DE102011106990B3 - Compounds as glycogen synthase kinase 3 (GSK-3) inhibitors for the treatment of GSK-3-mediated diseases - Google Patents

Compounds as glycogen synthase kinase 3 (GSK-3) inhibitors for the treatment of GSK-3-mediated diseases Download PDF

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DE102011106990B3
DE102011106990B3 DE102011106990A DE102011106990A DE102011106990B3 DE 102011106990 B3 DE102011106990 B3 DE 102011106990B3 DE 102011106990 A DE102011106990 A DE 102011106990A DE 102011106990 A DE102011106990 A DE 102011106990A DE 102011106990 B3 DE102011106990 B3 DE 102011106990B3
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Hagit Eldar-Finkelmann
Fred Van Leuven
Boris Schmidt
Fabio Lo Monte
Thomas Kramer
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Abstract

Die vorliegende Erfindung betrifft Verbindungen der folgenden allgemeinen Formel (I),die als Inhibitoren der GSK-3 wirken und für die Behandlung von GSK-3-vermittelten Erkrankungen verwendet werden können. Die erfindungsgemäßen Verbindungen wirken als Inhibitoren der GSK-3.The present invention relates to compounds of the following general formula (I) which act as inhibitors of GSK-3 and can be used for the treatment of GSK-3-mediated diseases. The compounds of the invention act as inhibitors of GSK-3.

Description

Die vorliegende Erfindung betrifft Verbindungen, die als selektive Liganden der Glykogen Synthase Kinase 3 (GSK-3) wirken und für die Behandlung von GSK-3-vermittelten Erkrankungen verwendet werden können. Die erfindungsgemäßen Verbindungen wirken als Inhibitoren der Glykogen Synthase Kinase 3 (GSK-3).The present invention relates to compounds which act as selective ligands of glycogen synthase kinase 3 (GSK-3) and can be used for the treatment of GSK-3 mediated diseases. The compounds according to the invention act as inhibitors of glycogen synthase kinase 3 (GSK-3).

GSK-3 ist eine hoch konservierte Familie von Serin/Threoninproteinkinasen. Beim Menschen kodieren zwei Gene zwei unterschiedliche, aber eng miteinander verbundenen GSK-3 Formen, die so genannte GSK-3α und GSK-3β. Sie zeigen insgesamt 84% Identität und 98% Identität innerhalb ihrer katalytischen Domäne, der Hauptunterschied zwischen den beiden Proteinkinasen besteht in einem Glycinreichen Abschnitt in der N-terminalen Domäne von GSK-3α. Dennoch hat sich in embryonal letalen Phänotypen der GSK-3β gezeigt, dass beide Formen der GSK-3 nicht funktionell austauschbar sind.GSK-3 is a highly conserved family of serine / threonine protein kinases. In humans, two genes encode two distinct but closely related GSK-3 forms, the so-called GSK-3α and GSK-3β. They show a total of 84% identity and 98% identity within their catalytic domain, the main difference between the two protein kinases is in a glycine-rich stretch in the N-terminal domain of GSK-3α. Nevertheless, in embryonic lethal phenotypes of GSK-3β, it has been shown that both forms of GSK-3 are not functionally interchangeable.

GSK-3 spielt eine wichtige Funktion im Wnt-Signalweg. Durch die Stimulation des Wnt-Signalweges wird GSK-3 inaktiviert, wodurch sich β-Catenin im Zellkern ansammelt, um dort mit TCF/LEF einen Transkriptionsfaktor zu formen, der eine Vielzahl von Genen reguliert. GSK-3 phosphoryliert unter anderem den Zellzyklusregulator β-Catenin, Cyclin D1, Cyclin E, p21ClP1 und c-Myc, wodurch diese Ubiquitin-abhängig abgebaut werden. In Abwesenheit von Insulin phosphoryliert aktive GSK-3 die Glykogen-Synthase und elF2B, wodurch diese inaktiviert werden. Die Bindung von Insulin an seinen Plasmamembran Rezeptor führt zur Aktivierung von PKB/Akt, was wiederum zur Phosphorylierung und Inaktivierung von GSK-3 führt. Folglich sind dadurch die Glykogen-Synthase und elF2B aktiviert, wodurch die Glykogen und Protein-Synthese stimuliert werden. GSK-3 hat weiterhin pro-apoptotische Funktion in neuronalen Zellen. Im Gegensatz dazu ist GSK-3 auch für das Überleben von Zellen beschrieben worden. In GSK-3β-Knockout-Mäusen führte die TNFα-induzierte Apoptose von Hepatozyten zu einem frühen Tod während der Embryonalentwicklung der Mäuse. Zudem wird der GSK-3 und CK1 eine Funktion bei der Regelung der zirkadianen Uhr bei Drosophila und in Säugetieren nachgesagt. Schließlich spielt sowohl die GSK-3 Aktivität/Inaktivität als auch die räumliche Verteilung eine wesentliche Rolle während der Entwicklung, insbesondere im Rahmen der Polaritätsbestimmung.GSK-3 plays an important role in the Wnt signaling pathway. By stimulating the Wnt signaling pathway, GSK-3 is inactivated, causing β-catenin to accumulate in the nucleus, where it forms a transcription factor with TCF / LEF that regulates a variety of genes. Among other things, GSK-3 phosphorylates the cell cycle regulators β-catenin, cyclin D1, cyclin E, p21ClP1 and c-Myc, causing them to undergo ubiquitin-dependent degradation. In the absence of insulin, active GSK-3 phosphorylates glycogen synthase and elF2B, thereby inactivating them. The binding of insulin to its plasma membrane receptor leads to the activation of PKB / Akt, which in turn leads to the phosphorylation and inactivation of GSK-3. Thus, glycogen synthase and elF2B are activated thereby stimulating glycogen and protein synthesis. GSK-3 also has pro-apoptotic function in neuronal cells. In contrast, GSK-3 has also been described for cell survival. In GSK-3β knockout mice, TNFα-induced hepatocyte apoptosis resulted in early death during embryonic development of the mice. In addition, the GSK-3 and CK1 is said to have a role in the regulation of the circadian clock in Drosophila and in mammals. Finally, both GSK-3 activity / inactivity and spatial distribution play an essential role during development, especially in the context of polarity determination.

Kaum ein anderes Enzym besitzt einen so großen Einfluss auf eine Vielzahl zellulärer Vorgänge wie GSK-3. Unter anderem wurde ein Einfluss von GSK-3 auf folgende physiologischen Funktionen beschrieben: den Wnt und Hedgehog Signalweg, in der Transkription, der Regulation des Zellteilungszyklus, der Antwort auf DNA-Schäden, der Regulation des Zelltods und dem Überleben der Zelle, kardiovaskuläre und neuronale Funktionen, dem Insulin-Transduktionsweg, der Differenzierung, Regulation des zirkadianen Rhythmus und der Entwicklung/Erhaltung von Stammzellen. Bis heute wurden rund 40 Substrate identifiziert, die von GSK-3 phosphoryliert werden.Hardly any other enzyme has such a large influence on a variety of cellular processes such as GSK-3. Among others, the influence of GSK-3 on the following physiological functions has been described: Wnt and hedgehog signaling, transcription, regulation of cell division cycle, response to DNA damage, regulation of cell death and cell survival, cardiovascular and neuronal Functions, insulin transduction pathway, differentiation, regulation of circadian rhythm and development / maintenance of stem cells. To date, around 40 substrates have been identified that are phosphorylated by GSK-3.

Fünf Studien haben die Suche nach pharmakologischen Inhibitoren der GSK-3 besonders angeregt: Erstens, die Stimmungsstabilisierenden Eigenschaften von Lithium, dem ersten GSK-3-Inhibitor überhaupt. Zweitens die Insulin-mimetischen Eigenschaften von GSK-3-Inhibitoren. Drittens die Wechselwirkung von GSK-3 mit Presenilin-1, die GSK-3-abhängigen Amyloid-β Produktion und abnorme tau-Phosphorylierung in der Alzheimer-Krankheit. Viertens, die Beteiligung der GSK-3 im neuronalen Zelltod und der Neuroprotektion durch GSK-3-Inhibitoren und fünftens die Aufrechterhaltung der Pluripotenz von embryonalen Stammzellen in der Abwesenheit von Feeder-Zellen durch GSK-3-Inhibitoren. Über 30 GSK-3-Inhibitoren wurden bisher identifiziert. An der Identifizierung neuer GSK-3-Inhibitoren besteht daher nach wie vor ein fortlaufend großes Interesse.Five studies have particularly stimulated the search for pharmacological inhibitors of GSK-3: First, the mood-stabilizing properties of lithium, the first GSK-3 inhibitor ever. Second, the insulin-mimetic properties of GSK-3 inhibitors. Third, the interaction of GSK-3 with presenilin-1, GSK-3-dependent amyloid-β production, and abnormal tau phosphorylation in Alzheimer's disease. Fourth, the involvement of GSK-3 in neuronal cell death and neuroprotection by GSK-3 inhibitors and, fifth, the maintenance of pluripotency of embryonic stem cells in the absence of feeder cells by GSK-3 inhibitors. Over 30 GSK-3 inhibitors have been identified so far. The identification of new GSK-3 inhibitors therefore continues to be of great interest.

Zu den Krankheiten, die mit GSK-3 Inhibitoren behandelt werden können, gehören insbesondere die Alzheimer-Krankheit und andere Tauopathien, Asthma, bipolare affektive Störungen, Depression, Nervenzelltod und Schlaganfall, Parkinson, Huntington, Skelettmuskelatrophie, Kardioprotektion, Haarverlust, verringerte Spermienmotilität, Diabetes und damit in Zusammenhang stehende Folgeerkrankungen, z. B. Syndrom X und Adipositas, Erkrankungen, die durch einzellige Parasiten verursacht werden, transmissible spongiforme Enzephalopathie, Schizophrenie, Krankheiten des zirkadianen Rhythmus und Krebs.Diseases that can be treated with GSK-3 inhibitors include, in particular, Alzheimer's disease and other tauopathies, asthma, bipolar affective disorders, depression, neuronal death and stroke, Parkinson's, Huntington's, skeletal muscle atrophy, cardioprotection, hair loss, reduced sperm motility, diabetes and related sequelae, e.g. Syndrome X and obesity, diseases caused by unicellular parasites, transmissible spongiform encephalopathy, schizophrenia, circadian rhythm diseases and cancer.

Im Stand der Technik sind bereits einige GSK-3 Inhibitoren und ihr therapeutisches Potential beschrieben worden. In einem Review von Cohen and Goedert, Nat. Rev. Drug. Discov., 2004, 3: 480–87, wurden einige potentielle GSK-3 Inhibitoren, wie z. B. SB 216763, SB 415286, CHIR 98014, CHIR 99021, AR A014418, 1-Azakenpaullone und Bis-7-indolylmaleimide für eine Vielzahl von therapeutischen Anwendungen beschrieben.The prior art has already described some GSK-3 inhibitors and their therapeutic potential. In a review by Cohen and Goedert, Nat. Rev. Drug. Discov., 2004, 3: 480-87, some potential GSK-3 inhibitors, such as. SB 216763, SB 415286, CHIR 98014, CHIR 99021, AR A014418, 1-azakenpaullone and bis-7-indolylmaleimides have been described for a variety of therapeutic applications.

Im Stand der Technik sind (R)-Roscovitin, Aloisin A, Indirubin-3'-oxim, Pyrazolpyridin, Aminothiazol, Alsterpaullon und 1-Aza-9-oxafluoren als GSK-3 Inhibitoren identifiziert worden. In the prior art, (R) -roscovitin, aloisin A, indirubin-3'-oxime, pyrazolopyridine, aminothiazole, alsterpaullone and 1-aza-9-oxafluorene have been identified as GSK-3 inhibitors.

Obwohl bereits einige GSK-3 Inhibitoren im Stand der Technik bekannt sind, spielt die GSK-3 bei klassischen Krankheiten wie Alzheimer und Krebs eine so entscheidende Rolle, dass weiterhin und auch zukünftig ein großes Interesse daran besteht, weitere GSK-3 Inhibitoren zu identifizieren.Although some GSK-3 inhibitors are already known in the art, GSK-3 plays such a crucial role in classical diseases such as Alzheimer's and cancer that further and also in the future there is great interest in identifying further GSK-3 inhibitors.

Aufgabe der vorliegenden Erfindung ist es daher, weitere Verbindungen bereitzustellen, die in der Lage sind, die GSK-3 zu inhibieren.The object of the present invention is therefore to provide further compounds which are capable of inhibiting GSK-3.

Diese Aufgabe wird erfindungsgemäß durch die technische Lehre der unabhängigen Ansprüche gelöst. Weitere vorteilhafte Ausgestaltungen der Erfindung ergeben sich aus den abhängigen Ansprüchen, der Beschreibung, den Figuren sowie den Beispielen.This object is achieved by the technical teaching of the independent claims. Further advantageous embodiments of the invention will become apparent from the dependent claims, the description, the figures and the examples.

Überraschend wurde gefunden, dass die Verbindungen gemäß allgemeiner Formel (I) Inhibitoren der Glykogen Synthase Kinase 3 (GSK-3) sind und damit auch für die Prophylaxe und Behandlung von GSK-3-vermittelten Erkrankungen geeignet sind.Surprisingly, it has been found that the compounds according to general formula (I) are inhibitors of glycogen synthase kinase 3 (GSK-3) and are thus also suitable for the prophylaxis and treatment of GSK-3-mediated diseases.

