ml of water and 100ml of ethyl acetate and the phases are separated. The organic phase is washed once with 100ml of water, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The residue was purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 3: 2). 1.45g (65% of theory) of the title compound are obtained with a purity of 86% according to LC-MS. Approximately 10% of the starting material (compound from example 79A) was obtained as an impurity.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.31 (d, 1H), 8.23 (d, 2H), 7.47 (d, 1H), 7.40 (dd, 1H), 7.33 (d, 2H), 6.82 (s, 1H), 5.41 (s, 2H), 2.32 (s, 3H).

LC/MS (method E, ESIpos) R_t = 2.54 min, m/z = 480 [M+H]⁺。

Examples 101A

2-iodo-5- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridine compound

To a solution of 100mg (0.229 mmol) of the compound from example 79A in 0.5ml of propionitrile at RT in a microwave reaction vessel are added 103mg (0.688 mmol) of sodium iodide and 27mg (0.252 mmol) of chloro (trimethyl) silane. The reaction mixture then rapidly takes the form of a solid. The mixture was then heated in a microwave apparatus at 120 ℃ for 1h (CEM Discover, initial radiant power 250W). After cooling to RT, the reaction mixture was diluted with 2ml acetonitrile and 1ml water. Two liquid phases are formed, which are separated from each other. The organic phase is purified directly by preparative HPLC without further work-up (method O). 61mg (50% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.29 (d, 1H), 8.24 (d, 2H), 7.71 (d, 1H), 7.32 (d, 2H), 7.18 (dd, 1H), 6.82 (s, 1H), 5.39 (s, 2H), 2.31 (s, 3H).

LC/MS (method F, ESIpos) R_t = 1.52 min, m/z = 528 [M+H]⁺。

Examples 102A

4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridine-2-carbonitriles

200mg (0.459 mmol) of the compound from example 81A are initially added to 3.4ml of dimethylacetamide, 31mg (0.266 mmol) of zinc cyanide, 6.7mg (0.020 mmol) of palladium (II) trifluoroacetate, 16mg (0.040 mmol) of racemic 2- (di-tert-butylphosphino) -1,1' -binaphthyl and 6mg (0.092 mmol) of zinc powder (97.5%, 325 mesh) are added in succession at RT and the mixture is stirred at 90 ℃ overnight. After cooling to RT, 6.7g (0.020 mmol) of palladium (II) trifluoroacetate are further added and the mixture is stirred for a further 24h at 90 ℃. After cooling to RT, 6.7mg (0.020 mmol) of palladium (II) trifluoroacetate, 16mg (0.040 mmol) of racemic 2- (di-tert-butylphosphino) -1,1' -binaphthyl and 6mg (0.092 mmol) of zinc powder (97.5%, 325 mesh) are added again and the mixture is stirred again at 90 ℃ overnight. After cooling to RT, the solid components are then filtered off and the remaining mixture is purified by preparative HPLC (method O). The combined product-containing fractions are concentrated on a rotary evaporator to a small residual volume and then sodium bicarbonate is added, after which a solid precipitates out. It was filtered off and dried in vacuo. 21mg (11% of theory) of the title compound are obtained in this way.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.71 (d, 1H), 8.24 (d, 2H), 7.41 (s, 1H), 7.34 (d, 2H), 7.24 (s, 1H), 6.90 (s, 1H), 5.51 (s, 2H), 2.32 (s, 3H).

LC/MS (method D, ESIpos) R_t = 2.52 min, m/z = 427 [M+H]⁺。

Examples 103A

1- (2-fluoroethyl) piperazine dihydrochloride

Step (ii) of 1 ： 4- (2-fluoroethyl) piperazine-1-carboxylic acid tert-butyl ester

A mixture of 1.00g (5.37 mmol) of tert-butyl piperazine-1-carboxylate, 937. mu.l (8.05 mmol) of 1-bromo-2-fluoroethane and 1.86g (13.4 mmol) of potassium carbonate in 15ml of acetonitrile was heated at 60 ℃ for 16 h. After cooling to RT, the undissolved material was filtered off and the filtrate was freed of the solvent on a rotary evaporator. The residue obtained is purified by MPLC (silica gel; mobile phase: cyclohexane/ethyl acetate 1: 2). 1.12g (89% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 4.58 (td, 2H), 3.46 (t, 4H), 2.71 (td, 2H), 2.48 (t, 4H), 1.46 (s, 9H).

GC/MS (method L, EI) R_t = 4.74 min, m/z = 232 [M]⁺。

Step (ii) of 2 ： 1- (2-fluoroethyl) piperazine dihydrochloride

To 1.10g (4.72 mmol) of the compound from example 103A/step 1 was added 30ml of hydrogen chloride in 1, 4-bisA 4M solution in alkane and the mixture was stirred at RT for 16 h. All volatile components were then removed on a rotary evaporator. The residue obtained is stirred with diethyl ether, filtered off with suction and rinsed again with diethyl ether. After drying under high vacuum 938mg (97% of theory) of the title compound are obtained.

MS (DCI, NH₃): m/z = 133 [M+H]⁺。

Examples 104A

1- (2, 2-difluoroethyl) piperazine dihydrochloride

Step (ii) of 1 ： 4- (2, 2-Difluoroethyl) piperazine-1-carboxylic acid tert-butyl ester

To a solution of 408. mu.l (6.44 mmol) of 2, 2-difluoroethanol in 10ml of anhydrous dichloromethane were added 1.35ml (9.66 mmol) of anhydrous triethylamine and 1.27ml (7.52 mmol) of trifluoromethanesulfonic acid anhydride at 0 ℃. After stirring at 0 ℃ for 30min, a solution of 1.0g (5.37 mmol) of piperazine-1-carboxylic acid tert-butyl ester in 10ml of anhydrous dichloromethane was added. The reaction mixture was then warmed to RT. After 16h, about 20ml of water were added and the phases were separated. The organic phase was washed with water and dried over anhydrous magnesium sulfate. After filtration, the solvent is removed on a rotary evaporator and the residue is purified by MPLC (silica gel; mobile phase: cyclohexane/ethyl acetate 1: 2). 538mg (45% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 5.88 (tt, 1H), 3.43 (t, 4H), 2.75 (dt, 2H), 2.53 (t, 4H), 1.45 (s, 9H).

GC/MS (method L, EI) R_t = 4.41 min, m/z = 250 [M]⁺。

Step (ii) of 2 ： 1- (2, 2-difluoroethyl) piperazineOxazine dihydrochloride

In analogy to the procedure described under example 103A/step 2, from 314mg (1.26 mmol) of the compound from example 104A/step 1 257mg (92% of theory) of the title compound are obtained.

MS (DCI, NH₃): m/z = 151 [M+H]⁺。

Examples 105A

5-methyl-1- {3- [ (4-methylpiperazin-1-yl) carbonyl]Benzyl radical 1H-pyrazole-3-carboxylic acid

Step (ii) of 1 ： 1- [3- (tert-butoxycarbonyl) benzyl]-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester

At 0 ℃ to a solution of 2.38g (15.4 mmol) of 5-methyl-1 HTo a solution of ethyl-pyrazole-3-carboxylate and 4.60g (17.0 mmol) of tert-butyl-3- (bromomethyl) benzoate in 50ml of anhydrous THF was added 1.90g (17.0 mmol) of solid potassium tert-butoxide. The reaction mixture was stirred at RT for 16 h. About 250ml of water are then added and the mixture is extracted three times with about 150ml of ethyl acetate each time. The combined organic extracts were washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and the solvent was removed on a rotary evaporator. The residue obtained is purified by MPLC (silica gel, mobile phase: cyclohexane/ethyl acetate 10: 1 → 2: 1). 4.45g (84% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.90 (d, 1H), 7.77 (s, 1H), 7.36 (t, 1H), 7.19 (d, 1H), 6.63 (s, 1H), 5.42 (s, 2H), 4.42 (quart, 2H), 2.19 (s, 3H), 1.58 (s, 9H), 1.40 (t, 3H).

MS (DCI, NH₃): m/z = 345 [M+H]⁺。

Step (ii) of 2 ： 3- { [3- (ethoxycarbonyl) -5-methyl-1H-pyrazol-1-yl]Methyl benzoic acid

To a solution of 4.47g (13.0 mmol) of the compound from example 105A/step 1 in 50ml dichloromethane was added 10ml trifluoroacetic acid. After the reaction mixture had been stirred at RT for 6h, all volatile constituents were removed on a rotary evaporator. The residue obtained is stirred with diethyl ether and filtered off with suction. After drying under high vacuum, 3.19g (85% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆δ/ppm) 13.05 (s, width, 1H), 7.87 (d, 1H), 7.69 (s, 1H), 7.49 (t, 1H), 7.37 (d, 1H), 6.60 (s, 1H), 5.49 (s, 2H), 4.25 (quart, 2H), 2.24 (s, 3H), 1.27 (t, 3H).

HPLC (method A) R_t = 3.71 min.

MS (ESIpos): m/z = 289 [M+H]⁺.

The LC/MS (method F, ESIpos): R_t = 0.94 min, m/z = 289 [M+H]⁺。

step (ii) of 3 ： 5-methyl-1- {3- [ (4-methylpiperazin-1-yl) carbonyl]Benzyl radical 1H-pyrazole-3-carboxylic acid ethyl ester

Under inert conditions, 3.15g (10.9 mmol) of the compound from example 105A/step 2 are dissolved in 100ml of anhydrous dichloromethane and 4.8ml (54.6 mmol) of oxalyl chloride and one drop of DMF are added. After the mixture had been stirred at RT for about 2.5h, it was concentrated to dryness on a rotary evaporator. The residue obtained is dried under high vacuum for about 1h and then dissolved in 40ml of anhydrous THF. To a mixture of 2.19g (21.9 mmol) of 1-methylpiperazine and 5.7ml (32.8 mmol)N,N-diisopropylethylamine in 60ml anhydrous THF. After stirring for 16h at RT, the reaction mixture is diluted with approximately 400ml of water and extracted three times with approximately 100ml of ethyl acetate each time. The combined organic extracts were washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and the solvent was removed on a rotary evaporator. 4.04g (99% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 7.36 (t, 1H), 7.31 (d, 1H), 7.13 (d, 1H), 7.09 (s, 1H), 6.62 (s, 1H), 5.40 (s, 2H), 4.40 (quart, 2H), 3.77 (Wide, 2H), 3.36 (Wide, 2H), 2.46 (Wide, 2H), 2.31 (s, 3H), 2.30 (Wide, 2H), 2.20 (s, 3H), 1.40 (t, 3H).

LC/MS (method I, ESIpos) R_t = 0.61 min, m/z = 371 [M+H]⁺。

Step (ii) of 4 ： 5-methyl-1- {3- [ (4-methylpiperazin-1-yl) carbonyl]Benzyl radical 1H-pyrazole-3-carboxylic acid

To a solution of 4.0g (10.8 mmol) of the compound from example 105A/step 3 in 70ml ethanol was added dropwise 21.6ml (21.6 mmol) of 1M sodium hydroxide solution and the mixture was heated at 70 ℃ for 2 h. Most of the ethanol was then removed on a rotary evaporator. To the remaining aqueous solution maintained at 0 ℃ was added 3M hydrochloric acid while stirring until the pH reached about 4. The solid thus precipitated out and was removed by suction filtration. The filtrate was evaporated to dryness on a rotary evaporator and the solid residue was then stirred with dichloromethane overnight. After filtration, the filtrate was freed of the solvent on a rotary evaporator. 2.35g (63% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆δ/ppm) 7.43 (t, 1H), 7.30 (d, 1H), 7.21 (d, 1H), 7.07 (s, 1H), 6.51 (s, 1H), 5.76 (s, 1H), 5.41 (s, 2H), 3.57 (Wide, 2H), 3.24 (Wide, 2H), 2.34 (Wide, 2H), 2.23 (S, 3H), 2.20 (Wide, 2H), 2.18 (s, 3H).

LC/MS (method I, ESIpos) R_t = 0.33 min, m/z = 343 [M+H]⁺。

Examples 106A

5-methyl-1- {3- [ (4-methylpiperazin-1-yl) carbonyl]Benzyl radical 1H-pyrrole-3-carboxylic acid

Step (ii) of 1 ： 3- [ (4-methylpiperazin-1-yl) carbonyl ]Benzonitrile

To a solution of 4.57g (45.6 mmol) of 1-methylpiperazine and 8.5ml (60.8 mmol) of triethylamine in 100ml of dichloromethane was added dropwise a solution of 3-cyanobenzoyl chloride in 100ml of dichloromethane at 0 ℃. The mixture was then stirred at RT for 6 h. 200ml of water are then added, the phases are separated and the organic phase is washed with water. After drying over anhydrous magnesium sulfate, the mixture was filtered and the solvent was removed on a rotary evaporator. 6.9g (99% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 7.72 (d, 1H), 7.70 (s, 1H), 7.65 (d, 1H), 7.55 (t, 1H), 3.80 (Wide, 2H), 3.40 (Wide, 2H), 2.50 (Wide, 2H), 2.37 (Wide, 2H), 2.34 (s, 3H).

LC/MS (method I, ESIpos) R_t = 0.21 min, m/z = 230 [M+H]⁺.

GC/MS (method L, ESIpos) R_t = 7.36 min, m/z = 229 [M]⁺。

Step (ii) of 2 ： [3- (aminomethyl) phenyl group](4-methylpiperazin-1-yl) methanone

A solution of 1.0g (4.36 mmol) of the compound from example 106A/step 1 in 100ml of ethanol was placed in a flow-through hydrogenation unit ("H-Cube", Budapest, Hungary; Raney nickel from Thales NanoCatalyst, "full H₂"mode, 0.5ml/min, 50 ℃) in a hydrogenation. After the solvent has evaporated, 1.0g (99% of theory) of the title compound are obtained.

LC/MS (method D, ESIpos) R _t = 0.19 min, m/z = 234 [M+H]⁺。

Step (ii) of 3 ： 5-methyl-1- {3- [ (4-methylpiperazin-1-yl) carbonyl]Benzyl radical 1H-pyrrole-3-carboxylic acid methyl ester

1.0g (4.41 mmol) of the compound from example 106A/step 2 are dissolved in 10ml of methanol and 698mg (4.41 mmol) of the compound from example 50A/step 1 are added. After the reaction mixture had been stirred at RT for 1h, the solvent was removed again on the rotary evaporator and the residue was purified by MPLC (silica gel; mobile phase: dichloromethane/methanol 10: 1). 1.07g (68% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 7.37 (t, 1H), 7.32 (d, 1H), 7.27 (d, 1H), 7.04 (d, 1H), 7.03 (d, 1H), 5.05 (s, 2H), 3.79 (s, 3H), 3.77 (wide, 2H), 3.36 (wide, 2H), 2.48 (wide, 2H), 2.31 (s, 3H), 2.11 (s, 3H), 1.95 (wide, 2H).

LC/MS (method I, ESIpos): R_t = 0.63 min, m/z = 356 [M+H]⁺。

Step (ii) of 4 ： 5-methyl-1- {3- [ (4-methylpiperazin-1-yl) carbonyl]Benzyl radical 1H-pyrrole-3-carboxylic acid

0.90g (2.53 mmol) of the compound from example 106A/step 3 are dissolved in 17.5ml of methanol and 5ml (5.0 mmol) of 1M sodium hydroxide solution are added. The mixture was reacted in portions for 30min in each case at 80 ℃ in a microwave oven (CEM Discover, initial radiant power 250W). The reaction mixture is subsequently adjusted to a pH of approximately 4 to 5 by addition of 6M hydrochloric acid and then purified by preparative HPLC in portions (method N). 344mg (39% of theory) of the title compound are obtained.

LC/MS (method I, ESIpos) R_t = 0.53 min, m/z = 342 [M+H]⁺。

Examples 107A

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

Step (ii) of 1 ： 4- (tetrahydro-2)H-pyran-4-yl) benzonitrile

To 2.91g (19.8 mmol) of 4-cyanophenylboronic acid [ M. Nishimura et al,Tetrahedron 2002，58 （ 29 ），5779-5788]to a solution in 20ml of isopropanol were added 186mg (0.594 mmol) of nickel (II) iodide, 90mg (0.594 mmol) of trans-2-aminocyclohexanol hydrochloride and 3.63g (19.8 mmol)Sodium hexamethyldisilazide (dililazid). The suspension obtained in this way was stirred at RT for 5min under argon atmosphere. Then 2.1g (9.90 mmol) of 4-iodotetrahydropyran [ Heuberger et al,J. Chem. Soc. 1952，910]. After the reaction mixture had been stirred at 75 ℃ for 15h, it was cooled to RT and the inorganic salts were largely removed with dichloromethane by filtration through approximately 50g of silica gel. The crude product is purified by MPLC (silica gel, mobile phase: dichloromethane). 986mg (53% of theory) of the title compound are obtained in this way.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 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 L, EIpos) R_t = 5.97 min, m/z = 187 [M]⁺。

Step (ii) of 2 ： N'-hydroxy-4- (tetrahydro-2)H-pyran-4-yl) benzoylimine amide

In analogy to the procedure described under example 1A/step 5, 480mg (2.56 mmol) of the compound from example 107A/step 1 were reacted to yield 525mg (93% of theory) of the title compound.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 7.58 (d, 2H), 7.26 (d, 2H), 6.79 (width, 1H), 4.82 (s, width, 2H), 4.11-4.05 (m, 2H), 3.57-3.50 (m, 2H), 2.83-2.74 (m, 1H), 1.87-1.73 (m, 4H).

LC/MS (method D, ESIpos) R_t = 0.92 min, m/z = 221 [M+H]⁺。

Examples 108A

N'-hydroxy-3-methyl-4- (tetrahydro-2)H-pyran-4-yl) benzoylimine amide

Step (ii) of 1 ： 3-methyl-4- (tetrahydro-2)H-pyran-4-yl) benzonitrile

In analogy to the procedure described in example 107A, step 1, from 4.17g (25.9 mmol) 4-cyano-2-methylphenylboronic acid [ D. Stones et al,Chem. Eur. J. 2004，10 （ 1 ），92-100]and 2.75g (13.0 mmol) of 4-iodotetrahydropyran [ Heuberger et al,J. Chem. Soc. 1952，910]481ml (18% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.49 (dd, 1H), 7.43 (d, 1H), 7.31 (d, 1H), 4.12-4.09 (m, 2H), 3.59-3.52 (m, 2H), 3.05-2.97 (m, 1H), 2.39 (s, 3H), 1.86-1.75 (m, 2H), 1.69-1.64 (m, 2H).

GC/MS (method L, EIpos) R_t = 6.31 min, m/z = 201 [M]⁺。

Step (ii) of 2 ： N'-hydroxy-3-methyl-4- (tetrahydro-2)H-pyran-4-yl) benzoylimine amide

In analogy to the procedure described under example 1A/step 5, 492mg (84% of theory) of the title compound are obtained from 500mg (2.48 mmol) of the compound from example 108A/step 1.

¹H-NMR (400 MHz, DMSO-d₆Delta/ppm) 9.49 (s, 1H), 7.45 (d, 1H), 7.44 (s, 1H), 7.21 (d, 1H), 5.69 (s, width, 2H), 3.97-3.93 (m, 2H), 3.50-3.43 (m, 2H), 3.00-2.92 (m, 1H), 2.33 (s, 3H), 1.72-1.57 (m, 4H).

LC/MS (method I, ESIpos) R_t = 0.49 min, m/z = 235 [M+H]⁺。

Examples 109A

1-[4-（N' -hydroxycarbamimidoyl) phenyl ]Cyclobutanecarboxylic acid ethyl ester

Step (ii) of 1 ： 1- (4-bromophenyl) cyclobutanecarboxylic acid ethyl ester

To a solution of 10.0g (41.1 mmol) of ethyl 4-bromophenylacetate in 250ml of anhydrous THF at 0 deg.C was added 45ml (45.2 mmol) of a 1M solution of lithium hexamethyldisilazide in THF. After 15min, 5.4ml (53.5 mmol) of 1, 3-dibromopropane are added. The reaction mixture was allowed to warm to RT and then stirred at this temperature for 1 h. It was then cooled again to 0 ℃ and a further 45ml (45.2 mmol) of lithium hexamethyldisilazide solution (1M in THF) were added. After this time, the mixture was warmed to RT again. After 1h, the reaction was quenched by the addition of about 10ml of saturated aqueous ammonium chloride solution. Most of the THF was removed on a rotary evaporator. The residue was diluted with water and extracted with ethyl acetate. The organic extract was washed with water followed by saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and the filtrate was freed of solvent on a rotary evaporator. The crude product obtained in this way was passed through approximately 300g of silica gel with cyclohexane/ethyl acetate 3: 1 crude purification by suction filtration. 7.1g (44% of theory, purity 73%) of the title compound are obtained, which are reacted further in this form.

¹H-NMR (400 MHz, CDCl₃, 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, NH₃): m/z = 300/302 [M+NH₄]⁺.

LC/MS (method D, ESIpos) R_t = 2.70 min, m/z = 283/285 [M+H]⁺。

Step (ii) of 2 ： 1- (4-cyanophenyl) cyclobutanecarboxylic acid ethyl ester

A mixture of 160mg (0.565 mmol) of the compound from example 109A/step 1, 76mg (0.644 mmol) of zinc cyanide, 26mg (0.028 mmol) of tris (dibenzylidene-acetone) dipalladium and 23mg (0.057 mmol) of dicyclohexyl- (2 ',6' -dimethoxybiphenyl-2-yl) phosphine-ane in 6ml of DMF/water (99: 1) is heated at 120 ℃ for 1h in the absence of oxygen. After cooling to RT, the mixture is diluted with about 30ml of water and extracted three times with about 20ml of ethyl acetate each time. The combined organic extracts were washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed on a rotary evaporator. The residue obtained is first pre-purified by MPLC (silica gel, mobile phase: cyclohexane/ethyl acetate 10: 1). The product was then isolated in pure form by preparative HPLC (method N). 110mg (85% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.62 (d, 2H), 7.39 (d, 2H), 4.10 (quart, 2H), 2.90-2.83 (m, 2H), 2.52-2.44 (m, 2H), 2.15-2.03 (m, 1H), 1.93-1.83 (m, 1H), 1.17 (t, 3H).

LC/MS (method D, ESIpos) R_t = 2.32 min, m/z = 230 [M+H]⁺。

Step (ii) of 3 ： 1-[4-（N'-hydroxycarbamimidoyl) phenyl]Cyclobutanecarboxylic acid ethyl ester

In analogy to the procedure described under example 1A/step 5, from 105mg (0.458 mmol) of the compound from example 109A/step 2 122mg (91% of theory, purity 90%) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 7.59 (d, 2H), 7.33 (d, 2H), 4.84 (width, 2H), 4.10 (quart, 2H), 2.88-2.80 (m, 2H), 2.53-2.46 (m, 2H), 2.10-1.99 (m, 1H), 1.92-1.82 (m, 1H), 1.17 (t, 3H).

LC/MS (method I, ESIpos) R_t = 0.67 min, m/z = 263 [M+H]⁺。

Examples 110A

N'-hydroxy-4- [1- (methoxymethyl) cyclobutyl ] -n]Benzoylimide amides

Step (ii) of 1 ： [1- (4-bromophenyl) cyclobutyl group]Methanol

7.20g (25.4 mmol) of the compound from example 109A/step 1 are dissolved in 150ml of anhydrous THF, and 25ml (25 mmol) of a 1M solution of lithium aluminium hydride in THF are added dropwise at 0 ℃. When the addition had ended, the ice/water bath was removed and stirring was continued at RT. After 1h, the reaction was terminated by the careful addition of approximately 450ml of saturated aqueous ammonium chloride solution. The mixture was then extracted with ethyl acetate. After drying over anhydrous magnesium sulfate and subsequent filtration of the organic extract, the solvent was removed on a rotary evaporator. 6.04g (88% of theory, about 90% purity) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.43 (d, 2H), 7.02 (d, 2H), 3.72 (d, 2H), 2.33-2.20 (m, 4H), 2.13-2.01 (m, 1H), 1.93-1.83 (m, 1H).

MS (DCI, NH₃): m/z = 258/260 [M+NH₄]⁺.

GC/MS (method L, ESIpos) R_t = 5.77 min, m/z = 240/242 [M]⁺。

Step (ii) of 2 ： 1-bromo-4- [1- (methoxymethyl) cyclobutyl]Benzene and its derivatives

To a solution of 7.0g (29.0 mmol) of the compound from example 110A/step 1 in 120ml of anhydrous DMF at about 5 ℃ is added a suspension of 1.28g (31.9 mmol) of 60% strength sodium hydride in mineral oil. After the mixture has been stirred at this temperature for 1h, 2.2ml (34.8 mmol) of methyl iodide are added. The reaction mixture was allowed to warm to RT and stirring was continued for 15 h. The reaction mixture was then concentrated on a rotary evaporator to a volume of about 20 ml. About 500ml of water are added and the mixture is extracted three times with about 200ml of diethyl ether each time. The combined organic extracts were washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration and removal of the solvent on a rotary evaporator, the crude product obtained is used as the mobile phase cyclohexane/ethyl acetate 50: 1 was purified by suction filtration through about 200g of silica gel. 4.92g (66% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, 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, NH₃): m/z = 272/274 [M+NH₄]⁺.

GC/MS (method L, ESIpos) R_t = 5.25 min, m/z = 254/256 [M]⁺。

Step (ii) of 3 ： 4- [1- (methoxymethyl) cyclobutyl group]Benzonitrile

In analogy to the procedure described under example 109A/step 2, from 4.80g (18.8 mmol) of the compound from example 110A/step 2 were obtained 1.82g (48% of theory) of the title compound.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.58 (d, 2H), 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 F, ESIpos) R_t = 1.22 min, m/z = 202 [M+H]⁺。

Step (ii) of 4 ： N'-hydroxy-4- [1- (methoxymethyl) cyclobutyl ] -n]Benzoylimide amides

In analogy to the procedure described under example 1A/step 5, from 1.82g (9.04 mmol) of the compound from example 110A/step 3 were obtained 2.04g (96% of theory) of the title compound.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 7.55 (d, 2H), 7.20 (d, 2H), 7.10 (width, 1H), 4.83 (width, 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 I, ESIpos) R_t = 0.61 min, m/z = 235 [M+H]⁺。

Examples 111A

N'-hydroxy-4- (1, 1, 1-trifluoro-2-methoxypropan-2-yl) benzoylimine amide (racemate)

Step (ii) of 1 ： 4- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) benzonitrile (racemate)

5.0g (21.8 mmol) of 4-iodobenzonitrile are dissolved in 100ml of anhydrous THF and the solution is cooled to-40 ℃. 11.5ml (22.9 mmol) of a 2M solution of isopropyl magnesium chloride in diethyl ether are added dropwise so that the temperature of the reaction mixture is maintained in the range of-30 ℃ to-40 ℃. When the addition has ended, the mixture is stirred for a further 15h in this temperature range before it is cooled to-78 ℃. 11.2g (100 mmol) of 1,1, 1-trifluoroacetone are then added dropwise. The mixture was brought to RT over a period of several hours and stirred at RT for about 5 h. Then approximately 5ml of water was carefully added. Most of the solvent was then removed on a rotary evaporator until approximately 50ml of residual volume remained. To the residue was added about 100ml of 0.5M hydrochloric acid and the mixture was extracted three times with about 100ml of ethyl acetate each time. The combined organic extracts were washed successively with water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the solvent is removed on a rotary evaporator and the residue obtained is purified by MPLC (approximately 200g of silica gel, mobile phase: cyclohexane/ethyl acetate 20: 1 → 5: 1). 3.63g (73% of theory, purity approx. 95%) of the title compound are obtained.

LC/MS (method I, ESIneg) R_t = 0.89 min, m/z = 214 [M–H]^-, 260 [M–H+HCO₂H]^-。

Step (ii) of 2 ： 4- (1, 1, 1-trifluoro-2-methoxypropan-2-yl) benzonitrile (racemate)

In analogy to the procedure described under example 110A/step 2, from 1.6g (7.44 mmol) of the compound from example 111A/step 1 and 555. mu.l (8.92 mmol) of methyl iodide were obtained 1.01g (59% of theory) of the title compound. Cyclohexane/ethyl acetate 100 used as mobile phase: 0 → 20: 1, carrying out chromatographic purification.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.71 (d, 2H), 7.63 (d, 2H), 3.27 (s, 3H), 1.80 (s, 3H).

HPLC (method A) R_t = 4.01 min.

GC/MS (method L, EIpos) R_t = 4.13 min, m/z = 214 [M–CH₃]⁺, 160 [M–CF₃]⁺。

Step (ii) of 3 ： N'-hydroxy-4- (1, 1, 1-trifluoro-2-methoxypropan-2-yl) benzoylimine amide (racemate)

In analogy to the procedure described under example 1A/step 5, from 990mg (4.32 mmol) of the compound from example 111A/step 2 was obtained 1.07g (89% of theory, purity 94%) of the title compound.

LC/MS (method D, ESIpos) R_t = 1.23 min, m/z = 263 [M+H]⁺。

Examples 112A

3-fluoro-N'-hydroxy-4- (tetrahydro-2)H-pyran-4-yl) benzoylimine amide

Step (ii) of 1 ： (4-cyano-2-fluorophenyl) boronic acid

To a solution of 10.0g (40.5 mmol) of 3-fluoro-4-iodobenzonitrile in a mixture of 120ml of anhydrous THF and 120ml of anhydrous ether at-78 deg.C was added dropwise a 2M solution of 24.3ml (48.6 mmol) of isopropylmagnesium chloride in ether. When the addition had ended, the mixture was stirred at-78 ℃ for a further 75 min. Then 15ml (64.8 mmol) of triisopropyl borate were added dropwise. The cold bath was removed and the reaction mixture was allowed to warm to RT before the mixture was then stirred at-78 ℃ for a further 15 min. After 3h at RT, 80ml of 2M hydrochloric acid are added and the mixture is stirred vigorously at RT for 20 min. Thereafter, it was diluted with about 400ml of water. The phases are separated and the aqueous phase is extracted three times with approximately 150ml of ethyl acetate each time. The combined organic extracts were washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and the filtrate was concentrated to dryness on a rotary evaporator. 3.68g (55% of theory) of the title compound are obtained, which are used without further purification in the subsequent reaction.

LC/MS (method F, ESIneg) R_t = 0.53 min, m/z = 164 [M–H]^-。

Step (ii) of 2 ： 4-bromo-3, 6-dihydro-2H-pyrans

To a solution of 8.52g (27.5 mmol) triphenyl phosphite in 78ml anhydrous dichloromethane was added 4.79g (30.0 mmol) bromine dropwise at-60 ℃. After addition of 4.5ml (32.5 mmol) of triethylamine, 2.5g (25.0 mmol) of tetrahydro-4 are added dropwiseH-a solution of pyran-4-one in 2ml of dichloromethane. The reaction mixture was allowed to warm slowly (over about 5 h) to RT and stirring continued at RT for about 10 h. All volatile components are then removed on a rotary evaporator and the residue obtained is chromatographed by suction filtration through approximately 100g of silica gel with dichloromethane as mobile phase. After the solvent had evaporated again, the product was isolated by bulb tube distillation (pressure: 8 mbar; temperature: to 120 ℃ C.). 2.51g (62% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 6.07 (m, 1H), 4.13 (m, 2H), 3.83 (m, 2H), 2.55-2.50 (m, 2H).

GC/MS (method L, ESIpos) R_t = 2.32 min, m/z = 162/164 [M]⁺。

Step (ii) of 3 ： 4- (3, 6-dihydro-2)H-pyran-4-yl) -3-fluorophenylcyanide

A mixture of 300mg (1.84 mmol) of the compound from example 112A/step 2, 334mg (2.02 mmol) of the compound from example 112A/step 1, 8mg (0.037 mmol) of palladium (II) acetate, 1.17g (5.52 mmol) of potassium phosphate and 44mg (0.092 mmol) of 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (XPhos) in 4ml of anhydrous THF is degassed and stirred at 80 ℃ in a microwave oven under argon (CEM Discover, initial radiant power 250W) for 1 h. After cooling to RT, all volatile components were removed on a rotary evaporator. The product was isolated from the residue by MPLC (approximately 50g silica gel, mobile phase: cyclohexane/dichloromethane 100: 0, → 50: 50 → 5: 95). 160mg (43% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.42 (d, 1H), 7.37 (d, 1H), 7.36 (d, 1H), 6.18 (m, 1H), 4.33 (m, 2H), 3.92 (t, 2H), 2.52-2.48 (m, 2H).

GC/MS (method L, ESIpos) R_t = 5.79 min, m/z = 203 [M]⁺。

Step (ii) of 4 ： 3-fluoro-4- (tetrahydro-2)H-pyran-4-yl) benzonitrile

330mg (1.62 mmol) of the compound from example 112A/step 3 are dissolved in a mixture of 22ml of ethyl acetate and 22ml of ethanol. The hydrogenation was carried out in a flow-through hydrogenation apparatus ("H-Cube", Budapest, Hungary; conditions: cartridge with 5% palladium on charcoal, 10 bar hydrogen pressure, temperature 20 ℃, flow rate 1 ml/min). The solution was passed through the apparatus a total of four times until the reaction was complete. The solvent was then removed on a rotary evaporator. 211mg (63% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.43 (d, 1H), 7.37 (d, 1H), 7.32 (d, 1H), 4.11-4.07 (m, 2H), 3.59-3.53 (m, 2H), 3.21-3.13 (m, 1H), 1.88-1.72 (m, 4H).