Somit betrifft die vorliegende Erfindung Verbindungen der allgemeinen Formel (I)

Figure 00030001
worin
R1 für einen der folgenden Reste steht:
Figure 00040001
Figure 00050001
Figure 00060001
Figure 00070001
Figure 00080001
Figure 00090001
Figure 00100001
R2 für einen der folgenden Reste steht -X15,
Figure 00100002
Figure 00110001
Figure 00120001
Figure 00130001
Figure 00140001
Figure 00150001
R3, R4, R5, R6, R7, R10, R11, R12, R13 unabhängig voneinander folgende Reste bedeuten:
-R14, -R15, -R16, -R17, -R18, -R19, -R20, -(CH2)n-R14, -(CH2)n-R15, -(CH2)n-R16, -(CH2)n-R17, -(CH2)n-R18, -(CH2)n-R19, -(CH2)n-R20;
Figure 00150002
Figure 00160001
-H, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, cyclo-C6H11, cyclo-C7H13, cyclo-C8H15, -Ph, -CH2-Ph, -CH2-CH2-Ph, -CH2-CH2-CH2-Ph, -CH=CH-Ph, -C≡C-Ph, -CPh3, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5 , -C(CH3)3, -C5H11, -CH(CH3)-C3H7, -CH2-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2, -C(CH3)2-C2H5, -CH2-C(CH3)3, -CH(C2H5)2, -C2H4-CH(CH3)2, -C6H13, -C7H15, -C8H17, -C3H6-CH(CH3)2, -C2H4-CH(CH3)-C2H5, -CH(CH3)-C4H9, -CH2-CH(CH3)-C3H7, -CH(CH3)-CH2-CH(CH3)2, -CH(CH3)-CH(CH3)-C2H5, -CH2-CH(CH3)-CH(CH3)2, -CH2-C(CH3)2-C2H5, -C(CH3)2-C3H7, -C(CH3)2-CH(CH3)2, -C2H4-C(CH3)3, -CH(CH3)-C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C2H4-CH=CH2, -CH2-CH=CH-CH3, -CH=CH-C2H5, -CH2-C(CH3)=CH2, -CH(CH3)-CH=CH, -CH=C(CH3)2, -C(CH3)=CH-CH3, -CH=CH-CH=CH2, -C3H6-CH=CH2, -C2H4-CH=CH-CH3, -CH2-CH=CH-C2H5, -CH=CH-C3H7, -CH2-CH=CH-CH=CH2, -CH=CH-CH=CH-CH3, -CH=CH-CH2-CH=CH2, -C(CH3)=CH-CH=CH2, -CH=C(CH3)-CH=CH2, -CH=CH-C(CH3)=CH2, -C2H4-C(CH3)=CH2, -CH2-CH(CH3)-CH=CH2, -CH(CH3)-CH2-CH=CH2, -CH2-CH=C(CH3)2, -CH2-C(CH3)=CH-CH3, -CH(CH3)-CH=CH-CH3, -CH=CH-CH(CH3)2, -CH=C(CH3)-C2H5, -C(CH3)=CH-C2H5, -C(CH3)=C(CH3)2, -C(CH3)2-CH=CH2, -CH(CH3)-C(CH3)=CH2, -C(CH3)=CH-CH=CH2, -CH=C(CH3)-CH=CH2, -CH=CH-C(CH3)=CH2, -C4H8-CH=CH2, -C3H6-CH=CH-CH3, -C2H4-CH=CH-C2H5, -CH2-CH=CH-C3H7, -CH=CH-C4H9, -C3H6-C(CH3)=CH2, -C2H4-CH(CH3)-CH=CH2, -CH2-CH(CH3)-CH2-CH=CH2, -CH(CH3)-C2H4-CH=CH2, -C2H4-CH=C(CH3)2, -C2H4-C(CH3)=CH-CH3, -CH2-CH(CH3)-CH=CH-CH3, -CH(CH3)-CH2-CH=CH-CH3, -CH2-CH=CH-CH(CH3)2, -CH2-CH=C(CH3)-C2H5, -CH2-C(CH3)=CH-C2H5, -CH(CH3)-CH=CH-C2H5, -CH=CH-CH2-CH(CH3)2, -CH=CH-CH(CH3)-C2H5, -CH=C(CH3)-C3H7, -C(CH3)=CH-C3H7, -CH2-CH(CH3)-C(CH3)=CH2, -CH(CH3)-CH2-C(CH3)=CH2, -CH(CH3)-CH(CH3)-CH=CH2, -CH2-C(CH3)2-CH=CH2, -C(CH3)2-CH2-CH=CH2, -CH2-C(CH3)=C(CH3)2, -CH(CH3)-CH=C(CH3)2, -C(CH3)2-CH=CH-CH3, -CH(CH3)-C(CH3)=CH-CH3, -CH=C(CH3)-CH(CH3)2, -C(CH3)=CH-CH(CH3)2, -C(CH3)=C(CH3)-C2H5, -CH=CH-C(CH3)3, -C(CH3)2-C(CH3)=CH2, -CH(C2H5)-C(CH3)=CH2, -C(CH3)(C2H5)-CH=CH2, -CH(CH3)-C(C2H5)=CH2, -CH2-C(C3H7)=CH2, -CH2-C(C2H5)=CH-CH3, -CH(C2H5)-CH=CH-CH3, -C(C4H9)=CH2, -C(C3H7)=CH-CH3, -C(C2H5)=CH-C2H5, -C(C2H5)=C(CH3)2, -C[C(CH3)3]=CH2, -C[CH(CH3)(C2H5)]=CH2, -C[CH2-CH(CH3)2]=CH2, -C2H4-CH=CH-CH=CH2, -CH2-CH=CH-CH2-CH=CH2, -CH=CH-C2H4-CH=CH2, -CH2-CH=CH-CH=CH-CH3, -CH=CH-CH2-CH=CH-CH3, -CH=CH-CH=CH-C2H5, -CH2-CH=CH-C(CH3)=CH2, -CH2-CH=C(CH3)-CH=CH2, -CH2-C(CH3)=CH-CH=CH2, -CH(CH3)-CH=CH-CH=CH2, -CH=CH-CH2-C(CH3)=CH2, -CH=CH-CH(CH3)-CH=CH2, -CH=C(CH3)-CH2-CH=CH2, -C(CH3)=CH-CH2-CH=CH2, -CH=CH-CH=C(CH3)2, -CH=CH-C(CH3)=CH-CH3, -CH=C(CH3)-CH=CH-CH3, -C(CH3)=CH-CH=CH-CH3, -CH=C(CH3)-C(CH3)=CH2, -C(CH3)=CH-C(CH3)=CH2, -C(CH3)=C(CH3)-CH=CH2, -CH=CH-CH=CH-CH=CH2, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -C2H4-C≡CH, -CH2-C≡C-CH3, -C≡C-C2H5, -C3H6-C≡CH, -C2H4-C≡C-CH3, -CH2-C≡C-C2H5, -C≡C-C3H7, -CH(CH3)-C≡CH, -CH2-CH(CH3)-C≡CH, -CH(CH3)-CH2-C≡CH, -CH(CH3)-C≡C-CH3, -C4H8-C≡CH, -C3H6-C≡C-CH3, -C2H4-C≡C-C2H5, -CH2-C≡C-C3H7, -C≡C-C4H9, -C2H4-CH(CH3)-C≡CH, -CH2-CH(CH3)-CH2-C≡CH, -CH(CH3)-C2H4-C≡CH, -CH2-CH(CH3)-C≡C-CH3, -CH(CH3)-CH2-C≡C-CH3, -CH(CH3)-C≡C-C2H5, -CH2-C≡C-CH(CH3)2, -C≡C-CH(CH3)-C2H5, -C≡C-CH2-CH(CH3)2, -C≡C-C(CH3)3, -CH(C2H5)-C≡C-CH3, -C(CH3)2-C≡C-CH3, -CH(C2H5)-CH2-C≡CH, -CH2-CH(C2H5)-C≡CH, -C(CH3)2-CH2-C≡CH, -CH2-C(CH3)2-C≡CH, -CH(CH3)-CH(CH3)-C≡CH, -CH(C3H7)-C≡CH, -C(CH3)(C2H5)-C≡CH, -C≡C-C≡CH, -CH2-C≡C-C≡CH, -C≡C-C≡C-CH3, -CH(C≡CH)2, -C2H4-C≡C-C≡CH, -CH2-C≡C-CH2-C≡CH, -C≡C-C2H4-C≡CH, -CH2-C≡C-C≡C-CH3, -C≡C-CH2-C≡C-CH3, -C≡C-C≡C-C2H5, -C≡C-CH(CH3)-C≡CH, -CH(CH3}-C≡C-C≡CH, -CH(C≡CH)-CH2-C≡CH, -C(C≡CH)2-CH3, -CH2-CH(C≡CH)2, -CH(C≡CH)-C≡C-CH3, -O-CH2-CH(OCH3)2, -O-CH2-CH(OC2H5)2, -O-C2H4-CH(OCH3)2, -O-C2H4-CH(OC2H5)2, -NH-CH2-CH(OCH3)2, -NH-CH2-CH(OC2H5)2, -NH-C2H4-CH(OCH3)2, -NH-C2H4-CH(OC2H5)2, -CH2-CH(OCH3)2 oder -CH2-CH(OC2H5)2;
Figure 00180001
R14, R15, R16, R17, R18, R19, R20, R21, R22, R24, R25, R27 unabhängig voneinander folgende Reste bedeuten:
-H, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, cyclo-C6H11, cyclo-C7H13, cyclo-C8H15, -Ph, -CH2-Ph, -CH2-CH2-Ph, -CH2-CH2-CH2-Ph, -CH=CH-Ph, -C≡C-Ph, -CPh3, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -C5H11, -CH(CH3)-C3H7, -CH2-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2, -C(CH3)2-C2H5, -CH2-C(CH3)3, -CH(C2H5)2, -C2H4-CH(CH3)2, -C6H13, -C7H15, -C8H17, -C3H6-CH(CH3)2, -C2H4-CH(CH3)-C2H5, -CH(CH3)-C4H9, -CH2-CH(CH3)-C3H7, -CH(CH3)-CH2-CH(CH3)2, -CH(CH3)-CH(CH3)-C2H5, -CH2-CH(CH3)-CH(CH3)2, -CH2-C(CH3)2-C2H5, -C(CH3)2-C3H7, -C(CH3)2-CH(CH3)2, -C2H4-C(CH3)3, -CH(CH3)-C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C2H4-CH=CH2, -CH2-CH=CH-CH3, -CH=CH-C2H5, -CH2-C(CH3)=CH2, -CH(CH3)-CH=CH, -CH=C(CH3)2, -C(CH3)=CH-CH3, -CH=CH-CH=CH2, -C3H6-CH=CH2, -C2H4-CH=CH-CH3, -CH2-CH=CH-C2H5, -CH=CH-C3H7, -CH2-CH=CH-CH=CH2, -CH=CH-CH=CH-CH3, -CH=CH-CH2-CH=CH2, -C(CH3)=CH-CH=CH2, -CH=C(CH3)-CH=CH2, -CH=CH-C(CH3)=CH2, -C2H4-C(CH3)=CH2, -CH2-CH(CH3)-CH=CH2, -CH(CH3)-CH2-CH=CH2, -CH2-CH=C(CH3)2, -CH2-C(CH3)=CH-CH3, -CH(CH3)-CH=CH-CH3, -CH=CH-CH(CH3)2, -CH=C(CH3)-C2H5, -C(CH3)=CH-C2H5, -C(CH3)=C(CH3)2, -C(CH3)2-CH=CH2, -CH(CH3)-C(CH3)=CH2, -C(CH3)=CH-CH=CH2, -CH=C(CH3)-CH=CH2, -CH=CH-C(CH3)=CH2, -C4H8-CH=CH2, -C3H6-CH=CH-CH3, -C2H4-CH=CH-C2H5, -CH2-CH=CH-C3H7, -CH=CH-C4H9, -C3H6-C(CH3)=CH2, -C2H4-CH(CH3)-CH=CH2, -CH2-CH(CH3)-CH2-CH=CH2, -CH (CH3)-C2H4-CH=CH2, -C2H4-CH=C(CH3)2, -C2H4-C(CH3)=CH-CH3, -CH2-CH(CH3)-CH=CH-CH3, -CH(CH3)-CH2-CH=CH-CH3, -CH2-CH=CH-CH(CH3)2, -CH2-CH=C(CH3)-C2H5, -CH2-C(CH3)=CH-C2H5, -CH(CH3)-CH=CH-C2H5, -CH=CH-CH2-CH(CH3)2, -CH=CH-CH(CH3)-C2H5, -CH=C(CH3)-C3H7, -C(CH3)=CH-C3H7, -CH2-CH(CH3)-C(CH3)=CH2, -CH(CH3)-CH2-C(CH3)=CH2, -CH(CH3)-CH(CH3)-CH=CH2, -CH2-C(CH3)2-CH=CH2, -C(CH3)2-CH2-CH=CH2, -CH2-C(CH3)=C(CH3)2, -CH(CH3)-CH=C(CH3)2, -C(CH3)2-CH=CH-CH3, -CH(CH3)-C(CH3)=CH-CH3, -CH=C(CH3)-CH(CH3)2, -C(CH3)=CH-CH(CH3)2, -C(CH3)=C(CH3)-C2H5, -CH=CH-C(CH3)3, -C(CH3)2-C(CH3)=CH2, -CH(C2H5)-C(CH3)=CH2, -C(CH3)(C2H5)-CH=CH2, -CH(CH3)-C(C2H5)=CH2, -CH2-C(C3H7)=CH2, -CH2-C(C2H5)=CH-CH3, -CH(C2H5)-CH=CH-CH3, -C(C4H9)=CH2, -C(C3H7)=CH-CH3, -C(C2H5)=CH-C2H5, -C(C2H5)=C(CH3)2, -C[C(CH3)3]=CH2, -C[CH(CH3)(C2H5)]=CH2, -C[CH2-CH(CH3)2]=CH2, -C2H4-CH=CH-CH=CH2, -CH2-CH=CH-CH2-CH=CH2, -CH=CH-C2H4-CH=CH2, -CH2-CH=CH-CH=CH-CH3, -CH=CH-CH2-CH=CH-CH3, -CH=CH-CH=CH-C2H5, -CH2-CH=CH-C(CH3)=CH2, -CH2-CH=C(CH3)-CH=CH2, -CH2-C(CH3)=CH-CH=CH2, -CH(CH3)-CH=CH-CH=CH2, -CH=CH-CH2-C(CH3)=CH2, -CH=CH-CH(CH3)-CH=CH2, -CH=C(CH3)-CH2-CH=CH2, -C(CH3)=CH-CH2-CH=CH2, -CH=CH-CH=C(CH3)2, -CH=CH-C(CH3)=CH-CH3, -CH=C(CH3)-CH=CH-CH3, -C(CH3)=CH-CH=CH-CH3, -CH=C(CH3)-C(CH3)=CH2, -C(CH3)=CH-C(CH3)=CH2, -C(CH3)=C(CH3)-CH=CH2, -CH=CH-CH=CH-CH=CH2, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -C2H4-C≡CH, -CH2-C≡C-CH3, -C≡C-C2H5, -C3H6-C≡