GC/MS (method L, EIpos) R_t = 5.59 min, m/z = 205 [M]⁺。

Step (ii) of 5 ： 3-fluoro-N'-hydroxy-4- (tetrahydro-2)H-pyran-4-yl) benzoylimine amide

In analogy to the procedure described under example 1A/step 5, 172mg (85% of theory) of the title compound are obtained from 175mg (0.853 mmol) of the compound from example 112A/step 4.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 7.40-7.24 (m, 3H), 7.08 (width, 1H), 4.81 (width, 2H), 4.10-4.06 (m, 2H), 3.59-3.52 (m, 2H), 3.17-3.10 (m, 1H), 1.89-1.71 (m, 4H).

LC/MS (method F, ESIpos): R_t = 0.46 min, m/z = 239 [M+H]⁺。

Examples 113A

4- [1- (2-fluoroethyl) cyclobutyl]-N'-hydroxybenzoylimidic amides

Step (ii) of 1 ： {1- [4- (dibenzylamino) phenyl ]Cyclobutyl } acetic acid ethyl ester

Starting with 20ml of 1, 4-bisTo the alkane was added 440mg (0.892 mmol) of bis [ (1, 5-cyclooctadiene) rhodium (I) chloride]And 15.5ml (23.2 mmol) of 1.5M potassium hydroxide solution were added. Then 2.5g (17.8 mmol) of cyclobutylidene-ethyl acetate [ M. Afzal etc.,J. Chem. Soc. Perkin Trans.2，1999（ 5 ），937-946]in 1ml of 1, 4-bisSolution in an alkane. 5.66g (17.8 mmol) of the compound from example 4A/step 1 in 100ml of 1, 4-bisSolution in an alkane. After the reaction mixture had been stirred at RT for 16h, it was concentrated to dryness on a rotary evaporator. The residue obtained is dissolved in a little dichloromethane and prepurified by suction filtration through about 100g of silica gel with dichloromethane as mobile phase. The product was isolated in pure form by MPLC (about 300g silica gel, mobile phase: cyclohexane/dichloromethane 100: 0, → 50: 50). 4.02g (54% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.32-7.30 (m, 4H), 7.26-7.21 (m, 6H), 6.97 (d, 2H), 6.67 (d, 2H), 4.61 (s, 4H), 3.93 (quart, 2H), 2.70 (s, 2H), 2.43-2.28 (m, 4H), 2.07-1.96 (m, 1H), 1.88-1.78 (m, 1H).

HPLC (method A) R_t = 4.74 min.

MS (DCI, NH₃): m/z = 414 [M+H]⁺。

Step (ii) of 2 ： 2- {1- [4- (dibenzylamino) phenyl]Cyclobutyl ethanol

To a solution of 15.0g (36.3 mmol) of the compound from example 113A/step 1 in 500ml of anhydrous THF at 0 ℃ are added dropwise 36.3ml (36.3 mmol) of a 1M solution of lithium aluminum hydride in THF. When the addition had ended, the reaction mixture was allowed to warm to RT and stirring was continued for 2 h. The reaction was then carefully quenched at 0 ℃ by the addition of 20g of diatomaceous earth and 20ml of water. The mixture was filtered by suction through a paper filter and the residue was rinsed with tert-butyl methyl ether. The filtrate was freed of most of the solvent on a rotary evaporator. The residue is taken up in approximately 400ml of ethyl acetate and the mixture is washed once in each case with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and the solvent was again evaporated in vacuo. The crude product was passed through about 250g of silica gel as mobile phase cyclohexane/ethyl acetate 10: 1 → 3: 1 purification by suction filtration. 11.6g (85% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.33-7.30 (m, 4H), 7.26-7.22 (m, 6H), 6.93 (d, 2H), 6.69 (d, 2H), 4.61 (s, 4H), 3.49-3.43 (m, 2H), 2.35-2.28 (m, 2H), 2.12-2.00 (m, 5H), 1.85-1.78 (m, 1H).

HPLC (method A) R_t = 4.81 min.

MS (DCI, NH₃): m/z = 372 [M+H]⁺。

Step (ii) of 3 ： N,N-dibenzyl-4- [1- (2-fluoroethyl) cyclobutyl]Aniline

To a solution of 3.0g (8.07 mmol) of the compound from example 113A/step 2 in 150ml of anhydrous dichloromethane are added dropwise 1.3ml (9.69 mmol) of diethylaminosulfur trifluoride (DAST) at a temperature of-78 ℃. After 30min at-78 ℃, the reaction mixture was warmed to about-20 ℃ for about 30 seconds and the reaction vessel was then immersed again in a cold bath at-78 ℃. After addition of 20ml of 1M sodium hydroxide solution, the mixture was warmed to RT. It is diluted with 75ml of water and extracted three times with approximately 75ml of dichloromethane each time. The combined organic extracts were washed with water and then dried over anhydrous magnesium sulfate. After filtration, the solvent was removed on a rotary evaporator. The product was isolated by MPLC (approximately 300g silica gel, mobile phase: cyclohexane/ethyl acetate 100: 0 → 20: 1). 1.48g (49% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.41-7.37 (m, 4H), 7.34-7.30 (m, 6H), 7.00 (d, 2H), 6.75 (d, 2H), 4.69 (s, 4H), 4.30 (td, 2H), 2.44-2.37 (m, 2H), 2.26-2.07 (m, 5H), 1.93-1.84 (m, 1H).

HPLC (method A) R_t = 5.31 min.

MS (DCI, NH₃): m/z = 374 [M+H]⁺。

Step (ii) of 4 ： 4- [1- (2-fluoroethyl) cyclobutyl]Aniline

In analogy to the procedure described under example 4A/step 6, 460mg (62% of theory) of the title compound are obtained from 1.43g (3.83 mmol) of the compound from example 113A/step 3. In this case, 180ml of a mixture of ethanol and ethyl acetate (3: 1) was used as solvent. The crude product obtained after evaporation of the solvent was used for the subsequent reaction without further purification by chromatography.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 6.93 (d, 2H), 6.64 (d, 2H), 4.23 (td, 2H), 3.60 (Width, 2H), 2.38-2.31 (m, 2H), 2.20-2.01 (m, 5H), 1.88-1.78 (m, 1H).

LC/MS (method I, ESIpos) R_t = 0.77 min, m/z = 194 [M+H]⁺。

Step (ii) of 5 ： 4- [1- (2-fluoroethyl) cyclobutyl]Benzonitrile

In analogy to the procedure described under example 4A/step 7, 259mg (56% of theory) of the title compound are obtained from 440mg (2.28 mmol) of the compound from example 113A/step 4.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.61 (d, 2H), 7.24 (d, 2H), 4.23 (td, 2H), 2.44-2.36 (m, 2H), 2.31-2.10 (m, 5H), 1.91-1.82 (m, 1H).

GC/MS (method L, EIpos) R_t = 5.63 min, m/z = 203 [M]⁺。

Step (ii) of 6 ： 4- [1- (2-fluoroethyl) cyclobutyl]-N'-hydroxybenzoylimidic amides

In analogy to the procedure described under example 1A/step 5, from 250mg (1.23 mmol) of the compound from example 113A/step 5 was obtained 102mg (35% of theory) of the title compound. The crude product was purified by preparative HPLC (method N).

LC/MS (method D, ESIpos) R_t = 1.37 min, m/z = 237 [M+H]⁺。

Examples 114A

N'-hydroxy-4- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) benzoylimine amide (racemate)

In analogy to the procedure described under example 1A/step 5, 1.0g (4.65 mmol) of the compound from example 111A/step 1 were reacted to give 1.12g (83% of theory, purity 85%) of the title compound.

LC/MS (method F, ESIpos) R_t = 0.36 min, m/z = 249 [M+H]⁺。

Examples 115A

Acetic acid {1- [4-, (N'-hydroxycarbamimidoyl) phenyl ]Cyclobutyl } methyl ester

Step (ii) of 1 ： Acetic acid [1- (4-bromophenyl) cyclobutyl group]Methyl ester

To a solution of 402mg (1.67 mmol) of the compound from example 110A/step 1 in 6ml of pyridine at 0 ℃ was added 236. mu.l (2.50 mmol) of acetic anhydride. After the reaction mixture had been stirred at RT for 16h, all volatile constituents were removed on a rotary evaporator. The product was separated from the residue obtained by MPLC (silica gel, mobile phase: cyclohexane/ethyl acetate 10: 1). 450mg (91% of theory, approximately 95% purity) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.42 (d, 2H), 7.02 (d, 2H), 4.21 (s, 2H), 2.38-2.30 (m, 2H), 2.29-2.21 (m, 2H), 2.16-2.03 (m, 1H), 1.98 (s, 3H), 1.93-1.83 (m, 1H).

MS (DCI, NH₃): m/z = 300/302 [M+NH₄]⁺。

Step (ii) of 2 ： Acetic acid [1- (4-cyanophenyl) cyclobutyl]Methyl ester

In analogy to the procedure described under example 109A/step 2, 440mg (1.55 mmol) of the compound from example 115A/step 1 were reacted to give 314mg (84% of theory, purity 95%) of the title compound. The purification of the crude product is carried out directly by preparative HPLC (method N).

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.60 (d, 2H), 7.25 (d, 2H), 4.26 (s, 2H), 2.42-2.26 (m, 4H), 2.20-2.09 (m, 1H), 1.98 (s, 3H), 1.98-1.87 (m, 1H).

MS (DCI, NH₃): m/z = 247 [M+NH₄]⁺。

Step (ii) of 3 ： Acetic acid {1- [4-, (N'-hydroxycarbamimidoyl) phenyl]Cyclobutyl } methyl ester

In analogy to the procedure described under example 1A/step 5, 260mg (1.13 mmol) of the compound from example 115A/step 2 are reacted to give 312mg (94% of theory, purity 90%) of the title compound.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 7.57 (d, 2H), 7.19 (d, 2H), 4.84 (width, 2H), 4.24 (s, 2H), 2.44-2.34 (m, 2H), 2.32-2.24 (m, 2H), 2.17-2.07 (m, 1H), 1.99 (s, 3H), 1.94-1.86 (m, 1H).

MS (DCI, NH₃): m/z = 263 [M+NH₄]⁺。

LC/MS (method F, ESIpos) R_t = 0.74 min, m/z = 263 [M+H]⁺。

Examples 116A

N'-hydroxy-4- [1- (2-hydroxyethyl) cyclobutyl]Benzoylimide amides

Step (ii) of 1 ： Acetic acid 2- {1- [4- (dibenzylamino) phenyl]Cyclobutyl } ethyl ester

In analogy to the procedure described under example 115A/step 1, 3.64g (87% of theory) of the title compound are obtained from 3.50g (9.42 mmol) of the compound from example 113A/step 2. Cyclohexane/ethyl acetate 20 as mobile phase was filtered through a final suction of silica gel: 1.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.35-7.30 (m, 4H), 7.28-7.22 (m, 6H), 6.91 (d, 2H), 6.67 (d, 2H), 4.62 (s, 4H), 3.86-3.82 (m, 2H), 2.37-2.29 (m, 2H), 2.15-2.00 (m, 5H), 1.94 (s, 3H), 1.86-1.77 (m, 1H).

HPLC (method A) R_t = 5.22 min.

MS (DCI, NH₃): m/z = 414 [M+H]⁺.

LC/MS (method I, ESIpos) R_t = 1.51 min, m/z = 414 [M+H]⁺。

Step (ii) of 2 ： Acetic acid 2- [1- (4-aminophenyl) cyclobutyl]Ethyl ester

In analogy to the procedure described under example 4A/step 6, from 3.50g (8.46 mmol) of the compound from example 116A/step 1 were obtained 1.79g (85% of theory, purity 94%) of the title compound. In this case, 300ml of a mixture of ethanol and ethyl acetate (3: 1) was used as the solvent. The crude product obtained after evaporation of the solvent was used for the subsequent reaction without further purification by chromatography.

LC/MS (method D, ESIpos) R_t = 1.46 min, m/z = 467 [2M+H]⁺, 234 [M+H]⁺。

Step (ii) of 3 ： Acetic acid 2- [1- (4-cyanophenyl) cyclobutyl]Ethyl ester

In analogy to the procedure described under example 4A/step 7, from 500mg (2.14 mmol) of the compound from example 116A/step 2 was prepared 152mg (29% of theory) of the title compound.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.60 (d, 2H), 7.23 (d, 2H), 3.83 (t, 2H), 2.42-2.33 (m, 2H), 2.27-2.21 (m, 2H), 2.17 (t, 2H), 2.15-2.08 (m, 1H), 1.93-1.82 (m, 1H), 1.89 (s, 3H).

MS (DCI, NH₃): m/z = 461 [M+NH₄]⁺。

Step (ii) of 4 ： N'-hydroxy-4- [1- (2-hydroxyethyl) cyclobutyl]Benzoylimide amides

In analogy to the procedure described in example 1A/step 5, from 150mg (0.617 mmol) of the compound from example 116A/step 3 164mg of the title compound were obtained together with the corresponding acetate (acetic acid 2- {1- [4-, (acetic acid 2)N'-hydroxycarbamimidoyl) phenyl]Cyclobutyl } ethyl ester). The mixture was not isolated but used as such for the subsequent reaction.

LC/MS (method I, ESIpos) the title compound R_t = 0.52 min, m/z = 234 [M+H]⁺The corresponding acetate ester R_t = 0.70 min, m/z = 277 [M+H]⁺。

Examples 117A

2-{1-[4-（N'-hydroxycarbamimidoyl) phenyl]Cyclobutyl } -N,N-dimethylacetamide

Step (ii) of 1 ： {1- [4- (dibenzylamino) phenyl]Cyclobutyl acetic acid

To a solution of 6.0g (14.5 mmol) of the compound from example 113A/step 1 in 90ml ethanol was added 43.5ml (43.5 mmol) of 1M sodium hydroxide solution and the mixture was heated at reflux for 3 h. After cooling to RT, the mixture was neutralized with 1M hydrochloric acid and the majority of ethanol was stripped off on a rotary evaporator. The aqueous solution obtained is extracted three times with approximately 100ml of ethyl acetate each time. The combined organic extracts were dried over anhydrous magnesium sulfate. After filtration, the solvent was removed on a rotary evaporator. The crude product was passed roughly through 200g of silica gel as mobile phase cyclohexane/ethyl acetate 4: 1 purification by suction filtration. 5.35g (86% of theory, purity 90%) of the title compound are obtained in this way.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 10.97 (very broad, 1H), 7.33-7.28 (m, 4H), 7.25-7.22 (m, 6H), 6.99 (d, 2H), 6.66 (d, 2H), 4.60 (s, 4H), 2.73 (s, 2H), 2.43-2.27 (m, 4H), 2.04-1.96 (m, 1H), 1.88-1.78 (m, 1H).

HPLC (method A) R_t = 4.76 min.

MS (DCI, NH₃): m/z = 386 [M+H]⁺.

LC/MS (method I, ESIpos) R_t = 1.35 min, m/z = 386 [M+H]⁺。

Step (ii) of 2 ： 2- {1- [4- (dibenzylamino) phenyl]Cyclobutyl } -N,N-dimethylacetamide

Under inert conditions, 2.65g (6.87 mmol) of the compound from example 117A/step 1 are dissolved in 70ml of anhydrous dichloromethane and 3ml (34.4 mmol) of oxalyl chloride and one drop of DMF are added. After the mixture had been stirred at RT for 2h, it was concentrated to dryness on a rotary evaporator. The residue obtained is dried under high vacuum for about 1h and then dissolved in 30ml of anhydrous THF. To a mixture of 10.3ml (20.6 mmol) of a 2M solution of dimethylamine in THF, which had previously been diluted with 30ml of THF, was added dropwiseThe solution was added dropwise 3.6ml (20.6 mmol)N,N-diisopropylethylamine. After stirring for 16h at RT, the reaction mixture was freed of all volatile constituents on a rotary evaporator. The residue obtained is taken up in 300ml of ethyl acetate and the mixture is washed successively with approximately 100ml each time of saturated sodium bicarbonate solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and the filtrate was concentrated on a rotary evaporator. 1.93g (68% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.33-7.29 (m, 4H), 7.26-7.22 (m, 6H), 6.94 (d, 2H), 6.65 (d, 2H), 4.61 (s, 4H), 2.69 (s, 2H), 2.67 (s, 3H), 2.47-2.31 (m, 4H), 2.25 (s, 3H), 2.12-2.01 (m, 1H), 1.87-1.77 (m, 1H).

LC/MS (method F, ESIpos) R_t = 1.53 min, m/z = 413 [M+H]⁺。

Step (ii) of 3 ： 2- [1- (4-aminophenyl) cyclobutyl]-N,N-dimethylacetamide

In analogy to the procedure described under example 4A/step 6, from 1.93g (4.68 mmol) of the compound from example 117A/step 2 were obtained 1.1g (99% of theory, purity 98%) of the title compound. In this case, 250ml of a mixture of ethanol and ethyl acetate (3: 1) was used as solvent. The product obtained after evaporation of the solvent was used for the subsequent reaction without further purification by chromatography.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 6.96 (d, 2H), 6.62 (d, 2H), 3.58 (broad, 2H), 2.74 (s, 3H), 2.72 (s, 2H), 2.50-2.43 (m, 2H), 2.39-2.32 (m, 2H), 2.33 (s, 3H), 2.17-2.03 (m, 1H),1.87-1.78 (m, 1H).

LC/MS (method F, ESIpos) R_t = 0.55 min, m/z = 233 [M+H]⁺。

Step (ii) of 4 ： 2- [1- (4-cyanophenyl) cyclobutyl]-N,N-dimethylacetamide

In analogy to the procedure described under example 4A/step 7, 776mg (74% of theory) of the title compound are obtained from 1.0g (4.30 mmol) of the compound from example 117 a/step 3. The crude product was purified by preparative HPLC (method N).

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.57 (d, 2H), 7.33 (d, 2H), 2.86 (s, 2H), 2.76 (s, 3H), 2.57 (s, 3H), 2.51-2.39 (m, 4H), 2.19-2.07 (m, 1H), 1.92-1.82 (m, 1H).

MS (DCI, NH₃): m/z = 260 [M+NH₄]⁺, 243 [M+H]⁺.

GC/MS (method L, EIpos) R_t = 7.39 min, m/z = 242 [M]⁺。

Step (ii) of 5 ： 2- {1- [4- (N' -hydroxycarbamimidoyl) phenyl]Cyclobutyl } -N,N-dimethylacetamide

In analogy to the procedure described under example 1A/step 5, 669mg (73% of theory, purity 91%) of the title compound are obtained from 730mg (3.01 mmol) of the compound from example 117A/step 4. The final stirring of the product here is not carried out in petroleum ether but in ethanol.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 9.53 (s, 1H), 7.56 (d, 2H), 7.17 (d, 2H), 5.73 (s, 2H), 2.82 (s, 2H), 2.62 (s, 3H), 2.53 (s, 3H), 2.41-2.23 (m, 2H), 2.32-2.25 (m, 2H), 2.10-1.98 (m, 1H), 1.80-1.70 (m, 1H).

HPLC (method A) R_t = 3.27 min.

MS (DCI, NH₃): m/z = 551 [2M+H]⁺, 276 [M+H]⁺。

Examples 118A

4- [ (diisopropylamino) methyl group]-N'-hydroxybenzoylimidic amides

Step (ii) of 1 ： 4- [ (diisopropylamino) methyl group]Benzonitrile

A mixture of 4.0g (20.4 mmol) of 4- (bromomethyl) benzonitrile and 6.19g (61.2 mmol) of diisopropylamine in 40ml of toluene is divided into two portions and heated at 150 ℃ for 3h in each case in a microwave apparatus (CEM Discover, initial radiant power 250W). After cooling to RT, the solid formed is filtered off and the filtrate is concentrated to obtain in this way 4.52g (92% of theory, purity 90%) of the title compound.

LC/MS (method F, ESIpos) R_t = 0.30 min, m/z = 217 [M+H]⁺。

Step (ii) of 2 ： 4- [ (diisopropylamino) methyl group]-N'-hydroxybenzoylimidic amides

In analogy to the procedure described under example 1A/step 5, from 6.80g (28.3 mmol, purity 90%) of the compound from example 118A/step 1 were obtained 4.93g (70% of theory) of the title compound.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 7.52 (d, 2H), 7.41 (d, 2H), 4.84 (s, width, 2H), 3.64 (s, 2H), 3.05-2.95 (m, 2H), 1.01 (d, 12H).

LC/MS (method I, ESIpos) R_t = 0.18 min, m/z = 250 [M+H]⁺。

Examples 119A

N'-hydroxy-4-, [N-methyl-S- (trifluoromethyl) sulphoimides]Benzoylimide amides (racemates)

Step (ii) of 1 ： 4-[S- (trifluoromethyl) sulphoimides ]Benzonitrile (racemate)

150mg (0.66 mmol) 1-fluoro-4- [ S- (trifluoromethyl) sulphoimido]Benzene [ n.v. Kondratenko,Zhurnal Organicheskoi Khimii 1986，22 （ 8 ），1716-1721；same as above1984，20 μ（ 10 ），2250-2252]Dissolved in 20ml of DMSO and added are 115mg (0.83 mmol) of potassium carbonate, 140mg (0.84 mmol) of potassium iodide and 130mg (2.0 mmol) of potassium cyanide. The mixture was heated at 110 ℃ overnight with stirring. After cooling to RT, about 10ml of water was added to the mixture and the mixture was extracted with ethyl acetate. After concentration of the organic phase, the residue is purified by flash chromatography on silica gel. 50mg (33% of theory) of the title compound are obtained.

Step (ii) of 2 ： 4-[N-methyl-S- (trifluoromethyl) sulphoimides]Benzonitrile (racemate)

400mg (1.60 mmol) of the compound from example 119A/step 1 under argon are dissolved in 8ml of THF and 224mg (2.0 mmol) of potassium tert-butoxide are added. The mixture is first stirred at RT for 1h, then 283mg (2.0 mmol) of iodomethane are added and the mixture is further stirred at RT overnight. Water was then added to the batch and the mixture was extracted with ethyl acetate. The organic extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel. 298mg (70% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.22 (d, 2H), 7.90 (d, 2H), 3.10 (s, 3H).

LC/MS (method D, ESIpos) R_t = 2.17 min, m/z = 249 [M+H]⁺。

Step (ii) of 3 ： N'-hydroxy-4-, [N-methyl-S- (trifluoromethyl) sulphoimides]Benzoylimide amides (racemates)

1.00g (4.03 mmol) of the compound from example 119A/step 2 are initially added to 20ml of ethanol. 616mg (8.86 mmol) of hydroxylamine hydrochloride and 1.2ml (8.86 mmol) of triethylamine are added and the mixture is heated at reflux for 1 h. It was then concentrated and the residue was taken up in a mixture of ethyl acetate and water. The phases were separated and the aqueous phase was extracted once with ethyl acetate. The combined ethyl acetate phases were washed once with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is purified by column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate 7: 3). The combined product fractions were concentrated and the residue was stirred with pentane. The resulting solid was filtered off and dried in vacuo. 775mg (66% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.12 (d, 2H), 8.04 (s, width, 1H), 7.87 (d, 2H), 4.93 (s, 2H), 3.10 (s, 3H).

LC/MS (method I, ESIpos) R_t = 0.76 min, m/z = 282 [M+H]⁺。

Examples 120A

3-chloro-N'-hydroxy-4- (trifluoromethoxy) benzoylimine amide

In analogy to the procedure described under example 1A/step 5, from 1.00g (4.51 mmol) 3-chloro-4- (trifluoromethoxy) benzonitrile 842mg (73% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 7.77 (d, 1H), 7.58-7.55 (dd, 1H), 7.37-7.33 (m, 1H), 4.82 (s, width, 1H).

LC/MS (method D, ESIpos) R_t = 1.64 min, m/z = 255/257 [M+H]⁺。

Examples 121A

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

Step (ii) of 1 ： 1-bromo-4- [1- (trifluoromethyl) cyclopropyl]Benzene and its derivatives

First, activated zinc bromide on montmorillonite was prepared as follows: 1.40g (6.22 mmol) of zinc bromide are initially added to 56ml of methanol, 5.64g of montmorillonite K10 are added and the mixture is stirred at RT for 1 h. After removal of the methanol, the remaining powder was heated in a sand bath at 200 ℃ bath temperature for 1h and then allowed to cool under argon.

The title compound was then prepared as follows: to a starting 50ml of pentane was added 10.0g (53.7 mmol) of 1-phenyl-1- (trifluoromethyl) cyclopropane. 6.1g (5.37 mmol) of activated zinc bromide on montmorillonite obtained above was added and then 27.7ml (537 mmol) of bromine was slowly added dropwise in the dark while stirring. The mixture was then further stirred at RT overnight in the dark. Subsequently, 150ml of a saturated aqueous sodium sulfite solution were slowly dropped while cooling with ice, and the mixture was stirred at RT for about 30min again until it was decolorized. The solid was filtered off and washed twice with pentane. After separation of the filtrate phases, the aqueous phase is extracted twice with 200ml of pentane each time. The combined organic phases were dried over sodium sulfate, filtered and concentrated under mild conditions (significant volatility of the target compound). In this way 17.1g (> 100% of theory) of the title compound are obtained, according to ¹H-NMR still contained pentane.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.47 (d, 2H), 7.32 (s, 2H),1.39-1.30 (m, 2H), 1.04-0.95 (m, 2H).

GC/MS (method L, ESIpos) R_t = 3.45 min, m/z = 264/266 [M+H]⁺。

Step (ii) of 2 ： 4- [1- (trifluoromethyl) cyclopropyl]Benzonitrile

6.00g (22.6 mmol) of the compound from example 121A/step 1 are initially introduced into 30ml of DMF under argon, 1.86g (15.8 mmol) of zinc cyanide and 1.57g (1.36 mmol) of tetrakis (triphenylphosphine) palladium (0) are added and the mixture is stirred at 80 ℃ overnight. After cooling to RT, 4.0g (34.1 mmol) of zinc cyanide and 3.0g (2.56 mmol) of tetrakis (triphenylphosphine) palladium (0) are further added and the mixture is heated again at 120 ℃ for 5h with stirring. After cooling to RT, the solids present were filtered off and washed once with DMF. The filtrate was combined with the eluate and concentrated. The residue was taken up in 200ml of ethyl acetate and the solution obtained was washed twice with 2M aqueous ammonia solution and once with saturated aqueous sodium chloride solution. After drying over sodium sulfate, filtration and concentration, the residue obtained is purified by flash chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate 40: 1). After brief drying in vacuo, 3.46g (72% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.66 (d, 2H), 7.58 (d, 2H), 1.47-1.41 (m, 2H), 1.09-1.03 (m, 2H).

GC/MS (method L, ESIpos) R_t = 3.81 min, m/z = 212 [M+H]⁺。

Step (ii) of 3 ： N'-hydroxy-4- [1- (trifluoromethyl) cyclopropyl ]Benzoylimide amides

In analogy to the procedure described under example 1A/step 5, from 3.40g (16.1 mmol) of the compound from example 121A/step 2 were obtained 3.82g (89% of theory) of the title compound.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 7.62 (d, 2H), 7.50 (d, 2H), 4.88 (s, width, 2H), 1.42-1.36 (m, 2H), 1.06-1.00 (m, 2H).

LC/MS (method F, ESIpos) R_t = 0.81 min, m/z = 245 [M+H]⁺。

Examples 122A

3-fluoro-N'-hydroxy-4- (trifluoromethoxy) benzoylimine amide

In analogy to the procedure described under example 1A/step 5, from 5.0g (23.9 mmol, purity 98%) 3-fluoro-4- (trifluoromethoxy) benzonitrile 5.7g (99% of theory, purity 98%) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 7.53-7.49 (dd, 1H), 7.45-7.41 (m, 1H), 7.37-7.31 (t, 1H), 4.87 (s, width, 2H).

LC/MS (method I, ESIpos) R_t = 0.74 min, m/z = 239 [M+H]⁺。

Examples 123A

4- [4- (fluoromethyl) tetrahydro-2H-pyran-4-yl]-N'-hydroxybenzoylimidic amides

Step (ii) of 1 ： 4- (4-bromophenyl) tetrahydro-2H-pyran-4-carboxylic acid ethyl ester

6.0g (24.7 mmol) of ethyl 4-bromophenylacetate are dissolved in 120ml of anhydrous DMF under argon, 1.48g (37.0 mmol, 60% strength) of sodium hydride are added while cooling in an ice bath, and the mixture is stirred for 30 min. 5.72g (24.7 mmol) of bis (2-bromoethyl) ether are then added while cooling in an ice bath constantly and the mixture is stirred at about 0 ℃ for 1 h. After a further addition of 1.48g of 60% strength sodium hydride, the mixture is stirred for a further 1h while cooling in an ice bath. Saturated aqueous ammonium chloride was then added and the mixture was extracted with ethyl acetate. The organic phase is washed with water and with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The residue was purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10: 1). 2.62g (33% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.47 (d, 2H), 7.25 (d, 2H), 4.14 (q, 2H), 3.93 (dt, 2H), 3.56 (td, 2H), 2.59 (dd, 2H), 1.93 (m, 2H), 1.19 (t, 3H).

MS (DCI, NH₃): m/z = 329 [M+NH₄]⁺.

LC/MS (method F, ESIpos) R_t= 1.33 min, no ionization.

Step (ii) of 2 ： [4- (4-bromophenyl) tetrahydro-2 ]H-pyran-4-yl]Methanol

1.14g (3.64 mmol) of the compound from example 123A/step 1 are dissolved in 18ml of THF, 3.64ml (3.64 mmol) of a 1M solution of lithium aluminium hydride in THF are added at 0 ℃ and the mixture is stirred for 1h while cooling in an ice bath. Saturated aqueous ammonium chloride solution was then added dropwise and the mixture was then diluted with ethyl acetate. The organic phase is washed with 1N sodium hydroxide solution, then with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. After the residue has been dried in vacuo, 780mg (79% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.51 (d, 2H), 7.22 (d, 2H), 3.79 (m, 2H), 3.59 (d, 2H), 3.54 (t, 2H), 2.09 (d, 2H), 1.91 (m, 2H).

GC/MS (method L) R_t = 7.09 min, m/z = 252 [M-H₂O]⁺。

Step (ii) of 3 ： 4- (4-bromophenyl) -4- (fluoromethyl) tetrahydro-2H-pyrans

To a solution of 400mg (1.47 mmol) of compound 123A from the example/step 2 in 4.0ml of dichloromethane at-78 ℃ are added dropwise a 50% strength solution of 0.63ml of bis (2-methoxyethyl) aminosulfur trifluoride in THF and the mixture is then stirred at RT overnight. A 1N sodium hydroxide solution was then added to the batch and the mixture was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and the solvent was removed on a rotary evaporator. The residue obtained is purified by preparative HPLC (method P). 131mg (33% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 7.50 (d, 2H), 7.18 (d, 2H), 3.69 (m, 2H), 3.49 (td, 2H), 2.92 (d, 2H), 1.79-1.62 (m, 2H), 1.54 (t, 2H).

GC/MS (method L) R_t = 6.03 min, m/z = 272 [M]⁺。

Step (ii) of 4 ： 4- [4- (fluoromethyl) tetrahydro-2H-pyran-4-yl]Benzonitrile

360mg (1.32 mmol) of the compound obtained in example 123A/step 3, 93mg (0.79 mmol) of zinc cyanide and 91mg (0.08 mmol) of tetrakis (triphenylphosphine) palladium (0) are added to 2.1ml of degassed DMF starting under argon and the mixture is stirred in a microwave oven for 1h at 110 ℃. After cooling to RT, the solid is filtered off and the filtrate is purified directly by preparative HPLC (method P). 195mg (67% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 7.78 (d, 2H), 7.43 (d, 2H), 3.71 (m, 2H), 3.48 (td, 2H), 3.05 (d, 2H), 1.81-1.65 (m, 2H), 1.54 (t, 2H).

GC/MS (method L) R_t = 6.32 min, m/z = 199 [M-HF]⁺。

Step (ii) of 5 ： 4- [4- (fluoromethyl) tetrahydro-2H-pyran-4-yl]-N'-hydroxybenzoylimidic amides

A mixture of 410mg (1.84 mmol) of the compound from example 123A/step 4, 286mg (4.11 mmol) of hydroxylamine hydrochloride and 0.57ml (4.11 mmol) of triethylamine in 9.1ml of ethanol is stirred at 80 ℃ for 2 h. After cooling to RT, the solvent was almost completely removed on a rotary evaporator. The residue was suspended with a little water under ultrasonic irradiation. The white solid was filtered off, washed with a little cold water and then stirred with pentane. The solid was filtered off again and dried in vacuo. 320mg (65% of theory) of the title compound are obtained in this way.

LC/MS (method I) R _t = 0.47 min, m/z = 253 [M+H]⁺。

Examples 124A

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

In analogy to the procedure described under example 28A, starting from 469mg (3.72 mmol) of 5-methyl-1HPyrazole-3-carboxylic acid and 820mg (3.72 mmol) of the compound from example 107A, 450mg of the title compound being obtained after extraction of the crude product by stirring in acetonitrile and further 97mg of the title compound being obtained after purification by preparative HPLC mother liquor (method N) (yield amounts to 47% of theory).

¹H-NMR (400 MHz, DMSO-d₆, 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 I, ESIpos) R_t = 0.98 min, m/z = 311 [M+H]⁺。

Examples 125A

3- (4-tert-butylphenyl) -5- (5-methyl-1)H-pyrazol-3-yl) -1,2,4-Diazoles

In analogy to the procedure described under example 28A, 2.50g (19.8 mmol) of 5-methyl-1HPyrazole-3-carboxylic acid and 4.19g (21.8 mmol) of 4-tert-butyl-N'-hydroxybenzenecarboximidamide to give 2.60g (46% of theory) of the title compound. The reaction mixture was first stirred here for 1h at RT and then for 30min at 140 ℃.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 11.08 (Width, 1H), 8.10 (d, 2H), 7.51 (d, 2H), 6.81 (s, 1H), 2.45 (s, 3H), 1.37 (s, 9H).

LC/MS (method I, ESIpos) R_t = 1.21 min, m/z = 283 [M+H]⁺, 565 [2M+H]⁺。

Examples 126A

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

Similar to the trueThe procedure described under example 28A, 1.08g (8.52 mmol) of 5-methyl-1HPyrazole-3-carboxylic acid and 2.0g (8.52 mmol) of the compound from example 110A are reacted to yield 1.87g (46% of theory) of the title compound. The reaction mixture was first stirred here for 1h at RT and then for 30min at 140 ℃.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 11.57 (Width, 1H), 8.10 (d, 2H), 7.30 (d, 2H), 6.81 (s, 1H), 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 F, ESIpos) R_t = 1.28 min, m/z = 325 [M+H]⁺。

Examples 127A

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

In analogy to the procedure described under example 28A, 180mg (1.43 mmol) of 5-methyl-1HPyrazole-3-carboxylic acid and 335mg (1.43 mmol) of the compound from example 108A were reacted to yield 189mg (39% of theory) of the title compound. The reaction mixture was first stirred here for 16h at RT and then for 30min at 140 ℃. Purification of the product was carried out by preparative HPLC (method N).

¹H-NMR (400 MHz, CDCl₃Delta/ppm) 10.63 (Width, 1H), 8.00 (d, 1H), 7.99 (s, 1H), 7.36 (d, 1H), 6.80 (s, 1H), 4.13-4.10 (m, 2H), 3.61-3.54 (m, 2H), 3.07-3.00 (m, 1H), 2.45 (s, 3H), 2.43 (s, 3H), 1 .92-1.80 (m, 2H), 1.73-1.68 (m, 2H).

LC/MS (method I, ESIpos) R_t = 1.02 min, m/z = 325 [M+H]⁺。

Examples 128A

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

Analogously to the process described under example 28A, 631mg (5.00 mmol) of 5-methyl-1HPyrazole-3-carboxylic acid and 1.27g (5.00 mmol) of the compound from example 120A are reacted to yield 1.08g (60% of theory, purity 95%) of the title compound. The reaction mixture is first stirred here for about 30min at RT and then for about 1h at 150 ℃. The product was obtained by a step in which the solid which had precipitated out after the addition of water was filtered off after the reaction had ended, washed with water and dried in vacuo.

LC/MS (method I, ESIpos) R_t = 1.20 min, m/z = 345/347 [M+H]⁺。

Examples 129A

5- (5-methyl-1)H-pyrazol-3-yl) -3- {4- [1- (trifluoromethyl) cyclopropyl]Phenyl } -1,2,4-Diazoles

In analogy to the procedure described under example 28A, 1.19g (9.42 mmol) of 5-methyl-1HPyrazole-3-carboxylic acid and 2.30g (9.42 mmol) of the compound from example 121A are reacted to yield 1.05g (62% of theory) of the title compound. The crude product was purified by preparative HPLC (method O).

¹H-NMR (400 MHz, CDCl₃δ/ppm) 11.0-10.5 (s, width, 1H), 8.16 (d, 2H), 7.60 (d, 2H), 6.82 (s, 1H), 1.43-1.39 (m, 2H), 1.12-1.08 (m, 2H).

LC/MS (method I) R_t = 1.17 min, m/z = 335 [M+H]⁺。

Examples 130A

5- (5-methyl-1)H-pyrazol-3-yl) -3- {4-, [ 2 ]N-methyl-S- (trifluoromethyl) sulphoimides]Phenyl } -1,2,4-Diazoles (racemates)

In analogy to the procedure described under example 28A, 89mg (0.709 mmol) of 5-methyl-1HPyrazole-3-carboxylic acid and 206mg (0.709 mmol, purity 97%) of the compound from example 119A are reacted to yield 103mg (39% of theory) of the title compound. The crude product was purified by preparative HPLC (method O).

¹H-NMR (400 MHz, CDCl₃Delta/ppm) 10.59 (s, width, 1H), 8.42 (d, 2H), 8.22 (d, 2H), 6.83 (s, 1H), 3.12 (d, 3H), 2.47 (s, 3H).

LC/MS (method I, ESIpos) R_t = 1.10 min, m/z = 372 [M+H]⁺。

Examples 131A

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

In analogy to the procedure described under example 28A, 2.0g (15.9 mmol) of 5-methyl-1HPyrazole-3-carboxylic acid and 3.78g (15.9 mmol) of compound 122A from the example are reacted to yield 3.15g (56% of theory, purity 92%) of the title compound. The product is in this case obtained not by chromatographic purification but by washing the crude product with water and pentane and subsequent drying in vacuo.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 12.0-9.5 (s, width, 1H), 8.10-7.97 (m, 2H), 7.46-7.41 (t, 1H), 6.81 (s, 1H), 2.47 (s, 3H).

LC/MS (method I, ESIpos) R_t = 1.16 min, m/z = 329 [M+H]⁺。

Examples 132A

N-isopropyl-N- {4- [5- (5-methyl-1)H-pyrazol-3-yl) -1,2,4-Diazol-3-yl]Benzyl propan-2-amine

In analogy to the procedure described under example 28A, 2.00g (15.9 mmol) of 5-methyl-1HPyrazole-3-carboxylic acid and 3.95g (15.9 mmol) of the compound from example 118A are reacted to yield 1.49g (26% of theory, purity 93%) of the title compound.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 11.50 (s, width, 1H), 8.08 (d, 2H), 7.51 (d, 2H), 6.81 (s, 1H), 3.70 (s, 2H), 3.10-2.98 (m, 2H), 2.42 (s, 3H), 1.02 (d, 12H).

LC/MS (method F, ESIpos) R_t = 0.73 min, m/z = 340 [M+H]⁺。

Examples 133A

2-bromo-4- (bromomethyl) pyridine

In analogy to the procedure described under example 47A/step 3, from 1.50g (7.66 mmol) 2-bromo-4- (hydroxymethyl) pyridine was prepared 1.83mg (95% of theory) of the title compound.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.36 (d, 1H), 7.52 (s, 1H), 7.27 (d, 1H), 4.32 (s, 2H).

HPLC (method A) R_t = 3.47 min.

MS (DCI, NH₃): m/z = 250/252/254 [M+H]⁺。

Examples 134A

3- (bromomethyl) benzenesulfonyl chloride

To a solution of 5.0g (26.2 mmol) of m-toluenesulfonyl chloride in 50ml of acetonitrile were added 5.13g (28.8 mmol) of N-bromosuccinimide and 43mg (0.26 mmol) of 2,2' -azobis-2-methylpropanenitrile and the mixture was heated at reflux overnight. The batch is then concentrated on a rotary evaporator and the residue is purified directly by MPLC (silica gel, mobile phase: cyclohexane/ethyl acetate 10: 1). 4.58g (65% of theory) of the title compound are obtained.

GC/MS (method L) R_t = 6.14 min, m/z = 189 [M-Br]⁺。

Examples 135A

1- [4- (chloromethyl) pyridin-2-yl ] -4-cyclopropylpiperazine

Step (ii) of 1 ： [2- (piperazin-1-yl) pyridin-4-yl]Methanol

To 10.0g (69.6 mmol) of (2-chloropyridin-4-yl) methanol under argon was added 120g(1.39 mol) piperazine. The mixture was heated at 150 ℃ overnight with stirring. After cooling to RT, part of the excess piperazine that had precipitated in the upper part of the reaction vessel was removed and the resinous contents of the flask were taken up in 700ml of dichloromethane and the mixture was stirred at RT for 30 min. The solids present were filtered off and washed with dichloromethane, the solids were discarded and the filtrate was concentrated. The residue was dried in vacuo. 13.3g (about 99% of theory) of the title compound are obtained, according to¹H-NMR it still contains piperazine.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.14 (d, 1H), 6.67 (s, 1H), 6.58 (d, 1H), 4.64 (s, 2H), 3.55-3.45 (m, 4H), 3.01-2.94 (m, 4H).

LC/MS (method D, ESIpos) R_t = 0.19 min, m/z = 194 [M+H]⁺。

Step (ii) of 2 ： [2- (4-Cyclopropylpiperazin-1-yl) pyridin-4-yl]Methanol

13.1g (67.9 mmol) of the compound from example 135A/step 1 are dissolved in a mixture of 535ml of methanol and 39ml (679 mmol) of acetic acid. 9.2g of molecular sieve (3A) and 82ml (407 mmol) of [ (1-ethoxycyclopropyl) oxy ] (trimethyl) silane are added. After stirring at RT for 10min, 12.8g (203 mmol) of sodium cyanoborohydride are added and the mixture is heated at reflux for 2h with stirring. After cooling to RT, the solids present are filtered off and rinsed twice with 20ml of methanol each time. The filtrate was concentrated and the residue was taken up in 550ml dichloromethane. The mixture was washed twice with 500ml of saturated aqueous sodium bicarbonate solution each time and once with 500ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is purified by column chromatography (silica gel, mobile phase: dichloromethane/methanol 95: 5). After drying in vacuo, 9.59g (61% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.13 (d, 1H), 6.67 (s, 1H), 6.57 (d, 1H), 4.63 (s, 2H), 3.58-3.46 (m, 4H), 2.77-2.66 (m, 4H), 1.70-1.60 (m, 1H), 0.55-0.41 (m, 4H).

LC/MS (method I, ESIpos) R_t = 0.17 min, m/z = 234 [M+H]⁺。

Step (ii) of 3 ： 1- [4- (chloromethyl) pyridin-2-yl]-4-cyclopropylpiperazine

9.59g (41.1 mmol) of the compound from example 135A/step 2 are initially added to 60ml of dichloromethane. 15ml (205 mmol) of thionyl chloride are added slowly at RT and the mixture is first stirred at RT for 10min and then at reflux for 4.5 h. After cooling to RT, 40ml of water are added to the mixture and the mixture is made basic with 460ml of saturated aqueous sodium bicarbonate solution and extracted three times with 500ml of dichloromethane each time. The combined dichloromethane phases were dried over magnesium sulfate, filtered and concentrated. The residue is purified by column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate 7: 3). After drying in vacuo, 5.47g (53% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.16 (d, 1H), 6.68-6.56 (m, 2H), 4.45 (s, 2H), 3.61-3.45 (m, 4H), 2.79-2.67 (m, 4H), 1.69-1.62 (m, 1H), 0.58-0.35 (m, 4H).

LC/MS (method I, ESIpos) R_t = 0.43 min, m/z = 252/254 [M+H]⁺。

Examples 136A

1- { [3- (bromomethyl) phenyl ] sulfonyl } -4-hydroxypiperidine

50mg (0.5 mmol) of 4-hydroxypiperidine are initially added to 2ml of THF, and 133mg (0.5 mmol) of the compound from example 134A and then 69. mu.l (0.5 mmol) of triethylamine are added, while cooling in an ice bath. After stirring for two hours at RT, the batch is diluted with 5ml of ethyl acetate, washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and the solvent is removed on a rotary evaporator. The residue obtained (about 70% purity according to HPLC) was used without further purification in the subsequent reaction.

Examples 137A

1- { [3- (bromomethyl) phenyl ] sulfonyl } -4-methylpiperazine

0.11ml (1.0 mmol) of 1-methylpiperazine are initially added to 2ml of THF, and 269mg (1.0 mmol) of the compound from example 134A and then 139. mu.l (1.0 mmol) of triethylamine are added, while cooling in an ice bath. After stirring for 30 minutes at RT, the precipitate was filtered off and the filtrate was reacted further directly as a solution of the title compound in THF.

Examples 138A

1- (2, 2, 2-trifluoroethyl) piperazine dihydrochloride

Step (ii) of 1 ： 4- (2, 2, 2-trifluoroethyl) piperazine-1-carboxylic acid tert-butyl ester

In analogy to the procedure described under example 104A/step 1, 805mg (56% of theory) of the title compound were obtained from 1.0g (5.37 mmol) of piperazine-1-carboxylic acid tert-butyl ester, 391. mu.l (5.37 mmol) of 2,2, 2-trifluoroethanol, 1ml (6.44 mmol) of trifluoromethanesulfonic anhydride and 1.2ml (8.05 mmol) of triethylamine.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 3.44 (dd, 4H), 2.98 (quart, 2H), 2.61 (dd, 4H), 1.47 (s, 9H).

MS (DCI, NH₃): m/z = 269 [M+H]⁺.

GC/MS (method L, EIpos) R_t = 3.87 min, m/z = 212 [M-C₄H₉+H]⁺。

Step (ii) of 2 ： 1- (2, 2, 2-trifluoroethyl) piperazine dihydrochloride

In analogy to the procedure described under example 103A/step 2, starting from 790mg (2.94 mmol) of the compound from example 138A/step 1 241mg (93% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆Delta/ppm) 9.14 (Wide, 2H), 3.30 (quart, 2H), 3.08-3.03 (m, 4H), 2.87-2.83 (m, 4H).

MS (DCI, NH₃): m/z = 169 [M+H]⁺。

Examples 139A

2-bromo-4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl)]-1,2,4-Oxadiazol-6-yl } -1H-pyrazol-1-yl) methyl]Pyridine compound

In analogy to the procedure described under example 76A, 1.05g (4.19 mmol) of the compound from example 133A are reacted with 1.0g (3.22 mmol) of the compound from example 28A to give 0.71g (45% of theory) of the title compound. The product was purified by MPLC (silica gel, mobile phase: cyclohexane/ethyl acetate 4: 1).

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.35 (d, 1H), 8.24 (d, 2H), 7.33 (d, 2H), 7.22 (d, 1H), 6.99 (dd, 1H), 6.89 (s, 1H), 5.42 (s, 2H), 2.31 (s, 3H).

LC/MS (method I, ESIpos) R_t = 1.32 min, m/z = 480/482 [M+H]⁺。

Examples 140A

2-chloro-4- [ (5-methyl-3- {3- [4- (tetrahydro-2)H-pyran-4-yl) phenyl]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridine compound

To a solution of 204mg (1.26 mmol) of the compound from example 43A and 300mg (0.967 mmol) of the compound from example 124A in 10ml of anhydrous THF at 0 ℃ were added 119mg (1.06 mmol) of solid potassium tert-butoxide. The reaction mixture was then stirred first at RT for 15h and then at the boiling point of the solvent for 4.5 h. After cooling to RT, approximately 1ml of water and methanol were added in an amount to form a clear solution. It was separated directly into its components by preparative HPLC (method N). After removal of the solvent on a rotary evaporator, 220mg (52% of theory) of the title compound are obtained from the combined product fractions.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.37 (d, 1H), 8.14 (d, 2H), 7.35 (d, 2H), 7.05 (d, 1H), 6.96 (dd, 1H), 6.88 (s, 1H), 5.43 (s, 2H), 4.12-4.08 (m, 2H), 3.58-3.52 (m, 2H), 2.88-2.79 (m, 1H), 2.31 (s, 3H), 1.92-1.79 (m, 4H).

LC/MS (method I, ESIpos) R_t = 1.16 min, m/z = 436 [M+H]⁺。

Examples 141A

4- ({ 3- [3- (4-tert-butylphenyl) -1,2,4-Diazol-5-yl]-5-methyl-1H-pyrazol-1-yl } methyl-2-chloropyridine

To a solution of 1.15g (7.08 mmol) of the compound from example 43A and 1.00g (3.54 mmol) of the compound from example 125A in 30ml of anhydrous THF at 0 deg.C was added 596mg (5.31 mmol) of solid potassium tert-butoxide. The reaction mixture was then first stirred at RT for 15h and then at the boiling point of the solvent for 4 h. After cooling to RT, about 120ml of water are added and the mixture is extracted three times with about 60ml of ethyl acetate each time. The combined organic extracts were washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration and evaporation, the crude product obtained is purified by MPLC (silica gel, mobile phase: cyclohexane/ethyl acetate 4: 1 → 1: 2). 578mg (40% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.37 (d, 1H), 8.12 (d, 2H), 7.51 (d, 2H), 7.06 (s, 1H), 6.97 (d, 1H), 6.88 (s, 1H), 5.43 (s, 2H), 2.31 (s, 3H), 1.37 (s, 9H).

LC/MS (method F, ESIpos) R_t = 1.55 min, m/z = 408/410 [M+H]⁺。

Examples 142A

2-chloro-4- { [3- (3- {4- [1- (methoxymethyl) cyclobutyl ] butyl]Phenyl } -1,2,4-Oxadiazol-5-yl) -5-methyl-1H-pyrazol-1-yl]Methyl pyridine

519mg (4.62 mmol) of solid potassium tert-butoxide are added at 0 ℃ to a solution of 749mg (4.62 mmol) of the compound from example 43A and 750mg (2.31 mmol) of the compound from example 126A in 22.5ml of anhydrous THF. The reaction mixture was then stirred at the boiling point of the solvent for 5 h. After cooling to RT, about 3 drops of water were added and all volatile components were removed on a rotary evaporator. The residue obtained is purified by MPLC (approximately 100g of silica gel, mobile phase: cyclohexane/ethyl acetate 2: 1). For further purification, the combined concentrated product fractions are then stirred with 1ml of ethanol and the solids are filtered off with suction. 447mg (43% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.37 (d, 1H), 8.13 (d, 2H), 7.30 (d, 2H), 7.06 (s, 1H), 6.97 (d, 1H), 6.88 (s, 1H), 5.43 (s, 2H), 3.57 (s, 2H), 3.28 (s, 3H), 2.41-2.28 (m, 4H), 2.30 (s, 3H), 2.16-2.04 (m, 1H), 1.93-1.83 (m, 1H).

LC/MS (method I, ESIpos) R_t = 1.34 min, m/z = 450/452 [M+H]⁺。

Examples 143A

2-chloro-4- [ (5-methyl-3- {3- [ 3-methyl-4- (tetrahydro-2)H-pyran-4-yl) phenyl]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridine compound

To a solution of 187mg (0.576 mmol) of the compound from example 127A and 121mg (0.749 mmol) of the compound from example 43A in 6ml of anhydrous THF at 0 ℃ were added 71mg (0.634 mmol) of solid potassium tert-butoxide. The reaction mixture was then first stirred at RT for 16 h. Since the conversion was incomplete, the mixture was further heated under reflux for another 8 h. After cooling to RT, approximately 1ml of water and methanol were added in an amount to form a clear solution. The solution was then separated directly into its components by preparative HPLC (method N). The product fractions were combined and the solvent was removed on a rotary evaporator. 150mg (58% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.37 (d, 1H), 8.02 (d, 1H), 8.01 (dd, 1H), 7.34 (d, 1H), 7.05 (d, 1H), 6.96 (dd, 1H), 6.88 (s, 1H), 5.43 (s, 2H), 4.13-4.09 (m, 2H), 3.61-3.53 (m, 2H), 3.07-2.99 (m, 1H), 2.43 (s, 3H), 2.31 (s, 3H), 1.92-1.81 (m, 2H), 1.74-1.69 (m, 2H).

LC/MS (method F, ESIpos) R_t = 1.34 min, m/z = 448 [M+H]⁺。

Examples 144A

2-chloro-4- [ (3- {3- [ 3-chloro-4- (trifluoromethoxy) phenyl)]-1,2,4-Oxadiazol-5-yl } -5-methyl-1H-pyrazol-1-yl) methyl]Pyridine compound

In analogy to the procedure described under example 75A, 500mg (1.38 mmol, purity 95%) of the compound from example 128A and 290mg (1.79 mmol) of the compound from example 43A were reacted to yield 386mg (57% of theory, purity 96%) of the title compound, in which case the reaction components were stirred with one another at reflux for 14 h.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.40-8.37 (m, 2H), 8.12 (d, 1H), 7.44 (d, 1H), 7.05 (s, 1H), 6.96 (d, 1H), 6.89 (s, 1H), 5.45 (s, 2H), 2.31 (s, 3H).

LC/MS (method I, ESIpos) R_t = 1.36 min, m/z = 469 [M+H]⁺。

Examples 145A

2-chloro-4- { [ 5-methyl-3- (3- {4- [1- (trifluoromethyl) cyclopropyl ] methyl]Phenyl } -1,2,4-Oxadiazol-5-yl) -1H-pyrazol-1-yl]Methyl pyridine

A mixture of 450mg (1.35 mmol) of the compound from example 129A, 284mg (1.75 mmol) of 2-chloro-4- (chloromethyl) pyridine and 166mg (1.48 mmol) of potassium tert-butoxide in 12ml of THF is heated at reflux overnight with stirring. After cooling to RT, ethyl acetate and water were added to the mixture. The phases were separated and the aqueous phase was 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 is purified by column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate 7: 3). After drying in vacuo, 352mg (57% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.37 (d, 1H), 8.19 (d, 2H), 7.60 (d, 2H), 7.05 (s, 1H), 6.96 (d, 1H), 6.88 (s, 1H), 5.44 (s, 2H), 2.30 (s, 3H), 1.48-1.33 (m, 2H), 1.09 (s, width, 2H).

LC/MS (method F, ESIpos) R_t = 1.48 min, m/z = 460/462 [M+H]⁺。

Examples 146A

4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl ]-3',6' -dihydro-2, 4' -bipyridine-1 ' (2 'H) -formic acid tert-butyl ester

To a solution of 480mg (1.00 mmol) of the compound from example 139A in 7.5ml DME was added 464mg (1.50 mmol) of 4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2)H) -tert-butyl formate [ P.R. Eastwood,Tetrahedron Lett. 2000，41 （ 19 ），3705-3708]70mg (0.10 mmol) of bis (triphenylphosphine) palladium (II) dichloride and 1.5ml (3.0 mmol) of 2M aqueous sodium carbonate solution. After the reaction mixture had been heated at reflux for 13h, it was cooled to RT and diluted with approximately 50ml of water. The mixture was extracted three times with approximately 20ml of ethyl acetate each time. The combined organic extracts were washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the solvent is removed on a rotary evaporator and the residue obtained is purified by suction filtration through silica gel (mobile phase: dichloromethane/ethyl acetate 100: 1 → 1: 1). 318mg (54% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.52 (d, 1H), 8.25 (d, 2H), 7.33 (d, 2H), 7.09 (s, 1H), 6.88 (d, 1H), 6.87 (s, 1H), 6.58-6.55 (m, 1H), 5.45 (s, 2H), 4.13-4.10 (m, 2H), 3.63-3.60 (m, 1H), 2.61-2.56 (m, 2H), 2.29 (s, 3H), 1.47 (s, 9H).

LC/MS (method D, ESIpos) R_t = 2.88 min, m/z = 583 [M+H]⁺。

Examples 147A

3- [ (5-methyl-3- {3- [4- (tetrahydro-2)H-pyran-4-yl) phenyl]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) -methyl]Benzoic acid

Step (ii) of 1 ： 3- [ (5-methyl-3- {3- [4- (tetrahydro-2H-pyran-4-yl) phenyl ]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Benzoic acid methyl ester

In analogy to the procedure described under example 76A, 168mg (0.733 mmol) of methyl 3- (bromomethyl) benzoate and 175mg (0.564 mmol) of the compound from example 124A were reacted to give 208mg (80% of theory) of the title compound.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.15 (d, 2H), 7.98 (d, 1H), 7.39 (s, 1H), 7.42 (t, 2H), 7.35 (d, 2H), 7.34 (d, 1H), 6.82 (s, 1H), 5.50 (s, 2H), 4.12-4.08 (m, 2H), 3.91 (s, 3H), 3.55 (dt, 2H), 2.87-2.80 (m, 1H), 2.29 (s, 3H), 1.92-1.77 (m, 4H).

LC/MS (method I, ESIpos) R_t = 1.24 min, m/z = 459 [M+H]⁺。

Step (ii) of 2 ： 3- [ (5-methyl-3- {3- [4- (tetrahydro-2)H-pyran-4-yl) phenyl]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) -methyl]Benzoic acid

In analogy to the procedure described under example 93A, from 100mg (0.218 mmol) of the compound from example 147A/step 1 85mg (87% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆Delta/ppm) 13.07 (Width, 1H), 8.01 (d, 2H), 7.89 (d, 1H), 7.78 (s, 1H), 7.53-7.44 (m, 4H), 6.93 (s, 1H), 5.59 (s, 2H), 3.99-3.94 (m, 2H), 3.47 (dt, 2H), 2.92-2.83 (m, 1H), 2.34 (s, 3H), 1.77-1.66 (m, 4H).

LC/MS (method F, ESIpos) R_t = 1.22 min, m/z = 445 [M+H]⁺。

Examples 148A

N'-hydroxy-5-methyl-1- {3- [ (4-methylpiperazin-1-yl) carbonyl]Benzyl radical 1H-pyrazole-3-carbodiimides amides

Step (ii) of 1 ： 5-methyl-1- {3- [ (4-methylpiperazin-1-yl) carbonyl]Benzyl radical 1H-pyrazole-3-carboxamides

At RT, 34.4ml (0.394 mol) of oxalyl chloride are slowly added dropwise to a mixture of 27.0g (78.9 mmol) of the compound from example 105A and a few drops of DMF in 100ml of dichloromethane and the mixture is stirred at RT for 1h and then concentrated. The residue is added portionwise to 300ml of a 33% strength aqueous ammonia solution cooled to 0 ℃. The mixture was stirred at RT for 1h and then the solid formed was filtered off to obtain, after washing with water and drying in vacuo, the first batch of the title compound was obtained. The mother liquor was concentrated to dryness, toluene was added to the residue and the mixture was concentrated again to dryness. After this step had been repeated twice, the residue was stirred with methanol and the solid was filtered off, washed with methanol and dried in vacuo. The second batch of the title compound obtained in this way was combined with the first batch. In total 33.0g (94% of theory, purity 77%) of the title compound are obtained.

LC/MS (method D, ESIpos) R_t= 0.88 and 0.93 min, M/z = 342 [ M + H ] in each case]⁺。

Step (ii) of 2 ： 5-methyl-1- {3- [ (4-methylpiperazin-1-yl) carbonyl]Benzyl radical 1H-pyrazole-3-carbonitriles

To 21.0g (30.7 mmol, 50% purity) of the compound from example 148A/step 1 was added 10.9ml (76.9 mmol) trifluoroacetic anhydride and the mixture was stirred at RT for 1 h. Saturated aqueous sodium bicarbonate solution was then added and the mixture was extracted three times with ethyl acetate. The combined ethyl acetate phases were dried over magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography (silica gel, mobile phase: dichloromethane/methanol 95: 5). After concentration and drying of the product fractions, 2.50g (25% of theory) of the title compound are obtained.

LC/MS (method D, ESIpos) R_t = 1.07 min, m/z = 324 [M+H]⁺。

Step (ii) of 3 ： N'-hydroxy-5-methyl-1- {3- [ (4-methylpiperazin-1-yl) carbonyl]Benzyl radical 1H-pyrazole-3-carbodiimides amides

8.00g (24.7 mmol) of the compound from example 148A/step 2 are dissolved in 320ml of ethanol, 3.78g (54.4 mmol) of hydroxylamine hydrochloride and 7.6ml (54.4 mmol) of triethylamine are added and the mixture is heated at reflux for 5 h. After cooling to RT, the mixture was concentrated. The residue is stirred with a mixture of dichloromethane and methanol (8: 1) and the solid formed is filtered off with suction. After drying, the first batch of the title compound was obtained in this way. The mother liquor was concentrated and the residue was purified by flash chromatography (silica gel, mobile phase: dichloromethane/methanol 8: 2). After concentration and drying of the product fractions, a second crop of the title compound was obtained. Taken together, 6.70g (68% of theory, purity 90%) of the title compound are obtained.

LC/MS (method I, ESIpos) R_t = 0.81 min, m/z = 357 [M+H]⁺。

Embodiment examples:

examples 1

(4-Methylpiperazin-1-yl) {5- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl ]]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl ketone

Under inert conditions 85mg (0.191 mmol) of the compound from example 92A are dissolved in 3ml of anhydrous dichloromethane and 83. mu.l (0.954 mmol) of oxalyl chloride and a droplet of DMF are added. After having been stirred at RT for 1h, it was concentrated to dryness on a rotary evaporator. The residue obtained is dried under high vacuum for about 1h and then dissolved in 2ml of anhydrous THF. To a mixture of 29mg (0.286 mmol) of 1-methylpiperazine and 66. mu.l (0.382 mmol)N,N-diisopropylethylamine in 1ml anhydrous THF to which the solution was added dropwise. After stirring for 16h at RT, 3ml of water and the mixture are added to the reaction mixture and the fractions thereof are separated by preparative HPLC (method N). The product fractions were combined and the solvent was removed on a rotary evaporator. The residue was redissolved in a few ml of methanol and the solution passed through a bicarbonate cartridge (Polymerlabs, Stratospheres SPE, PL-HCO)₃MP SPE, capacity 0.9 mmol). After re-evaporation of the solvent, 93mg (93% of theory) of the title compound are obtained in this way.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.45 (d, 1H), 8.24 (d, 2H), 7.64 (d, 1H), 7.60 (dd, 1H), 7.33 (d, 2H), 6.85 (s, 1H), 5.50 (s, 2H), 3.82 (dd, 2H), 3.60 (dd, 2H), 2.51 (dd, 2H), 2.40 (dd, 2H), 2.34 (s, 3H), 2.32 (s, 3H).

HPLC (method B) R_t = 4.32 min.

MS (ESIpos): m/z = 528 [M+H]⁺。

Examples 2

1-methyl-4- [ ({ 5- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl } amino) methyl]Piperidin-4-ols

A mixture of 100mg (0.229 mmol) of the compound from example 79A and 249mg (1.15 mmol) of 4- (aminomethyl) -1-methylpiperidin-4-ol is heated at 180 ℃ for 3h in a microwave oven (CEM Discover, initial radiant power 250W) with stirring. After cooling to RT, the liquid present was decanted off from the solid. The solid is then dissolved in a mixture of 2ml acetonitrile and 1ml water and purified by preparative HPLC (method O). The combined product-containing fractions were concentrated to the remaining volume on a rotary evaporator, saturated aqueous sodium bicarbonate solution was added and the solid formed was filtered. After drying in vacuo, 15mg (12% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.26 (d, 2H), 7.92 (d, 1H), 7.37-7.32 (m, 3H), 6.77 (s, 1H), 6.43 (d, 1H), 5.36 (s, width, 1H), 5.28 (s, 2H), 4.84 (t, 1H), 3.40 (d, 2H), 2.66-2.60 (m, 2H), 2.45-2.36 (m, 2H), 2.31 (s, 6H), 1.75-1.58 (m, 4H).

LC/MS (method F, ESIpos) R_t = 1.01 min, m/z = 544 [M+H]⁺。

Examples 3

（3R) -1- {5- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl) ]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl } pyrrolidin-3-amines

150mg (0.344 mmol) of the compound from example 79A and 641mg (3.44 mmol) of tert-butyl-, (3R) A mixture of-pyrrolidin-3-ylcarbamate in 1ml ethylene glycol dimethyl ether was heated in a microwave apparatus (CEM Discover, initial radiant power 250W) at 180 ℃ for 3h while stirring. After cooling to RT, the mixture is diluted with 3ml of acetonitrile and 1ml of water and then purified by preparative HPLC (method O). The product-containing fractions were combined, brought to a basic pH with sodium bicarbonate and part of the liquid was removed on a rotary evaporator. The extraction was then carried out three times with 30ml of ethyl acetate each time, the combined ethyl acetate phases were dried over sodium sulfate and filtered and the solvent was removed on a rotary evaporator. The residue was again purified by preparative HPLC (modification of method O: replacing 0.1% aqueous trifluoroacetic acid with 0.1% aqueous ammonia solution). 49mg (29% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 8.20 (d, 2H), 8.07 (d, 1H), 7.60 (d, 2H), 7.40 (dd, 1H), 6.88 (s, 1H), 6.38 (d, 1H), 5.32 (s, 2H), 3.56-3.42 (m, 3H), 3.38-3.28 (m, 1H), 3.02 (dd, 1H), 2.38 (s, 3H), 2.06-1.96 (m, 1H), 1.81-1.65 (m, 3H).

LC/MS (method D, ESIpos) R_t = 1.69 min, m/z = 486 [M+H]⁺。

The compounds in the following table were prepared from the compound from example 79A and the corresponding amine component in analogy to one of the methods described under examples 2 and 3:

。

examples 15

1-methyl-4- {4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl-piperazines

A mixture of 150mg (0.344 mmol) of the compound from example 81A and 690mg (6.88 mmol) of 1-methylpiperazine in 1ml of ethylene glycol dimethyl ether was heated at 180 ℃ for 3h while stirring in a microwave apparatus (CEM Discover, initial radiation power 250W). After cooling to RT, the mixture is purified directly by preparative HPLC (method O). The combined product-containing fractions are concentrated on a rotary evaporator to a small liquid residual volume, adjusted to a slightly basic pH with sodium bicarbonate and then extracted three times with 30ml of dichloromethane each time. The combined dichloromethane phases were dried over magnesium sulfate and filtered and the solvent was removed on a rotary evaporator. After crystallization from hexane, 114mg (66% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.27 (d, 2H), 8.12 (d, 1H), 7.33 (d, 2H), 6.84 (s, 1H), 6.36-6.32 (m, 2H), 5.36 (s, 2H), 3.55-3.48 (m, 4H), 2.55-2.45 (m, 4H), 2.31 (s, 3H), 2.29 (s, 3H).