CH, -C2H4-C≡C-CH3, -CH2-C≡C-C2H5, -C≡C-C3H7, -CH(CH3)-C≡CH, -CH2-CH(CH3)-C≡CH, -CH(CH3)-CH2-C≡CH, -CH(CH3)-C≡C-CH3, -C4H8-C≡CH, -C3H6-C≡C-CH3, -C2H4-C≡C-C2H5, -CH2-C≡C-C3H7, -C≡C-C4H9, -C2H4-CH(CH3)-C≡CH, -CH2-CH(CH3)-CH2-C≡CH, -CH(CH3)-C2H4-C≡CH, -CH2-CH(CH3)-C≡C-CH3, -CH(CH3)-CH2-C≡C-CH3, -CH(CH3)-C≡C-C2H5, -CH2-C≡C-CH(CH3)2, -C≡C-CH(CH3)-C2H5, -C≡C-CH2-CH(CH3)2, -C≡C-C(CH3)3, -CH(C2H5)-C≡C-CH3, -C(CH3)2-C≡C-CH3, -CH(C2H5)-CH2-C≡CH, -CH2-CH(C2H5)-C≡CH, -C(CH3)2-CH2-C≡CH, -CH2-C(CH3)2-C≡CH, -CH(CH3)-CH(CH3)-C≡CH, -CH(C3H7)-C≡CH, -C(CH3)(C2H5)-C≡CH, -C≡C-C≡CH, -CH2-C≡C-C≡CH, -C≡C-C≡C-CH3, -CH(C≡CH)2, -C2H4-C≡C-C≡CH, -CH2-C≡C-CH2-C≡CH, -C≡C-C2H4-C≡CH, -CH2-C≡C-C≡C-CH3, -C≡C-CH2-C≡C-CH3, -C≡C-C≡C-C2H5, -C≡C-CH(CH3)-C≡CH, -CH(CH3)-C≡C-C≡CH, -CH(C≡CH)-CH2-C≡CH, -C(C≡CH)2-CH3, -CH2-CH(C≡CH)2, -CH(C≡CH)-C≡C-CH3, -OH, -OCH3, -OC2H5, -OC3H7, -O-cyclo-C3H5, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OPh, -OCH2-Ph, -OCPh3, -SH, -NO2, -SCH3, -SC2H5, -SC3H7, -S-cyclo-C3H5, -SCH(CH3)2, -SC(CH3)3, -F, -Cl, -Br, -I, -P(O)(OH)2, -P(O)(OCH3)2, -P(O)(OC2H5)2, -P(O)(OCH(CH3)2)2, -C(OH)[P(O)(OH)2]2, -Si(CH3)2(C(CH3)3), -Si(C2H5)3, -Si(CH3)3, -N3, -CN, -OCN, -NCO, -SCN, -NCS, -CHO, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -COCN, -COOCH3, -COOC2H5, -COOC3H7, -COO-cyclo-C3H5, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-C2H5, -OOC-C3H7, -OOC-cyclo-C3H5, -OOC-CH(CH3)2, -OOC-C(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-C3H5, -CONH[CH(CH3)2], -CONH[C(CH3)3], -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON(cyclo-C3H5)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -NHCOCH3, -NHCOC2H5, -NHCOC3H7, -NHCO-cyclo-C3H5, -NHCO-CH(CH3)2, -NHCO-C(CH3)3, -NHCO-OCH3, -NHCO-OC2H5, -NHCO-OC3H7, -NHCO-O-cyclo-C3H5, -NHCO-OCH(CH3)2, -NHCO-OC(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NH-cyclo-C3H5, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N(cyclo-C3H5)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -SOCH3, -SOC2H5, -SOC3H7, -SO-cyclo-C3H5, -SOCH(CH3)2, -SOC(CH3)3, -SO2CH3, -SO2C2H5, -SO2C3H7, -SO2-cyclo-C3H5, -SO2CH(CH3)2, -SO2C(CH3)3, -SO3H, -SO3CH3, -SO3C2H5, -SO3C3H7, -SO3-cyclo-C3H5, -SO3CH(CH3)2, -SO3C(CH3)3, -O-SO2CH3, -O-SO2C2H5, -O-SO2C3H7, -O-SO2-cyclo-C3H5, -O-SO2CH(CH3)2, -O-SO2C(CH3)3, -SO2NH2, -OCF3, -OC2F5, -O-COOCH3, -O-COOC2H5, -O-COOC3H7, -O-COO-cyclo-C3H5, -O-COOCH(CH3)2, -O-COOC(CH3)3, -NH-CO-NH2, -NH-CO-NHCH3, -NH-CO-NHC2H5, -NH-CO-NHC3H7, -NH-CO-NH-cyclo-C3H5, -NH-CO-NH[CH(CH3)2], -NH-CO-NH[C(CH3)3], -NH-CO-N(CH3)2, -NH-CO-N(C2H5)2, -NH-CO-N(C3H7)2, -NH-CO-N(cyclo-C3H5)2, -NH-CO-N[CH(CH3)2]2, -NH-CO-N[C(CH3)3]2, -NH-CS-NH2, -NH-CS-NHCH3, -NH-CS-NHC2H5, -NH-CS-NHC3H7, -NH-CS-NH-cyclo-C3H5, -NH-CS-NH[CH(CH3)2], -NH-CS-NH[C(CH3)3], -NH-CS-N(CH3)2, -NH-CS-N(C2H5)2, -NH-CS-N(C3H7)2, -NH-CS-N(cyclo-C3H5)2, -NH-CS-N[CH(CH3)2]2, -NH-CS-N[C(CH3)3]2, -NH-C(=NH)-NH2, -NH-C(=NH)-NHCH3, -NH-C(=NH)-NHC2H5, -NH-C(=NH)-NHC3H7, -NH-C(=NH)-NH-cyclo-C3H5, -NH-C(=NH)-NH[CH(CH3)2], -NH-C(=NH)-NH[C(CH3)3], -NH-C(=NH)-N(CH3)2, -NH-C(=NH)-N(C2H5)2, -NH-C(=NH)-N(C3H7)2, -NH-C(=NH)-N(cyclo-C3H5)2, -O-CO-NH2, -NH-C(=NH)-N[CH(CH3)2]2, -NH-C(=NH)-N[C(CH3)3]2, -O-CO-NHCH3, -O-CO-NHC2H5, -O-CO-NHC3H7, -O-CO-NH-cyclo-C3H5, -O-CO-NH[CH(CH3)2], -O-CO-NH[C(CH3)3], -O-CO-N(CH3)2, -O-CO-N(C2H5)2, -O-CO-N(C3H7)2, -O-CO-N(cyclo-C3H5)2 , -O-CO-N[CH(CH3)2]2, -O-CO-N[C(CH3)3]2, -O-CO-OCH3, -O-CO-OC2H5, -O-CO-OC3H7, -O-CO-O-cyclo-C3H5, -O-CO-OCH(CH3)2, -O-CO-OC(CH3)3, -O-CH2-CH(OCH3)2, -O-CH2-CH(OC2H5)2, -O-C2H4-CH(OCH3)2, -O-C2H4-CH(OC2H5)2, -NH-CH2-CH(OCH3)2, -NH-CH2-CH(OC2H5)2, -NH-C2H4-CH(OCH3)2, -NH-C2H4-CH(OC2H5)2, -CH2-OPh, -CH2-O-CH2Ph, -NH-CH2-OH, -NH-C2H4-OH, -NH-C3H6-OH, -NH-C4H8-OH, -NH-C5H10-OH, -NH-CH2-OCH3, -NH-C2H4-OCH3, -NH-C3H6-OCH3, -NH-C4H8-OCH3, -NH-C5H10-OCH3, -NH-CH2-OC2H5, -NH-C2H4-OC2H5, -NH-C3H6-OC2H5, -NH-C4H8-OC2H5, -NH-C5H10-OC2H5, -CH2-OH, -C2H4-OH, -C3H6-OH, -C4H8-OH, -C5H10-OH, -CH2-CH(OCH3)2 oder -CH2-CH(OC2H5)2;
X1, X2, X3, X4, X5, X6, X7, X8, X9, X10 ' X11, X12, X13 und X14 unabhängig voneinander folgende Reste bedeuten:
-H, -CF3, -CH3, -C2H5, -C3H7, -CH(CH3)2, -OH, -OCH3, -OC2H5, -OC3H7, -OPh, -NO2, -F, -Cl, -Br, -I, -CN, -COCH3, -COC2H5, -COC3H7, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -OCF3, -Ph, oder -CH2-Ph, Tetrazol;
X15 für einen der folgenden Reste steht:
-H, -CF3, -CH3, -C2H5, -C3H7, -CH(CH3)2, -OH, -OCH3, -OC2H5, -OC3H7, -OPh, -NO2, -F, -Cl, -Br, -I, -CN, -COCH3, -COC2H5, -COC3H7, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -OCF3, -CO-NH-R21, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -C5H11, -CH=CH2, -CH2-CH=CH2, -Ph, -CH2-Ph, -CH2-CH2-Ph, -CH2-CH2-CH2-Ph, -CH=CH-Ph oder -NH-CO-R21;
n ist eine ganze Zahl ausgewählt aus 1, 2, 3, 4 oder 5;
sowie deren Metallkomplexe, Salze, Enantiomere, Enantiomerengemische, Diastereomere, Diastereomerengemische, Tautomere, Hydrate, Solvate, und Racemate der vorgenannten Verbindungen.Thus, the present invention relates to compounds of general formula (I)
Figure 00030001
wherein
R 1 is one of the following radicals:
Figure 00040001
Figure 00050001
Figure 00060001
Figure 00070001
Figure 00080001
Figure 00090001
Figure 00100001
R 2 is one of the following radicals -X 15 ,
Figure 00100002
Figure 00110001
Figure 00120001
Figure 00130001
Figure 00140001
Figure 00150001
R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 independently of one another represent the following radicals:
-R 14 , -R 15 , -R 16 , -R 17 , -R 18 , -R 19 , -R 20 , - (CH 2 ) n -R 14 , - (CH 2 ) n -R 15 , - ( CH 2 ) n -R 16 , - (CH 2 ) n -R 17 , - (CH 2 ) n -R 18 , - (CH 2 ) n -R 19 , - (CH 2 ) n -R 20 ;
Figure 00150002
Figure 00160001
-H, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 Cl, -CH 2 Br, -CH 2 I, -CH 2 -CH 2 F, -CH 2 -CHF 2 , -CH 2 - CF 3 , -CH 2 -CH 2 Cl, -CH 2 -CH 2 Br, -CH 2 -CH 2 I, cyclo-C 3 H 5 , cyclo-C 4 H 7 , cyclo-C 5 H 9 , cyclo- C 6 H 11 , cyclo-C 7 H 13 , cyclo-C 8 H 15 , -Ph, -CH 2 -Ph, -CH 2 -CH 2 -Ph, -CH 2 -CH 2 -CH 2 -Ph, CH = CH-Ph, -C≡C-Ph, -CPh 3 , -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH (CH 3 ) 2 , -C 4 H 9 , -CH 2 -CH (CH 3 ) 2 , -CH (CH 3 ) -C 2 H 5 , -C (CH 3 ) 3 , -C 5 H 11 , -CH (CH 3 ) -C 3 H 7 , -CH 2 - CH (CH 3 ) - C 2 H 5 , -CH (CH 3 ) -CH (CH 3 ) 2 , -C (CH 3 ) 2 -C 2 H 5 , -CH 2 -C (CH 3 ) 3 , -CH (C 2 H 5 ) 2 , -C 2 H 4 -CH (CH 3 ) 2 , -C 6 H 13 , -C 7 H 15 , -C 8 H 17 , -C 3 H 6 -CH (CH 3 ) 2 , -C 2 H 4 is -CH (CH 3 ) -C 2 H 5 , -CH (CH 3 ) -C 4 H 9 , -CH 2 -CH (CH 3 ) -C 3 H 7 , -CH (CH 3 ) -CH 2 -CH (CH 3 ) 2 , -CH (CH 3 ) -CH (CH 3 ) -C 2 H 5 , -CH 2 -CH (CH 3 ) -CH (CH 3 ) 2 , -CH 2 -C (CH 3 ) 2 -C 2 H 5 , -C (CH 3 ) 2 -C 3 H 7 , -C (CH 3 ) 2 -CH (CH 3 ) 2 , -C 2 H 4 -C (CH 3 ) 3 , -CH (CH 3 ) -C (CH 3 ) 3 , -CH = CH 2 , -CH 2 -CH = CH 2 , -C (CH 3 ) = CH 2 , -CH = CH-CH 3 , -C 2 H 4 -CH = CH 2 , -CH 2 -CH = CH-CH 3 , -CH = CH-C 2 H 5 , -CH 2 -C (CH 3 ) = CH 2 , -CH (CH 3 ) -CH = CH, -CH = C (CH 3) 2, -C (CH 3) = CH-CH 3, -CH = CH-CH = CH 2, -C 3 H 6 -CH = CH 2, -C 2 H 4 -CH = CH-CH 3 , -CH 2 -CH = CH-C 2 H 5 , -CH = CH-C 3 H 7 , -CH 2 -CH = CH-CH = CH 2 , -CH = CH- CH = CH-CH 3, -CH = CH-CH 2 -CH = CH 2, -C (CH 3) = CH-CH = CH 2, -CH = C (CH 3) -CH = CH 2, -CH = CH-C (CH 3 ) = CH 2 , -C 2 H 4 -C (CH 3 ) = CH 2 , -CH 2 -CH (CH 3 ) -CH = CH 2 , -CH (CH 3 ) -CH 2 -CH = CH 2 , -CH 2 -CH = C (CH 3 ) 2 , -CH 2 -C (CH 3 ) = CH-CH 3 , -CH (CH 3 ) -CH = CH-CH 3 , -CH = CH-CH (CH 3 ) 2 , -CH = C ( CH 3 ) -C 2 H 5 , -C (CH 3 ) CHCH-C 2 H 5 , -C (CH 3 ) CC (CH 3 ) 2 , -C (CH 3 ) 2 -CH = CH 2 , -CH (CH 3) -C (CH 3) = CH 2, -C (CH 3) = CH-CH = CH 2, -CH = C (CH 3) -CH = CH 2, -CH = CH-C (CH 3 ) = CH 2 , -C 4 H 8 -CH = CH 2 , -C 3 H 6 -CH = CH-CH 3 , -C 2 H 4 -CH = CH-C 2 H 5 , -CH 2 -CH = CH-C 3 H 7 , -CH = CH-C 4 H 9 , -C 3 H 6 -C (CH 3 ) = CH 2 , -C 2 H 4 -CH (CH 3 ) -CH = CH 2 , -CH 2 -CH (CH 3 ) -CH 2 -CH = CH 2 , -CH (CH 3 ) -C 2 H 4 -CH = CH 2 , -C 2 H 4 -CH = C (CH 3 ) 2 , -C 2 H 4 -C (CH 3 ) CHCH-CH 3 , -CH 2 -CH (CH 3 ) -CH = CH-CH 3 , -CH (CH 3 ) -CH 2 -CH = CH- CH 3 , -CH 2 -CH = CH-CH (CH 3 ) 2 , -CH 2 -CH = C (CH 3 ) -C 2 H 5 , -CH 2 -C (CH 3 ) = CH-C 2 H 5 , -CH (CH 3 ) -CH = CH-C 2 H 5 , - CH = CH-CH 2 -CH (CH 3 ) 2 , -CH = CH-CH (CH 3 ) -C 2 H 5 , -CH = C (CH 3 ) -C 3 H 7 , -C (CH 3 ) = CH-C 3 H 7, -CH 2 -CH (CH 3) -C (CH 3) = CH 2, -CH (CH 3) -CH 2 -C (CH 3) = CH 2, -CH (CH 3 ) -CH (CH 3 ) -CH = CH 2 , -CH 2 -C (CH 3 ) 2 -CH = CH 2 , -C (CH 3 ) 2 -CH 2 -CH = CH 2 , -CH 2 - C (CH 3) = C (CH 3) 2, -CH (CH 3) -CH = C (CH 3) 2, -C (CH 3) 2 -CH = CH-CH 3, -CH (CH 3) -C (CH 3 ) = CH-CH 3 , -CH = C (CH 3 ) -CH (CH 3 ) 2 , -C (CH 3 ) = CH-CH (CH 3 ) 2 , -C (CH 3 ) = C (CH 3 ) -C 2 H 5 , -CH = CH-C (CH 3 ) 3 , -C (CH 3 ) 2 -C (CH 3 ) = CH 2 , -CH (C 2 H 5 ) - C (CH 3 ) = CH 2 , -C (CH 3 ) (C 2 H 5 ) -CH = CH 2 , -CH (CH 3 ) -C (C 2 H 5 ) = CH 2 , -CH 2 -C (C 3 H 7 ) = CH 2 , -CH 2 -C (C 2 H 5 ) = CH-CH 3 , -CH (C 2 H 5 ) -CH = CH-CH 3 , -C (C 4 H 9 ) = CH 2 , -C (C 3 H 7 ) = CH-CH 3 , -C (C 2 H 5 ) = CH-C 2 H 5 , -C (C 2 H 5 ) = C (CH 3 ) 2 , -C [C (CH 3 ) 3 ] = CH 2 , -C [CH (CH 3 ) (C 2 H 5 )] = CH 2 , -C [CH 2 -CH (CH 3 ) 2 ] = CH 2 , -C 2 H 4 -CH = CH-CH = CH 2 , -CH 2 -CH = CH-CH 2 -CH = CH 2 , -CH = CH-C 2 H 4 -CH = CH 2 , -CH 2 -CH = CH-CH = CH-CH 3 , -CH = CH-CH 2 -CH = CH-CH 3 , -CH = CH-CH = CH-C 2 H 5 , -CH 2 -CH = CH-C (CH 3 ) = CH 2 , -CH 2 -CH = C (CH 3 ) -CH = CH 2 , -CH 2 -C (CH 3 ) = CH-CH = CH 2 , -CH (CH 3 ) -CH = CH-CH = CH 2 , -CH = CH-CH 2 -C (CH 3 ) = CH 2 , -CH = CH-CH (CH 3 ) -CH = CH 2 , -CH = C (CH 3 ) -CH 2 -CH = CH 2 , -C (CH 3 ) = CH-CH 2 -CH = CH 2 , -CH = CH-CH = C (CH 3 ) 2 , -CH = CH-C (CH 3) = CH-CH 3, -CH = C (CH 3) -CH = CH-CH 3, -C (CH 3) = CH-CH = CH-CH 3, -CH = C (CH 3) -C (CH 3) = CH 2, -C (CH 3) = CH-C (CH 3) = CH 2, -C (CH 3) = C (CH 3) -CH = CH 2 , -CH = CH-CH = CH-CH = CH 2 , -C≡CH, -C≡C-CH 3 , -CH 2 -C≡CH, -C 2 H 4 -C≡CH, -CH 2 -C≡C-CH 3 , -C≡CC 2 H 5 , -C 3 H 6 -C≡CH, -C 2 H 4 -C≡C-CH 3 , -CH 2 -C≡CC 2 H 5 , -C≡CC 3 H 7 , -CH (CH 3 ) -C≡CH, -CH 2 -CH (CH 3 ) -C≡CH, -CH (CH 3 ) -CH 2 -C≡CH, -CH ( CH 3 ) -C≡C-CH 3 , -C 4 H 8 -C≡CH, -C 3 H 6 -C≡C-CH 3 , -C 2 H 4 -C≡CC 2 H 5 , -CH 2 -C≡CC 3 H 7 , -C≡CC 4 H 9 , -C 2 H 4 -CH (CH 3 ) -C≡CH, -CH 2 -CH (CH 3 ) -CH 2 -C≡CH, - CH (CH 3 ) -C 2 H 4 -C≡CH, -CH 2 -CH (CH 3 ) -C≡C-CH 3 , -CH (CH 3 ) -CH 2 -C≡C-CH 3 , CH (CH 3 ) -C≡CC 2 H 5 , -CH 2 -C≡C-CH (CH 3 ) 2 , -C≡C-CH (CH 3 ) -C 2 H 5 , -C≡C-CH 2 -CH (CH 3 ) 2 , -C≡CC (CH 3 ) 3 , -CH ( C 2 H 5 ) -C≡C-CH 3 , -C (CH 3 ) 2 -C≡C-CH 3 , -CH (C 2 H 5 ) -CH 2 -C≡CH, -CH 2 -CH ( C 2 H 5 ) -C≡CH, -C (CH 3 ) 2 -CH 2 -C≡CH, -CH 2 -C (CH 3 ) 2 -C≡CH, -CH (CH 3 ) -CH (CH 3 ) -C≡CH, -CH (C 3 H 7 ) -C≡CH, -C (CH 3 ) (C 2 H 5 ) -C≡CH, -C≡CC≡CH, -CH 2 -C≡ CC≡CH, -C≡CC≡C-CH 3 , -CH (C≡CH) 2 , -C 2 H 4 -C≡CC≡CH, -CH 2 -C≡C-CH 2 -C≡CH, -C≡CC 2 H 4 -C≡CH, -CH 2 -C≡CC≡C-CH 3 , -C≡C-CH 2 -C≡C-CH 3 , -C≡CC≡CC 2 H 5 , -C≡C-CH (CH 3 ) -C≡CH, -CH (CH 3 ) -C≡CC≡CH, -CH (C≡CH) -CH 2 -C≡CH, -C (C≡CH) 2 -CH 3 , -CH 2 -CH (C≡CH) 2 , -CH (C≡CH) -C≡C-CH 3 , -O-CH 2 -CH (OCH 3 ) 2 , -O-CH 2 -CH (OC 2 H 5 ) 2 , -OC 2 H 4 -CH (OCH 3 ) 2 , -OC 2 H 4 -CH (OC 2 H 5 ) 2 , -NH-CH 2 -CH (OCH 3 ) 2 , -NH-CH 2 -CH (OC 2 H 5 ) 2 , -NH-C 2 H 4 -CH (OCH 3 ) 2 , -NH-C 2 H 4 -CH (OC 2 H 5 ) 2 , -CH 2 -CH (OCH 3 ) 2 or -CH 2 -CH (OC 2 H 5 ) 2 ;
Figure 00180001
R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 24 , R 25 , R 27 independently of one another are the following radicals:
-H, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 Cl, -CH 2 Br, -CH 2 I, -CH 2 -CH 2 F, -CH 2 -CHF 2 , -CH 2 - CF 3 , -CH 2 -CH 2 Cl, -CH 2 -CH 2 Br, -CH 2 -CH 2 I, cyclo-C 3 H 5 , cyclo-C 4 H 7 , cyclo-C 5 H 9 , cyclo- C 6 H 11 , cyclo-C 7 H 13 , cyclo-C 8 H 15 , -Ph, -CH 2 -Ph, -CH 2 -CH 2 -Ph, -CH 2 -CH 2 -CH 2 -Ph, CH = CH-Ph, -C≡C-Ph, -CPh 3 , -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH (CH 3 ) 2 , -C 4 H 9 , -CH 2 -CH (CH 3 ) 2 , -CH (CH 3 ) -C 2 H 5 , -C (CH 3 ) 3 , -C 5 H 11 , -CH (CH 3 ) -C 3 H 7 , -CH 2 - CH (CH 3 ) -C 2 H 5 , -CH (CH 3 ) -CH (CH 3 ) 2 , -C (CH 3 ) 2 -C 2 H 5 , -CH 2 -C (CH 3 ) 3 , - CH (C 2 H 5 ) 2 , -C 2 H 4 -CH (CH 3 ) 2 , -C 6 H 13 , -C 7 H 15 , -C 8 H 17 , -C 3 H 6 -CH (CH 3 ) 2 , -C 2 H 4 -CH (CH 3 ) -C 2 H 5 , -CH (CH 3 ) -C 4 H 9 , -CH 2 -CH (CH 3 ) -C 3 H 7 , -CH ( CH 3 ) -CH 2 -CH (CH 3 ) 2 , -CH (CH 3 ) -CH (CH 3 ) -C 2 H 5 , -CH 2 -CH (CH 3 ) -CH (CH 3 ) 2 , - CH 2 -C (CH 3 ) 2 -C 2 H 5 , -C (CH 3 ) 2 -C 3 H 7 , -C (CH 3 ) 2 -CH (CH 3 ) 2 , -C 2 H 4 -C (CH 3 ) 3 , -CH (CH 3 ) -C (CH 3 ) 3 , -CH = CH 2 , -CH 2 -CH = CH 2 , -C (CH 3 ) = CH 2 , -CH = CH-CH 3 , -C 2 H 4 -CH = CH 2 , -CH 2 -CH = CH-CH 3 , -CH = CH-C 2 H 5 , -CH 2 -C (CH 3 ) = CH 2 , -CH (CH 3 ) -CH = CH, -CH = C (CH 3 ) 2 , -C (CH 3 ) = CH-CH 3 , -CH = CH-CH = CH 2 , -C 3 H 6 -CH = CH 2 , -C 2 H 4 -CH = CH-CH 3 , -CH 2 -CH = CH-C 2 H 5 , -CH = CH-C 3 H 7 , -CH 2 -CH = CH-CH = CH 2 , -CH = CH-CH = CH-CH 3 , -CH = CH-CH 2 -CH = CH 2 , -C (CH 3 ) = CH -CH = CH 2 , -CH = C (CH 3 ) -CH = CH 2 , -CH = CH-C (CH 3 ) = CH 2 , -C 2 H 4 -C (CH 3 ) = CH 2 , - CH 2 -CH (CH 3 ) -CH = CH 2 , -CH (CH 3 ) -CH 2 -CH = CH 2 , -CH 2 -CH = C (CH 3 ) 2 , -CH 2 -C (CH 3 ) = CH-CH 3, -CH (CH 3) -CH = CH-CH 3, -CH = CH-CH (CH 3) 2, -CH = C (CH 3) -C 2 H 5, -C ( CH 3 ) = CH-C 2 H 5 , -C (CH 3 ) = C (CH 3 ) 2 , -C (CH 3 ) 2 -CH = CH 2 , -CH (CH 3 ) -C (CH 3 ) = CH 2 , -C (CH 3 ) = CH-CH = CH 2 , -CH = C (CH 3 ) -CH = CH 2 , -CH = CH-C (CH 3 ) = CH 2 , -C 4 H 8 -CH = CH 2 , -C 3 H 6 -CH = CH-CH 3 , -C 2 H 4 -CH = CH-C 2 H 5 , -CH 2 -CH = CH-C 3 H 7 , -CH = CH-C 4 H 9 , -C 3 H 6 -C (CH 3 ) CHCH 2 , -C 2 H 4 -CH (CH 3 ) -CH = CH 2 , -CH 2 -CH (CH 3 ) - CH 2 -CH = CH 2 , -CH (CH 3 ) -C 2 H 4 -CH = CH 2 , -C 2 H 4 -CH = C (CH 3 ) 2 , -C 2 H 4 -C (CH 3 ) = CH-CH 3 , -CH 2 -CH (CH 3 ) -CH = CH-CH 3 , -CH (CH 3 ) -CH 2 -CH = CH-CH 3 , -CH 2 -CH = CH-CH (CH 3 ) 2 , -CH 2 -CH = C (CH 3 ) -C 2 H 5 , -CH 2 -C (CH 3 ) = CH-C 2 H 5 , -CH (CH 3 ) -CH = CH-C 2 H 5 , -CH = CH-CH 2 -CH (CH 3 ) 2 , -CH = CH-CH ( CH 3 ) -C 2 H 5 , -CH = C (CH 3 ) -C 3 H 7 , -C (CH 3 ) = CH-C 3 H 7 , -CH 2 -CH (CH 3 ) -C (CH 3 ) = CH 2 , -CH (CH 3 ) -CH 2 -C (CH 3 ) = CH 2 , -CH (CH 3 ) -CH (CH 3 ) -CH = CH 2 , -CH 2 -C (CH 3 ) 2 -CH = CH 2 , -C (CH 3 ) 2 -CH 2 -CH = CH 2 , -CH 2 -C (CH 3 ) = C (CH 3 ) 2 , -CH (CH 3 ) -CH = C (CH 3) 2, -C (CH 3) 2 -CH = CH-CH 3, -CH (CH 3) -C (CH 3) = CH-CH 3, -CH = C (CH 3) - CH (CH 3 ) 2 , -C (CH 3 ) = CH-CH (CH 3 ) 2 , -C (CH 3 ) = C (CH 3 ) -C 2 H 5 , -CH = CH-C (CH 3 ) 3 , -C (CH 3 ) 2 -C (CH 3 ) = CH 2 , -CH (C 2 H 5 ) -C (CH 3 ) = CH 2 , -C (CH 3 ) (C 2 H 5 ) -CH = CH 2 , -CH (CH 3 ) -C (C 2 H 5 ) = CH 2 , -CH 2 -C (C 3 H 7 ) = CH 2 , -CH 2 -C (C 2 H 5 ) = CH-CH 3 , -CH (C 2 H 5 ) -CH = CH-CH 3 , -C (C 4 H 9 ) = CH 2 , -C (C 3 H 7 ) = CH-CH 3 , -C (C 2 H 5 ) = CH-C 2 H 5 , -C (C 2 H 5 ) = C (CH 3 ) 2 , -C [C (CH 3 ) 3 ] = CH 2 , -C [CH (CH 3 ) (C 2 H 5 )] = CH 2 , -C [CH 2 -CH (CH 3 ) 2 ] = CH 2 , -C 2 H 4 -CH = CH-CH = CH 2 , -CH 2 -CH = CH-CH 2 -CH = CH 2 , -CH = CH-C 2 H 4 -CH = CH 2 , -CH 2 -CH = CH-CH = CH- CH 3 , -CH = CH-CH 2 -CH = CH-CH 3 , -CH = CH-CH = CH-C 2 H 5 , -CH 2 -CH = CH-C (CH 3 ) = CH 2 , CH 2 -CH = C (CH 3 ) -CH = CH 2 , -CH 2 -C (CH 3 ) = CH-CH = CH 2 , -CH (CH 3 ) -CH = CH-CH = CH 2 , CH = CH-CH 2 -C (CH 3 ) = CH 2 , -CH = CH-CH (CH 3 ) -CH = CH 2 , -CH = C (CH 3 ) -CH 2 -CH = CH 2 , - C (CH 3) = CH-CH 2 -CH = CH 2, -CH = CH-CH = C (CH 3) 2, -CH = CH-C (CH 3) = CH-CH 3, -CH = C (CH 3) -CH = CH-CH 3, -C (CH 3) = CH-CH = CH-CH 3, -CH = C (CH 3) -C (CH 3) = CH 2, -C (CH 3) = CH-C (CH 3) = CH 2, -C (CH 3) = C (CH 3) -CH = CH 2, -CH = CH-CH = CH-CH = CH 2, -C≡CH , -C≡C-CH 3 , -CH 2 -C≡CH, -C 2 H 4 -C≡CH, -CH 2 -C≡C-CH 3 , -C≡CC 2 H 5 , -C 3 H 6 -C≡CH, -C 2 H 4 -C≡C-CH 3 , -CH 2 -C≡CC 2 H 5 , -C≡CC 3 H 7 , -CH (CH 3 ) -C≡CH, - CH 2 -CH (CH 3 ) -C≡CH, -CH (CH 3 ) -CH 2 -C≡CH, -CH (CH 3 ) -C≡C-CH 3 , -C 4 H 8 -C≡CH , -C 3 H 6 -C≡C-CH 3 , -C 2 H 4 -C≡CC 2 H 5 , -CH 2 -C≡CC 3 H 7 , -C≡CC 4 H 9 , -C 2 H 4 -CH (CH 3 ) -C≡CH, -CH 2 -CH (CH 3 ) -CH 2 -C≡CH, -CH (CH 3 ) -C 2 H 4 -C≡CH, -CH 2 -CH (CH 3 ) -C≡C-CH 3 , -CH (CH 3 ) -CH 2 -C≡C-CH 3 , -CH (CH 3 ) -C≡CC 2 H 5 , -CH 2 -C≡C-CH (CH 3 ) 2 , -C≡C-CH (CH 3 ) -C 2 H 5 , -C≡C- CH 2 -CH (CH 3 ) 2 , -C≡CC (CH 3 ) 3 , -CH (C 2 H 5 ) -C≡C-CH 3 , -C (CH 3 ) 2 -C≡C-CH 3 , -CH (C 2 H 5 ) -CH 2 -C≡CH, -CH 2 -CH (C 2 H 5 ) -C≡CH, -C (CH 3 ) 2 -CH 2 -C≡CH, -CH 2 -C (CH 3 ) 2 -C≡CH, -CH (CH 3 ) -CH (CH 3 ) -C≡CH, -CH (C 3 H 7 ) -C≡CH, -C (CH 3 ) ( C 2 H 5 ) -C≡CH, -C≡CC≡CH, -CH 2 -C≡CC≡CH, -C≡CC≡C-CH 3 , -CH (C≡CH) 2 , -C 2 H 4 -C≡CC≡CH, -CH 2 -C≡C-CH 2 -C≡CH, -C≡CC 2 H 4 -C≡CH, -CH 2 -C≡CC≡C-CH 3 , -C ≡C-CH 2 -C≡C-CH 3 , -C≡CC≡CC 2 H 5 , -C≡C-CH (CH 3 ) -C≡CH, -CH (CH 3 ) -C≡CC≡CH , -CH (C≡CH) -CH 2 -C≡CH, -C (C≡CH) 2 -CH 3 , -CH 2 -CH (C≡CH) 2 , -CH (C≡CH) -C≡ C-CH 3 , -OH, -OCH 3 , -OC 2 H 5 , -OC 3 H 7 , -O-cyclo-C 3 H 5 , -OCH (CH 3 ) 2 , -OC (CH 3 ) 3 , -OC 4 H 9 , -OPh, -OCH 2 -Ph, -OCPh 3 , -SH, -NO 2 , -SCH 3 , -SC 2 H 5 , -SC 3 H 7 , -S-cyclo-C 3 H 5 , - SCH (CH 3) 2, -SC (CH 3) 3, -F, -Cl, -Br, -I, -P (O) (OH) 2, -P (O) (OCH 3) 2, -P (O) (OC 2 H 5 ) 2 , -P (O) (OCH (CH 3 ) 2 ) 2 , -C (OH) [P (O) (OH) 2 ] 2 , -Si (CH 3 ) 2 (C (CH 3 ) 3 ) -Si (C 2 H 5 ) 3 , -Si (CH 3 ) 3 , -N 3 , -CN, -OCN, -NCO, -SCN, -NCS, -CHO, - COCH 3 , -COC 2 H 5 , -COC 3 H 7 , -CO-cyclo-C 3 H 5 , -COCH (CH 3 ) 2 , -COC (CH 3 ) 3 , -COOH, -COCN, -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 7 , -COO-cyclo-C 3 H 5 , -COOCH (CH 3 ) 2 , -COOC (CH 3 ) 3 , -OOC-CH 3 , -OCO-C 2 H 5 , -OOC-C 3 H 7 , -OOC-cyclo-C 3 H 5 , -OOC-CH (CH 3 ) 2 , -OOC-C (CH 3 ) 3 , -CONH 2 , -CONHCH 3 , - CONHC 2 H 5 , -CONHC 3 H 7 , -CONH -cycloC 3 H 5 , -CONH [CH (CH 3 ) 2 ], -CONH [C (CH 3 ) 3 ], -CON (CH 3 ) 2 , -CON (C 2 H 5 ) 2 , -CON (C 3 H 7 ) 2 , -CON (cyclo-C 3 H 5 ) 2 , -CON [CH (CH 3 ) 2 ] 2 , -CON [C ( CH 3 ) 3 ] 2 , -NHCOCH 3 , -NHCOC 2 H 5 , -NHCOC 3 H 7 , -NHCO-cyclo-C 3 H 5 , -NHCO-CH (CH 3 ) 2 , -NHCO-C (CH 3 ) 3 , -NHCO- OCH 3 , -NHCO-OC 2 H 5 , -NHCO-OC 3 H 7 , -NHCO-O-cyclo-C 3 H 5 , -NHCO-OCH (CH 3 ) 2 , -NHCO-OC (CH 3 ) 3 , -NH 2 , -NHCH 3 , -NHC 2 H 5 , -NHC 3 H 7 , -NH-cyclo-C 3 H 5 , -NHCH (CH 3 ) 2 , -NHC (CH 3 ) 3 , -N ( CH 3 ) 2 , -N (C 2 H 5 ) 2 , -N (C 3 H 7 ) 2 , -N (cyclo-C 3 H 5 ) 2 , -N [CH (CH 3 ) 2 ] 2 , - N [C (CH 3 ) 3 ] 2 , -SOCH 3 , -SOC 2 H 5 , -SOC 3 H 7 , -SO-cyclo-C 3 H 5 , -SOCH (CH 3 ) 2 , -SOC (CH 3 ) 3 , -SO 2 CH 3 , -SO 2 C 2 H 5 , -SO 2 C 3 H 7 , -SO 2 -cyclo-C 3 H 5 , -SO 2 CH (CH 3 ) 2 , -SO 2 C (CH 3 ) 3 , -SO 3 H, -SO 3 CH 3 , -SO 3 C 2 H 5 , -SO 3 C 3 H 7 , -SO 3 -cyclo-C 3 H 5 , -SO 3 CH (CH 3 ) 2 , -SO 3 C (CH 3 ) 3 , -O-SO 2 CH 3 , -O-SO 2 C 2 H 5 , -O-SO 2 C 3 H 7 , -O-SO 2 -cyclo- C 3 H 5 , -O-SO 2 CH (CH 3 ) 2 , -O-SO 2 C (CH 3 ) 3 , -SO 2 NH 2 , -OCF 3 , -OC 2 F 5 , -O-COOCH 3 , -O-COOC 2 H 5 , -O-COOC 3 H 7 , -O-COO-cyclo-C 3 H 5 , -O-COOCH (CH 3 ) 2 , -O-COOC (CH 3 ) 3 , - NH-CO-NH 2 , -NH-CO-NHCH 3 , -NH-CO-NHC 2 H 5 , -NH-CO-NHC 3 H 7 , -NH-CO-NH-cyclo-C 3 H 5 , NH-CO-NH [CH (CH 3 ) 2 ], -NH-CO-NH [C (CH 3 ) 3 ], -NH-CO-N (CH 3 ) 2 , -NH-CO-N (C 2 H 5 ) 2 , -NH-CO- N (C 3 H 7 ) 2 , -NH-CO-N (cycloC 3 H 5 ) 2 , -NH-CO-N [CH (CH 3 ) 2 ] 2 , -NH-CO-N [C ( CH 3 ) 3 ] 2 , -NH-CS-NH 2 , -NH-CS-NHCH 3 , -NH-CS-NHC 2 H 5 , -NH-CS-NHC 3 H 7 , -NH-CS-NH- cyclo-C 3 H 5 , -NH-CS-NH [CH (CH 3 ) 2 ], -NH-CS-NH [C (CH 3 ) 3 ], -NH-CS-N (CH 3 ) 2 , NH-CS-N (C 2 H 5 ) 2 , -NH-CS-N (C 3 H 7 ) 2 , -NH-CS-N (cyclo-C 3 H 5 ) 2 , -NH-CS-N [ CH (CH 3 ) 2 ] 2 , -NH-CS-N [C (CH 3 ) 3 ] 2 , -NH-C (= NH) -NH 2 , -NH-C (= NH) -NHCH 3 , NH-C (= NH) -NHC 2 H 5 , -NH-C (= NH) -NHC 3 H 7 , -NH-C (= NH) -NH-cyclo-C 3 H 5 , -NH-C ( = NH) -NH [CH (CH 3 ) 2 ], -NH-C (= NH) -NH [C (CH 3 ) 3 ], -NH-C (= NH) -N (CH 3 ) 2 , - NH-C (= NH) -N (C 2 H 5 ) 2 , -NH-C (= NH) -N (C 3 H 7 ) 2 , -NH-C (= NH) -N (cyclo-C 3 H 5 ) 2 , -O-CO-NH 2 , -NH-C (= NH) -N [CH (CH 3 ) 2 ] 2 , -NH-C (= NH) -N [C (CH 3 ) 3 ] 2 , -O-CO-NHCH 3 , -O-CO-NHC 2 H 5 , -O-CO-NHC 3 H 7 , -O-CO-NH-cyclo-C 3 H 5 , -O-CO- NH [CH (CH 3 ) 2 ], -O-CO-NH [C (CH 3 ) 3 ], -O-CO-N (CH 3 ) 2 , -O-CO-N (C 2 H 5 ) 2 , -O-CO-N (C 3 H 7 ) 2 , -O-CO-N (cyclo-C 3 H 5 ) 2 , -O-CO-N [CH (CH 3 ) 2 ] 2 , -O-CO-N [C (CH 3 ) 3 ] 2 , -O-CO-OCH 3 , -O-CO-OC 2 H 5 , -O-CO-OC 3 H 7 , -O-CO-O-cyclo-C 3 H 5 , -O-CO -OCH (CH 3 ) 2 , -O-CO-OC (CH 3 ) 3 , -O-CH 2 -CH (OCH 3 ) 2 , -O-CH 2 -CH (OC 2 H 5 ) 2 , -OC 2 H 4 -CH (OCH 3 ) 2 , -OC 2 H 4 -CH (OC 2 H 5 ) 2 , -NH-CH 2 -CH (OCH 3 ) 2 , -NH-CH 2 -CH (OC 2 H 5 ) 2 , -NH-C 2 H 4 -CH (OCH 3 ) 2 , -NH-C 2 H 4 -CH (OC 2 H 5 ) 2 , -CH 2 -OPh, -CH 2 -O-CH 2 Ph, -NH-CH 2 -OH, -NH-C 2 H 4 -OH, -NH-C 3 H 6 -OH, -NH-C 4 H 8 -OH, -NH-C 5 H 10 -OH, -NH-CH 2 -OCH 3 , -NH-C 2 H 4 -OCH 3 , -NH-C 3 H 6 -OCH 3 , -NH-C 4 H 8 -OCH 3 , -NH-C 5 H 10 - OCH 3 , -NH-CH 2 -OC 2 H 5 , -NH-C 2 H 4 -OC 2 H 5 , -NH-C 3 H 6 -OC 2 H 5 , -NH-C 4 H 8 -OC 2 H 5 , -NH-C 5 H 10 -OC 2 H 5 , -CH 2 -OH, -C 2 H 4 -OH, -C 3 H 6 -OH, -C 4 H 8 -OH, -C 5 H 10 -OH, -CH 2 -CH (OCH 3 ) 2 or -CH 2 -CH (OC 2 H 5 ) 2 ;
X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 ' X 11 , X 12 , X 13 and X 14 independently of one another are the following radicals:
- H, -CF 3 , -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH (CH 3 ) 2 , -OH, -OCH 3 , -OC 2 H 5 , -OC 3 H 7 , - OPh, -NO 2 , -F, -Cl, -Br, -I, -CN, -COCH 3 , -COC 2 H 5 , -COC 3 H 7 , -COOH, -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 7 , -OCF 3 , -Ph, or -CH 2 -Ph, tetrazole;
X 15 stands for one of the following radicals:
-H, -CF 3 , -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH (CH 3 ) 2 , -OH, -OCH 3 , -OC 2 H 5 , -OC 3 H 7 , -OPh, -NO 2 , -F, -Cl, -Br, -I, -CN, -COCH 3 , -COC 2 H 5 , -COC 3 H 7 , -COOH, -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 7 , -OCF 3 , -CO-NH-R 21 , -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH (CH 3 ) 2 , -C 4 H 9 , - CH 2 -CH (CH 3 ) 2 , -CH (CH 3 ) -C 2 H 5 , -C (CH 3 ) 3 , -C 5 H 11 , -CH = CH 2 , -CH 2 -CH = CH 2 , -Ph, -CH 2 -Ph, -CH 2 -CH 2 -Ph, -CH 2 -CH 2 -CH 2 -Ph, -CH = CH-Ph or -NH-CO-R 21 ;
n is an integer selected from 1, 2, 3, 4 or 5;
and their metal complexes, salts, enantiomers, enantiomer mixtures, diastereomers, diastereomer mixtures, tautomers, hydrates, solvates, and racemates of the abovementioned compounds.