LC/MS (method F, ESIpos) R_t = 0.97 min, m/z = 500 [M+H]⁺。

Examples 16

N,N-dimethyl-1- {4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl } piperidin-4-amines

To 200mg (0.459 mmol) of the compound from example 81A under argon at RT are added 294mg (2.29 mmol)N,N-dimethylpiperidin-4-amine. The mixture was then stirred at a bath temperature of 150 ℃ overnight. After cooling to RT, the mixture is taken up in acetonitrile and purified directly by preparative HPLC (method O). The combined product-containing fractions were made basic with saturated sodium bicarbonate solution and concentrated on a rotary evaporator to a low residual volume of solvent. The solid thus formed is filtered off, washed twice with water and twice with pentane and dried in vacuo. 137mg (57% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.26 (d, 2H), 8.12 (d, 1H), 7.32 (d, 2H), 6.82 (s, 1H), 6.32 (d, 1H), 6.31 (s, 1H), 5.35 (s, 2H), 3.51 (t, 4H), 2.76-2.67 (m, 1H), 2.62 (t, 4H), 2.30 (s, 3H), 1.08 (d, 6H).

LC/MS (method F, ESIpos) R_t = 1.12 min, m/z = 528 [M+H]⁺。

The compounds in the following table were prepared from the compound from example 81A and the corresponding amine component in analogy to one of the methods described under examples 15 and 16:

。

examples 32

(4-Methylpiperazin-1-yl) {3- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl ]]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl ketone

Under inert conditions 80mg (0.180 mmol) of the compound from example 93A are dissolved in 2ml of anhydrous dichloromethane and 79. mu.l (0.90 mmol) of oxalyl chloride and a droplet of DMF are added. After having been stirred at RT for 1h, it was concentrated to dryness on a rotary evaporator. The residue obtained is dried under high vacuum for about 1h and then dissolved in 1ml of anhydrous THF. To a mixture of 36mg (0.360 mmol) of 1-methylpiperazine and 94. mu.l (0.540 mmol)N,N-diisopropylethylamine in 1ml anhydrous THF to which the solution was added dropwise. After stirring for 16h at RT, 3ml of water are added to the reaction mixture and the mixture is separated into its components by preparative HPLC (method N). The product fractions were combined and the solvent was removed on a rotary evaporator. The residue was redissolved in a few ml of methanolThe solution was passed through a bicarbonate cartridge (Polymerlabs, Stratospheres SPE, PL-HCO) ₃MP SPE, capacity 0.9 mmol). After re-evaporation of the solvent, 78mg (82% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.25 (d, 2H), 7.41-7.33 (m, 4H), 7.20 (d, 1H), 7.17 (s, 1H), 6.83 (s, 1H), 5.48 (s, 2H), 3.76 (wide, 2H), 3.37 (wide, 2H), 2.44 (wide, 2H), 2.30 (s, 3H), 2.29 (wide, 2H), 2.26 (s, 3H).

HPLC (method B) R_t = 4.45 min.

MS (DCI, NH₃): m/z = 527 [M+H]⁺.

LC/MS (method C, ESIpos) R_t = 1.71 min, m/z = 527 [M+H]⁺。

The compounds in the table below were prepared from the compound from example 93A and the corresponding amine in analogy to the procedure described under example 32. These amines are commercially available or their preparation has been described above or in the literature: 1-cyclopropylpiperazine [ F, Zaragoza, etc.,J. Med. Chem. 2004，47 （ 11 ），2833-2838]1- (2, 2, 2-trifluoroethyl) piperazine [ H. -L. Wang et al,J. Med. Chem. 2007，50 （ 15 ），3528-3539]. If the amines are used in the form of their hydrochlorides or dihydrochloride salts, the bases used (A), (B), (CN,NDiisopropylethylamine) is increased in each case by the corresponding equivalent.

。

Examples 38

{3- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl } (piperazin-1-yl) methanone

Step (ii) of 1 ： 4- ({ 3- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl ]Phenyl } carbonyl) piperazine-1-carboxylic acid tert-butyl ester

In analogy to the procedure described under example 32, from 80mg (0.180 mmol) of the compound from example 93A and 67mg (0.360 mmol) of piperazine-1-carboxylic acid tert-butyl ester 110mg (96% of theory) of the title compound are obtained. In contrast to the method described under example 32, the permeation through the sodium bicarbonate cartridge (after HPLC purification) was omitted here.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.25 (d, 2H), 7.40 (t, 1H), 7.33 (2 d, together with 3H), 7.22 (d, 1H), 7.20 (s, 1H), 6.83 (s, 1H), 5.48 (s, 2H), 3.70 (wide, 2H), 3.49 (wide, 2H), 3.35 (wide, 4H), 2.31 (s, 3H), 1.13 (s, 9H).

HPLC (method B) R_t = 5.22 min.

MS (DCI, NH₃): m/z = 613 [M+H]⁺.

LC/MS (methods C, E)SIpos): R_t = 2.98 min, m/z = 613 [M+H]⁺。

Step (ii) of 2 ： {3- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl } (piperazin-1-yl) methanone

To 70mg (0.114 mmol) of the compound from example 38/step 1 was added 5ml of hydrogen chloride at RT in 1, 4-bis4M solution in alkane and the mixture was stirred at RT for 15 h. Precipitation of the product was then accomplished by addition of 10ml of diethyl ether. The solid is filtered off with suction, washed with a little cold ether and dried under high vacuum. The solid is then dissolved in a few ml of methanol and passed through a bicarbonate cartridge (Polymerlabs, Stratospheres SPE, PL-HCO) in order to release the alkaline solution ₃MP SPE, capacity 0.9 mmol). After re-evaporation of the solvent and drying under high vacuum, 40mg (68% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.24 (d, 2H), 7.41-7.33 (m, 4H), 7.20 (d, 1H), 7.19 (s, 1H), 6.83 (s, 1H), 5.48 (s, 2H), 3.73 (width, 2H), 3.33 (width, 2H), 2.92 (width, 2H), 2.77 (width, 2H), 2.30 (s, 3H).

HPLC (method B) R_t = 4.40 min.

LC/MS (method C, ESIpos) R_t = 1.68 min, m/z = 513 [M+H]⁺。

The compounds in the following table were prepared from the compound from example 93A and the corresponding mono-tert-butoxycarbonyl-protected diamine component in analogy to the two-stage preparation described under example 38:

。

examples 41

(4-Methylpiperazin-1-yl) (3- { [ 5-methyl-3- (3- {4- [ (trifluoromethyl) sulfonyl ] sulfonyl]Phenyl } -1,2,4-Oxadiazol-5-yl) -1H-pyrazol-1-yl]Methyl } phenyl) methanones

To a solution of 100mg (0.292 mmol) of the compound from example 105A in 3ml of anhydrous dichloromethane at 0 ℃ under inert conditions was added 76. mu.l (0.876 mmol) of oxalyl chloride. The reaction mixture was stirred at RT for 2 h. All volatile constituents were then removed on a rotary evaporator and the residue obtained in this way was dried under high vacuum for 20 min. The residue is subsequently dissolved again in 2ml of anhydrous dichloromethane and to a solution of 94mg (0.350 mmol) of the compound from example 3A and 81. mu.l (0.584 mmol) of triethylamine in 1ml of dichloromethane at 0 ℃ the solution is added dropwise. After the reaction mixture had been stirred for 16h at RT, all volatile constituents were removed again on a rotary evaporator and the residue was dissolved in 4ml DMSO. The solution was then heated in a microwave oven at 120 ℃ for 30min (CEM Discover, initial radiant power 250W). After cooling to RT, the reaction mixture is purified directly by preparative HPLC (method N). Product fractions were rotary evaporated Drying on a hair drier. The residue was dissolved in about 5ml of methanol and the solution passed through a bicarbonate cartridge (Polymerlabs, Stratospheres SPE, PL-HCO)₃MP SPE, capacity 0.9 mmol). After re-evaporation of the solvent, 47mg (28% of theory) of the title compound are obtained in this way.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.52 (d, 2H), 8.18 (d, 2H), 7.40 (t, 1H), 7.34 (d, 1H), 7.21 (d, 1H), 7.18 (s, 1H), 6.85 (s, 1H), 5.49 (s, 2H), 3.76 (Wide, 2H), 3.37 (Wide, 2H), 2.45 (Wide, 2H), 2.31 (S, 3H), 2.29 (Wide, 2H), 2.27 (S, 3H).

HPLC (method A) R_t = 4.28 min.

MS (DCI, NH₃): m/z = 575 [M+H]⁺。

In analogy to the procedure described under example 41, the compounds in the table below were prepared from the compound from example 105A or the compound from example 106A and the corresponding N' -hydroxyformamidide (hydroxyamidine).

Examples 53

1-cyclopropyl-4- {5- [ (5-methyl-3- {3- [4- (1, 1, 1-trifluoro-2-methylpropan-2-yl) phenyl]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl-piperazines

A dispersion of 431mg (2.17 mmol) of 1-cyclopropylpiperazine dihydrochloride and 729mg (8.68 mmol) of sodium bicarbonate in approximately 50ml of methanol was stirred vigorously at RT for 2 h. Undissolved material was then filtered off and the filtrate was evaporated to dryness. Half of the 1-cyclopropylpiperazine obtained in this way was dissolved in 0.5ml of ethylene glycol dimethyl ether and the other half was dissolved in 0.5ml N,N-dimethylacetamide. To each of the two solutions was added 50mg (0.108 mmol) of the compound from example 78A and the mixture was then heated at 150 ℃ for 36h, respectively. After this time, the conversion was about the same for both batches (LC/MS control). The reaction mixtures were thus combined, diluted with approximately 2ml of acetonitrile and separated directly into their components by preparative HPLC (method N). 31mg (26% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.19 (d, 2H), 8.10 (d, 1H), 7.61 (d, 2H), 7.41 (dd, 1H), 6.77 (s, 1H), 6.60 (d, 1H), 5.30 (s, 2H), 3.52-3.49 (m, 5H), 2.71-2.68 (m, 4H), 2.31 (s, 3H), 1.62 (s, 6H), 0.49-0.44 (m, 4H).

LC/MS (method F, ESIpos) R_t = 1.22 min, m/z = 552 [M+H]⁺。

Examples 54

1- {5- [ (5-methyl-3- {3- [4- (trimethylsilyl) phenyl ] methyl ester]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl-piperazines

A mixture of 200mg (0.472 mmol) of the compound from example 87A and 813mg (9.43 mmol) of piperazine is stirred at a temperature of 150 ℃ for 16h under argon. After cooling, about 50ml of water are added and the mixture is extracted three times with about 50ml of ethyl acetate each time. The combined organic extracts were washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and the filtrate was freed of the solvent on a rotary evaporator. The product was isolated by preparative HPLC (method N). 133mg (59% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.17 (d, 2H), 8.11 (d, 1H), 7.63 (d, 2H), 7.41 (dd, 1H), 6.78 (s, 1H), 6.60 (d, 1H), 5.31 (s, 2H), 3.52-3.49 (m, 4H), 2.99-2.95 (m, 4H), 2.32 (s, 3H), 0.32 (s, 9H).

LC/MS (method F, ESIpos) R_t = 1.23 min, m/z = 474 [M+H]⁺。

Examples 55

1-cyclopropyl-4- {5- [ (5-methyl-3- {3- [4- (trimethylsilyl) phenyl ] methyl ester]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl-piperazines

Mu.l (2.11 mmol) of glacial acetic acid, 30mg of dried, pulverulent molecular sieve (3A) and 255. mu.l (1.27 mmol) of 1-ethoxy-1- (trimethylsilyl) oxycyclopropane were added in succession to a solution of 100mg (0.211 mmol) of the compound from example 54 in 2ml of methanol. After stirring at RT for 10min, 40mg (0.633 mmol) of solid sodium cyanoborohydride are added and the mixture is heated at reflux for 2 h. After cooling to RT, the solid is first filtered off with suction and rinsed with methanol and the filtrate is freed of all volatile constituents on a rotary evaporator. To the residue obtained, approximately 50ml of half-saturated sodium bicarbonate solution were added and the mixture was extracted three times with approximately 50ml of ethyl acetate each time. The combined organic extracts were washed successively with water and saturated sodium chloride solution. After drying over anhydrous sodium sulfate, the mixture was filtered and the filtrate was freed of the solvent on a rotary evaporator. The product was isolated by MPLC (silica gel, mobile phase: cyclohexane/ethyl acetate 1: 1 → 1: 3). 57mg (53% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.17 (d, 2H), 8.11 (d, 1H), 7.63 (d, 2H), 7.40 (dd, 1H), 6.78 (s, 1H), 6.60 (d, 1H), 5.30 (s, 2H), 3.52-3.49 (m, 4H), 2.71-2.68 (m, 4H), 2.31 (s, 3H), 1.66-1.61 (m, 1H), 0.49-0.43 (m, 4H), 0.30 (s, 9H).

LC/MS (method I, ESIpos) R_t = 1.08 min, m/z = 514 [M+H]⁺。

Examples 56

5- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]-2- (pyrrolidin-1-yl) pyridine

A mixture of 200mg (0.459 mmol) of the compound from example 79A and 2ml (23.9 mmol) of pyrrolidine is stirred in a microwave oven (CEM Discover, initial radiation power 250W) at 160 ℃ for 3 h. The excess pyrrolidine was then removed on a rotary evaporator. The crude product obtained in this way is purified by MPLC (silica gel, mobile phase: cyclohexane/ethyl acetate 100: 0 → 2: 1). 53mg (24% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.25 (d, 2H), 8.09 (d, 1H), 7.38 (dd, 1H), 7.33 (d, 2H), 6.76 (s, 1H), 6.31 (d, 1H), 5.30 (s, 2H), 3.45-3.40 (m, 4H), 2.32 (s, 3H), 2.02-1.97 (m, 4H).

LC/MS (method I, ESIpos) R_t = 1.00 min, m/z = 471 [M+H]⁺。

Examples 57

1-cyclopropyl-4- {5- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl-piperazines

In analogy to the procedure described under example 53, the free base was prepared from 457mg (2.29 mmol) of 1-cyclopropylpiperazine dihydrochloride and was then heated at 150 ℃ for 4 days together with 100mg (0.229 mmol) of the compound from example 79A. After cooling to RT, the solidified melt was dissolved in about 4ml of acetonitrile and separated into its components by preparative HPLC (method N). The product fractions were combined and concentrated to dryness on a rotary evaporator. The product obtained for the removal of viscous formic acid by HPLC purification is dissolved in about 5ml of methanol and the solution is passed through a bicarbonate cartridge (Polymerlabs, Stratospheres SPE, PL-HCO) ₃MP SPE, capacity 0.9 mmol). 42mg (35% of theory) of the title compound are obtained in this way.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.25 (d, 2H), 8.10 (d, 1H), 7.41 (dd, 1H), 7.33 (d, 2H), 6.77 (s, 1H), 6.60 (d, 1H), 5.30 (s, 2H), 3.52-3.49 (m, 4H), 2.71-2.68 (m, 4H), 2.31 (s, 3H), 1.66-1.60 (m, 1H), 0.49-0.44 (m, 4H).

HPLC (method A) R_t = 4.12 min.

LC/MS (method I, ESIpos) R_t = 1.03 min, m/z = 526 [M+H]⁺。

Examples 58

1- {5- [ (5-methyl-3- {3- [4- (trifluoromethyl) phenyl ] methyl ester]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl-piperazines

In analogy to the procedure described under example 54, from 200mg (0.476 mmol) of the compound from example 88A and 821mg (9.53 mmol) of piperazine 149mg (67% of theory) of the title compound are obtained. The product was isolated by MPLC (silica gel, mobile phase: dichloromethane/methanol 20: 1 → 5: 1).

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.33 (d, 2H), 8.11 (d, 1H), 7.76 (d, 2H), 7.41 (dd, 1H), 6.79 (s, 1H), 6.60 (d, 1H), 5.31 (s, 2H), 3.53-3.49 (m, 4H), 2.99-2.96 (m, 4H), 2.32 (s, 3H).

LC/MS (method F, ESIpos) R_t = 1.09 min, m/z = 470 [M+H]⁺。

Examples 59

1-cyclopropyl-4- {5- [ (5-methyl-3- {3- [4- (trifluoromethyl) phenyl ] methyl ester]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl-piperazines

In analogy to the procedure described under example 55, from 100mg (0.213 mmol) of the compound from example 58 and 257. mu.l (1.28 mmol) of 1-ethoxy-1- (trimethylsilyl) oxycyclopropane were obtained 43mg (39% of theory) of the title compound.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.33 (d, 2H), 8.11 (d, 1H), 7.76 (d, 2H), 7.41 (dd, 1H), 6.78 (s, 1H), 6.60 (d, 1H), 5.30 (s, 2H), 3.52-3.49 (m, 4H), 2.72-2.68 (m, 4H), 2.33 (s, 3H), 1.67-1.60 (m, 1H), 0.49-0.43 (m, 4H).

LC/MS (method I, ESIpos) R_t = 0.96 min, m/z = 510 [M+H]⁺。

Examples 60

5- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]-2- (piperidin-1-yl) pyridine

In analogy to the procedure described under example 56, from 200mg (0.459 mmol) of from example 79A and 2.3ml (22.9 mmol) of piperidine 154mg (69% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.25 (d, 2H), 8.09 (d, 1H), 7.39 (dd, 1H), 7.33 (d, 2H), 6.77 (s, 1H), 6.60 (d, 1H), 5.30 (s, 2H), 3.53-3.50 (m, 4H), 2.32 (s, 3H), 1.64-1.60 (m, 6H).

HPLC (method A) R_t = 4.39 min.

MS (DCI, NH₃): m/z = 485 [M+H]⁺.

LC/MS (method F, ESIpos) R_t = 1.33 min, m/z = 485 [M+H]⁺。

Examples 61

2- (azetidin-1-yl) -5- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridine compound

In analogy to the procedure described under example 16, 200mg (0.495 mmol) of the compound from example 79A and 310. mu.l (4.59 mmol) of azetidine were reacted to give 81mg (39% of theory) of the title compound.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.25 (d, 2H), 8.07 (d, 1H), 7.41-7.29 (m, 3H), 6.77 (s, 1H), 6.22 (d, 1H), 5.30 (s, 2H), 4.03 (t, 4H), 2.42-2.37 (m, 2H), 2.31 (s, 3H).

LC/MS (method D, ESIpos) R_t = 2.00 min, m/z = 457 [M+H]⁺。

Examples 62

4- {4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl } piperidine-1-carboxylic acid tert-butyl ester

A solution of 301mg (0.517 mmol) of the compound from example 146A in 30ml of methanol was purified in a flow-through hydrogenation unit [ H-Cube from Thales Nano, Budapest, Hungary; conditions are as follows: pd cartridge (10% on charcoal), 10 bar H₂At 25 ℃ and a flow rate of 1ml/min]And (4) medium hydrogenation. Since the reaction was incomplete in the first pass, the reaction mixture was passed through the cartridge again. After evaporation of the solvent on a rotary evaporator, the crude product is purified by preparative HPLC (method N). 165mg (53% of theory, purity 97%) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.50 (d, 1H), 8.25 (d, 2H), 7.33 (d, 2H), 6.87-6.83 (m, 3H), 5.43 (s, 2H), 4.28-4.17 (m, 2H), 2.85-2.75 (m, 3H), 2.29 (s, 3H), 1.88-1.82 (m, 2H), 1.72-1.62 (m, 2H), 1.45 (s, 9H).

LC/MS (method I, ESIpos) R_t = 1.34 min, m/z = 585 [M+H]⁺。

Examples 63

4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]-2- (piperidin-4-yl) pyridine hydrochloride

To 150mg (0.257 mmol) of the compound from example 62 in 1ml twoTo the solution in the alkane was added 641. mu.l (2.57 mmol) of hydrogen chloride in bis4M solution in alkane. After the reaction mixture had been stirred at RT for 2h, it was concentrated to dryness on a rotary evaporator. The residue obtained is taken up in a reaction mixture of about 5ml of pentane/diThe alkane (10: 1) was ground together. After drying under high vacuum 143mg (97% of theory, 91% purity) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆δ/ppm) 8.96 (s, width, 1H), 8.70 (s, width, 1H), 8.57 (d, 1H), 8.20 (d, 2H), 7.61 (d, 2H), 7.18 (d, 1H), 7.11 (dd, 1H), 7.01 (s, 1H), 5.65 (s, 2H), 3.38-3.32 (m, 2H), 3.14-3.06 (m, 1H), 3.03-2.93 (m, 2H), 2.32 (s, 3H), 2.03-1.86 (m, 4H).

LC/MS (method F, ESIpos) R_t = 1.06 min, m/z = 485 [M+H]⁺。

Examples 64

1- {4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl-piperazines

91.5g (0.210 mol) of the compound from example 81A and 362g (4.20 mol) of piperazine were heated at 150 ℃ for 1h without addition of solvent. After the melt had cooled to RT, 6l of water and 4 l of ethyl acetate were added and the mixture was stirred vigorously. After the organic phase has been separated off, it is washed in each case after a further washing with about 2.5 l of water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and the filtrate was then freed from the solvent on a rotary evaporator. The residue obtained is chromatographed over approximately 3kg of silica gel (0.04-0.06 mm) (mobile phase: dichloromethane/methanol 9: 1, 12L → 8: 2, 12L → 7: 3, 16L → 6: 1, 8L). The product fractions were combined and concentrated on a rotary evaporator. 67.1g (66% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.25 (d, 2H), 8.13 (d, 1H), 7.33 (d, 2H), 6.84 (s, 1H), 6.35 (d, 1H), 6.32 (s, 1H), 5.35 (s, 2H), 3.48-3.45 (m, 4H), 2.97-2.94 (m, 4H), 2.30 (s, 3H).

LC/MS (method D, ESIpos) R_t = 1.89 min, m/z = 486 [M+H]⁺。

Examples 65

1-cyclopropyl-4- {4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl-piperazines

66ml (1.15 mmol) of glacial acetic acid, 13.9g of dried, pulverulent molecular sieve (3. mu.) and 139ml (0.692 mmol) of 1-ethoxy-1- (trimethylsilyl) oxycyclopropane were added in succession to a solution of 56.0g (0.115 mol) of the compound from example 64 in 1.13 l of methanol. After stirring for 10min at RT, 21.7g (0.346 mol) of solid sodium cyanoborohydride are added. The mixture was then heated at reflux for 1 h. After cooling to RT, the undissolved material is filtered off with suction and the filtrate is concentrated on a rotary evaporator. The residue obtained is taken up in 1 l of ethyl acetate and the mixture is washed twice with approximately 750ml of saturated sodium bicarbonate solution and then with approximately 750ml of saturated sodium chloride solution each time. After drying over anhydrous sodium sulfate, the mixture was filtered and the filtrate was freed of the solvent on a rotary evaporator. The residue (53 g) was recrystallized from a boiling mixture of 293ml ethanol and 59ml water. When the crystallization is complete (after about 20h at RT), the mixture is filtered with suction. The solid was washed with 36ml ethanol/water (5: 1) and then dried under high vacuum. 26.4g of the title compound are obtained in this way as a first batch. The mother liquor of the crystallization is concentrated on a rotary evaporator. Further 20.3g of product were obtained as formate by preparative HPLC (method N). For the liberation of the base, the suspension of the formate in 1 l of ethyl acetate is washed with approximately 200ml of saturated sodium bicarbonate solution, then water and saturated sodium chloride solution. After drying over anhydrous sodium sulfate, the mixture was filtered and the filtrate was freed of the solvent on a rotary evaporator. The residue (13 g) was recrystallized from a boiling mixture from 80ml ethanol and 16ml water. When the crystallization is complete (after about 4h at RT), the mixture is filtered with suction and the solid is dried under high vacuum. In this way, 11.2g of the title compound are obtained (yield amounting to 37.6g, 62% of theory).

Melting point: 140 deg.C

1H-NMR (400 MHz, CDCl3, δ/ppm): 8.26 (d, 2H), 8.13 (d, 1H), 7.33 (d, 2H), 6.83 (s, 1H), 6.33 (d, 1H), 6.32 (s, 1H), 5.35 (s, 2H), 3.47 (dd, 4H), 2.69 (dd, 4H), 2.30 (s, 3H), 1.65-1.60 (m, 1H), 0.48-0.42 (m, 4H).

LC/MS (method D, ESIpos) R_t = 1.91 min, m/z = 526 [M+H]⁺。

Examples 66

1-cyclopropyl-4- {4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl piperazine hydrochloride

To a solution of 362mg (0.690 mmol) of the compound from example 65 in 50ml THF at RT was added 690. mu.l of 1M hydrochloric acid and the mixture was stirred at RT for 1 h. The mixture was then concentrated thoroughly to dryness on a rotary evaporator. The residue obtained is recrystallized from a boiling mixture of 11.5ml of isopropanol and 5ml of ethanol. After drying under high vacuum 330mg (85% of theory) of the title compound are obtained, which are present in the crystals as a solvate with one equivalent of isopropanol.

Melting point: 206 ℃ C. -

¹H-NMR (400 MHz, DMSO-d₆Delta/ppm) 10.40 (Width, 1H), 8.20 (d, 2H), 8.12 (d, 1H), 7.60 (d, 2H), 6.97 (s, 1H), 6.83 (d, 1H), 6.40 (s, 1H), 5.47 (s, 2H), 4.41-4.31 (m, 2H), 3.77 (sept, 1H), 3.60-3.53 (Width, 2H), 3.30-3.20 (Width)4H), 2.90 (wide, 1H), 2.36 (s, 3H), 1.12-1.08 (wide, 2H), 1.03 (d, 6H), 0.84-0.79 (m, 2H).

LC/MS (method I, ESIpos) R_t = 0.97 min, m/z = 526 [M+H]⁺。

Examples 67

1-cyclopropyl-4- {4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl)]-1,2,4-Oxadiazol-5-yl } -1 H-pyrazol-1-yl) methyl]Pyridin-2-yl piperazine methanesulfonate

To a solution of 500mg (0.952 mmol) of the compound from example 65 in 30ml THF at RT was added 91.5mg (0.952 mmol) of methanesulfonic acid and the mixture was stirred at RT for 1 h. It was then concentrated thoroughly to dryness on a rotary evaporator. After the residue has been dried under high vacuum, 500mg (85% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆Delta/ppm) 9.12 (width, 1H), 8.20 (d, 2H), 8.13 (d, 1H), 7.60 (d, 2H), 6.98 (s, 1H), 6.83 (s, 1H), 6.41 (d, 1H), 5.47 (s, 2H), 4.44-4.36 (m, 2H), 3.63-3.56 (m, 2H), 3.32-3.23 (m, 2H), 3.14-3.03 (m, 2H), 2.96 (width, 1H), 2.37 (s, 3H), 2.30 (s, 3H), 1.00-0.97 (width, 2H), 0.89-0.82 (m, 2H).

Examples 68

1-cyclopropyl-4- {4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl } piperazine 4-sulfamoylbenzoate

To a solution of 522mg (0.994 mmol) of the compound from example 65 in 20ml THF at RT was added 206mg (0.994 mmol) of 4-sulfamoylbenzoic acid and the mixture was stirred at RT for 1 h. It was then concentrated thoroughly to dryness on a rotary evaporator. After the residue has been dried under high vacuum 632mg (88% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆δ/ppm) 13.37 (width, 1H), 8.20 (d, 2H), 8.11 (d, 2H), 8.04 (d, 1H), 7.93 (d, 2H), 7.59 (d, 2H), 7.53 (s, 2H), 6.96 (s, 1H), 6.68 (s, 1H), 6.27 (d, 1H), 5.43 (s, 2H), 3.44-3.40 (m, 4H), 2.62-2.58 (m, 4H), 2.33 (s, 3H), 1.67-1.61 (m, 1H), 0.47-0.41 (m, 2H), 0.37-0.33 (m, 2H).

Examples 69

1- (2, 2-Difluoroethyl) -4- {4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl ] methyl ester]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl-piperazines

65mg (0.149 mmol) of the compound from example 81A and 166mg (0.746 mmol) of the compound from example 104ACompound with 260. mu.l (1.49 mmol)N,NDiisopropylethylamine was stirred in a microwave oven (CEM Discover, initial radiant power 250W) at 160 ℃ for 3 h. After cooling to RT, the mixture was diluted with about 3ml of methanol and the reaction mixture was separated directly into its components by preparative HPLC (method N). The product fractions were combined and the solvent was removed on a rotary evaporator. The viscous formic acid residue is again dissolved in approximately 5ml of methanol for purification by HPLC and the solution is passed through a bicarbonate cartridge (Polymerlabs, Stratospheres SPE, PL-HCO)₃MP SPE, capacity 0.9 mmol). 65mg (78% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.25 (d, 2H), 8.12 (d, 1H), 7.33 (d, 2H), 6.83 (s, 1H), 6.37 (d, 1H), 6.31 (s, 1H), 5.90 (tt, 1H), 5.34 (s, 2H), 3.50 (dd, 4H), 2.77 (dt, 2H), 2.66 (dd, 4H), 2.29 (s, 3H).

LC/MS (method I, ESIpos) R_t = 1.19 min, m/z = 550 [M+H]⁺。

Examples 70

1- {4- [ (5-methyl-3- {3- [4- (tetrahydro-2)H-pyran-4-yl) phenyl]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl piperazine formate salt

A mixture of 220mg (0.505 mmol) of the compound from example 140A and 869mg (10.1 mmol) of piperazine was stirred at 160 ℃ for 16h without addition of solvent. After the melt had cooled to RT, approximately 50ml of water were added and the mixture was extracted three times with approximately 20ml of ethyl acetate each time. The combined organic extracts were washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the solvent is removed on a rotary evaporator and the residue is purified by preparative HPLC (method N). 178mg (66% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.33 (s, 1H), 8.15 (2d, 2H+1H), 7.35 (d, 2H), 6.83 (s, 1H), 6.43 (d, 1H), 6.34 (s, 1H), 5.37 (s, 2H), 4.13-4.08 (m, 2H), 3.70-3.67 (m, 4H), 3.58-3.52 (m, 2H), 3.15-3.11 (m, 4H), 2.88-2.80 (m, 1H), 2.29 (s, 3H), 1.92-1.78 (m, 4H).

LC/MS (method I, ESIpos) R_t = 0.83 min, m/z = 486 [M+H]⁺。

Examples 71

1-cyclopropyl-4- {4- [ (5-methyl-3- {3- [4- (tetrahydro-2)H-pyran-4-yl) phenyl]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl-piperazines

206 μ l (3.60 mmol) of glacial acetic acid, 51mg of dried, pulverulent molecular sieve (3A) and 435 μ l (2.17 mmol) of 1-ethoxy-1- (trimethylsilyl) oxycyclopropane were added in succession to a solution of 175mg (0.360 mmol) of the compound from example 70 in 5ml of methanol. After stirring at RT for 10min, 68mg (1.08 mmol) of solid sodium cyanoborohydride are added. The mixture was then heated at reflux for 2 h. After cooling to RT, the undissolved material is filtered off with suction and the filtrate is concentrated on a rotary evaporator. The product was separated from the residue by MPLC (silica gel, mobile phase: dichloromethane/methanol 30: 1). The viscous oil obtained was converted to a solid by trituration with pentane, which was stirred with acetonitrile/methanol (10: 1). After drying under high vacuum, 30mg (15% of theory, purity 95%) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.15 (d, 2H), 8.12 (d, 1H), 7.35 (d, 2H), 6.83 (s, 1H), 6.33 (d, 1H), 6.32 (s, 1H), 5.35 (s, 2H), 4.13-4.08 (m, 2H), 3.59-3.52 (m, 2H), 3.49-3.44 (m, 4H), 2.88-2.79 (m, 1H), 2.71-2.66 (m, 4H), 2.28 (s, 3H), 1.92-1.78 (m, 4H), 1.67-1.58 (m, 1H), 0.49-0.42 (m, 4H).

LC/MS (method F, ESIpos) R_t = 0.83 min, m/z = 526 [M+H]⁺。

Examples 72

1- {4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl } -4- (2, 2, 2-trifluoroethyl) piperazine

100mg (0.229 mmol) of the compound from example 81A and 277mg (1.15 mmol) of the compound from example 138A together with 400. mu.l (2.30 mmol)N,NDiisopropylethylamine was stirred in a microwave oven (CEM Discover, initial radiant power 250W) at 160 ℃ for 3 h. After cooling to RT, the mixture was diluted with about 3ml of methanol and the reaction mixture was separated directly into its components by preparative HPLC (method N). The product fractions were combined and the solvent was removed on a rotary evaporator. The viscous formic acid residue is again dissolved in approximately 5ml of methanol for purification by HPLC and the solution is passed through a bicarbonate cartridge (C.)Polymerlabs，Stratospheres SPE，PL-HCO₃MP SPE, capacity 0.9 mmol). 64mg (49% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.24 (d, 2H), 8.12 (d, 1H), 7.33 (d, 2H), 6.83 (s, 1H), 6.37 (d, 1H), 6.31 (s, 1H), 5.35 (s, 2H), 3.51 (dd, 4H), 3.00 (quart, 2H), 2.73 (dd, 4H), 2.29 (s, 3H).

LC/MS (method I, ESIpos) R_t = 1.31 min, m/z = 568 [M+H]⁺。

Examples 73

1-cyclobutyl-4- {4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl-piperazines

200mg (0.412 mmol) of the compound from example 64 and 37. mu.l (0.494 mmol) of cyclobutanone are dissolved in 5ml of absolute ethanol and the solution is stirred for 1h at RT. 47mg (1.24 mmol) of solid sodium borohydride are then added dropwise. After the reaction mixture has been stirred at RT for 16h, 25ml of water are added and the mixture is extracted twice with approximately 20ml of dichloromethane each time. The combined organic extracts were dried over anhydrous magnesium sulfate. After filtration, the solvent is removed on a rotary evaporator and the crude product is purified by preparative HPLC (method N). The product obtained for the removal of the viscous formic acid by HPLC purification is again dissolved in about 5ml of methanol and the solution is passed through a bicarbonate cartridge (Polymerlabs, Stratospheres SPE, PL-HCO) ₃MP SPE, capacity 0.9 mmol). 74mg (31% of theory, purity approx. 95%) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.25 (d, 2H), 8.12 (d, 1H), 7.33 (d, 2H), 6.83 (s, 1H), 6.33 (d, 1H), 6.31 (s, 1H), 5.35 (s, 2H), 3.50 (dd, 4H), 2.73 (quint, 1H), 2.39 (dd, 4H), 2.29 (s, 3H), 2.07-2.00 (m, 2H), 1.94-1.85 (m, 2H), 1.77-1.65 (m, 2H).

LC/MS (method I, ESIpos) R_t = 0.93 min, m/z = 540 [M+H]⁺。

Examples 74

1- [4- ({ 3- [3- (4-tert-butylphenyl) -1,2,4-Diazol-5-yl]-5-methyl-1H-pyrazol-1-yl } methyl) pyridin-2-yl]Piperazine derivatives

A solution of 400mg (0.981 mmol) of the compound from example 141A and 1.69g (10.6 mmol) of piperazine in 12ml of ethanol is automatically controlled in a microwave apparatus (Biotage Initiator 2.5) at 140 ℃ and then manually heated to 190 ℃ during 3 min. After 1h at 190 ℃ the reaction mixture was cooled to RT. 100ml of water are added and the mixture is extracted three times with approximately 50ml of ethyl acetate each time. The combined organic extracts were washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration and evaporation, the crude product is obtained, which is purified by MPLC (about 30g silica gel, mobile phase: dichloromethane/methanol 10: 1). 339mg (76% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.12 (2d, 2H+1H), 7.51 (d, 2H), 6.83 (s, 1H), 6.37 (d, 1H), 6.32 (s, 1H), 5.36 (s, 2H), 3.50-3.47 (m, 4H), 2.98-2.95 (m, 4H), 2.29 (s, 3H), 1.37 (s, 9H).

LC/MS (method I, ESIpos) R_t = 0.96 min, m/z = 458 [M+H]⁺。

Examples 75

1- [4- ({ 3- [3- (4-tert-butylphenyl) -1,2,4-Diazol-5-yl]-5-methyl-1H-pyrazol-1-yl } methyl) pyridin-2-yl]-4-cyclopropylpiperazine

In analogy to the procedure described under example 55, 135mg (0.295 mmol) of the compound from example 74 are reacted to give 60mg (40% of theory, purity 98%) of the title compound.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.13 (d, 2H), 8.12 (d, 1H), 7.51 (d, 2H), 6.83 (s, 1H), 6.34 (d, 1H), 6.32 (s, 1H), 5.34 (s, 2H), 3.48-3.45 (m, 4H), 2.70-2.67 (m, 4H), 2.29 (s, 3H), 1.65-1.60 (m, 1H), 1.37 (s, 9H), 0.48-0.43 (m, 4H).

LC/MS (method D, ESIpos) R_t = 2.04 min, m/z = 498 [M+H]⁺。

Examples 76

1- (4- { [3- (3- {4- [1- (methoxymethyl) cyclobutyl ] s]Phenyl } -1,2,4-Oxadiazol-5-yl) -5-Methyl-1H-pyrazol-1-yl]Methyl } pyridin-2-yl) piperazine formate salt

In analogy to the procedure described under example 74, 766mg (8.89 mmol) piperazine and 200mg (0.444 mmol) of the compound from example 142A were reacted to yield 198mg (82% of theory) of the title compound. The crude product was purified by preparative HPLC (method N).

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.39 (s, 1H), 8.13 (d, 1H), 8.12 (d, 2H), 7.30 (d, 2H), 6.83 (s, 1H), 6.44 (d, 1H), 6.33 (s, 1H), 5.37 (s, 2H), 3.71-3.69 (m, 4H), 3.55 (s, 2H), 3.29 (s, 3H), 3.15-3.12 (m, 4H), 2.42-2.29 (m, 4H), 2.29 (s, 3H), 2.16-2.03 (m, 1H), 1.93-1.83 (m, 1H).

LC/MS (method D, ESIpos) R_t = 1.86 min, m/z = 500 [M+H]⁺。

Examples 77

1-cyclopropyl-4- (4- { [3- (3- {4- [1- (methoxymethyl) cyclobutyl ] s]Phenyl } -1,2,4-Oxadiazol-5-yl) -5-methyl-1H-pyrazol-1-yl]Methyl-pyridin-2-yl) -piperazines

In analogy to the procedure described under example 55, 100mg (0.183 mmol) of the compound from example 76 are reacted to yield 65mg (65% of theory, purity 98%) of the title compound.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.13 (d, 2H), 8.12 (d, 1H), 7.30 (d, 2H), 6.83 (s, 1H), 6.34 (d, 1H), 6.32 (s, 1H), 5.35 (s, 2H), 3.56 (s, 2H), 3.48-3.45 (m, 4H), 3.29 (s, 3H), 2.70-2.67 (m, 4H), 2.44-2.29 (m, 4H), 2.29 (s, 3H), 2.16-2.03 (m, 1H), 1.93-1.83 (m, 1H), 1.65-1.60 (m, 1H), 0.49-0.43 (m, 4H).

LC/MS (method F, ESIpos) R_t = 1.15 min, m/z = 540 [M+H]⁺。

Examples 78

1- [4- ({ 3- [3- (4-tert-butylphenyl) -1,2,4-Diazol-5-yl]-5-methyl-1H-pyrazol-1-yl } methyl) pyridin-2-yl]-4- (2, 2, 2-trifluoroethyl) piperazine

To a solution of 32. mu.l (0.437 mmol) of 2,2, 2-trifluoroethanol in 2ml of anhydrous dichloromethane at 0 ℃ are first added 76. mu.l (0.546 mmol) of triethylamine and 74. mu.l (0.437 mmol) of trifluoromethanesulfonic anhydride. After stirring at 0 ℃ for 2h, a solution of 100mg (0.219 mmol) of the compound from example 74 in 1ml of dichloromethane is added. Stirring was continued at RT. After 15h, about 20ml of water were added and the mixture was extracted with dichloromethane. The organic extract was washed with water and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed on a rotary evaporator and the product was isolated by preparative HPLC (method N). 34mg (28% of theory, approximately 98% purity) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.13 (2d, 2H+1H), 7.52 (d, 2H), 6.83 (s, 1H), 6.38 (d, 1H), 6.31 (s, 1H), 5.35 (s, 2H), 3.53-3.50 (m, 4H), 3.00 (quart, 2H), 2.76-2.73 (m, 4H), 2.28 (s, 3H), 1.37 (s, 9H).

LC/MS (method Q, ESIpos) R_t = 2.70 min, m/z = 540 [M+H]⁺。

Examples 79

1- {4- [ (5-methyl-3- {3- [ 3-methyl-4- (tetrahydro-2)H-pyran-4-yl) phenyl]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl-piperazines

In analogy to the procedure described under example 54, from 145mg (0.322 mmol) of the compound from example 143A and 555mg (6.45 mmol) of piperazine 160mg (95% of theory, purity 95%) of the title compound are obtained. In this case the crude product is purified not by preparative HPLC but by trituration with pentane.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.12 (d, 1H), 8.02 (s, 1H), 8.01 (d, 1H), 7.34 (d, 1H), 6.83 (s, 1H), 6.36 (d, 1H), 6.32 (s, 1H), 5.35 (s, 2H), 4.13-4.10 (m, 2H), 3.67-3.54 (m, 4H), 3.64 (dd, 4H), 3.07-3.00 (m, 1H), 2.94 (dd, 4H), 2.42 (s, 3H), 2.28 (s, 3H), 1.91-1.81 (m, 2H).

LC/MS (method D, ESIpos) R_t = 1.72 min, m/z = 500 [M+H]⁺。

Examples 80

1- {4- [ (3- {3- [ 3-chloro-4- (trifluoromethoxy) phenyl)]-1,2,4-Oxadiazol-5-yl } -5-methyl-1H-pyrazol-1-yl) methyl]Pyridin-2-yl-piperazines

In analogy to the procedure described under example 16, 340mg (0.723 mmol) of the compound from example 144A and 1.24g (14.5 mmol) of piperazine were reacted to give 114mg (30% of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆δ/ppm) 8.04 (d, 1H), 8.01-7.93 (m, 2H), 7.30 (d, 1H), 6.93 (s, 1H), 6.61 (s, 1H), 6.26 (d, 1H), 5.42 (s, 2H), 4.10 (s, width, 1H), 3.35-3.25 (t, 4H), 2.80-2.70 (t, 4H), 2.32 (s, 3H).

LC/MS (method D, ESIpos) R_t = 1.27 min, m/z = 520/522 [M+H]⁺。

Examples 81

1-cyclopropyl-4- {4- [ (5-methyl-3- {3- [ 3-methyl-4- (tetrahydro-2) H-pyran-4-yl) phenyl]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl-piperazines

In analogy to the procedure described under example 71, from 150mg (0.30 mmol) of the compound from example 79 and 362. mu.l (1.80 mmol) of 1-ethoxy-1- (trimethylsilyl) oxycyclopropane 23mg (13% of theory, purity 93%) of the title compound were obtained. Purification of the crude product was carried out by preparative HPLC (method N).

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.12 (d, 1H), 8.02 (s, 1H), 8.01 (d, 1H), 7.34 (d, 1H), 6.83 (s, 1H), 6.33 (d, 1H), 6.32 (s, 1H), 5.34 (s, 2H), 4.15-4.09 (m, 2H), 3.60-3.53 (m, 2H), 3.50-3.44 (m, 4H), 3.08-2.99 (m, 1H), 2.70-2.67 (m, 4H), 2.42 (s, 3H), 2.28 (s, 3H), 1.92-1.80 (m, 2H), 1.75-1.69 (m, 2H), 1.65-1.59 (m, 1H), 0.50-0.42 (m, 4H).

LC/MS (method I, ESIpos) R_t = 0.93 min, m/z = 540 [M+H]⁺。

Examples 82

N- {4- [5- (1- { [2- (4-Cyclopropylpiperazin-1-yl) pyridin-4-yl]Methyl } -5-methyl-1H-pyrazol-3-yl) -1,2,4-Diazol-3-yl]Benzyl } -N-isopropyl propan-2-amine

Initially 365mg (1.00 mmol, purity 93%) of the compound from example 132A are added together with 277mg (1.10 mmol) of the compound from example 135A to 10ml of THF. The mixture was cooled to 0 ℃, 146mg (1.30 mmol) potassium tert-butoxide was added and the mixture was first stirred at RT for 1h and then at reflux for 24 h. After cooling to RT, the mixture was diluted with ethyl acetate and washed once with water and the aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (method O). The combined product fractions were concentrated to the remaining volume of water, saturated aqueous sodium bicarbonate solution was added and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate phases were dried over magnesium sulfate, filtered and concentrated. The residue was finally dried in vacuo. 259mg (47% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃Delta/ppm of 8.13-8.10 (m, 3H), 7.50 (d, 2H), 6.82 (s, 1H), 6.36-6.30 (m, 2H), 5.35 (s, 2H), 3.70 (s, 2H), 3.45 (s, width, 4H), 3.10-3.00 (m, 2H), 2.69 (s, width, 4H), 3.30 (s, 3H), 1.67-1.60 (m, 1H), 1.05 (d, 12H), 0.50-0.45 (m, 4H).

LC/MS (method D, ESIpos) R_t = 1.19 min, m/z = 555 [M+H]⁺。

Examples 83

4- {4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl morpholine

In analogy to the procedure described under example 56, 156mg (69% of theory, purity 98%) of the title compound are obtained from 200mg (0.459 mmol) of from example 81A and 2.1ml (23.9 mmol) of morpholine. The crude product was purified by preparative HPLC (method N).

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.26 (d, 2H), 8.14 (d, 1H), 7.33 (d, 2H), 6.83 (s, 1H), 6.40 (d, 1H), 6.31 (s, 1H), 5.37 (s, 2H), 3.78 (dd, 4H), 3.46 (dd, 4H), 2.30 (s, 3H).

LC/MS (method D, ESIpos) R_t = 2.25 min, m/z = 587 [M+H]⁺。

Examples 84

1- {4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl } piperidin-4-ols

In analogy to the procedure described under example 56, from 200mg (0.459 mmol) of the 4-hydroxypiperidine from example 81A and 464mg (4.59 mmol) 33mg (14% of theory) of the title compound are obtained. The crude product was purified by preparative HPLC (method N).

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.25 (d, 2H), 8.12 (d, 1H), 7.33 (d, 2H), 6.83 (s, 1H), 6.36 (s, 1H), 6.32 (d, 1H), 5.34 (s, 2H), 4.02-3.96 (m, 2H), 3.94-3.88 (m, 1H), 3.17-3.10 (m, 2H), 2.29 (s, 3H), 1.98-1.91 (m, 2H), 1.59-1.51 (m, 2H).

LC/MS (method D, ESIpos) R_t = 2.25 min, m/z = 501 [M+H]⁺。

Examples 85

1- {4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group) ]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl } piperidine-4-carbonitrile

A mixture of 120mg (0.275 mmol) of the compound from example 81A and 606mg (5.51 mmol) of 4-cyanopiperidine is stirred in a microwave oven (CEM Discover, initial radiant power 250W) for 3h at 160 ℃. Approximately 4ml of methanol were then added and the reaction mixture was purified directly by preparative HPLC (method N). The product fractions were combined and the solvent was removed on a rotary evaporator. The residue was triturated with about 5ml cyclohexane/ethyl acetate (20: 1). After drying under high vacuum 103mg (73% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.25 (d, 2H), 8.13 (d, 1H), 7.33 (d, 2H), 6.84 (s, 1H), 6.38 (d, 1H), 6.34 (s, 1H), 5.35 (s, 2H), 3.80-3.73 (m, 2H), 3.48-3.41 (m, 2H), 2.88-2.82 (m, 1H), 2.29 (s, 3H), 2.00-1.93 (m, 2H), 1.92-1.83 (m, 2H).

LC/MS (method F, ESIpos) R_t = 1.28 min, m/z = 510 [M+H]⁺。

Examples 86

1-methyl-4- {4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl } piperazin-2-one

In analogy to the procedure described under example 56, from 200mg (0.459 mmol) of the starting material from examples 81A and 524mg (4.59 mmol) of 1-methylpiperazin-2-one [ H.R. Buerki et al,Eur. J. Med. Chem. 1978（ 13 ），479-485]154mg (65% of theory) of the title compound are obtained. The crude product was purified by preparative HPLC (method N).

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.25 (d, 2H), 8.13 (d, 1H), 7.33 (d, 2H), 6.84 (s, 1H), 6.42 (d, 1H), 6.23 (s, 1H), 5.37 (s, 2H), 4.02 (s, 2H), 3.90 (dd, 2H), 3.43 (dd, 2H), 3.03 (s, 3H), 2.29 (s, 3H).

LC/MS (method F, ESIpos) R_t = 1.24 min, m/z = 514 [M+H]⁺。

Examples 87

1- (4- {4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl) ]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl } piperazin-1-yl) ethanones

To a solution of 300mg (0.618 mmol) of the compound from example 64 in 50ml of anhydrous dichloromethane are added 128. mu.l (0.927 mmol) of triethylamine and 44. mu.l (0.618 mmol) of acetyl chloride at 0 ℃. The mixture was then stirred at RT for 16 h. Then 50ml of saturated aqueous sodium bicarbonate solution were added. After extraction by shaking, the organic phase which had been separated off was washed with water and then dried over anhydrous magnesium sulfate. After filtration, the solvent was removed on a rotary evaporator. The crude product was purified by preparative HPLC (method N). The product obtained is stirred with 3ml of ethanol. After filtration and drying under high vacuum, 234mg (72% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.25 (d, 2H), 8.14 (d, 1H), 7.33 (d, 2H), 6.85 (s, 1H), 6.40 (d, 1H), 6.33 (s, 1H), 5.37 (s, 2H), 3.73-3.70 (m, 2H), 2.60-2.53 (m, 4H), 3.49-3.46 (m, 2H), 2.30 (s, 3H), 2.13 (s, 3H).

LC/MS (method Q, ESIpos) R_t = 2.14 min, m/z = 528 [M+H]⁺。

Examples 88

2- (4-methylpiperidin-1-yl) -4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl ] methyl ester]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridine compound

In analogy to the procedure described under example 56, from 200mg (0.459 mmol) of from example 81A and 2.8ml (23.9 mmol) of 4-methylpiperidine 136mg (59% of theory) of the title compound are obtained. The crude product was purified by preparative HPLC (method N).

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.25 (d, 2H), 8.10 (d, 1H), 7.33 (d, 2H), 6.83 (s, 1H), 6.33 (s, 1H), 6.28 (d, 1H), 5.33 (s, 2H), 4.22-4.15 (m, 2H), 2.82-2.74 (m, 2H), 2.29 (s, 3H), 1.72-1.67 (m, 2H), 1.63-1.53 (m, 1H), 1.22-1.13 (m, 2H), 0.95 (d, 3H).

LC/MS (method D, ESIpos) R_t = 2.27 min, m/z = 499 [M+H]⁺。

Examples 89

1- (cyclopropylmethyl) -4- {4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl ]]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl-piperazines

In analogy to the procedure described under example 73, from 200mg (0.412 mmol) of the compound from example 64 and 37 μ l (0.494 mmol) of cyclopropanecarboxaldehyde 52mg (23% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.25 (d, 2H), 8.12 (d, 1H), 7.33 (d, 2H), 6.83 (s, 1H), 6.33 (d, 1H), 6.32 (s, 1H), 5.35 (s, 2H), 3.52 (dd, 4H), 2.60 (dd, 4H), 2.29 (s, 3H), 2.28 (d, 2H), 0.93-0.83 (m, 1H), 0.54-0.51 (m, 2H), 0.13-0.10 (m, 2H).

LC/MS (method I, ESIpos) R_t = 0.99 min, m/z = 540 [M+H]⁺。

Examples 90

1- (4- { [ 5-methyl-3- (3- {4- [1- (trifluoromethyl) cyclopropyl)]Phenyl } -1,2,4-Oxadiazol-5-yl) -1H-pyrazol-1-yl]Methyl-pyridin-2-yl) -piperazines

A mixture of 175mg (0.381 mmol) of the compound from example 145A and 656mg (7.61 mmol) of piperazine was stirred at 150 ℃ at bath temperature under argon overnight. After cooling to RT, ethyl acetate and water were added and the phases were separated. The aqueous phase is extracted three times with ethyl acetate, the combined ethyl acetate phases are concentrated and the residue is dried in vacuo to yield 195mg (98% of theory, 97% purity) of the title compound in this way.

LC/MS (method F, ESIpos) R_t = 1.10 min, m/z = 510 [M+H]⁺。

Examples 91

1-cyclopropyl-4- (4- { [ 5-methyl-3- (3- {4- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Phenyl } -1,2,4-Oxadiazol-5-yl) -1 H-pyrazol-1-cyclopropyl-4-yl]Methyl-pyridin-2-yl) -piperazines

Start adding 195mg (0.371 mmol, purity 97%) of the compound from example 90 and 50mg of molecular sieve (3 a) and 448 μ l (2.23 mmol) of [ (1-ethoxycyclopropyl) oxy ] (trimethyl) silane to a mixture of 55ml of methanol and 213 μ l (3.71 mmol) of acetic acid under argon at RT. After stirring at RT for 10min, 70mg (1.11 mmol) of sodium cyanoborohydride are added and the mixture is heated at reflux for 2 h. After cooling to RT, the solids present were filtered off and washed once with methanol and the filtrate was concentrated. The residue was purified by preparative HPLC (method O). The combined product fractions were concentrated to the remaining volume of the aqueous phase. Saturated aqueous sodium bicarbonate was added and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate phases were dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from ether. After drying in vacuo, 86mg (42% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.18 (d, 2H), 8.12 (d, 1H), 7.59 (d, 2H), 6.84 (s, 1H), 6.34 (s, 1H), 6.33 (s, 1H), 5.38 (s, 2H), 3.50-3.42 (m, 4H), 2.72-2.66 (m, 4H), 2.28 (s, 3H), 1.68-1.58 (m, 1H), 1.47-1.36 (m, 2H), 1.09 (s, 2H), 0.50-0.40 (m, 4H).

LC/MS (method F, ESIpos) R_t = 1.17 min, m/z = 550 [M+H]⁺。

Examples 92

1-cyclopropyl-4- (4- { [ 5-methyl-3- (3- {4- [ N-methyl-S- (trifluoromethyl) sulphoimides]Phenyl } -1,2,4-Oxadiazol-5-yl) -1H-pyrazol-1-yl ]Methyl-pyridin-2-yl) -piperazines

80mg (0.215 mmol) of the compound from example 130A are initially introduced together with 54mg (0.215 mmol) of the compound from example 135A into 1ml of THF. The mixture was cooled to 0 ℃, 31mg (0.280 mmol) potassium tert-butoxide was added and the mixture was first stirred at RT for 1h and then at reflux for 24 h. It was then concentrated and the residue was purified twice by preparative HPLC (method O). The combined product fractions were concentrated to the remaining volume of water and saturated aqueous sodium bicarbonate solution was added. The solid formed was filtered off, washed twice with water and dried in vacuo. 28mg (22% of theory) of the title compound are obtained in this way.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.44 (s, Width, 2H), 8.30-8.00 (m, 3H), 6.86 (s, Width, 1H), 6.34 (s, Width, 2H), 5.36 (s, Width, 2H), 3.50 (s, Width, 4H), 3.12 (s, Width, 3H), 2.70 (s, Width, 4H), 2.30 (s, Width, 3H), 1.60 (s, Width, 1H), 0.50 (s, Width, 4H).

LC/MS (method I, ESIpos) R_t = 0.97 min, m/z = 587 [M+H]⁺。

Examples 93

1-cyclopropyl-4- {4- [ (3- {3- [ 3-fluoro-4- (trifluoromethoxy) phenyl)]-1,2,4-Oxadiazol-5-yl } -5-methyl-1H-pyrazol-1-yl) methyl]Pyridin-2-yl-piperazines

To a mixture of 357mg (1.0 mmol, purity 92%) of the compound from example 131A and 277mg (1.10 mmol) of the compound from example 135A in 10ml of THF were added 146mg (1.30 mmol) of potassium tert-butoxide and the mixture was heated at reflux overnight with stirring. After cooling to RT, the mixture was diluted with ethyl acetate and washed once with water. The aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (method O). The combined product fractions were concentrated to the remaining volume of the aqueous phase, saturated aqueous sodium bicarbonate solution was added and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate phases were dried over magnesium sulfate, filtered and concentrated. After the residue has been dried in vacuo, 269mg (49% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.11 (d, 1H), 8.10-8.01 (m, 2H), 7.46-7.41 (t, 1H), 6.83 (s, 1H), 6.32 (s, 2H), 5.35 (s, 2H), 3.49-3.44 (m, 4H), 2.71-2.66 (m, 4H), 2.29 (s, 3H), 1.68-1.60 (m, 1H), 0.50-0.40 (m, 4H).

LC/MS (method D, ESIpos) R_t = 1.97 min, m/z = 544 [M+H]⁺。

Examples 94

4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]-2- (pyrrolidin-1-yl) pyridine

In analogy to the procedure described under example 56, from 200mg (0.459 mmol) of the compound from example 81A and 770. mu.l (9.18 mmol) of pyrrolidine 63mg (28% of theory) of the title compound are obtained. For work-up, the reaction mixture is first concentrated to dryness on a rotary evaporator when the reaction has ended and the residue is then stirred with acetonitrile. The solid thus obtained was filtered off. The product was isolated from the filtrate by preparative HPLC (method N).

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.26 (d, 2H), 8.10 (d, 1H), 7.34 (d, 2H), 6.83 (s, 1H), 6.27 (d, 1H), 6.02 (s, 1H), 5.35 (s, 2H), 3.41-3.36 (m, 4H), 2.28 (s, 3H), 1.99-1.97 (m, 4H).

LC/MS (method I, ESIpos) R_t = 0.99 min, m/z = 471 [M+H]⁺。

Examples 95

2- (azetidin-1-yl) -4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridine compound

In analogy to the procedure described under example 16, 150mg (0.344 mmol) of the compound from example 81A and 232. mu.l (3.44 mmol) of azetidine were reacted to give 66mg (42% of theory) of the title compound.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.25 (d, 2H), 8.09 (d, 1H), 7.34 (d, 2H), 6.83 (s, 1H), 6.31 (d, 1H), 5.93 (s, 1H), 5.34 (s, 2H), 4.03-3.98 (m, 4H), 2.42-2.31 (m, 2H), 2.28 (s, 3H).

LC/MS (method I, ESIpos) R_t = 0.96 min, m/z = 457 [M+H]⁺。

Examples 96

4- [ (5-methyl-3- {3- [4- (pyrrolidin-1-yl) phenyl ] methyl ester]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl ]-2- (pyrrolidin-1-yl) pyridine

Obtained in analogy to the procedure described under example 56, from 200mg (0.459 mmol) of the compound from example 81A and 770. mu.l (9.18 mmol) of pyrrolidine 89mg (40% of theory) of the title compound are obtained. For work-up, the reaction mixture is first concentrated to dryness on a rotary evaporator when the reaction has ended and the residue is then stirred with acetonitrile. The product is thus retained in undissolved form and separated off and dried under high vacuum.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.09 (d, 1H), 8.04 (d, 2H), 6.80 (s, 1H), 6.60 (d, 2H), 6.27 (d, 1H), 6.00 (s, 1H), 5.34 (s, 2H), 3.40-3.34 (m, 8H), 2.27 (s, 3H), 2.05-2.01 (m, 4H), 1.99-1.95 (m, 4H).

LC/MS (method I, ESIpos) R_t = 0.99 min, m/z = 456 [M+H]⁺。

Examples 97

2- (4-tert-butylpiperidin-1-yl) -4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl ]]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridine compound

In analogy to the procedure described under example 56, from 120mg (0.275 mmol) of the compound from example 81A and 778mg (5.51 mmol) of morpholine 99mg (69% of theory, purity 98%) of the title compound are obtained. The product was isolated by preparative HPLC (method N) and finally stirred with pentane/diethyl ether (20: 1).

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.25 (d, 2H), 8.11 (d, 1H), 7.33 (d, 2H), 6.83 (s, 1H), 6.33 (s, 1H), 6.28 (d, 1H), 5.33 (s, 2H), 4.31-4.26 (m, 2H), 2.72-2.65 (m, 2H), 2.28 (s, 3H), 1.77-1.72 (m, 2H), 1.31-1.14 (m, 3H), 0.86 (s, 9H).

LC/MS (method I, ESIpos) R_t = 1.33 min, m/z = 541 [M+H]⁺。

Examples 98

1- {4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl } -4- (2, 2, 2-trifluoroethyl) -1, 4-diazepane

100mg (0.23 mmol) of the compound from example 81A and 209mg (1.15 mmol) of 1- (2, 2, 2-trifluoroethyl) -1, 4-diazepane are heated in a microwave oven at 160 ℃ for 3 h. After cooling to RT, the reaction mixture is purified directly by preparative HPLC (method P). The combined product fractions were concentrated on a rotary evaporator. After the residue has been dried in vacuo, 92mg (65% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 8.20 (d, 2H), 8.00 (d, 1H), 7.59 (d, 2H), 6.95 (s, 1H), 6.44 (s, 1H), 6.20 (d, 1H), 5.43 (s, 2H), 3.67 (t, 2H), 3.57 (t, 2H), 3.27 (m, 2H), 2.92 (d, 2H), 2.75 (d, 2H), 2.33 (s, 3H), 1.80 (m, 2H).

LC/MS (method D, ESIpos) R_t = 2.26 min, m/z = 581 [M+H]⁺。

Examples 99

2- (1-Cyclopropylpiperidin-4-yl) -4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl ]]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridine compound

130mg (0.250 mmol) of the compound from example 63 are dissolved in approximately 10ml of methanol and passed through a bicarbonate cartridge (Polymerlabs, Stratospheres SPE, PL-HCO)₃MP SPE, capacity 0.9 mmol) was osmotically converted to the free base. After the solvent had been evaporated off, the residue was taken up again in 3.5ml of methanol, and 143. mu.l (2.49 mmol) of glacial acetic acid, 301. mu.l (1.50 mmol) of 1-ethoxy-1- (trimethylsiloxy) cyclopropane and 40mg of dried, pulverulent molecular sieve (3A) were added. After stirring at RT for 10min, 47mg (0.749 mmol) of solid sodium cyanoborohydride are added. The reaction mixture was then heated at reflux for 4 h. After cooling to RT, the mixture was diluted with about 10ml of dichloromethane and the undissolved material was filtered off. The filtrate was concentrated to dryness on a rotary evaporator and the residue was then dissolved again in approximately 4ml of methanol. The product was prepurified by preparative HPLC (method N). The product fractions were combined and the solvent was removed. The residue obtained was passed through a bicarbonate cartridge (Polymerlabs, Stratospheres SPE, PL-HCO) ₃MP SPE, capacity 0.9 mmol) to remove formic acid from the preparative HPLC. The final purification was carried out by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate 10: 1 → 1: 1). 74mg (54% of theory, purity 96%) of the title compound are obtained in this way.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.48 (d, 1H), 8.25 (d, 2H), 7.33 (d, 2H), 6.89 (s, 1H), 6.85 (s, 1H), 6.83 (d, 1H), 5.41 (s, 2H), 3.17-3.11 (m, 2H), 2.76-2.68 (m, 1H), 2.33-2.27 (m, 2H), 2.28 (s, 3H), 1.92-1.87 (m, 2H), 1.74-1.63 (m, 2H), 1.62-1.58 (m, 1H), 0.48-0.39 (m, 4H).

LC/MS (method I, ESIpos) R_t = 0.97 min, m/z = 525 [M+H]⁺。

Examples 100

{3- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl } (1, 2-Oxazolidin-2-yl) methanones

Analogously to the method described under example 32, starting from 100mg (0.225 mmol) of the compound from example 93A and 49mg (0.450 mmol) of 1,2-Oxazolidine hydrochloride gives 68mg (60% of theory) of the title compound. In deviation from the teaching mentioned, further equivalents are used hereN,N-diisopropylethylamine as base. The final permeation through the bicarbonate cartridge was omitted.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.25 (d, 2H), 7.73 (d, 1H), 7.62 (s, 1H), 7.39 (t, 1H), 7.33 (d, 2H), 7.25 (d, 1H), 6.81 (s, 1H), 5.49 (s, 2H), 3.95 (t, 2H), 3.88 (t, 2H), 2.33 (quint, 2H), 2.29 (s, 3H).

HPLC (method A) R_t = 4.58 min.

MS (DCI, NH₃): m/z = 500 [M+H]⁺, 517 [M+NH₄]⁺.

LC/MS (method F, ESIpos) R_t = 1.39 min, m/z = 500 [M+H]⁺。

Examples 101

(4-hydroxypiperidin-1-yl) {3- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl ]]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl ketone

In analogy to the procedure described under example 32, from 100mg (0.225 mmol) of the compound from example 93A and 46mg (0.450 mmol) of 4-hydroxypiperidine 117mg (98% of theory) of the title compound are obtained. The final permeation through the bicarbonate cartridge is omitted here.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.25 (d, 2H), 7.39 (t, 1H), 7.33 (2d, 2H +1H), 7.20 (d, 1H), 7.19 (s, 1H), 6.82 (s, 1H), 5.48 (s, 2H), 4.15 (wide, 1H), 3.95 (wide, 1H), 3.59 (wide, 1H), 3.37 (wide, 1H), 3.14 (wide, 1H), 2.30 (s, 3H), 1.95 (wide, 1H), 1.79 (wide, 1H), 1.59 (wide, 2H), 1.45 (wide, 1H).

HPLC (method A) R_t = 4.41 min.

MS (DCI, NH₃): m/z = 528 [M+H]⁺, 545 [M+NH₄]⁺.