Die vorliegende Erfindung betrifft ferner Verbindungen gemäß der allgemeinen Formel (I) zur Verwendung als Inhibitoren oder Antagonisten, insbesondere bevorzugt als kompetitive Antagonisten oder inverse Agonisten von GSK-3.The present invention further relates to compounds according to general formula (I) for use as inhibitors or antagonists, more preferably as competitive antagonists or inverse agonists of GSK-3.

Antagonisten sind hierbei Verbindungen, welche durch vorrangige Interaktion mit der Kinase deren Aktivierung durch einen Agonisten verhindern oder hemmen können. Ein kompetitiver Antagonist konkurriert mit einem Agonisten um die Bindung an die Kinase und kann durch höhere Agonistenkonzentrationen entsprechend dem Massenwirkungsgesetz wieder verdrängt werden. Es kommt durch einen kompetitiven Antagonisten zu einer Parallelverschiebung der Dosis-Wirkungskurve eines Agonisten.Antagonists are compounds which, by preferential interaction with the kinase, can prevent or inhibit their activation by an agonist. A competitive antagonist competes with an agonist for binding to the kinase and can be repressed by higher agonist concentrations in accordance with the law of mass action. It comes through a competitive antagonist to a parallel shift of the dose-response curve of an agonist.

Inverse Agonisten sind hierin Verbindungen, die an die Kinase mit konstitutiver Aktivität binden und deren Aktivität herabsetzen. Ein inverser Agonist führt im Gegensatz zu einem vollen Agonisten somit zu einem negativen Effekt, bzw. einem pharmakologischen Effekt, welcher dem des Agonisten entgegengesetzt ist. Dies kann stattfinden, indem solche Verbindungen die Bindung eines Korepressors bewirken bzw. fördern. Die Verbindungen gemäß allgemeiner Formel (I) werden hierin allgemein als Inhibitoren von GSK-3 bezeichnet.Inverse agonists herein are compounds that bind to the kinase with constitutive activity and decrease its activity. An inverse agonist, in contrast to a full agonist thus leads to a negative effect, or a pharmacological effect, which is opposite to that of the agonist. This can take place by causing such compounds to bind a corepressor. The compounds of general formula (I) are generally referred to herein as inhibitors of GSK-3.

GSK-3 Inhibitoren sind für die Verwendung in der Medizin relevant, da GSK-3 in den letzten Jahren zunehmend mit schwer wiegenden Erkrankungen, wie Alzheimer-Krankheit und andere Tauopathien, Asthma, bipolare affektive Störungen, Depression, Nervenzelltod und Schlaganfall, Parkinson, Huntington, Skelettmuskelatrophie, Kardioprotektion, Haarverlust, verringerte Spermienmotilität, Diabetes und damit in Zusammenhang stehende Folgeerkrankungen, wie Syndrom X und Adipositas, Erkrankungen, die durch einzellige Parasiten verursacht werden, transmissible spongiforme Enzephalopathie, Schizophrenie, Krankheiten des zirkadianen Rhythmus und Krebs in Verbindung gebracht wurde.GSK-3 inhibitors are relevant for use in medicine, as GSK-3 has been increasingly associated with serious illnesses in recent years, such as Alzheimer's disease and other tauopathies, asthma, bipolar affective disorders, depression, neuronal death and stroke, Parkinson's, Huntington's , Skeletal muscle atrophy, cardioprotection, hair loss, decreased sperm motility, diabetes and related sequelae such as syndrome X and obesity, diseases caused by unicellular parasites, transmissible spongiform encephalopathy, schizophrenia, circadian rhythm diseases and cancer.

Des weiteren sind die folgenden subgenerischen Formeln der allgemeinen Formel (I) bevorzugt:

Figure 00230001
Figure 00240001
Figure 00250001
Furthermore, the following subgeneric formulas of the general formula (I) are preferred:
Figure 00230001
Figure 00240001
Figure 00250001

Herstellungmanufacturing

Die erfindungsgemäßen Verbindungen lassen sich nach folgenden Verfahren herstellen:

Figure 00260001
Z# = linearer oder verzweigter, gesättigter oder ungesättigter Alkylrest mit 1-10 Kohlenstoffatomen oder Arylrest mit 6 bis 14 Kohlenstoffatomen
Z = Schutzgruppe, z. B. BOC
Z* = Proton oder Kation

  • a) Umsetzung des Esters zum Carbohydrazid möglich durch: • Die Umsetzung erfolgt mittels Hydrazin*Hydrat als Lösungsmittel sowie Reagenz bei entsprechender Temperatur (im allgemeinen Rückfluss). Die Reaktionsführung verläuft solange bis ein vollständiger Umsatz resultiert. • Die Reaktion kann in verschiedenen Alkoholen als Lösungsmittel und unter Hinzugabe unterschiedlicher Äquivalente an Hydrazin*Hydrat (bis der Umsatz vollständig ist) bei entsprechender Temperatur (im allgemeinen Rückfluss) durchgeführt werden. Die Reaktionsführung erfolgt solange bis ein vollständiger Umsatz resultiert.
  • b) Verseifung des Esters zur Carbonsäure/Carboxylat: • Als Lösungsmittel dient Wasser, sowie ein Alkohol. Zur Verseifung werden Basen verwendet (beispielsweise NaOH, 1M). Es wird bei einer entsprechenden Temperatur (im allgemeinen Raumtemperatur) solange gerührt, bis die ein vollständiger Umsatz resultiert.
  • c) Synthese des Säurechlorids: • Die Umsetzung erfolgt in Thionylchlorid oder mit Thionylchlorid in einem entsprechenden Lösungsmittel (z. B. Toluol) oder durch ein anderes Chlorierungsreagenz, wie z. B. Triphosgen. Es wird bei einer entsprechenden Temperatur (im allgemeinen Raumtemperatur) solange gerührt, bis die ein vollständiger Umsatz resultiert.
  • d) Umsetzung zum Thiosemicarbazid: • Die Synthese vom Thiosemicarbazid erfolgt unter Zugabe von Kohlenstoffdisulfid und einer entsprechenden Base, beispielsweise Kaliumhydroxid, in einem Alkohol als Lösungsmittel, bei entsprechender Temperatur (im allgemeinen Raumtemperatur). Die Reaktionsführung erfolgt solange bis ein vollständiger Umsatz resultiert.
  • e) Umsetzung zum Oxadiazol ausgehend vom Carbazid: • Die Zyklisierung erfolgt unter Zugabe von einer entsprechenden Base, beispielsweise Triethylamin oder Kaliumhydroxid, in einem Alkohol als Lösungsmittel. Bei entsprechender Temperatur (im allgemeinen Rückfluss) erfolgt die Reaktionsführung solange bis ein vollständiger Umsatz resultiert.
  • f) Kupplungsreaktion zum Carbazid: • Die Kupplungsreaktion erfolgt unter Standardbedingungen. Neben einem Kupplungsreagenz (z. B. Carbodiimid), einer Base (z. B. HOBt*Hydrat) und evtl. einer Hilfsbase (z. B. NMP) wird die Reaktion bei entsprechender Temperatur (im allgemeinen Raumtemperatur) solange durchgeführt, bis ein vollständiger Umsatz resultiert.
  • g) Synthese des Carbazids: • Die Umsetzung erfolgt unter Verwendung von Hydrazin*Hydrat (pur oder in einem entsprechenden Lösungsmittel) oder des geschützten Analogons in einem entsprechenden Lösungsmittel und evtl. unter Verwendung einer Base. Bei entsprechender Temperatur erfolgt die Reaktionsführung solange bis ein vollständiger Umsatz resultiert.
  • h) Umsetzung zum Oxadiazol ausgehend vom Thiosemicarbazid: • Die Zyklisierung erfolgt unter Zugabe einer entsprechenden Base, beispielsweise Kaliumhydroxid. Als Lösungsmittel kommen Alkohole zum Einsatz. Bei entsprechender Temperatur (im allgemeinen Rückfluss), erfolgt die Reaktionsführung solange bis ein vollständiger Umsatz resultiert.
  • i) Substitutionsreaktion zum Thioether: • Die Umsetzung zum Thioether erfolgt mittels Zugabe einer entsprechenden Base, beispielsweise Triethylamin, in einem entsprechenden Lösungsmittel (z. B. DMF), bei entsprechender Temperatur (im allgemeinen Raumtemperatur) solange bis ein vollständiger Umsatz resultiert.
  • j) Entschützen: • Das Entschützen erfolgt, je nach Schutzgruppe, mit den gängigen Methoden.
The compounds according to the invention can be prepared by the following processes:
Figure 00260001
Z # = linear or branched, saturated or unsaturated alkyl radical having 1-10 carbon atoms or aryl radical having 6 to 14 carbon atoms
Z = protecting group, e.g. BOC
Z * = proton or cation
  • a) Reaction of the ester to the carbohydrazide is possible by: The reaction is carried out by means of hydrazine * hydrate as solvent and reagent at the appropriate temperature (generally reflux). The reaction runs until a complete conversion results. The reaction can be carried out in various alcohols as solvent and with addition of different equivalents of hydrazine * hydrate (until the conversion is complete) at the appropriate temperature (generally reflux). The reaction is carried out until a complete conversion results.
  • b) Saponification of the ester to the carboxylic acid / carboxylate: • The solvent used is water, as well as an alcohol. For saponification bases are used (for example NaOH, 1M). It is stirred at an appropriate temperature (generally room temperature) until complete conversion results.
  • c) Synthesis of the acid chloride: The reaction is carried out in thionyl chloride or with thionyl chloride in an appropriate solvent (eg toluene) or by another chlorinating reagent, such as e.g. B. triphosgene. It is stirred at an appropriate temperature (generally room temperature) until complete conversion results.
  • d) conversion to thiosemicarbazide: The thiosemicarbazide is synthesized by adding carbon disulfide and a corresponding base, for example potassium hydroxide, in an alcohol solvent, at a suitable temperature (generally room temperature). The reaction is carried out until a complete conversion results.
  • e) Reaction to the oxadiazole starting from the carbazide: The cyclization takes place with addition of an appropriate base, for example triethylamine or potassium hydroxide, in an alcohol as solvent. At the appropriate temperature (generally reflux), the reaction is carried out until a complete conversion results.
  • f) Coupling reaction to the carbazide: • The coupling reaction takes place under standard conditions. In addition to a coupling reagent (eg carbodiimide), a base (eg HOBt * hydrate) and possibly an auxiliary base (eg NMP), the reaction is carried out at a corresponding temperature (generally room temperature) until a full turnover results.
  • g) Synthesis of the carbazide: The reaction is carried out using hydrazine * hydrate (neat or in a suitable solvent) or the protected analogue in a suitable solvent and possibly using a base. At appropriate temperature, the reaction is carried out until a complete conversion results.
  • h) Reaction to oxadiazole starting from the thiosemicarbazide: The cyclization takes place with the addition of a corresponding base, for example potassium hydroxide. The solvents used are alcohols. At the appropriate temperature (generally reflux), the reaction is carried out until a complete conversion results.
  • i) Substitution reaction to thioether: The reaction to give thioether is carried out by addition of an appropriate base, for example triethylamine, in a suitable solvent (eg DMF) at the appropriate temperature (generally room temperature) until a complete conversion results.
  • j) Deprotection: • The deprotection takes place, depending on the protective group, with the usual methods.

Die vorliegende Erfindung betrifft daher auch die Verbindungen der allgemeinen Formel (I) zur Verwendung in der Medizin.The present invention therefore also relates to the compounds of general formula (I) for use in medicine.

Die erfindungsgemäßen Substanzen sind geeignet zur Prophylaxe und Behandlung und/oder Prävention von Erkrankungen, bei denen die Inhibition der GSK-3 zu einer Verbesserung des Krankheitsbildes der Erkrankung führt. Die erfindungsgemäßen Substanzen sind auch geeignet zur Prophylaxe und Behandlung und/oder Prävention von Erkrankungen, bei denen die Inhibition der GSK-3 zu einem Stillstand der Progression einer Erkrankung führt, das heißt, dass durch die Behandlung mit einer Verbindung der allgemeinen Formel (I) die Erkrankung nicht weiter fortschreitet.The substances according to the invention are suitable for the prophylaxis and treatment and / or prevention of diseases in which the inhibition of GSK-3 leads to an improvement in the clinical picture of the disease. The substances according to the invention are also suitable for the prophylaxis and treatment and / or prevention of diseases in which the inhibition of GSK-3 leads to a standstill of the progression of a disease, that is, by treatment with a compound of general formula (I) the disease does not progress.