LC/MS (Square)Method I, ESIpos) R_t = 1.12 min, m/z = 528 [M+H]⁺。

Examples 102

{3- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl } (morpholin-4-yl) methanone

In analogy to the procedure described under example 32, from 100mg (0.225 mmol) of the compound from example 93A and 40. mu.l (0.450 mmol) of morpholine 76mg (66% of theory) of the title compound are obtained. In this case purification by preparative HPLC and final permeation through a bicarbonate cartridge were omitted; after addition of water to the reaction mixture, the product precipitates out and is filtered off with suction and dried under high vacuum.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.24 (d, 2H), 7.40 (t, 1H), 7.33 (2d, 2H +1H), 7.21 (d, 1H), 7.20 (s, 1H), 6.83 (s, 1H), 5.48 (s, 2H), 3.74 (wide, 4H), 3.60 (wide, 2H), 3.39 (wide, 2H), 2.31 (s, 3H).

HPLC (method A) R_t = 4.54 min.

MS (DCI, NH₃): m/z = 514 [M+H]⁺, 531 [M+NH₄]⁺.

LC/MS (method I, ESIpos) R _t = 1.19 min, m/z = 514 [M+H]⁺。

Examples 103

{3- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl } (pyrrolidin-1-yl) methanone

In analogy to the procedure described under example 32, from 100mg (0.225 mmol) of the compound from example 93A and 38. mu.l (0.450 mmol) of pyrrolidine 72mg (64% of theory) of the title compound are obtained. The final permeation through the bicarbonate cartridge is omitted here.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.25 (d, 2H), 7.46 (d, 1H), 7.38 (t, 1H), 7.33 (d, 2H), 7.31 (s, 1H), 7.19 (d, 1H), 6.82 (s, 1H), 5.47 (s, 2H), 3.61 (t, 2H), 3.35 (t, 2H), 2.29 (s, 3H), 1.94 (quint, 2H), 1.85 (quint, 2H).

HPLC (method A) R_t = 4.68 min.

MS (ESIpos): m/z = 498 [M+H]⁺, 995 [2M+H]⁺.

LC/MS (method F, ESIpos) R_t = 1.43 min, m/z = 498 [M+H]⁺。

Examples 104

Azetidin-1-yl {3- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl ]]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl ketone

In analogy to the procedure described under example 32, from 100mg (0.225 mmol) of the compound from example 93A and 79. mu.l (0.450 mmol) of azetidine 84mg (78% of theory) of the title compound are obtained. The final permeation through the bicarbonate cartridge is omitted here.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.25 (d, 2H), 7.55 (d, 1H), 7.45 (s, 1H), 7.39 (t, 1H), 7.32 (s, 2H), 7.24 (d, 1H), 6.82 (s, 1H), 5.48 (s, 2H), 4.24-4.18 (m, 4H), 2.32 (quint, 2H), 2.29 (s, 3H).

HPLC (method A) R_t = 4.62 min.

MS (DCI, NH₃): m/z = 484 [M+H]⁺, 501 [M+NH₄]⁺.

LC/MS (method F, ESIpos) R_t = 1.39 min, m/z = 484 [M+H]⁺。

Examples 105

(3-Fluoroazetidin-1-yl) {3- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl ]]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl ketone

In analogy to the procedure described under example 32, from 100mg (0.225 mmol) of the compound from example 93A and 50mg (0.450 mmol) 3-fluoroazetidine hydrochloride [ B. Hulin et al,Bioorg. Med. Chem. Lett. 2005，15 （ 21 ），4770-4773]95mg (84% of theory) of the title compound are obtained. In deviation from the teaching mentioned, further equivalents are used hereN,N-diisopropylethylamine as base. The final permeation through the bicarbonate cartridge was omitted.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.24 (d, 2H), 7.74 (d, 1H), 7.47 (s, 1H), 7.41 (t, 1H), 7.34 (d, 2H), 7.29 (d, 1H), 6.83 (s, 1H), 5.48 (s, 2H), 5.41-5.22 (m, 1H), 4.50-4.39 (m, 2H), 4.38-4.24 (m, 2H), 2.30 (s, 3H).

HPLC (method A) R_t = 4.59 min.

MS (ESIpos): m/z = 502 [M+H]⁺, 1003 [2M+H]⁺.

LC/MS (method F, ESIpos) R_t = 1.40 min, m/z = 502 [M+H]⁺。

Examples 106

(3-Methoxyazetidin-1-yl) {3- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl ]]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl ketone

In analogy to the procedure described under example 32, from 100mg (0.225 mmol) of the compound from example 93A and 56mg (0.450 mmol) of 3-methoxyazetidine hydrochloride [ L. Pro-vins et al,Bioorg. Med. Chem. Lett. 2007，17 （ 11 ），3077-3080]72mg (60% of theory, purity 96%) of the title compound are obtained. In deviation from the teaching mentioned, further equivalents are used hereN,N-diisopropylethylamine as base. The final permeation through the bicarbonate cartridge was omitted.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.25 (d, 2H), 7.55 (d, 1H), 7.44 (s, 1H), 7.39 (t, 1H), 7.33 (d, 2H), 7.25 (d, 1H), 6.83 (s, 1H), 5.48 (s, 2H), 4.37-4.29 (m, 2H), 4.22-4.17 (m, 1H), 4.10-4.01 (m, 2H), 3.26 (s, 3H), 2.30 (s, 3H).

HPLC (method A) R_t = 4.58 min.

MS (ESIpos): m/z = 514 [M+H]⁺, 1027 [2M+H]⁺.

LC/MS (method F, ESIpos) R_t = 1.38 min, m/z = 514 [M+H]⁺。

Examples 107

(3-Methylazazetidin-1-yl) {3- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl ]]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl ketone

In analogy to the procedure described under example 32, from 100mg (0.225 mmol) of the compound from example 93A and 48mg (0.450 mmol) of 3-methylazetidine hydrochloride [ L. Pro-vins et al, Bioorg. Med. Chem. Lett. 2007，17 （ 11 ），3077-3080]72mg (60% of theory, purity 96%) of the title compound are obtained. In deviation from the teaching mentioned, further equivalents are used hereN,N-diisopropylethylamine as base. The final permeation through the bicarbonate cartridge was omitted.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.25 (d, 2H), 7.55 (d, 1H), 7.45 (s, 1H), 7.38 (t, 1H), 7.33 (d, 2H), 7.23 (d, 1H), 6.82 (s, 1H), 5.48 (s, 2H), 4.32-4.27 (m, 2H), 3.79-3.71 (m, 2H), 2.79-2.69 (m, 1H), 2.29 (s, 3H), 1.23 (d, 3H).

LC/MS (method F, ESIpos) R_t = 1.45 min, m/z = 498 [M+H]⁺。

Examples 108

1- {4- [5- (5-methyl-1- {3- [ (4-methylpiperazin-1-yl) carbonyl ] carbonyl]Benzyl radical 1H-pyrazol-3-yl) -1,2,4-Diazol-3-yl]Phenyl } cyclobutanecarboxylic acid ethyl ester

To a solution of 155mg (0.409 mmol) of the hydrochloride of the compound from example 105A in 2ml of anhydrous DMF were added 86mg (0.450 mmol) EDC and 69mg (0.450 mmol) HOBt and the mixture was stirred at RT for 30 min. A solution of 118mg (0.450 mmol) of the compound from example 109A in 2ml of anhydrous DMF is then added and stirring is continued at RT for 15 h. After this time, the reaction batch was immersed in an oil bath preheated to 140 ℃ and left there for 1 h. After cooling to RT, the reaction mixture was separated directly into its components by preparative HPLC (method N). The product fractions were combined and concentrated to dryness on a rotary evaporator. For purification by HPLC to remove viscous formic acid, the residue obtained is dissolved in approximately 5ml of methanol and the solution is passed through a bicarbonate cartridge (Polymerlabs, Stratospheres SPE, PL-HCO) ₃MP SPE, capacity0.9 mmol). After concentration and drying, 58mg (24% of theory, purity 95%) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.15 (d, 2H), 7.42 (d, 2H), 7.38 (t, 1H), 7.33 (d, 1H), 7.19 (d, 1H), 7.15 (s, 1H), 6.83 (s, 1H), 5.47 (s, 2H), 4.12 (quart, 2H), 3.76 (wide, 2H), 3.37 (wide, 2H), 2.91-2.83 (m, 2H), 2.58-2.50 (m, 2H), 2.43 (wide, 2H), 2.30 (s, 3H), 2.28 (wide, 2H), 2.24 (s, 3H), 2.13-2.02 (m, 1H), 1.94-1.85 (m, 1H), 1.17 (t, 3H).

LC/MS (method F, ESIpos) R_t = 1.13 min, m/z = 569 [M+H]⁺。

Examples 109

(4-Methylpiperazin-1-yl) (3- { [ 5-methyl-3- (3- {4- [ (trifluoromethyl) thio ] thio]Phenyl } -1,2,4-Oxadiazol-5-yl) -1H-pyrazol-1-yl]Methyl } phenyl) methanones

To a solution of 160mg (0.422 mmol) of the hydrochloride of the compound from example 105A in 2ml of anhydrous DMF were added 89mg (0.465 mmol) EDC, 71mg (0.465 mmol) HOBt and 59. mu.l (0.422 mmol) triethylamine and the mixture was stirred at RT for 30 min. A solution of 120mg (0.507 mmol) of the compound from example 15A in 2ml of anhydrous DMF is then added and stirring is continued at RT for 1 h. After this time, the reaction batch was immersed in an oil bath preheated to 140 ℃ and left there for 1 h. After cooling to RT, the reaction mixture was separated directly into its components by preparative HPLC (method N). The product fractions were combined and concentrated on a rotary evaporator to about half the original volume. The pH was then brought to about 8-9 by the addition of solid sodium bicarbonate. The mixture was extracted three times with approximately 20ml of ethyl acetate each time. The combined organic extracts were washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate and filtration, the solvent was removed on a rotary evaporator. 48mg (21% of theory, purity approx. 95%) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆δ/ppm) 8.21 (d, 2H), 7.93 (d, 2H), 7.45 (t, 1H), 7.32 (d, 1H), 7.30 (d, 1H), 7.15 (s, 1H), 6.96 (s, 1H), 5.55 (s, 2H), 3.55 (Wide, 2H), 3.24 (Wide, 2H), 2.34 (s, 3H), 2.32 (Wide, 2H), 2.18 (Wide, 2H), 2.11 (s, 3H).

LC/MS (method D, ESIpos) R_t = 2.00 min, m/z = 543 [M+H]⁺。

Examples 110

(3- { [3- (3- {4- [1- (methoxymethyl) cyclobutyl ] butyl]Phenyl } -1,2,4-Oxadiazol-5-yl) -5-methyl-1H-pyrazol-1-yl]Methyl } phenyl) (4-methylpiperazin-1-yl) methanone

To a solution of 180mg (0.475 mmol) of the hydrochloride of the compound from example 105A in 3ml of anhydrous DMF were added 100mg (0.523 mmol) EDC and 80mg (0.523 mmol) HOBt and the mixture was stirred at RT for 30 min. A solution of 122mg (0.523 mmol) of the compound from example 110A in 2ml of anhydrous DMF is then added and stirring is continued at RT for 1 h. After this time, the reaction batch was immersed in an oil bath preheated to 140 ℃ and left there for 30 min. After cooling to RT, the reaction mixture is separated directly by preparative HPLCTo its component (method N). The product fractions were combined and concentrated to dryness on a rotary evaporator. For purification by HPLC to remove viscous formic acid, the residue obtained is dissolved in approximately 5ml of methanol and the solution is passed through a bicarbonate cartridge (Polymerlabs, Stratospheres SPE, PL-HCO) ₃MP SPE, capacity 0.9 mmol). After concentration and drying, 67mg (25% of theory, purity 95%) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.13 (d, 2H), 7.38 (t, 1H), 7.33 (d, 1H), 7.29 (d, 2H), 7.19 (d, 1H), 7.14 (s, 1H), 6.82 (s, 1H), 5.47 (s, 2H), 3.75 (wide, 2H), 3.54 (s, 2H), 3.36 (wide, 2H), 3.28 (s, 3H), 2.50-2.25 (m, 8H), 2.29 (s, 3H), 2.24 (s, 3H), 2.15-2.03 (m, 1H), 1.93-1.83 (m, 1H).

LC/MS (method I, ESIpos) R_t = 1.01 min, m/z = 541 [M+H]⁺。

Examples 111

{3- [ (3- {3- [4- (1-fluorocyclobutyl) phenyl group]-1,2,4-Oxadiazol-5-yl } -5-methyl-1H-pyrazol-1-yl) methyl]Phenyl } (4-methylpiperazin-1-yl) methanone

In analogy to the procedure described under example 41, from 100mg (0.292 mmol) of the compound from example 105A and 73mg (0.350 mmol) of the compound from example 26A 57mg (38% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.23 (d, 2H), 7.59 (d, 2H), 7.39 (t, 1H), 7.34 (d, 1H), 7.20 (d,1H) 7.16 (s, 1H), 6.84 (s, 1H), 5.48 (s, 2H), 3.76 (Wide, 2H), 3.36 (Wide, 2H), 2.77-2.55 (m, 4H), 2.44 (Wide, 2H), 2.30 (s, 3H), 2.28 (Wide, 2H), 2.25 (s, 3H), 2.19-2.07 (m, 1H), 1.87-1.75 (m, 1H).

HPLC (method A) R_t = 4.24 min.

MS (DCI, NH₃): m/z = 515 [M+H]⁺。

Examples 112

(4-Methylpiperazin-1-yl) {3- [ (5-methyl-3- {3- [4- (1, 1, 1-trifluoro-2-methoxypropan-2-yl) phenyl ]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl } methanone (racemate)

In analogy to the procedure described under example 110, 500mg (1.32 mmol) of the hydrochloride of the compound from example 105A and 381mg (1.45 mmol) of the compound from example 111A are reacted to yield 190mg (24% of theory, purity 95%) of the title compound.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.23 (d, 2H), 7.64 (d, 2H), 7.39 (t, 1H), 7.33 (d, 1H), 7.20 (d, 1H), 7.16 (s, 1H), 6.83 (s, 1H), 5.48 (s, 2H), 3.75 (Wide, 2H), 3.36 (Wide, 2H), 3.27 (s, 3H), 2.44 (Wide, 2H), 2.30 (s, 3H), 2.29 (Wide, 2H), 2.26 (s, 3H), 1.82 (s, 3H).

LC/MS (method I, ESIpos) R_t = 0.95 min, m/z = 569 [M+H]⁺。

Examples 113

(4-Methylpiperazin-1-yl) {3- [ (5-methyl-3- {3- [4- (1, 1, 1-trifluoro-2-methoxypropan-2-yl) phenyl]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl } methanone (enantiomer 1)

160mg (0.281 mmol) of the racemic compound from example 112 are dissolved in a mixture of 4ml of isopropanol and 11 ml of isohexane and the enantiomers are separated by chromatography on a chiral phase [ column packing material: daicel Chiralpak AD-H, 5 μm, 250 mm. times.20 mm; injection volume: 0.3 ml; flow rate: 15 ml/min; temperature: 40 ℃; and (4) UV detection: 220 nm; mobile phase: 50% isohexane, 49.8% isopropanol, 0.2% diethylamine ]. 72mg (90% of theory, ee > 98.5%) of the title compound (enantiomer 1) and 76mg (95% of theory, ee > 99.0%) of the other enantiomer are obtained (example 114).

Analytical HPLC [ Daicel Chiracel AD-H, 5 μm, 250 mm. times.4.6 mm; mobile phase: 40% isohexane, 59.8% isopropanol, 0.2% diethylamine; flow rate: 1 ml/min; temperature: 40 deg.C]：R_t=5.27min。

Examples 114

(4-Methylpiperazin-1-yl) {3- [ (5-methyl-3- {3- [4- (1, 1, 1-trifluoro-2-methoxypropan-2-yl) phenyl]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl } methanone (enantiomer 2)

160mg (0.281 mmol) of the racemic compound from example 112 are dissolved in a mixture of 4ml of isopropanol and 11ml of isohexane and the enantiomers are separated by chromatography on a chiral phase [ column packing material: daicel Chiralpak AD-H, 5 μm, 250 mm. times.20 mm; injection volume: 0.3 ml; flow rate: 15 ml/min; temperature: 40 ℃; and (4) UV detection: 220 nm; mobile phase: 50% isohexane, 49.8% isopropanol, 0.2% diethylamine ]. 76mg (95% of theory ee > 99.0%) of the title compound (enantiomer 2) and 72mg (90% of theory ee > 98.5%) of the other enantiomer were obtained (example 113).

Analytical HPLC [ Daicel Chiracel AD-H, 5 μm, 250 mm. times.4.6 mm; mobile phase: 40% isohexane, 59.8% isopropanol, 0.2% diethylamine; flow rate: 1 ml/min; temperature: 40 deg.C]：R_t=5.68 min。

Examples 115

{3- [ (3- {3- [ 3-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl ]-1,2,4-Oxadiazol-5-yl } -5-methyl-1H-pyrazol-1-yl) methyl]Phenyl } (4-methylpiperazin-1-yl) methanone

In analogy to the procedure described under example 110, 230mg (0.607 mmol) of the hydrochloride of the compound from example 105A and 159mg (0.668 mmol) of the compound from example 112A are reacted to yield 43mg (13% of theory, purity 98%) of the title compound.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 7.96 (d, 1H), 7.87 (d, 1H), 7.41-7.33 (m, 3H), 7.20 (d, 1H), 7.16 (s, 1H), 6.82 (s, 1H), 5.47 (s, 2H), 4.12-4.08 (m, 2H), 3.76 (width, 2H), 3.61-3.54 (m, 2H), 3.36 (width, 2H), 3.22-3.14 (m, 1H), 2.43 (width, 2H), 2.30 (s, 3H), 2.28 (width, 2H), 2.24 (s, 3H), 1.93-1.76 (m, 4H).

LC/MS (method I, ESIpos) R_t = 0.89 min, m/z = 545 [M+H]⁺。

Examples 116

[3- ({ 3- [3- (4-chlorophenyl) -1,2,4-Diazol-5-yl]-5-methyl-1H-pyrazol-1-yl } methyl) phenyl](4-methyl-piperazin-1-yl) methanone

In analogy to the procedure described under example 109, from 160mg (0.422 mmol) of the hydrochloride of the compound from example 105A and 86mg (0.507 mmol) of 4-chloro-N-hydroxybenzamidine are prepared 40mg (20% of theory, purity 98%) of the title compound. To remove the viscous formic acid, after purification by preparative HPLC, the product is dissolved in approximately 5ml of methanol and the solution is passed through a bicarbonate cartridge (Polymerlabs, Stratospheres SPE, PL-HCO) ₃MP SPE, capacity 0.9 mmol).

¹H-NMR (400 MHz, DMSO-d₆δ/ppm) 8.07 (d, 2H), 7.67 (d, 2H), 7.46 (t, 1H), 7.32 (d, 1H), 7.30 (d, 1H), 7.14 (s, 1H), 6.93 (s, 1H), 5.54 (s, 2H), 3.56 (Wide, 2H), 3.23 (Wide, 2H), 2.34 (s, 3H), 2.30 (Wide, 2H), 2.18 (Wide, 2H), 2.11 (s, 3H).

LC/MS (method D, ESIpos) R_t = 1.82 min, m/z = 477 [M+H]⁺。

Examples 117

(4-Methylpiperazin-1-yl) {3- [ (5-methyl-3- {3- [4- (tetrahydro-2-yl) methyl ] amideH-pyran-4-yl) phenyl]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl ketone

In analogy to the procedure described under example 110, from 125mg (0.330 mmol) of the hydrochloride of the compound from example 105A and 80mg (0.363 mmol) of the compound from example 113A 27mg (15% of theory, purity 96%) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.04 (d, 2H), 7.40-7.30 (m, 4H), 7.20 (d, 1H), 7.15 (s, 1H), 6.82 (s, 1H), 5.47 (s, 2H), 4.12-4.08 (m, 2H), 3.75 (Wide, 2H), 3.58-3.52 (m, 2H), 3.36 (Wide, 2H), 2.88-2.80 (m, 1H), 2.43 (Wide, 2H), 2.30 (s, 3H), 2.28 (Wide, 2H), 2.25 (s, 3H), 1.91-1.77 (m, 4H).

LC/MS (method F, ESIpos) R_t = 0.97 min, m/z = 527 [M+H]⁺。

Examples 118

(3- { [3- (3- {4- [1- (2-fluoroethyl) cyclobutyl)]Phenyl } -1,2,4-Oxadiazol-5-yl) -5-methyl-1 H-pyrazol-1-yl]Methyl } phenyl) (4-methylpiperazin-1-yl))

In analogy to the procedure described under example 110, from 140mg (0.370 mmol) of the hydrochloride of the compound from example 105A and 96mg (0.406 mmol) of the compound from example 113A 36mg (17% of theory, purity 95%) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.14 (d, 2H), 7.41-7.33 (m, 2H), 7.30-7.23 (m, 2H), 7.20 (d, 1H), 7.16 (s, 1H), 6.83 (s, 1H), 5.47 (s, 2H), 4.31 (td, 2H), 3.75 (width, 2H), 3.37 (width, 2H), 2.50-2.40 (m, 4H), 2.33-2.09 (m, 7H), 2.30 (s, 3H), 2.25 (s, 3H), 1.93-1.84 (m, 1H).

LC/MS (method I, ESIpos) R_t = 1.01 min, m/z = 543 [M+H]⁺。

Examples 119

(4-Methylpiperazin-1-yl) {3- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl ]]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl ketone hydrochloride

89mg (0.465 mmol) of EDC, 71mg (0.465 mmol) of HOBt and 59. mu.l (0.422 mmol) of triethylamine are successively added to 160mg (0.422 mmol) of the compound from example 105AThe hydrochloride salt of substance was dissolved in 2ml of anhydrous DMF. After stirring for 30min at RT, 112mg (0.507 mmol) of 3-trifluoromethoxy-N-a solution of hydroxybenzamidine in 2ml of anhydrous DMF. The reaction mixture was first stirred at RT for 1h and then at 140 ℃ for 1 h. After cooling to RT, the reaction mixture was separated directly into its components by preparative HPLC (method N). The product fractions were combined and evaporated to dryness. The residue obtained is dissolved in about 3ml of methanol and the solution is passed through a bicarbonate cartridge (Polymerlabs, Stratospheres SPE, PL-HCO) ₃MP SPE, capacity 0.9 mmol) to remove viscous formic acid by permeation. The product is then purified again by suction filtration (silica gel, mobile phase: dichloromethane/methanol 20: 1). After evaporation of the product fractions, the residue is dissolved in about 2ml of dichloromethane and about 5ml of hydrogen chloride in bis4M solution in alkane. After evaporation to dryness, the residue is redissolved in dichloromethane and hydrogen chloride is added again in the solvent4M solution in alkane. After re-evaporation and drying under high vacuum, 61mg (26% of theory, purity 90%) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆Delta/ppm) 10.38 (width, 1H), 8.11 (d, 1H), 7.95 (s, 1H), 7.77 (t, 1H), 7.65 (d, 1H), 7.49 (t, 1H), 7.41 (d, 1H), 7.33 (d, 1H), 7.30 (s, 1H), 5.56 (s, 2H), 3.73-3.64 (m, 4H), 3.50-3.44 (m, 2H), 3.41-3.28 (m, 2H), 3.12-3.01 (m, 2H), 2.78 (s, 3H), 2.37 (s, 3H).

LC/MS (method D, ESIpos) R_t = 1.92 min, m/z = 527 [M+H]⁺。

Examples 120

{3- [ (5-methyl-3- {3- [4- (tetrahydro-2))H-pyran-4-yl) phenyl]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl } (morpholin-4-yl) methanone

In analogy to the procedure described under example 32, from 80mg (0.180 mmol) of the compound from example 147A and 31. mu.l (0.360 mmol) of morpholine 81mg (88% of theory) of the title compound are obtained. The final permeation through the bicarbonate cartridge is omitted here.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.14 (d, 2H), 7.41-7.32 (m, 4H), 7.21 (d, 1H), 7.20 (s, 1H), 6.83 (s, 1H), 5.47 (s, 2H), 4.12-4.08 (m, 2H), 3.80-3.70 (wide, 4H), 3.61 (wide, 2H), 3.54 (dt, 2H), 3.40 (wide, 2H), 2.87-2.79 (m, 1H), 2.30 (s, 3H), 1.92-1.78 (m, 4H).

LC/MS (method F, ESIpos) R_t = 1.20 min, m/z = 514 [M+H]⁺。

Examples 121

(4-Methylpiperazin-1-yl) {3- [ (5-methyl-3- {3- [4- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) phenyl]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl } methanone (racemate)

In analogy to the procedure described under example 110, 500mg (1.32 mmol) of the hydrochloride salt of the compound from example 105A and 360mg (1.45 mmol) of the compound from example 114A are reacted to give 72mg (10% of theory, purity 97%) of the title compound. Deviations from the teaching mentioned are that the reaction mixture is worked up as follows: most of the solvent DMF was first removed on a rotary evaporator. About 50ml of water were added to the residue and the mixture was extracted three times with about 50ml of ethyl acetate each time. The combined organic extracts were washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, the crude product is prepurified by MPLC (approximately 100g silica gel, mobile phase: cyclohexane/ethyl acetate 1: 1). The product fractions were combined and the solvent was removed and subsequently purified by preparative HPLC as described.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.23 (d, 2H), 7.72 (d, 2H), 7.39 (t, 1H), 7.34 (d, 1H), 7.20 (d, 1H), 7.16 (s, 1H), 6.83 (s, 1H), 5.48 (s, 2H), 3.76 (Wide, 2H), 3.37 (Wide, 2H), 2.78 (Wide, 1H), 2.43 (Wide, 2H), 2.31 (s, 3H), 2.29 (Wide, 2H), 2.24 (s, 3H), 1.82 (s, 3H).

LC/MS (method I, ESIpos) R_t = 0.85 min, m/z = 555 [M+H]⁺。

Examples 122

(4-Methylpiperazin-1-yl) {3- [ (5-methyl-3- {3- [4- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) phenyl]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl } methanone (enantiomer 1)

62mg (0.108 mmol) of the racemic compound from example 121 are dissolved in 1ml of ethanol and the enantiomers are separated by chromatography on the chiral phase [ column packing material: daicel Chiralpak AD-H, 5 μm, 250 mm. times.20 mm; injection volume: 0.5 ml; flow rate: 15 ml/min; temperature: 40 ℃; and (4) UV detection: 220 nm; mobile phase: 50% isohexane, 49.8% ethanol, 0.2% diethylamine ]. 24mg (80% of theory, ee > 99.5%) of the title compound (enantiomer 1) and 27mg (90% of theory, ee > 99.5%) of the other enantiomer were obtained (example 123).

Analytical HPLC [ Daicel Chiralpak AD-H, 5 μm, 250 mm. times.4.6 mm; mobile phase: 40% isohexane, 59.8% ethanol, 0.2% diethylamine; flow rate: 1 ml/min; temperature: 40 deg.C ]：R_t=7.20min。

Examples 123

(4-Methylpiperazin-1-yl) {3- [ (5-methyl-3- {3- [4- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) phenyl]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl } methanone (enantiomer 2)

62mg (0.108 mmol) of the racemic compound from example 121 are dissolved in 1ml of ethanol and the enantiomers are separated by chromatography on the chiral phase [ column packing material: daicel Chiralpak AD-H, 5 μm, 250 mm. times.20 mm; injection volume: 0.5 ml; flow rate: 15 ml/min; temperature: 40 ℃; and (4) UV detection: 220 nm; mobile phase: 50% isohexane, 49.8% ethanol, 0.2% diethylamine ]. 27mg (90% of theory, ee > 99.5%) of the title compound (enantiomer 2) and 24mg (80% of theory, ee > 99.5%) of the other enantiomer are obtained (example 122).

Analytical HPLC [ DaicelChiralpak AD-H, 5 μm, 250mm × 4.6 mm; mobile phase: 40% isohexane, 59.8% ethanol, 0.2% diethylamine; flow rate: 1 ml/min; temperature: 40 deg.C]：R_t=9.26min。

Examples 124

{3- [ (3- {3- [4- (1-methoxycyclobutyl) phenyl group]-1,2,4-Oxadiazol-5-yl } -5-methyl-1H-pyrazol-1-yl) methyl]Phenyl } (4-methylpiperazin-1-yl) methanone

In analogy to the procedure described under example 41, from 100mg (0.292 mmol) of the compound from example 105A and 77mg (0.350 mmol) of the compound from example 25A 66mg (43% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.21 (d, 2H), 7.56 (d, 2H), 7.39 (t, 1H), 7.33 (d, 1H), 7.20 (d, 1H), 7.17 (s, 1H), 6.83 (s, 1H), 5.48 (s, 2H), 3.76 (wide, 2H), 3.37 (wide, 2H), 2.97 (s, 3H), 2.47-2.38 (m, 6H), 2.30 (s, 3H), 2.27 (wide, 2H), 2.26 (s, 3H), 2.02-1.93 (m, 1H), 1.78-1.67 (m, 1H).

HPLC (method A) R_t = 4.14 min.

MS (DCI, NH₃): m/z = 527 [M+H]⁺。

Examples 125

[3- ({ 5-methyl-3- [3- (4-tolyl) -1,2,4-Diazol-5-yl]-1H-pyrazol-1-yl } methyl) phenyl](4-methylpiperazin-1-yl) methanone

In analogy to the procedure described under example 119, starting from 160mg (0.422 mmol) of the hydrochloride of the compound from example 105A and 76mg (0.507 mmol) of 4-methyl-NHydroxybenzamidine to yield 48mg (25% of theory, purity 97%) of the title compound. A deviation from the teaching mentioned is that the subsequent chromatography over silica gel and conversion into the corresponding hydrochloride after permeation through the bicarbonate cartridge is omitted here.

¹H-NMR (400 MHz, DMSO-d₆δ/ppm) 7.96 (d, 2H), 7.46 (t, 1H), 7.40 (d, 2H), 7.32 (d, 1H), 7.30 (d, 1H), 7.13 (s, 1H), 6.93 (s, 1H), 5.54 (s, 2H), 3.56 (Wide, 2H), 3.23 (Wide, 2H), 2.40 (s, 3H), 2.34 (s, 3H), 2.30 (Wide, 2H), 2.18 (Wide, 2H), 2.11 (s, 3H).

LC/MS (method I, ESIpos) R _t = 0.87 min, m/z = 457 [M+H]⁺。

Examples 126

[3- ({ 3- [3- (4-fluorophenyl) -1,2,4-Diazol-5-yl]-5-methyl-1H-pyrazol-1-yl } methyl) phenyl](4-methylpiperazin-1-yl) methanone

In analogy to the procedure described under example 119, from 160mg (0.422 mmol) of the hydrochloride of the compound from example 105A and 78mg (0.507 mmol) of 4-fluoro-N-hydroxybenzamidine 45mg (23% of theory, purity 98%) of the title compound are obtained. A deviation from the teaching mentioned is that the subsequent chromatography over silica gel and conversion into the corresponding hydrochloride after permeation through the bicarbonate cartridge is omitted here.

¹H-NMR (400 MHz, DMSO-d₆δ/ppm) 8.12 (dd, 2H), 7.47-7.41 (m, 3H), 7.32 (d, 1H), 7.30 (d, 1H), 7.15 (s, 1H), 6.94 (s, 1H), 5.55 (s, 2H), 3.55 (Wide, 2H), 3.26 (Wide, 2H), 2.34 (s, 3H), 2.29 (Wide, 2H), 2.21 (Wide, 2H), 2.12 (s, 3H).

LC/MS (method I, ESIpos) R_t = 0.85 min, m/z = 461 [M+H]⁺。

Examples 127

Acetic acid (1- {4- [5- (5-methyl-1- {3- [ (4-methylpiperazin-1-yl) carbonyl)]Benzyl radical 1H-pyrazol-3-yl) -1,2,4-Diazol-3-yl]Phenyl } cyclobutyl) methyl formate salt

In analogy to the procedure described under example 110, from 300mg (0.792 mmol) of the hydrochloride salt of the compound from example 105A and 287mg (0.871 mmol) of the compound from example 115A 131mg (26% of theory, purity 95%) of the title compound are obtained. In this case no final permeation through the bicarbonate cartridge is performed.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.18 (s, 1H) 8.13 (d, 2H), 7.40 (t, 1H), 7.34 (d, 1H), 7.28 (d, 2H), 7.23 (d, 1H), 7.18 (s, 1H), 6.83 (s, 1H), 5.97 (s, 2H), 4.28 (s, 2H), 3.86 (wide, 2H), 3.51 (wide, 2H), 2.69 (wide, 2H), 2.47-2.38 (m, 2H), 2.39 (s, 3H), 2.33-2.27 (m, 2H), 2.30 (s, 3H), 2.22-2.08 (m, 1H), 1.99 (s, 3H), 1.97-1.88 (m, 1H).