Die Verbindungen der allgemeinen Formel (I) sind nützlich für die Prophylaxe und Behandlung von GSK-3-vermittelten Erkrankungen, insbesondere zur Prophylaxe und Behandlung von Alzheimer-Krankheit und anderen Tauopathien, Asthma, bipolaren affektiven Störungen, Depression, Nervenzelltod und Schlaganfall, Parkinson, Huntington, Skelettmuskelatrophie, Kardioprotektion, Haarverlust, verringerte Spermienmotilität, Diabetes und damit in Zusammenhang stehende Folgeerkrankungen, wie Syndrom X und Adipositas, Erkrankungen, die durch einzellige Parasiten verursacht werden, transmissible spongiforme Enzephalopathie, Schizophrenie, Krankheiten des zirkadianen Rhythmus und Krebs.The compounds of general formula (I) are useful for the prophylaxis and treatment of GSK-3-mediated diseases, in particular for the prophylaxis and treatment of Alzheimer's disease and other tauopathies, asthma, bipolar affective disorders, depression, neuronal death and stroke, Parkinson's, Huntington's disease, skeletal muscle atrophy, cardioprotection, hair loss, reduced sperm motility, diabetes and related sequelae such as syndrome X and obesity, diseases caused by unicellular parasites, transmissible spongiform encephalopathy, schizophrenia, circadian rhythm diseases and cancer.

Die Verbindungen der allgemeinen Formel (I) sind besonders nützlich für die Prophylaxe und Behandlung von GSK-3-vermittelten neurodegenerativen Erkrankungen. Hiermit sind alle Arten von Krankheiten eingeschlossen, die zu einem fortschreitenden Verlust von Nervenzellen führen. Die Klassifikation neurodegenerativer Erkrankungen basiert sowohl auf der klinischen Präsentation mit topographisch typischer Verteilung und involviertem Zelltyp des degenerativen Prozesses als auch auf Basis der Ablagerung von strukturell veränderten Proteinen wie Prion-Protein, Tau, Beta-Amyloid, Alpha-Synuclein, TDP-43, oder Huntingtin.The compounds of general formula (I) are particularly useful for the prophylaxis and treatment of GSK-3 mediated neurodegenerative diseases. This includes all types of diseases that lead to progressive loss of nerve cells. The classification of neurodegenerative diseases is based both on the clinical presentation with typical topographical distribution and cell type of the degenerative process as well as on the deposition of structurally altered proteins such as prion protein, tau, beta-amyloid, alpha-synuclein, TDP-43, or huntingtin.

Die hierin offenbarten Verbindungen sind besonders vorteilhaft für die Prophylaxe und Behandlung von neurodegenerativen Erkrankungen aus der Gruppe der Tauopathien. Die Gruppe der Tauopathien umfasst neurodegenerative Krankheitsbilder, deren gemeinsames Merkmal die Ansammlung des Tau-Proteins, eines niedermolekularen Phosphoproteins, welches sich in Zellen an stützende Zytoskelett-Proteine (Mikrotubuli) anlagert und deren Zusammenbau reguliert, im Gehirn ist. In einer bevorzugten Ausführungsform werden die hierin genannten Verbindungen für die Prophylaxe und Behandlung von Tauopathien genutzt, wie z. B. Morbus Alzheimer, kortikobasale Degeneration, agryophilic grain disease, Morbus Pick, FTDP-17 (Frontotemporale Demenz und Parkinsonismus des Chromosoms 17) oder progressive supranukleäre Blickparese.The compounds disclosed herein are particularly advantageous for the prophylaxis and treatment of neurodegenerative diseases from the group of tauopathies. The group of tauopathies includes neurodegenerative diseases, the common feature of which is the accumulation of the tau protein, a small molecule phosphoprotein that attaches to and regulates the assembly of supporting cytoskeletal proteins (microtubules) in the brain. In a preferred embodiment, the compounds mentioned herein are used for the prophylaxis and treatment of tauopathies, such as. B. Morbus Alzheimer's, corticobasal degeneration, agryophilic grain disease, Pick's disease, FTDP-17 (frontotemporal dementia and parkinsonism of chromosome 17) or progressive supranuclear palsy.

Die Verbindungen sind erfindungsgemäß weiterhin vorteilhaft für die Prophylaxe und Behandlung von neurodegenerativen Erkrankungen aus der Gruppe der Synucleinopathien. Die Gruppe der Synucleinopathien umfasst neurodegenerative Krankheitsbilder, deren gemeinsames Merkmal die Ansammlung des α-Synuclein-Proteins im Gehirn ist, wie z. B. Morbus Parkinson. Das α-Synuclein-Protein ist ein Protein von 140 Aminosäuren, das normalerweise nur in den presynaptischen Fortsätzen von Neuronen vorkommt. α-Synuclein ist ein Hauptbestandteil von neuronalen intrazellulären Proteinaggregaten (= Levy-Körperchen), dem charakteristischen neuropathologischen Merkmal der Synucleinopathien.The compounds according to the invention are furthermore advantageous for the prophylaxis and treatment of neurodegenerative diseases from the group of synucleinopathies. The group of synucleinopathies includes neurodegenerative diseases, whose common feature is the accumulation of the α-synuclein protein in the brain, such as. B. Parkinson's disease. The α-synuclein protein is a protein of 140 amino acids that normally occurs only in the presynaptic processes of neurons. α-Synuclein is a major component of neuronal intracellular protein aggregates (= Levy bodies), the characteristic neuropathological feature of synucleinopathies.

Die erfindungsgemäßen Verbindungen der Formel (I) sind weiterhin insbesondere zur Prophylaxe und Behandlung von neurodegenerativen Erkrankungen wie z. B. Alzheimer und Parkinson geeignet.The compounds of the formula (I) according to the invention are furthermore especially for the prophylaxis and treatment of neurodegenerative diseases such. B. Alzheimer's and Parkinson's.

Der Ausdruck ”GSK-3” bzw. „Glykogen Synthase Kinase 3” wird verwendet, um GSK-3α; und/oder GSK-3β; zu bezeichnen.The term "GSK-3" or "glycogen synthase kinase 3" is used to refer to GSK-3α; and / or GSK-3β; to call.

Der Ausdruck ”Diabetes” wird verwendet, um Typ I und/oder Typ II Diabetes zu bezeichnen.The term "diabetes" is used to refer to type I and / or type II diabetes.

Weiterhin sind die erfindungsgemäßen Verbindungen der Formel (I) nützlich zur Prophylaxe und Behandlung von Diabetes mellitus, insbesondere Typ 2 Diabetes, inklusive der Prävention assoziierter Folgeerscheinungen, wie beispielsweise Hyperglykämie, Zunahme der Insulinresistenz, gestörte Glukosehomöostase, Schutz der beta-Zellen des Pankreas, Verhinderung makro- und mikrovaskulärer Erkrankungen. Weiterhin gehören dazu Dyslipidämien und ihre Folgen, wie zum Beispiel Arteriosklerose, koronare Herzerkrankungen, zerebrovaskuläre Erkrankungen, insbesondere solche, die durch folgende Faktoren charakterisiert sind: hohe Plasma-Triglycerid-Konzentrationen, hohe postprandiale Plasma-Triglycerid-Konzentrationen, niedrige HDL Cholesterol-Konzentrationen, niedrige ApoA Lipoprotein-Konzentrationen, hohe LDL Cholesterol-Konzentrationen, LDL Cholesterol-Partikel mit geringer Dichte, hohe ApoB Lipoprotein-Konzentrationen. Verschiedene andere Erkrankungen können mit dem metabolischen Syndrom assoziiert sein: Übergewicht, Thrombosen, Hyperkoagulations- und prothrombotische Stadien (arteriell und venös), hoher Blutdruck, Herzversagen wie zum Beispiel, aber nicht beschränkt auf Myokardinfarkt, hypertensive Herzerkrankung oder Kardiomyopathie.Furthermore, the compounds of formula (I) according to the invention are useful for the prophylaxis and treatment of diabetes mellitus, especially type 2 diabetes, including the prevention of associated sequelae, such as hyperglycemia, increase in insulin resistance, impaired glucose homeostasis, protection of pancreatic beta cells, prevention macrovascular and microvascular diseases. These include dyslipidaemias and their consequences, such as arteriosclerosis, coronary heart disease, cerebrovascular diseases, especially those characterized by the following factors: high plasma triglyceride concentrations, high postprandial plasma triglyceride concentrations, low HDL cholesterol concentrations, low apoA lipoprotein concentrations, high LDL cholesterol concentrations, low density LDL cholesterol particles, high apoB lipoprotein concentrations. Various other disorders may be associated with the metabolic syndrome: obesity, thrombosis, hypercoagulation and prothrombotic stages (arterial and venous), high blood pressure, heart failure such as but not limited to myocardial infarction, hypertensive heart disease or cardiomyopathy.

Erfindungsgemäß können die Verbindungen der allgemeinen Formel (I) zur Behandlung bei folgenden Tumoren bzw. Krebsarten eingesetzt werden: akute und chronische myeloische Leukämie, akute und chronische lymphatische Leukämie, Analkarzinom, Astrozytom, Basaliom, kleinzelliges und nichtkleinzelliges Bronchialkarzinom, Burkitt-Lymphom, CUP-Syndrom, Dünndarmtumore, Endometriumkarzinom, Ependymom, Ewing-Sarkom, Gallenblasen- und Gallengangkarzinom, Glioblastom, Haarzell-Leukämie, Hirntumoren (Gliome), Hirnmetastasen, Hodenkrebs, Morbus Hodgkin, Hypophysentumore, Karzinoide, Kaposi-Sarkom, Kehlkopfkrebs, Keimzellentumor, Knochenkrebs, Kopf-Hals-Tumore, Kolonkarzinom, Kraniopharyngeome, Krebs im Mundbereich und auf der Lippe, Leberzellkarzinom, Lebermetastasen, Lidtumor, Magenkrebs, Malignes Melanom, Mammakarzinom, Medulloblastome, Meningeome, Mycosis fungoides, Neurinom, Nierenzellkarzinom, Non-Hodgkin-Lymphome, Oligodendrogliom, Osophaguskarzinom, Osteosarkom, Ovarial-Karzinom, Pankreaskarzinom, Peniskarzinom, Plasmozytom, Prostatakarzinom, Rektumkarzinom, Retinoblastom, Schilddrüsenkarzinom, Spinaliom, Thymom, Tubenkarzinom, Tumoren des Auges, Urethrakrebs, Urothelkarzinom, Vulvakarzinom, Warzenbeteiligung, Weichteiltumoren, Wilms Tumor, Zervixkarzinom und Zungenkrebs.According to the invention, the compounds of general formula (I) can be used for the treatment of the following tumors or cancers: acute and chronic myeloid leukemia, acute and chronic lymphocytic leukemia, anal carcinoma, astrocytoma, basal cell carcinoma, small cell and non-small cell lung carcinoma, Burkitt's lymphoma, CUP Syndrome, small intestinal tumors, endometrial carcinoma, ependymoma, Ewing's sarcoma, gallbladder and bile duct carcinoma, glioblastoma, hairy cell leukemia, brain tumors (gliomas), brain metastases, testicular cancer, Hodgkin's disease, pituitary tumors, carcinoids, Kaposi's sarcoma, throat cancer, germ cell tumor, bone cancer, head -Hales tumors, colon carcinoma, craniopharyngiomas, oropharyngeal and lip cancer, hepatocellular carcinoma, liver metastases, eyelid tumors, gastric cancer, malignant melanoma, breast carcinoma, medulloblastomas, meningiomas, mycosis fungoides, neuroma, renal cell carcinoma, non-Hodgkin's lymphoma, oligodendroglioma, esophageal carcinoma , Osteosarcoma, ovarian carcinoma, pancre ascarcinoma, penile carcinoma, plasmocytoma, prostate carcinoma, rectal cancer, retinoblastoma, thyroid carcinoma, spinal, thymoma, tubal carcinoma, tumors of the eye, urethral cancer, urothelial carcinoma, vulvar carcinoma, wart involvement, soft tissue tumors, Wilms tumor, cervical carcinoma and tongue cancer.

Pharmazeutische ZusammensetzungenPharmaceutical compositions

Ferner betrifft die vorliegende Erfindung pharmazeutische Zusammensetzungen, welche unter Verwendung mindestens einer erfindungsgemäßen Verbindung oder eines Salzes davon hergestellt wurden. Neben mindestens einer Verbindung der allgemeinen Formel (I) enthalten die pharmazeutischen Zusammensetzungen einen pharmakologisch verträglichen Träger, Hilfsstoff und/oder Lösungsmittel.Further, the present invention relates to pharmaceutical compositions prepared using at least one compound of the invention or a salt thereof. In addition to at least one compound of general formula (I), the pharmaceutical compositions contain a pharmacologically acceptable carrier, excipient and / or solvent.

Die pharmazeutischen Zusammensetzungen enthaltend mindestens eine Verbindung der allgemeinen Formel (I) sind besonders wirksam für die Prophylaxe und Behandlung der Alzheimer-Krankheit und anderer Tauopathien, Asthma, bipolarer affektiver Störungen, von Depression, Nervenzelltod und Schlaganfall, Parkinson, Huntington, Skelettmuskelatrophie, Kardioprotektion, Haarverlust, verringerter Spermienmotilität, Diabetes und damit in Zusammenhang stehender Folgeerkrankungen, wie Syndrom X und Adipositas, Erkrankungen, die durch einzellige Parasiten verursacht werden, transmissible spongiforme Enzephalopathie, Schizophrenie, Krankheiten des zirkadianen Rhythmus und Krebs.The pharmaceutical compositions containing at least one compound of the general formula (I) are particularly effective for the prophylaxis and treatment of Alzheimer's disease and other tauopathies, asthma, bipolar affective disorders, depression, neuronal death and stroke, Parkinson's, Huntington's, skeletal muscle atrophy, cardioprotection, Hair loss, reduced sperm motility, diabetes and related sequelae such as syndrome X and obesity, diseases caused by unicellular parasites, transmissible spongiform encephalopathy, schizophrenia, circadian rhythm diseases and cancer.