LC/MS (method D, ESIpos) R_t = 1.90 min, m/z = 569 [M+H]⁺。

Examples 128

(3- { [3- (3- {4- [1- (2-hydroxyethyl) cyclobutyl ] butyl]Phenyl } -1,2,4-Oxadiazol-5-yl) -5-methyl-1H-pyrazol-1-yl]Methyl } phenyl) (4-methylpiperazin-1-yl) methanone

To a solution of 200mg (0.528 mmol) of the hydrochloride of the compound from example 105A in 5ml of anhydrous DMF were added 111mg (0.581 mmol) EDC, 89mg (0.581 mmol) HOBt and 110. mu.l (0.792 mmol) triethylamine and the mixture was stirred at RT for 30 min. A solution of 160mg (0.581 mmol) of the compound from example 116A in 2ml of anhydrous DMF is then added and stirring is continued at RT for 1 h. After this time, the reaction batch was immersed in an oil bath preheated to 140 ℃ and left there for 1 h. After cooling to RT, most of the solvent was stripped off on a rotary evaporator. To the residue obtained 50ml of water were added and the mixture was extracted three times with approximately 50ml of ethyl acetate each time. The combined organic extracts were washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the solvent is removed on a rotary evaporator and the residue is separated into its components by preparative HPLC (method N). Slightly contaminated fractions of the title compound (13 mg) and the corresponding acetate ester (27 mg) were obtained. The last mentioned fraction was dissolved in 1ml ethanol and 100. mu.l of 1M sodium hydroxide solution was added. After stirring for 1h at RT, the mixture was neutralized by addition of 90 μ l of 1M hydrochloric acid and concentrated to dryness on a rotary evaporator. The residue was combined with 13mg of the product fractions obtained above and the mixture was then purified again by MPLC (silica gel, mobile phase: cyclohexane/ethyl acetate 20: 1 → 1: 1). 26mg (9% of theory, purity 93%) of the title compound are obtained in this way.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.13 (d, 2H), 7.39 (t, 1H), 7.33 (d, 1H), 7.25 (d, 2H), 7.20 (d, 1H), 7.15 (s, 1H), 6.83 (s, 1H), 5.47 (s, 2H), 3.75 (Wide, 2H), 3.47 (t, 2H), 3.36 (Wide, 2H), 2.47-2.39 (m, 4H), 2.29 (s, 3H), 2.28 (Wide, 2H), 2.25 (s, 3H), 2.24 (Wide, 2H), 2.19-2.10 (m, 1H), 2.14 (t, 2H), 1.92-1.83 (m, 1H).

LC/MS (method I, ESIpos) R_t = 0.86 min, m/z = 541 [M+H]⁺。

Examples 129

(3- { [3- (3- {4- [1- (hydroxymethyl) cyclobutyl)]Phenyl } -1,2,4-Oxadiazol-5-yl) -5-methyl-1H-pyrazol-1-yl]Methyl } phenyl) (4-methylpiperazin-1-yl) methanone

To a solution of 125mg (0.203 mmol) of the compound from example 127 in 5ml of ethanol was added 0.5ml of 1M sodium hydroxide solution and the mixture was stirred at RT for 30 min. The reaction mixture was then separated directly into its components by preparative HPLC (method N). Combined product gradeSeparated and concentrated to dryness on a rotary evaporator. The viscous formic acid residue is dissolved in about 5ml of methanol for purification by HPLC and the solution is passed through a bicarbonate cartridge (Polymerlabs, Stratospheres SPE, PL-HCO)₃MP SPE, capacity 0.9 mmol). After concentration and drying, 93mg (85% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.16 (d, 2H), 7.39 (t, 1H), 7.33 (d, 1H), 7.27 (d, 2H), 7.20 (d, 1H), 7.15 (s, 1H), 6.83 (s, 1H), 5.48 (s, 2H), 3.80 (d, 2H), 3.77 (wide, 2H), 3.35 (wide, 2H), 2.49-2.33 (m, 4H), 2.29 (s, 3H), 2.28 (wide, 4H), 2.25 (s, 3H), 2.17-2.06 (m, 1H), 1.97-1.88 (m, 1H), 1.29 (t, 1H).

LC/MS (method I, ESIpos) R_t = 0.84 min, m/z = 527 [M+H]⁺。

Examples 130

{3- [ (5-methyl-3- {3- [ 3-methyl-4- (tetrahydro-2)H-pyran-4-yl) phenyl]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl } (4-methylpiperazin-1-yl) methanone

In analogy to the procedure described under example 110, 220mg (0.581 mmol) of the hydrochloride salt of the compound from example 105A and 150mg (0.639 mmol) of the compound from example 108A were reacted to give 57mg (17% of theory) of the title compound.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.02-8.00 (m, 2H), 7.41-7.33 (m, 3H), 7.20 (d, 1H), 7.15 (s, 1H), 6.83 (s1H), 5.47 (s, 2H), 4.13-4.10 (m, 2H), 3.77 (wide, 2H), 3.60-3.54 (m, 2H), 3.37 (wide, 2H), 3.07-3.00 (m, 1H), 2.45 (wide, 2H), 2.43 (s, 3H), 2.30 (s, 3H), 2.29 (wide, 2H), 2.27 (s, 3H), 1.92-1.81 (m, 2H), 1.73-1.69 (m, 2H).

LC/MS (method I, ESIpos) R_t = 0.89 min, m/z = 541 [M+H]⁺。

Examples 131

N,N-dimethyl-2- (1- {4- [5- (5-methyl-1- {3- [ (4-methylpiperazin-1-yl) carbonyl)]Benzyl radical 1H-pyrazol-3-yl) -1,2,4-Diazol-3-yl]Phenyl } cyclobutyl) acetamide

In analogy to the procedure described under example 121, 300mg (0.792 mmol) of the hydrochloride salt of the compound from example 105A and 300mg (0.871 mmol) of the compound from example 117A were reacted to yield 68mg (15% of theory) of the title compound. After permeation through a bicarbonate cartridge for purification by HPLC to remove viscous formic acid, the product was finally purified by stirring with ethanol.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.11 (d, 2H), 7.38 (t, 1H), 7.33 (d, 1H), 7.31 (d, 2H), 7.20 (d, 1H), 7.15 (s, 1H), 6.82 (s, 1H), 5.47 (s, 2H), 3.76 (wide, 2H), 3.36 (wide, 2H), 2.83 (s, 2H), 2.73 (s, 3H), 2.60-2.52 (m, 2H), 2.51-2.40 (m, 4H), 2.35 (s, 3H), 2.30 (s, 3H), 2.28 (wide, 2H), 2.25 (s, 3H), 2.22-2.10 (m, 1H), 1.93-1.83 (m, 1H).

LC/MS (method I, ESIpos) R_t = 0.85 min, m/z = 582 [M+H]⁺。

Examples 132

(3- { [3- (3- {4- [ (diisopropylamino) methyl group)]Phenyl } -1,2,4-Oxadiazol-5-yl) -5-methyl-1H-pyrazol-1-yl]Methyl } phenyl) (4-methylpiperazin-1-yl) methanone

In analogy to the procedure described under example 41, 100mg (0.292 mmol) of the compound from example 105A and 73mg (0.292 mmol) of the compound from example 118A were reacted to give 45mg (28% of theory) of the title compound. The DMSO contained in the mixture was removed by freeze-drying before the reaction mixture was purified by preparative HPLC (method O).

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.03 (d, 2H), 7.50-7.40 (m, 2H), 7.33-7.23 (m, 2H), 7.12 (d, 1H), 7.08 (s, 1H), 6.75 (s, 1H), 5.40 (s, 2H), 3.75-3.60 (m, wide, 4H), 3.35-3.25 (m, wide, 2H), 3.06-2.93 (m, wide, 2H), 2.42-2.30 (m, wide, 2H), 2.30-2.18 (m, wide, 2H), 2.22 (s, 3H), 2.20 (s, 3H), 1.08-0.89 (m, 12H).

LC/MS (method I, ESIpos) R_t = 0.62 min, m/z = 556 [M+H]⁺。

Examples 133

(4-Methylpiperazin-1-yl) {3- [ (5-methyl-3- {3- [4- (trifluoromethyl) phenyl ] methyl ester]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl ketone

In analogy to the procedure described under example 41, 100mg (0.292 mmol) of the compound from example 105A and 60mg (0.292 mmol) of N' -hydroxy-4- (trifluoromethyl) -benzoylimide amide are reacted to give 56mg (38% of theory) of the title compound. The DMSO contained in the mixture was removed by freeze-drying before the reaction mixture was purified by preparative HPLC (method O).

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.32 (d, 2H), 7.77 (d, 2H), 7.41-7.33 (m, 2H), 7.22-7.16 (m, 2H), 6.83 (s, 1H), 5.49 (s, 2H), 3.77 (s, width, 2H), 3.37 (s, width, 2H), 2.43 (s, width, 2H), 2.31 (s, 3H), 2.33-2.23 (m, 2H), 2.28 (s, 3H).

LC/MS (method I, ESIpos) R_t = 0.93 min, m/z = 511 [M+H]⁺。

Examples 134

(4-Methylpiperazin-1-yl) {3- [ (5-methyl-3- {3- [4- (trimethylsilyl) phenyl ] methyl ester]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl ketone

At 0 ℃ 100mg (0.292 mmol) of the compound from example 105A are initially added to 3ml of dichloromethane, one drop of DMF is added and then 76. mu.l (0.876 mmol) of oxalyl chloride are added dropwise. The mixture was stirred at RT for 1h and then concentrated and the residue was dried in vacuo. The residue is then dissolved again in 2ml of dichloromethane and this solution is added at 0 ℃ to a mixture of 68mg (0.292 mmol, 90% purity) of the compound from example 17A and 81. mu.l (0.584 mmol) of triethylamine in 1ml of dichloromethane. The mixture was stirred at RT for 1h and concentrated again and the residue was dried in vacuo. The residue was then dissolved in 3ml DMSO and the solution was heated in a microwave apparatus (CEM Discover, initial radiant power 250W) for 30min at 120 ℃. After cooling to RT, the reaction mixture is purified directly by preparative HPLC (method O). The product fractions were combined and concentrated to the remaining volume of water. Saturated aqueous sodium bicarbonate was added and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate phases were dried over magnesium sulfate, filtered and concentrated. After the residue has been dried in vacuo, 76mg (50% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.18 (d, 2H), 7.65 (d, 2H), 7.41-7.32 (m, 2H), 7.21 (d, 1H), 7.17 (s, 1H), 6.82 (s, 1H), 5.49 (s, 2H), 3.78 (s, wide, 2H), 3.38 (s, wide, 2H), 2.45 (s, wide, 2H), 2.31 (s, 3H), 2.33-2.23 (m, 2H), 2.28 (s, 3H), 0.31 (s, 9H).

LC/MS (method I, ESIpos) R_t = 1.03 min, m/z = 515 [M+H]⁺。

Examples 135

(3- { [ 5-methyl-3- (3- {4-, [ 2 ])N-methyl-S- (trifluoromethyl) sulphoimides]Phenyl } -1,2,4-Oxadiazol-5-yl) -1H-pyrazol-1-yl]Methyl } phenyl) (4-methylpiperazin-1-yl) methanone (racemate)

162mg (0.427 mmol) of the compound from example 105A are initially added to 4ml of dichloromethane, 0.74ml (8.53 mmol) of oxalyl chloride are added and the mixture is stirred at RT for 1 h. The mixture was then concentrated and the residue was dried in vacuo. The residue is then dissolved in 2ml of dichloromethane, a solution of 120mg (0.427 mmol) of the compound from example 119A and 0.18ml (1.28 mmol) of triethylamine in 1ml of dichloromethane is added and the mixture is stirred at RT for 1 h. The mixture was then concentrated and the residue was dried in vacuo. The residue was then dissolved in 3ml DMSO and the solution was heated at 120 ℃ for 1.5h while stirring. After cooling to RT, the reaction mixture is purified directly by preparative HPLC (method O). The combined product fractions were concentrated to the remaining volume of the small aqueous phase, saturated aqueous sodium bicarbonate solution was added and the mixture was extracted three times with ethyl acetate. The combined ethyl acetate phases were dried over sodium sulfate, filtered and concentrated. After drying of the residue, 48mg (19% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.44 (d, 2H), 8.21 (d, 2H), 7.44-7.30 (m, 2H), 7.23-7.13 (m, 2H), 6.85 (s, 1H), 5.48 (s, 2H), 3.76 (s, width, 2H), 3.37 (s, width, 2H), 3.12 (s, 3H), 2.50-2.36 (m, 2H), 2.35-2.25 (m, width, 2H), 2.30 (s, 3H), 2.27 (s, 3H).

LC/MS (method I, ESIpos) R_t = 0.94 min, m/z = 588 [M+H]⁺。

Examples 136

{3- [ (3- {3- [ 3-chloro-4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -5-methyl-1H-pyrazol-1-yl) methyl]Phenyl } (4-methylpiperazin-1-yl) methanone

In analogy to the procedure described under example 41, 200mg (0.528 mmol) of the compound from example 105A and 134mg (0.528 mmol) of the compound from example 120A are reacted to yield 11.2mg (4% of theory) of the title compound.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.37 (d, 1H), 8.19-8.05 (m, 1H), 7.49-7.30 (m, 3H), 7.23-7.11 (m, 2H), 6.83 (s, 1H), 5.48 (s, 2H), 3.80 (s, width, 2H), 3.42 (s, width, 2H), 2.60-2.30 (m, width, 4H), 2.32 (s, 3H), 2.30 (s, 3H).

LC/MS (method I, ESIpos) R_t = 1.01 min, m/z = 561/563 [M+H]⁺。

Examples 137

(4-Methylpiperazin-1-yl) (3- { [ 5-methyl-3- (3- {4- [1- (trifluoromethyl) cyclopropyl ] methyl]Phenyl } -1,2,4-Oxadiazol-5-yl) -1H-pyrazol-1-yl]Methyl } phenyl) methanones

450mg (1.19 mmol) of the compound from example 105A are initially added to 12ml of dichloromethane at 0 ℃, a drop of DMF is added and then 311. mu.l (3.56 mmol) of oxalyl chloride are added dropwise. The mixture was stirred at RT for 1h and then concentrated and the residue was dried in vacuo. The residue is then taken up in 8ml of dichloromethane and the solution is added at 0 ℃ to a mixture of 290mg (1.19 mmol) of the compound from example 121A and 331. mu.l (2.38 mmol) of triethylamine in 4ml of dichloromethane. The mixture was stirred at RT for 1h and then concentrated and the residue was dried in vacuo. The residue was then dissolved in 12ml DMSO and the mixture was heated in a microwave apparatus (CEM Discover, initial radiant power 250W) for 30min at 120 ℃. After cooling, the reaction mixture was purified directly by preparative HPLC (method O). The combined product fractions were concentrated to the remaining volume of the aqueous phase. Saturated aqueous sodium bicarbonate was added and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate phases were dried over magnesium sulfate, filtered and concentrated. After the residue has been dried in vacuo, 109mg (17% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.10 (d, 2H), 7.52 (d, 2H), 7.38-7.23 (m, 2H), 7.18-7.05 (m, 2H), 6.76 (s, 1H), 5.40 (s, 2H), 3.70 (s, width, 2H), 3.30 (s, width, 2H), 2.49-2.07 (m, 4H), 2.22 (s, 3H), 2.19 (s, 3H), 1.34 (s, width, 2H), 1.02 (s, width, 2H).

LC/MS (method I, ESIpos) R_t = 0.97 min, m/z = 551 [M+H]⁺。

Examples 138

[3- ({ 3- [5- (4-cyclopropylphenyl) -1,2, 4-)Diazol-3-yl]-5-methyl-1H-pyrazol-1-yl } methyl) phenyl](4-methylpiperazin-1-yl) methanone

To 2ml of dichloromethane 68mg (0.421 mmol) of 4-cyclopropylbenzoic acid are initially added, a drop of DMF is added and the mixture is cooled to 0 ℃. Then 160mg (1.26 mmol) of oxalyl chloride are added at this temperature and the mixture is subsequently stirred at 40 ℃ for 20 min. Thereafter 5ml of dichloromethane were added, the mixture was concentrated and the residue was dried in vacuo. The residue is taken up in 3ml of dichloromethane and the mixture is added at RT to a mixture of 150mg (0.421 mmol) of the compound from example 148A and 140. mu.l of triethylamine in 5ml of dichloromethane. The mixture was stirred at RT for 3h and concentrated again and the residue was dried in vacuo. The residue was then dissolved in 2ml of anhydrous DMSO and the solution was heated in a microwave apparatus (CEM Discover, initial radiant power 250W) for 1h at 140 ℃. After cooling to RT, 60ml of water are added and the mixture is extracted three times with 30ml of ethyl acetate each time. The combined ethyl acetate phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is taken up in acetonitrile and purified by preparative HPLC (method O). The combined product fractions were concentrated to the remaining volume of the aqueous phase, saturated aqueous sodium bicarbonate solution was added and the mixture was extracted three times with approximately 30ml of dichloromethane each time. The combined dichloromethane phases were washed once with water, dried over magnesium sulfate, filtered and concentrated. After the residue has been dried in vacuo, 65mg (32% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.13 (d, 2H), 7.44-7.30 (m, 2H), 7.23-7.15 (m, 3H), 7.12 (s, 1H), 6.74 (s, 1H), 5.47 (s, 2H), 3.82-3.58 (m, 4H), 3.45-3.28 (s, width, 2H), 2.54-2.34 (m, 2H), 2.28 (s, 3H), 2.22 (s, 3H), 2.04-1.90 (m, 1H), 1.14-1.01 (m, 2H), 0.85-0.74 (m, 2H).

LC/MS (method I, ESIpos) R_t = 0.91 min, m/z = 483 [M+H]⁺。

Examples 139

(3- { [3- (3- {4- [4- (fluoromethyl) tetrahydro-2)H-pyran-4-yl]Phenyl } -1,2,4-Oxadiazol-5-yl) -5-methyl-1H-pyrazol-1-yl]Methyl } phenyl) (4-methylpiperazin-1-yl) methanone

To the hydrochloride of the compound from example 105A, 100mg (0.26 mmol) in 2.6ml DMF were added in succession 74. mu.l (0.53 mmol) triethylamine, 51mg (0.26 mmol) EDC and 40mg (0.26 mmol) HOBt. After stirring for 10min at RT, 66mg (0.26 mmol) of the compound from example 123A were added and the mixture was first stirred for a further 10min at RT and then heated for 30min at 140 ℃. After cooling, the reaction mixture is purified directly by preparative HPLC (method P). 7.0mg (5% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆δ/ppm) 8.01 (d, 2H), 7.44 (m, 3H), 7.32 (t, 2H), 7.15 (s, 1H), 6.94 (s, 1H), 5.55 (s, 2H), 3.72 (d, width, 2H), 3.62-3.45 (m, width, 4H), 3.24 (m, width, 2H), 3.05 (d, 2H), 2.34 (s, 3H), 2.37-2.12 (m, width, 4H), 2.12 (s, 3H), 1.84-1.65 (m, 2H), 1.59 (t, 2H).

LC/MS (method D, ESIpos) R_t = 1.75 min, m/z = 559 [M+H]⁺。

Examples 140

1- ({ 3- [ (5-methyl-3- {3- [4- (1, 1, 1-trifluoro-2-methylpropan-2-yl) phenyl)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl } sulfonyl) piperidin-4-ol

To a solution of 95mg (0.28 mmol) of the compound from example 29A and 35mg (0.31 mmol) of potassium tert-butoxide in 3ml of THF were added a solution of 162mg (0.34 mmol) of the compound from example 136A in 1ml of THF while cooling in an ice bath, and the mixture was then stirred at RT overnight. It was then diluted with ethyl acetate and magnesium sulfate was added. After filtration, the filtrate is freed of solvent on a rotary evaporator and the residue obtained is purified by preparative HPLC (method P). 77mg (38% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 8.09 (d, 2H), 7.77 (d, 2H), 7.70-7.60 (m, 3H), 7.49 (d, 1H), 6.96 (s, 1H), 5.66 (s, 2H), 4.65 (d, 1H), 3.50 (m, 1H), 3.11 (m, 2H), 2.69 (m, 2H), 2.35 (s, 3H), 1.69 (m, 2H), 1.61 (s, 6H), 1.40 (m, 2H).

LC/MS (method I) R_t = 1.24 min, m/z = 590 [M+H]⁺。

Examples 141

1-methyl-4- ({ 3- [ (5-methyl-3- {3- [4- (1, 1, 1-trifluoro-2-methylpropan-2-yl) phenyl]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl } sulfonyl) piperazines

In analogy to the procedure described under example 140, from 140mg (0.42 mmol) of the compound from example 29A and 1.0ml (approx. 0.5 mmol) of the intermediate solution obtained in example 137A in THF are obtained 126mg (43% of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 8.09 (d, 2H), 7.77 (d, 2H), 7.69-7.64 (m, 2H), 7.57 (s, 1H), 7.53 (d, 1H), 6.97 (s, 1H), 5.66 (s, 2H), 2.84 (s, 4H), 2.35 (s, 3H), 2.29 (s, 4H), 2.07 (s, 3H), 1.61 (s, 6H).

LC/MS (method I) R_t = 1.02 min, m/z = 589 [M+H]⁺。

Examples 142

1-methyl-4- ({ 3- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenyl } sulfonyl) piperazines

In analogy to the procedure described under example 140, from 129mg (0.42 mmol) of the compound from example 28A and 1.0ml (approx. 0.5 mmol) of the intermediate solution obtained in example 137A in THF were obtained 75mg (27% of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 8.20 (d, 2H), 7.69-7.64 (m, 2H), 7.61 (s, 1H), 7.58 (d, 2H), 7.53 (d, 1H), 6.96 (s, 1H), 5.66 (s, 2H), 2.84 (s, 4H), 2.36 (s, 3H), 2.29 (s, 4H), 2.07 (s, 3H).

LC/MS (method I) R_t = 0.98 min, m/z = 563 [M+H]⁺。

Examples 143

[3- ({ 4- [3- (4-tert-butylphenyl) -1,2,4-Diazol-5-yl]-2-methyl-1H-pyrrol-1-yl } methyl) phenyl](4-methylpiperazin-1-yl) methanone

To 100mg (0.281 mmol) of the compound from example 106A/step 3 and 60mg (0.309 mmol) of 4-tert-butyl-N'To a suspension of hydroxybenzamidine in 3ml of ethanol is added 100mg (0.309 mmol) of a 21% strength solution of sodium ethoxide in mineral ethanol. The mixture was heated in a microwave oven (CEM Discover, initial radiant power 250W) at 160 ℃ for 30 min. After cooling to RT, the reaction batch was separated directly into its components by preparative HPLC (method N). The product fractions were combined and concentrated to dryness on a rotary evaporator. For purification by HPLC to remove viscous formic acid, the residue obtained is dissolved in approximately 5ml of methanol and the solution is passed through a bicarbonate cartridge (Polymerlabs, Stratospheres SPE, PL-HCO) ₃MP SPE, capacity 0.9 mmol). After concentration and drying, 6.4mg (5% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.03 (d, 2H), 7.49 (d, 2H), 7.48 (s, 1H), 7.39 (t, 1H), 7.33 (d, 1H), 7.09 (d, 1H), 7.08 (s, 1H), 6.58 (s, 1H), 5.11 (s, 2H), 3.76 (wide, 2H), 3.37 (wide, 2H), 2.44 (wide, 2H), 2.28 (wide, 2H), 2.26 (s, 3H), 2.19 (s, 3H), 1.35 (s, 9H).

LC/MS (method I, ESIpos) R_t = 1.06 min, m/z = 498 [M+H]⁺。

Examples 144

(4-Methylpiperazin-1-yl) {3- [ (2-methyl-4- {3- [4- (1, 1, 1-trifluoro-2-methylpropan-2-yl) phenyl]-1,2,4-Oxadiazol-5-yl } -1H-pyrrol-1-yl) methyl]Phenyl ketone

In analogy to the procedure described under example 41, 100mg (0.293 mmol) of the compound from example 106A and 79mg (0.322 mmol) of the compound from example 1A are reacted to yield 21mg (13% of theory) of the title compound.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.10 (d, 2H), 7.60 (d, 2H), 7.48 (s, 1H), 7.39 (t, 1H), 7.33 (d, 1H), 7.10 (d, 1H), 7.09 (s, 1H), 6.59 (s, 1H), 5.12 (s, 2H), 3.77 (Wide, 2H), 3.37 (Wide, 2H), 2.44 (Wide, 2H), 2.28 (Wide, 2H), 2.26 (s, 3H), 2.19 (s, 3H), 1.62 (s, 6H).

LC/MS (method F, ESIpos) R_t = 1.21 min, m/z = 552 [M+H]⁺。

Examples 145

(4-Methylpiperazin-1-yl) {3- [ (2-methyl-4- {3- [4- (trimethylsilyl) phenyl ] methyl ester ]-1,2,4-Oxadiazol-5-yl } -1H-pyrrol-1-yl) methyl]Phenyl ketone

In analogy to the procedure described under example 41, 100mg (0.293 mmol) of the compound from example 106A and 67mg (0.322 mmol) of the compound from example 17A are reacted to yield 11mg (7.4% of theory) of the title compound.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.08 (d, 2H), 7.62 (d, 2H), 7.49 (s, 1H), 7.39 (t, 1H), 7.33 (d, 1H), 7.10 (d, 1H), 7.09 (s, 1H), 6.59 (s, 1H), 5.12 (s, 2H), 3.76 (wide, 2H), 3.37 (wide, 2H), 2.43 (wide, 2H), 2.29 (wide, 2H), 2.25 (s, 3H), 2.19 (s, 3H), 0.30 (s, 9H).

LC/MS (method F, ESIpos) R_t = 1.27 min, m/z = 514 [M+H]⁺。

Examples 146

{3- [ (4- {3- [4- (4-Fluorotetrahydro-2-yl) tetrahydro-2)H-pyran-4-yl) phenyl]-1,2,4-Oxadiazol-5-yl } -2-methyl-1H-pyrrol-1-yl) methyl]Phenyl } (4-methylpiperazin-1-yl) methanone

In analogy to the procedure described under example 41, 120mg (0.351 mmol) of the compound from example 106A and 92mg (0.387 mmol) of the compound from example 7A are reacted to give 20mg (10% of theory) of the title compound.

¹H-NMR (400 MHz, CDCl₃Delta/ppm) 8.14 (d, 2H), 7.50 (d, 2H), 7.49 (s, 1H), 7.39 (t, 1H), 7.33 (d, 1H), 7.10 (d, 1H), 7.09 (s, 1H), 6.59 (s, 1H), 5.12 (s, 2H), 3.99-3.86 (m, 4H), 3.76 (width) 2H), 3.37 (wide, 2H), 2.44 (wide, 2H), 2.29 (wide, 2H), 2.26 (s, 3H), 2.23-2.10 (m, 2H), 2.18 (s, 3H), 1.97-1.91 (m, 2H).

LC/MS (method I, ESIpos) R_t = 0.90 min, m/z = 544 [M+H]⁺。

Examples 147

(4-Methylpiperazin-1-yl) {3- [ (2-methyl-4- {3- [4- (trifluoromethyl) phenyl ] methyl ester]-1,2,4-Oxadiazol-5-yl } -1H-pyrrol-1-yl) methyl]Phenyl ketone

In analogy to the procedure described under example 41, 120mg (0.351 mmol) of the compound from example 106A and 79mg (0.387 mmol) of 4-trifluoromethyl-N'-hydroxybenzamidine to yield 15mg (8.4% of theory) of the title compound.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.25 (d, 2H), 7.74 (d, 2H), 7.49 (s, 1H), 7.40 (t, 1H), 7.33 (d, 1H), 7.11-7.08 (m, 2H), 6.59 (s, 1H), 5.13 (s, 2H), 3.77 (wide, 2H), 3.37 (wide, 2H), 2.43 (wide, 2H), 2.29 (wide, 2H), 2.27 (s, 3H), 2.20 (s, 3H).

LC/MS (method I, ESIpos) R_t = 0.99 min, m/z = 510 [M+H]⁺。

Examples 148

1-methyl-4- {3- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Phenoxy } piperidines

To a solution of 69mg (0.264 mmol) of triphenylphosphine and 52. mu.l (0.264 mmol) of diisopropyl azodicarboxylate (DIAD) in 3ml of anhydrous THF are initially added 30mg (0.264 mmol) of 4-hydroxy-1-methylpiperidine and, after 5min, 100mg (0.240 mmol) of the compound from example 95A. After the reaction mixture had been stirred at RT for 16h, the same amount of DIAD was added again. After a further 5 days at RT, a further 30mg (0.264 mmol) of 4-hydroxy-1-methylpiperidine are added. After a further 16h at RT, 1ml of water and about 3ml of DMF are added to the reaction mixture. This solution was separated directly into its components by preparative HPLC (method N). The product fractions were combined and the solvent was removed on a rotary evaporator. The product obtained in this way is subsequently purified again by MPLC (silica gel, mobile phase: dichloromethane/methanol 10: 1). 32mg (26% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.25 (d, 2H), 7.33 (d, 2H), 7.22 (t, 1H), 6.82 (d, 1H), 6.81 (s, 1H), 6.72 (d, 1H), 6.71 (s, 1H), 5.40 (s, 2H), 4.31-4.24 (m, 1H), 2.69 (Wide, 2H), 2.30 (s, 3H), 2.29 (Wide, 2H), 2.28 (s, 3H), 1.98 (Wide, 2H), 1.81 (Wide, 2H).

HPLC (method A) R_t = 4.41 min.

LC/MS (method I, ESIpos) R_t = 0.99 min, m/z = 514 [M+H]⁺。

Examples 149

2- [4- (methoxymethyl)Piperidin-1-yl radical]-4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridine compound

445mg (3.44 mmol) of 4- (methoxymethyl) pyridine and 100mg (0.229 mmol) of the compound from example 81A were heated in a microwave oven (Biotage Initiator 2.5, automatic control of the radiation power) at 160 ℃ for 3h without addition of solvent. After cooling to RT, the reaction mixture was taken up in about 2ml of methanol. This solution was separated directly into its components by preparative HPLC (method N). The product fractions were combined and the solvent was removed and the residue was stirred with pentane. 77mg (60% of theory, approximately 94% pure) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.25 (d, 2H), 8.11 (d, 1H), 7.33 (d, 2H), 6.83 (s, 1H), 6.35 (s, 1H), 6.29 (d, 1H), 5.33 (s, 2H), 4.26-4.20 (m, 2H), 3.33 (s, 3H), 3.23 (d, 2H), 2.83-2.77 (m, 2H), 2.29 (s, 3H), 1.88-1.77 (m, 3H), 1.29-1.18 (m, 2H).

LC/MS (method I, ESIpos) R_t = 1.09 min, m/z = 529 [M+H]⁺。

Examples 150

2- (4-Methoxypiperidin-1-yl) -4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl ] ]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridine compound

1.06g (9.18 mmol) of 4-methoxypyridine and 200mg (0.229 mmol) of the compound from example 81A were heated in a microwave oven (Biotage Initiator 2.5, automatic control of the radiation power) at 160 ℃ for 3h without addition of solvent. After cooling to RT, about 50ml of water were added to the reaction mixture and the mixture was extracted three times with about 50ml of ethyl acetate each time. The combined organic extracts were washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and the filtrate was freed of the solvent on a rotary evaporator. The crude product was purified by MPLC (approximately 50g silica gel, mobile phase: cyclohexane/ethyl acetate 3: 1 → 1: 1). 167mg (70% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.26 (d, 2H), 8.11 (d, 1H), 7.33 (d, 2H), 6.83 (s, 1H), 6.36 (s, 1H), 6.31 (d, 1H), 5.33 (s, 2H), 3.93-3.87 (m, 2H), 3.44-3.38 (m, 1H), 3.37 (s, 3H), 3.21-3.14 (m, 2H), 2.29 (s, 3H), 1.97-1.90 (m, 2H), 1.63-1.54 (m, 2H).

LC/MS (method I, ESIpos) R_t = 1.10 min, m/z = 515 [M+H]⁺。

Examples 151

6- {4- [ (5-methyl-3- {3- [4- (trifluoromethoxy) phenyl group)]-1,2,4-Oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl]Pyridin-2-yl } -2-oxa-6-azaspiro [3.3]Heptane (Heptane)

662mg (2.30 mmol) 2-oxa-6-azaspiro [3.3]Heptane hemioxalate [ M, Roger-Evans et al,Angew. Chem. Intl. Ed. Engl. 2008，47 （ 24 ），4512-4515]100mg (0.229 mmol) of the compound from example 81A and 0.8ml (4.59 mmol)N,NDiisopropylethylamine was dissolved in 2.5ml of methanol and the solution was first automatically controlled to 140 ℃ in a microwave oven (Biotage Initiator 2.5, automatic control of the radiation power). When this temperature was reached, the temperature was manually increased to 160 ℃. After 15h at 160 ℃ the mixture was allowed to cool to RT. The reaction mixture was diluted with a further approximately 3ml of methanol and separated directly into its components by preparative HPLC (method N). The product fractions were combined and the solvent was removed on a rotary evaporator. For further purification, the residue is then chromatographed on a Chromabond cartridge (1.5 g of silica gel, mobile phase: cyclohexane/ethyl acetate 1: 1 → 1: 5). 22mg (19% of theory) of the title compound are obtained in this way.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.25 (d, 2H), 8.09 (d, 1H), 7.34 (d, 2H), 6.83 (s, 1H), 6.37 (d, 1H), 5.95 (s, 1H), 5.33 (s, 2H), 4.81 (s, 4H), 4.13 (s, 4H), 2.28 (s, 3H).

LC/MS (method D, ESIpos) R_t = 1.89 min, m/z = 499 [M+H]⁺。

Examples 152

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

In analogy to the procedure described under example 149 493mg (3.44 mmol) 2- (piperidin-4-yl) propan-2-ol and 100mg (0.229 mmol) of the compound from example 81A are reacted to yield 40mg (32% of theory) of the title compound. The product obtained after purification by preparative HPLC is finally stirred with ethanol (instead of pentane).

¹H-NMR (400 MHz, CDCl₃δ/ppm) 8.25 (d, 2H), 8.11 (d, 1H), 7.33 (d, 2H), 6.83 (s, 1H), 6.35 (s, 1H), 6.30 (d, 1H), 5.33 (s, 2H), 4.36-4.30 (m, 2H), 2.77-2.70 (m, 2H), 2.29 (s, 3H), 1.87-1.80 (m, 2H), 1.53-1.47 (m, 1H), 1.38-1.28 (m, 2H), 1.23 (s, width, 1H), 1.18 (s, 6H).

LC/MS (method I, ESIpos) R_t = 1.03 min, m/z = 543 [M+H]⁺。

B. Evaluation of pharmacological Activity

The pharmacological activity of the compounds according to the invention can be shown, for example, by in vitro and in vivo tests known to the person skilled in the art. The benefits of the substances according to the invention can be demonstrated, for example, by in vitro (tumor) cell experiments and in vivo tumor models, which are described below. The relationship between inhibition of HIF transcriptional activity and inhibition of tumor growth has been shown by a number of studies described in the literature (see, e.g., Warburg, 1956; Semenza, 2007).

B-1. HIF- Luciferase assay

HCT 116 cells were transfected in a stable manner with plasmids containing luciferase indicators under control of HIF-responsive sequences. These cell species were plated in microtiter plates [ 20,000 cells/well in RPMI 1640 medium with 10% Fetal Calf Serum (FCS) and 100. mu.g/ml hygromycin]In (1). Under standard conditions (5% CO)₂，21% O₂37 ℃ and humidified) was cultured overnight. The following morning the cells were treated with various concentrations of test substances (0-10. mu. mol/L) in a hypoxic chamber (1% O)₂) Culturing in medium. After 24h, Bright Glo reagent (Promega, Wis. Corstar, USA) was added according to the manufacturer's instructions and the luminescence was measured after 5 min. Cells cultured under normoxia served as background controls.

IC from the experiments of representative embodiment examples₅₀The values are listed in the following table:

example No. 2	IC₅₀ [nmol/l]
		16	4
18	5
		21	10
35	2
		41	6
45	10
		52	3
65	0.6
		71	1
72	1
		75	1
77	1
		78	0.5
85	2
		86	4
91	0.6
		93	0.8
100	2.5
		119	20
137	3
		140	4
150	3

B-2. In vitro HIF Inhibition of target genes

Human bronchial lung cancer cells (H460 and A549) were incubated with varying concentrations of test substance (1 nM to 10. mu.M) for 16H (see HIF-luciferase assay) under normoxic conditions and at 1% partial oxygen pressure. Total RNA was isolated from the cells and transcribed into cDNA and mRNA expression of HIF target genes was analyzed in real-time PCR. The active test agent has reduced mRNA expression of the HIF target gene compared to untreated cells under normoxic conditions, but first under hypoxic conditions.

B-3. Human xenograft and syngeneic tumor models:

human tumor xenograft models and syngeneic tumor mouse models in immunocompromised mice were used to evaluate the substance. For this purpose, tumor cells are cultured in vitro and implanted subcutaneously, or tumor xenografts are further implanted subcutaneously. Following tumor formation, the animals are treated orally, subcutaneously or intraperitoneally. The activity of the test substances is analyzed in monotherapy and in combination therapy with other pharmacologically active substances. Test substance for growth size (about 100 mm)²) The tumor inhibiting efficacy of (a) is more characterized. The health status of the animals was checked daily and treatment was performed according to the animal protection rules. Tumor area was measured with vernier calipers (length L, width B = shorter dimension). Tumor volume is given by the formula (L.times.B)²) And/2 calculation. Inhibition of tumor growth at the end of the study as T/C ratio of tumor area and tumor weight and as TGI value (tumor growth inhibition, by the formula [1- (T/C))]X 100 calculation) (T = tumor size in treated group; c = tumor size in untreated control group).

For the treated and untreated tumor-bearing mice, the influence of the test substances on the tumor tubular structure and the blood flow in the tumor was determined with the aid of computer microtomography and ultrasound microscopic studies.

B-4. Pharmacokinetic parameters were determined according to intravenous and oral dosing:

the substances to be investigated are administered intravenously to the animals (e.g. mice or rats) as a solution (e.g. in a corresponding slurry with a small addition of DMSO or in a PEG/ethanol/water mixture) and orally as a solution (e.g. in Solutol/ethanol/water or PEG/ethanol/water mixture) or as a suspension (e.g. in methylcellulose (tylose)), in each case via a gastric tube. After administration of the substance, blood was collected from the animals at the prescribed time points. It is heparinized and plasma is then obtained therefrom by centrifugation. The substance was quantified in plasma by LC-MS/MS analysis. From the plasma concentration/time profile determined in this way, pharmacokinetic parameters, e.g. AUC (area under the concentration/time curve), C_max(maximum pulp concentration), T_1/2(half clearance time (Halbwertszeit)), Vss (volume of distribution) and CL (clearance), and absolute and relative bioavailability (i.v./p.o. comparison after p.o. administration or suspension to solution comparison), using internal standards and with the aid of an effective computer program.

C. Embodiment examples for pharmaceutical compositions

The compounds according to the invention can be converted into the following pharmaceutical preparations.

And (3) tablet preparation:

consists of the following components:

100mg of the compound according to the invention, 50mg of lactose (monohydrate), 50mg of corn starch (domestic), 10mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2mg of magnesium stearate.

Tablet weight 212 mg. The diameter is 8mm, and the curvature radius is 12 mm.

Preparation:

the mixture of compound, lactose and starch according to the invention is granulated with a 5% strength solution (w/w) of PVP in water. After drying, the granules were mixed with magnesium stearate for 5 minutes. The mixture is compressed using a conventional tablet press (see above for tablet forms). A pressure of 15kN was used as recommended value for pressing.

Oral suspension

Consists of the following components:

1,000mg of a compound according to the invention, 1,000mg of ethanol (96%), 400mg of Rhodigel^®(xanthan gum from FMC, Pa., USA) and 99g water.

10ml of oral suspension corresponds to a single dose with 100mg of the compound according to the invention.

Preparation:

rhodigel is suspended in ethanol and a compound according to the invention is added to the suspension. Water was added with stirring. The mixture was stirred for about 6h until the Rhodigel had finished swelling.

Oral solution

Consists of the following components:

500 mg of a compound according to the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. 20 g of oral solution corresponds to a single dose of 100 mg of a compound of the invention.

Preparation:

the compound according to the invention is suspended in a mixture of polyethylene glycol and polysorbate while stirring. The stirring operation is continued until the compound of the present invention is completely dissolved.

i.v. Solution:

the compounds according to the invention are soluble in physiologically acceptable solvents (e.g. isotonic solutions, glucose solutions 5% and/or PEG 40030%) at concentrations below the saturation solubility. The solution was sterile filtered and transferred into sterile and pyrogen-free injection containers.

D. Reference to the literature

● Globocan 2002 Report

IARC International Agency for Research on Cancer: Globocan 2002,

http://www-dep.iarc.fr/globocan/downloads.htm

● American Cancer Society, Cancer Facts and Figures 2005

American Cancer Society: Cancer Facts and Figures 2007,

http://www.cancer.org/docroot/STT/content/STT_1x_Cancer_Facts_Figures_2007.asp

● Gibbs JB, 2000

Gibbs JB: Mechanism-based target identification and drug discovery in cancer research,

Science 2000, 287 (5460), 1969-1973.

● Semenza and Wang, 1992

Semenza GL, Wang GL: A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation,

Mol. Cell. Biol. 1992, 12 (12), 5447-5454.

● Wang and Semenza, 1995

Wang GL, Semenza GL: Purification and characterization of hypoxia-inducible factor 1,

J. Biol. Chem. 1995, 270 (3), 1230-1237.

● Wang, Jiang et al, 1995

Wang GL, Jiang BH, Rue EA, Semenza GL: Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O₂ tension, PNAS 1995, 92 (12), 5510-5514.

● Jiang, Rue et al, 1996

Jiang BH, Rue E, Wang GL, Roe R, Semenza GL: Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1, J. Biol. Chem. 1996, 271 (30), 17771-17778.

● Makino, Cao et al, 2001

Makino Y, Cao R, Svensson K, Bertilsson G, Asman M, Tanaka H, Cao Y, Poellinger L:

Nature 2001, 414 (6863), 550-554.

● Jiang, Semenza et al, 1996

Jiang BH, Semenza GL, Bauer C, Marti HH: Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O₂ tension, Am. J. Physiol. 1996, 271, 1172-1180.

● Maxwell, Wiesener et al, 1999

Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Ratcliffe PJ: The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis, Nature 1999, 399 (6733), 271-275.

● Hirota and Semenza, 2006

Hirota K, Semenza GL: Regulation of angiogenesis by hypoxia-inducible factor 1,

Crit. Rev. Oncol. Hematol. 2006, 59 (1), 15-26.

● Chen, ZHao et al, 2003

Chen J, Zhao S, Nakada K, Kuge Y, Tamaki N, Okada F, Wang J, Shindo M, Higashino F, Takeda K, Asaka M, Katoh H, Sugiyama T, Hosokawa M, Kobayashi M: Dominant-negative hypoxia-inducible factor-1alpha reduces tumorigenicity of pancreatic cancer cells through the suppression of glucose metabolism, Am. J. Pathol. 2003, 162 (4), 1283-1291.

● Stoeltzing, McCarty et al, 2004

Stoeltzing O, McCarty MF, Wey JS, Fan F, Liu W, Belcheva A, Bucana CD, Semenza GL, Ellis LM: Role of hypoxia-inducible factor-1alpha in gastric cancer cell growth, angiogenesis, and vessel maturation, J. Natl. Cancer Inst. 2004, 96 (12), 946-956.

● Li, Lin et al, 2005

Li L, Lin X, Staver M, Shoemaker A, Semizarov D, Fesik SW, Shen Y: Evaluating hypoxia-inducible factor-1alpha as a cancer therapeutic target via inducible RNA interference in vivo,

Cancer Res. 2005, 65 (16), 7249-7258.

● Mizukami, Jo et al, 2005

Mizukami Y, Jo WS, Duerr EM, Gala M, Li J, Zhang X, Zimmer MA, Iliopoulos O, Zukerberg LR, Kohgo Y, Lynch MP, Rueda BR, Chung DC: Induction of interleukin-8 preserves the angiogenic response in HIF-1alpha-deficient colon cancer cells, Nat. Med. 2005, 11 (9), 992-997.

● Li, Shi et al, 2006

Li J, Shi M, Cao Y, Yuan W, Pang T, Li B, Sun Z, Chen L, Zhao RC: Knockdown of hypoxia-inducible factor-1alpha in breast carcinoma MCF-7 cells results in reduced tumor growth and increased sensitivity to methotrexate, Biochem. Biophys. Res. Commun. 2006, 342, 1341-1351.

● Semenza, 2007

Semenza GL: Drug Discov. Today 2007, 12 (19-20), 853-859.

● Weidemann und Johnson, 2008

Weidemann A, Johnson RS: Cell Death and Differentiation 2008, 15, 621-627.

● Aiello et al, 1994

Aiello et al.: New Engl. J. Med. 1994, 331, 1480.

● Peer et al, 1995

Peer et al.: Lab. Invest. 1995, 72, 638.

● Lopez et al, 1996

Lopez et al.: Invest. Ophthalmol. Vis. Sci. 1996, 37, 855.

● Warburg, 1956

Warburg O: Science 1956, 123 (3191), 309-314.

Claims

1. A compound of formula (I)

(I),

Wherein

Ring (C)Represents a phenyl or pyridyl ring,

having substituent R³Ring ofRepresents a heteroaryl ring of formula

Therein is provided with

# denotes the adjacent CH₂Attachment point of group

And

# denotes and RingThe connection point of (a) is,

ring (C)Represents a heteroaryl ring of formula

Therein is provided with

Denotes and ringsIs connected to

And

indicates and ringsThe connection point of (a) is,

ring (C)Represents a phenyl or pyridyl ring,

ring (C)Represents saturated 4-to 10-a membered aza-heterocycle comprising at least one N atom as a ring member and in addition may comprise one or two further nitrogen atoms from the group consisting of N, O, S and/or S (O)₂The heterocyclic ring member of (a),

Represent and ringsIs connected to

And

diamond-solid denotes a ringThe connection point of (a) is,

q represents the number 0, 1 or 2

And

R¹represents and ringIs selected from fluorine, cyano and (C)₁-C₆) Alkyl, hydroxy, (C) ₁-C₆) -alkoxy, oxo, amino, mono- (C)₁-C₆) -alkylamino, di- (C)₁-C₆) -alkylamino and (C)₃-C₆) -a cycloalkyl group,

And

m represents the number 0, 1, 2, 3 or 4,

And

R³represents a methyl group, an ethyl group or a trifluoromethyl group,

R⁴represents hydrogen or is selected from halogen, cyano, pentafluorothio, (C)₁-C₆) Alkyl, tri- (C)₁-C₄) -alkylsilyl, -OR⁷，-NR⁷R⁸，-N（R⁷）-C（=O）-R⁸，-N（R⁷）-C（=O）-OR⁸，-N（R⁷）-S（=O）₂-R⁸，-C（=O）-OR⁷，-C（=O）-NR⁷R⁸，-SR⁷，-S（=O）-R⁷，-S（=O）₂-R⁷，-S（=O）₂-NR⁷R⁸，-S（=O）（=NH）-R⁷，-S（=O）（=NCH₃）-R⁷，（C₃-C₆) -substituents of cycloalkyl, 4-to 6-membered heterocyclyl and 5-or 6-membered heteroaryl,

And therein

And

Wherein (C) is mentioned herein₁-C₄) The alkyl substituents may themselves be substituted by hydroxy, (C)₁-C₄) -alkoxy, trifluoromethoxy, (C)₁-C₄) -carbonyloxy, carboxamido, mono- (C)₁-C₄) -alkylaminocarbonyl or di- (C)₁-C₄) -alkylaminocarbonyl or up to three times by fluorine,

and therein

in thatWherein (C)₁-C₆) Alkyl may be substituted up to three times by fluorine and is selected from hydroxy in the same or different manner, (C) ₁-C₄) -alkoxy, trifluoromethoxy, amino, mono- (C)₁-C₄) -alkylamino, di- (C)₁-C₄) -alkylamino, (C)₁-C₄) -alkoxycarbonyl, (C)₃-C₆) Up to two substitutions of the radicals of-cycloalkyl and 4-to 6-membered heterocyclyl

And

or

R⁷And R⁸In which both are attached to the nitrogen atom, together with the nitrogen atom form a 4-to 6-membered heterocyclic ring which may contain further substituents from the group consisting of N, O, S or S (O)₂And which may be selected in the same or different manner from fluorine, (C)₁-C₄) -alkyl, trifluoromethyl, hydroxy, (C)₁-C₄) -alkoxy, oxo, amino, mono- (C)₁-C₄) -alkylamino, di- (C)₁-C₄) -alkylamino, (C)₁-C₄) -alkylcarbonyl and (C)₁-C₄) The radical of alkoxycarbonyl is substituted up to two times,

And

p represents the number 0, 1 or 2,

and salts, solvates and solvates of salts thereof.

2. A compound of formula (I) according to claim 1, wherein

Ring (C)X and CH, representing phenyl or pyridyl rings and adjacent radicals₂Andare linked to one another in a 1,3 or 1,4 relationship

And

ring (C)With a substituent R⁴And R⁵Represents a phenyl ring of formula

Therein of which

Indicates and ringThe connection point of (a) is,

and salts, solvates and solvates of salts thereof.

3. A compound of formula (I) according to claim 1 or 2, wherein

And

ring (C)With a substituent R⁴And R⁵Represents a phenyl ring of the formula

Therein of which

Indicates and ringThe connection point of (a) is,

and salts, solvates and solvates of salts thereof.

4. A compound of formula (I) according to claim 1 or 2, wherein

ring (C)With a substituent R³Represents a heteroaryl ring of formula

Therein is provided with

# denotes the adjacent CH₂Attachment point of group

And

# denotes and RingThe connection point of (a) is,

and

ring (C)With a substituent R⁴And R⁵Represents a phenyl ring of formula

Therein of which

Indicates and ringThe connection point of (a) is,

and salts, solvates and solvates of salts thereof.

5. A compound of formula (I) according to claim 1 or 2, wherein

ring (C)With a substituent R³Represents a heteroaryl ring of formula

Therein of which

# denotes the adjacent CH₂Attachment point of group

And

# denotes and RingThe connection point of (a) is,

ring (C)With a substituent R⁴And R⁵Represents a phenyl ring of formula

Therein of which

Indicates and ringThe connection point of (a) is,

And

R²represents and ringIs selected from (C)₁-C₆) -alkyl, (C)₁-C₆) -alkylcarbonyl group, ((iii))C₁-C₆) -alkoxycarbonyl, (C)₁-C₆) -alkylsulfonyl and (C)₃-C₆) -a cycloalkyl group,

And

m represents the number 0, 1, 2, 3 or 4,

And

in which the sum of m and n is not equal to the number 0,

and salts, solvates and solvates of salts thereof.

6. A compound of formula (I) according to claim 1, 2 or 3, wherein

Ring (C)Represents a pyridyl ring and the adjacent radicals X and CH₂To the ring carbon atoms of the pyridyl ring in a 1,3 or 1,4 relationship to each other,

ring (C)With a substituent R³Represents a heteroaryl ring of formula

Therein is provided with

# denotes the adjacent CH₂Attachment point of group

And

# denotes and RingThe connection point of (a) is,

ring (C)Represents a heteroaryl ring of formula

Therein is provided with

Denotes and ringsIs connected to

And

chartIndicating ringThe connection point of (a) is,

ring (C)With a substituent R⁴And R⁵Represents a phenyl ring of formula

Therein of which

Indicates and ringThe connection point of (a) is,

x represents a bond or represents [. diamond.. sup. -. sup. ₂）_q-N（R⁶）-◆◆，-O-，-S-，-C（=O）-，-S（=O）₂-or-N (R)⁶) -C (= O) -. diamond-solid, in which

Represent and ringsIs connected to

And

diamond-solid denotes a ringThe connection point of (a) is,

q represents the number 0, 1 or 2

And

R¹represents and ringIs selected from fluorine, cyano and (C)₁-C₄) Alkyl, hydroxy, (C)₁-C₄) -alkoxy, oxo, amino, mono- (C)₁-C₄) -alkylamino, di- (C)₁-C₄) -alkylamino and (C)₃-C₆) -a cycloalkyl group,

and

m represents the number 0, 1 or 2,

R²represents and ringIs selected from (C) ₁-C₄) -alkyl, (C)₁-C₄) -alkylcarbonyl group, (C)₁-C₄) -alkoxycarbonyl, (C)₁-C₄) -alkylsulfonyl and (C)₃-C₆) -a cycloalkyl group,

in which is at (C)₁-C₄) -alkyl, (C)₁-C₄) -alkylcarbonyl group, (C)₁-C₄) -alkoxycarbonyl and (C)₁-C₄) The alkyl group in the alkylsulfonyl radical may itself be chosen from hydroxyl, (C)₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) -alkylamino, di- (C)₁-C₄) -alkylamino, (C)₃-C₆) Up to three times with substituents of cycloalkyl and 4-to 6-membered heterocyclyl and with fluorine

And

n represents the number 0 or 1,

R³represents a methyl group, an ethyl group or a trifluoromethyl group,

And therein

And

and therein

And

Or

R⁵represents a substituent selected from fluorine, chlorine and methyl

And

p represents the number 0 or 1,

and salts, solvates and solvates of salts thereof.

7. A compound of formula (I) according to claim 1, 2 or 4, wherein

ring (C)With a substituent R³Represents a heteroaryl ring of formula

Therein is provided with

# denotes the adjacent CH₂Attachment point of group

And

# denotesAnd ringThe connection point of (a) is,

ring (C)Represents a heteroaryl ring of formula

Therein is provided with

Is represented byAttachment point for a ring

And

indicates and ringsThe connection point of (a) is,

ring (C)With a substituent R⁴And R⁵Represents a phenyl ring of formula

Therein of which

Indicates and ringThe connection point of (a) is,

Represent and ringsIs connected to

And

diamond-solid denotes a ringThe connection point of (a) is,

q represents the number 0, 1 or 2

And

（C₃-C₆) The cycloalkyl radicals may themselves be identical or differentIs selected from fluorine, (C)₁-C₄) Alkyl, hydroxy, (C)₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) Alkylamino and di- (C)₁-C₄) -the radical of alkylamino is substituted up to two times,

m represents the number 0, 1 or 2

And

（C₃-C₆) Cycloalkyl groups themselves may be selected, in the same or different ways, from fluorine, (C)₁-C₄) Alkyl, hydroxy, (C)₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) Alkylamino and di- (C) ₁-C₄) -the radical of alkylamino is substituted up to two times,

n represents the number 0 or 1,

R³represents a methyl group, an ethyl group or a trifluoromethyl group,

And therein

And

And therein

And

Or

R⁵represents a substituent selected from fluorine, chlorine and methyl

And

p represents the number 0 or 1,

And salts, solvates and solvates of salts thereof.

8. A compound of formula (I) according to claim 1, 2 or 5, wherein

ring (C)With a substituent R³Represents a heteroaryl ring of formula

Therein of which

# denotes the adjacent CH₂Attachment point of group

And

# denotes and RingThe connection point of (a) is,

ring (C)Represents a heteroaryl ring of formula

Therein is provided with

Denotes and ringsIs connected to

And

indicates and ringsThe connection point of (a) is,

ring (C)With a substituent R⁴And R⁵Represents a phenyl ring of formula

Therein of which

Indicates and ringThe connection point of (a) is,

Represent and ringsIs connected to

And

diamond-solid denotes a ringThe connection point of (a) is,

q represents the number 0, 1 or 2

And

R¹represents and ringIs selected from cyano, (C) ₁-C₄) -alkyl, oxo and (C)₃-C₆) -a cycloalkyl group,

and

in which is at (C)₁-C₄) -alkyl, (C)₁-C₄) -alkylcarbonyl group, (C)₁-C₄) -alkoxycarbonyl and (C)₁-C₄) The alkyl group in the alkylsulfonyl radical may itself be chosen from hydroxyl, (C)₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) -alkylamino, di- (C)₁-C₄) -alkylamino (C)₃-C₆) Up to three times with substituents of cycloalkyl and 4-to 6-membered heterocyclyl and with fluorine

And

m represents the number 0, 1 or 2

n represents the number 0 or 1,

in which the sum of m and n is equal to the number 1, 2 or 3,

R³represents a methyl group, an ethyl group or a trifluoromethyl group,

And therein

And

and therein

And

Or

R⁷And R⁸In which both are attached to the nitrogen atom, together with the nitrogen atom form a 4-to 6-membered heterocyclic ring which may contain further substituents from the group consisting of N, O, S or S (O) ₂And which may beSelected from fluorine, (C) in the same or different manner₁-C₄) -alkyl, trifluoromethyl, hydroxy, (C)₁-C₄) -alkoxy, oxo and (C)₁-C₄) -the radical of alkylcarbonyl is substituted up to two times,

R⁵represents a substituent selected from fluorine, chlorine and methyl

And

p represents the number 0 or 1,

and salts, solvates and solvates of salts thereof.

9. A compound of formula (I) according to claim 1, 2, 3 or 6, wherein

Ring (C)Represents a pyridyl ring of the formula

Therein of which

Denotes the point of attachment to the adjacent radical X

And

indicating neighboring CH₂The point of attachment of the group,

ring (C)With a substituent R³Represents a heteroaryl ring of formula

Therein of which

# denotes the adjacent CH₂Attachment point of group

And

# denotes and RingThe connection point of (a) is,

ring (C)Represents a heteroaryl ring of formula

Therein of which

Denotes and ringsIs connected to

And

indicates and ringsThe connection point of (a) is,

ring (C)With a substituent R⁴And R⁵Represents a phenyl ring of formula

Therein of which

Indicates and ringThe connection point of (a) is,

ring (C)Represents a saturated 4-to 10-membered aza-heterocycle comprising at least one N atom as a ring member and may additionally comprise further substituents from the group consisting of N, O, S or S (O) ₂The heterocyclic ring member of (a),

x represents a bond or represents [. diamond.. sup. -. sup.₂）_q-N（R⁶) -. diamond solid, -C (= O) -or◆-N（R⁶) -C (= O) -. diamond-solid, in which

Represent and ringsIs connected to

And

diamond-solid denotes a ringThe connection point of (a) is,

q represents the number 0, 1 or 2

And

R⁶represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl,

m represents the number 0 or 1,

in which is at (C)₁-C₄) -alkyl, (C)₁-C₄) -alkylcarbonyl group, (C)₁-C₄) -alkoxycarbonyl and (C)₁-C₄) The alkyl group in the alkylsulfonyl radical may itself be chosen from hydroxyl, (C) ₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) -alkylamino, di- (C)₁-C₄) -alkylamino, (C)₃-C₅) -cycloalkyl and 4-or 5-membered heterocyclyl are substituted and up to three times by fluorine,

n represents the number 0 or 1,

R³represents a methyl group, and a salt thereof,

And

in which (C)₁-C₄) The alkyl substituents may themselves be substituted by methoxy, trifluoromethoxy or ethoxy,

and therein

in which (C)₁-C₄) The alkyl radical may itself be chosen from hydroxyl, (C)₁-C₄) -alkoxy, trifluoromethoxy and (C)₃-C₆) -radical substitution of cycloalkyl and up to three times by fluorine

And

or

R⁵represents fluorine and is selected from the group consisting of,

and

p represents the number 0 or 1,

and salts, solvates and solvates of salts thereof.

10. A compound of formula (I) according to claim 1, 2, 4 or 7 wherein

Ring (C)The radicals X and CH representing a phenyl ring and being adjacent₂With the phenyl ring by 1,3 orThe 1,4 relationships are linked to each other,

ring (C)With a substituent R³Represents a heteroaryl ring of formula

Therein of which

# denotes the adjacent CH₂Attachment point of group

And

# denotes and RingThe connection point of (a) is,

ring (C)Represents a heteroaryl ring of formula

Therein of which

Denotes and rings Is connected to

And

indicates and ringsThe connection point of (a) is,

ring (C)With a substituent R⁴And R⁵Represents a phenyl ring of formula

Therein of which

Indicates and ringThe connection point of (a) is,

x represents a bond or represents [. diamond.. sup. -. sup.₂）_q-N（R⁶) -. diamond-solid, -C (= O) -or-N (R)⁶) -C (= O) -. diamond-solid, in which

Represent and ringsIs connected to

And

diamond-solid denotes a ringThe connection point of (a) is,

q represents the number 0, 1 or 2

And

R⁶represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl,

R¹represents and ringIs selected from fluorine, cyano and (C)₁-C₄) Alkyl, hydroxy, (C)₁-C₄) -alkoxy, oxo, amino, mono- (C)₁-C₄) -alkylamino, di- (C)₁-C₄) Alkylamino, cyclopropyl and cyclobutyl，

m represents the number 0 or 1,

n represents the number 0 or 1,

R³represents a methyl group, and a salt thereof,

And

and therein

And

or

R⁷And R⁸In which both are attached to the nitrogen atom, together with the nitrogen atom form a 4-to 6-membered heterocyclic ring which may contain further substituents from the group consisting of N, O, S or S (O)₂And which may be selected in the same or different manner from fluorine, (C)₁-C₄) -alkyl, trifluoromethyl, hydroxy, (C)₁-C₄) -alkoxy, oxygenGeneration and combination (C)₁-C₄) -the radical of alkylcarbonyl is substituted up to two times,

R⁵represents fluorine and is selected from the group consisting of,

and

p represents the number 0 or 1,

and salts, solvates and solvates of salts thereof.

11. A compound of formula (I) according to claim 1, 2, 5 or 8, wherein

ring (C)With a substituent R³Represents a heteroaryl ring of formula

Therein of which

# denotes the adjacent CH₂Attachment point of group

And

# denotes and RingThe connection point of (a) is,

ring (C)Represents a heteroaryl ring of formula

Therein of which

Denotes and ringsIs connected to

And

indicates and ringsThe connection point of (a) is,

ring (C)With a substituent R⁴And R⁵Represents a phenyl ring of formula

Therein of which

Is represented byThe point of attachment of the loop or loops,

Represent and ringsIs connected to

And

diamond-solid denotes a ringThe connection point of (a) is,

q represents the number 0, 1 or 2

And

R⁶represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl,

R¹represents and ringIs selected from cyano, (C) ₁-C₄) Alkyl, oxo, cyclopropyl and cyclobutyl,

m represents the number 0 or 1,

n represents the number 0 or 1,

in which the sum of m and n is equal to the number 1 or 2,

R³represents a methyl group, and a salt thereof,

in which (C)₁-C₆) The alkyl radical may itself be chosen from-OR ⁷，-NR⁷R⁸，-C（=O）-NR⁷R⁸，（C₃-C₆) Up to three times with substituents of cycloalkyl and 4-to 6-membered heterocyclyl and with fluorine

And

and therein

And

cycloalkyl radicals mentionedThe radicals may be chosen from fluorine, (C) in the same or different ways₁-C₄) -alkyl, trifluoromethyl, hydroxy, (C)₁-C₄) Up to two substitutions of the groups alkoxy and trifluoromethoxy,

or

R⁵represents fluorine and is selected from the group consisting of,

and

p represents the number 0 or 1,

and salts, solvates and solvates of salts thereof.

12. A compound as defined in one of claims 1 to 11 for use in the treatment and/or prevention of a disease.

13. A compound as defined in one of claims 1 to 11 for use in a method for the treatment and/or prophylaxis of cancer diseases or tumor diseases.

14. A compound as defined in one of claims 1 to 11 for use in a method for the treatment and/or prophylaxis of ischemic cardiovascular diseases, cardiac insufficiency, myocardial infarction, arrhythmia, stroke, pulmonary hypertension, fibrotic diseases of the kidney and lung, psoriasis, diabetic retinopathy, macular degeneration, rheumatoid arthritis and Chugwash polycythemia.

15. Use of a compound as defined in one of claims 1 to 11 for the preparation of a medicament for the treatment and/or prophylaxis of cancer diseases or tumor diseases.

16. Use of a compound as defined in one of claims 1 to 11 for the preparation of a medicament for the treatment and/or prophylaxis of ischemic cardiovascular diseases, cardiac insufficiency, myocardial infarction, arrhythmia, stroke, pulmonary hypertension, fibrotic diseases of the kidney and lung, psoriasis, diabetic retinopathy, macular degeneration, rheumatoid arthritis and Chugwash polycythemia.

17. A medicament comprising a compound as defined in any one of claims 1 to 11 in association with one or more inert, non-toxic, pharmaceutically suitable auxiliary substances.

18. A medicament comprising a compound as defined in one of claims 1 to 11 in combination with one or more further active compounds.

19. The medicament according to claim 17 or 18 for the treatment and/or prevention of cancer diseases or tumor diseases.

20. The medicament according to claim 17 or 18 for the treatment and/or prophylaxis of ischemic cardiovascular diseases, cardiac insufficiency, myocardial infarction, arrhythmia, stroke, pulmonary hypertension, fibrotic diseases of the kidney and lung, psoriasis, diabetic retinopathy, macular degeneration, rheumatoid arthritis and Chugwash erythrocytosis.

21. Method of treatment and/or prophylaxis of cancer diseases or tumour diseases in humans and animals using an active amount of at least one compound as defined in one of claims 1 to 11, or of a medicament as defined in one of claims 17 to 19.

22. Method for the treatment and/or prophylaxis of ischemic cardiovascular diseases, cardiac insufficiency, myocardial infarction, arrhythmia, stroke, pulmonary hypertension, fibrotic diseases of the kidney and lung, psoriasis, diabetic retinopathy, macular degeneration, rheumatoid arthritis and Chugwash polycythemia in humans and animals, using an active amount of at least one compound as defined in one of claims 1 to 11 or a medicament as defined in one of claims 17, 18 and 20.

23. Process for the preparation of the compound of formula (I-D)

(I-D),

Wherein rings A and E and R¹，R²，R³，R⁴，R⁵M, n and p each have the meanings given in claims 1 to 11,

and

ring N represents ring N connected to ring a via a ring nitrogen atom, as defined in claims 1 to 11,

prepared by the following steps, wherein the formula (IX)N'Hydroxy amidines

(IX)

Wherein rings E and R⁴，R⁵And p has the meaning given above,

firstly, can

[A] By condensation with pyrazolecarboxylic acids of the formula (XXVII)

(XXVII)

Wherein R is³Having the meaning given above, the use of,

to give 1,2,4-  oxadiazole derivatives of the formula (XXVIII)

(XXVIII)

Wherein rings E and R³，R⁴，R⁵And p has the meaning given above,

(III),

Wherein ring a has the meaning given above,

y represents chlorine, bromine or iodine

And

to give a compound of the formula (XXIX)

(XXIX)

or

[B] By condensation with pyrazolecarboxylic acids of the formula (XXX)

(XXX)

Wherein rings A and R³Having the meaning given above, the use of,

and

y represents chlorine, bromine or iodine,

to give a compound of the formula (XXIX)

(XXIX)

(XXXI)

Wherein rings N and R¹，R²M and N have the meanings given above and the hydrogen atoms shown are linked to the nitrogen atom of the ring N.