Die pharmazeutischen Zusammensetzungen können in Form von Tropfen, Mundspray, Nasenspray, Pillen, Tabletten, Filmtabletten, Schichttabletten, Zäpfchen, Gelen, Salben, Sirup, Inhalationspulvern, Granulaten, Suppositorien, Emulsionen, Dispersionen, Mikrokapseln, Kapseln, Puder oder Injektionslösungen hergestellt und verabreicht werden. Zudem Umfassen die erfindungsgemäßen pharmazeutischen Zusammensetzungen Formulierungen wie Schichttabletten zur kontrollierten und/oder kontinuierlichen Freisetzung des Wirkstoffs sowie Mikroverkapselungen als spezielle Darreichungsform. The pharmaceutical compositions can be prepared and administered in the form of drops, mouth spray, nasal spray, pills, tablets, film-coated tablets, coated tablets, suppositories, gels, ointments, syrups, inhalation powders, granules, suppositories, emulsions, dispersions, microcapsules, capsules, powders or injection solutions , In addition, the pharmaceutical compositions according to the invention include formulations such as layered tablets for the controlled and / or continuous release of the active ingredient and microencapsulations as a special dosage form.

Als pharmakologisch verträgliche Träger können beispielsweise Lactose, Stärke, Sorbitol, Sucrose, Cellulose, Magnesiumstearat, Dicalciumphosphat, Calciumsulfat, Talk, Mannitol, Ethylalcohol und dergleichen eingesetzt werden. Puder als auch Tabletten können zu 5 bis 95% aus einem derartigen Träger bestehen.For example, lactose, starch, sorbitol, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol and the like can be used as pharmacologically acceptable carriers. Powders as well as tablets may consist of 5 to 95% of such a carrier.

Ferner können den pharmazeutischen Zusammensetzungen noch Sprengmittel, Farbstoffe, Geschmacksstoffe und/oder Bindemittel zugesetzt werden.Furthermore, disintegrating agents, dyes, flavorings and / or binders may be added to the pharmaceutical compositions.

Flüssige Formulierungen umfassen Lösungen, Suspensionen, Sprays und Emulsionen, beispielsweise Injektionslösungen auf Wasserbasis oder Wasser-Propylenglycol-Basis für parenterale Injektionen.Liquid formulations include solutions, suspensions, sprays and emulsions, for example water-based or water-propylene glycol based injection solutions for parenteral injections.

Für die Zubereitung von Suppositorien werden bevorzugt niedrigschmelzende Wachse, Fettsäureester und Glyceride eingesetzt.For the preparation of suppositories low-melting waxes, fatty acid esters and glycerides are preferably used.

Kapseln werden beispielsweise aus Methylcellulose, Polyvinylalkohole oder denaturierter Gelatine oder Stärke hergestellt.Capsules are made, for example, from methylcellulose, polyvinyl alcohols or denatured gelatin or starch.

Abhängig von den Substituenten (z. B. Carboxylgruppe) an den erfindungsgemäßen Verbindungen der vorliegenden Erfindung bilden diese auch mit organischen und anorganischen Basen pharmazeutisch verträgliche Salze. Beispiele für geeignete Basen für eine derartige Salzbildung sind wie zum Beispiel NaOH, KOH, NH4OH, Tetraalkylammoniumhydroxid und dergleichen, die dem Fachmann bekannt sind.Depending on the substituents (eg, carboxyl group) on the compounds of the present invention, they also form pharmaceutically acceptable salts with organic and inorganic bases. Examples of suitable bases for such salt formation are, for example, NaOH, KOH, NH 4 OH, tetraalkylammonium hydroxide and the like, which are known to the person skilled in the art.

Die Verbindungen der vorliegenden Erfindung sind basisch und können mit Säuren Salze bilden. Beispiele für geeignete Säuren für eine derartige Säureadditionssalzbildung sind Chlorwasserstoffsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Essigsäure, Zitronensäure, Oxalsäure, Apfelsäure, Salicylsäure, p-Aminosalicylsäure, Malonsäure, Fumarsäure, Bernsteinsäure, Ascorbinsäure, Maleinsäure, Sulfonsäure, Phosphonsäure, Perchlorsäure, Salpetersäure, Ameisensäure, Propionsäure, Gluconsäure, Milchsäure, Weinsäure, Hydroxymaleinsäure, Brenztraubensäure, Phenylessigsäure, Benzoesäure, p-Aminobenzoesäure, p-Hydroxybenzoesäure, Methansulfonsäure, Ethansulfonsäure, salpetrige Säure, Hydroxyethansulfonsäure, Ethylensulfonsäure, p-Toluolsulfonsäure, Naphthylsulfonsäure, Sulfanilsäure, Camphersulfonsäure, Chinasäure, Mandelsäure, o-Methylmandelsäure, Hydrogenbenzolsulfonsäure, Pikrinsäure, Adipinsäure, d-o-Tolylweinsäure, Tartronsäure, α-Toluylsäure, (o-, m-, p) Toluylsäure, Naphthylaminsulfonsäure und andere mineralische oder carboxylische Säuren, die dem Fachmann bekannt sind. Es ist auch möglich, Säureadditionssalze von den erfindungsgemäßen Sulfonamid-Verbindungen mit Aminosäuren, wie Methionin, Tryptophan, Lysin oder Arginin zu bilden.The compounds of the present invention are basic and can form salts with acids. Examples of suitable acids for such acid addition salt formation are hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, citric, oxalic, malic, salicylic, p-aminosalicylic, malonic, fumaric, succinic, ascorbic, maleic, sulfonic, phosphonic, perchloric, nitric, formic and the like , Propionic, gluconic, lactic, tartaric, hydroxymaleic, pyruvic, phenylacetic, benzoic, p-aminobenzoic, p-hydroxybenzoic, methanesulfonic, ethanesulfonic, nitrous, hydroxyethanesulfonic, ethylene sulfonic, p-toluenesulfonic, naphthylsulfonic, sulfanilic, camphorsulfonic, quinic, mandelic o-methylmandelic acid, hydrogenbenzenesulfonic acid, picric acid, adipic acid, do-tolyltartaric acid, tartronic acid, α-toluic acid, (o-, m-, p) toluic acid, naphthylamine sulfonic acid and other mineral or carboxylic acids known to those skilled in the art. It is also possible to form acid addition salts of the sulfonamide compounds of the present invention with amino acids such as methionine, tryptophan, lysine or arginine.

Überraschend wurde gezeigt, dass die Verbindungen der allgemeinen Formel (I) die Kinaseaktivität der GSK-3 effektiv inhibieren (s. Tabelle 1). Daraus folgt, dass die Verbindungen der allgemeinen Formel (I) für die Behandlung von GSK-3-vermittelten Erkrankungen geeignet sind. Die erfindungsgemäßen Verbindungen sind somit für die Behandlung von allen Erkrankungen geeignet, in denen die GSK-3 aktiver, vermehrt exprimiert oder generell eine Inhibition der GSK-3 förderlich ist.Surprisingly, it has been shown that the compounds of the general formula (I) effectively inhibit the kinase activity of GSK-3 (see Table 1). It follows that the compounds of general formula (I) are suitable for the treatment of GSK-3-mediated diseases. The compounds of the invention are thus suitable for the treatment of all diseases in which the GSK-3 is more active, more expressed or generally inhibiting GSK-3 is beneficial.

Die Verbindungen der allgemeinen Formel (I) können ferner in Form ihrer pharmazeutisch aktiven Salze optional unter Verwendung von im Wesentlichen nicht toxischen pharmazeutisch verträglichen Trägern, Hilfsstoffen oder Verdünnern verabreicht werden. Die Medikationen der vorliegenden Erfindung werden in einem herkömmlichen festen oder flüssigen Träger oder Verdünnern und einem herkömmlichen pharmazeutisch hergestellten Hilfsstoff mit einem geeigneten Dosisgrad in einer bekannten Weise hergestellt. Die bevorzugten Präparationen sind in einer verabreichbaren Form, die für orale Anwendung geeignet ist. Diese verabreichbaren Formen schließen zum Beispiel Pillen, Tabletten, Schichttabletten, Filmtabletten, beschichtete Tabletten, Kapseln, Pulver und Deposits ein.The compounds of general formula (I) may also be optionally administered in the form of their pharmaceutically active salts, optionally using substantially non-toxic pharmaceutically acceptable carriers, excipients or diluents. The medications of the present invention are prepared in a conventional solid or liquid carrier or diluent and a conventional pharmaceutically-produced excipient at a suitable dose level in a known manner. The preferred preparations are in an administrable form suitable for oral use. These administrable forms include, for example, pills, tablets, coated tablets, coated tablets, coated tablets, capsules, powders and deposits.

Die bevorzugten verabreichbaren Formen sind Tabletten, Filmtabletten, beschichtete Tabletten, Gelatinekapseln und opake Kapseln. Jede pharmazeutische Zusammensetzung enthält mindestens eine Verbindung der allgemeinen Formel (I) und vorzugsweise mindestens eine der Verbindungen 1–100 und/oder pharmazeutisch verträgliche Salze davon in einer Menge von 5 μg bis 500 mg, bevorzugt 10 mg bis 250 mg und am meisten bevorzugt in einer Menge von 50 mg bis 150 mg pro Formulierung.The preferred administrable forms are tablets, film-coated tablets, coated tablets, gelatin capsules and opaque capsules. Each pharmaceutical composition contains at least one compound of the general formula (I) and preferably at least one of the compounds 1-100 and / or pharmaceutically acceptable salts thereof in an amount of 5 μg to 500 mg, preferably 10 mg to 250 mg, and most preferably in an amount of 50 mg to 150 mg per formulation.

Außerdem schließt der Gegenstand der vorliegenden Erfindung auch pharmazeutische Präparationen für parenterale, einschließlich bukkale, dermale, intradermale, intragastrale, intrakutane, intravasale, intravenöse, intramuskuläre, intraperitoneale, intranasale, intravaginale, intrabukkale, mucokutane, perkutane, rektale, subkutane, sublinguale, topische oder transdermale Anwendung ein, die zusätzlich zu typischen Vehikeln und Verdünnern eine Verbindung der allgemeinen Formel (I) und/oder ein pharmazeutisch verträgliches Salz davon als einen aktiven Bestandteil enthalten.In addition, the subject of the present invention also includes pharmaceutical preparations for parenteral, including buccal, dermal, intradermal, intragastric, intracutaneous, intravascular, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, mucocutaneous, percutaneous, rectal, subcutaneous, sublingual, topical or transdermal application containing, in addition to typical vehicles and diluents, a compound of general formula (I) and / or a pharmaceutically acceptable salt thereof as an active ingredient.

Innerhalb der offenbarten Verfahren werden die pharmazeutischen Zusammensetzungen der vorliegenden Erfindung, die Verbindungen der allgemeinen Formel (I) als aktive Bestandteile enthalten, typischerweise in einer Mischung mit geeigneten Trägermaterialien verabreicht, ausgewählt im Hinblick auf die beabsichtigte Form der Verabreichung, d. h. orale Tabletten, Kapseln (entweder fest gefüllt, halbfest gefüllt oder flüssig gefüllt), Pulver für Zusammensetzungen, orale Gele, Elixiere, dispergierbare Granulate, Sirups, Suspensionen und dergleichen und in Übereinstimmung mit herkömmlichen pharmazeutischen Praktiken. Zum Beispiel kann für die orale Verabreichung in der Form von Tabletten oder Kapseln die aktive Wirkstoffkomponente mit einem beliebigen oralen nicht toxischen pharmazeutisch verträglichen inerten Träger, wie Laktose, Stärke, Sucrose, Zellulose, Magnesiumstearat, Dikalziumphosphat, Kalziumsulfat, Talkum, Mannitol, Ethylalkohol (flüssige Formen) und dergleichen kombiniert werden. Außerdem können bei Wunsch oder Bedarf geeignete Bindemittel, Gleitmittel, Sprengmittel und Färbemittel ebenfalls der Mischung beigefügt werden. Pulver und Tabletten können von etwa 5 bis zu etwa 95 Prozent der erfinderischen Zusammensetzung umfassen.Within the methods disclosed, the pharmaceutical compositions of the present invention containing compounds of general formula (I) as active ingredients are typically administered in admixture with suitable carrier materials selected with regard to the intended form of administration, i. H. oral tablets, capsules (either solid-filled, semi-solid or liquid-filled), powders for compositions, oral gels, elixirs, dispersible granules, syrups, suspensions and the like and in accordance with conventional pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid Forms) and the like. In addition, if desired or necessary, suitable binders, lubricants, disintegrants and colorants may also be added to the mixture. Powders and tablets may comprise from about 5 to about 95 percent of the inventive composition.

Geeignete Bindemittel schließen Stärke, Gelatine, natürliche Zucker, Maissüßstoffe, natürliche und synthetische Gummis, wie Akaziengummi, Natriumalginat, Carboxymethyl-Cellulose, Polyethylenglycol und Wachse ein. Unter den Gleitmitteln können für die Verwendung in diesen Dosierungsformen Borsäure, Natriumbenzoat, Natriumacetat, Natriumchlorid und dergleichen erwähnt werden. Sprengmittel schließen Stärke, Methylcellulose, Guargummi und dergleichen ein. Süßstoffe, Geschmacksstoffe und Konservierungsstoffe können, falls dienlich, ebenfalls eingeschlossen sein. Einige der oben angeführten Ausdrücke, nämlich Sprengmittel, Verdünner, Gleitmittel, Bindemittel und dergleichen werden unten genauer diskutiert.Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethyl cellulose, polyethylene glycol and waxes. Among the lubricants, boric acid, sodium benzoate, sodium acetate, sodium chloride and the like may be mentioned for use in these dosage forms. Disintegrants include starch, methyl cellulose, guar gum and the like. Sweetening, flavoring and preservatives may also be included, if appropriate. Some of the above-mentioned terms, namely disintegrants, thinners, lubricants, binders, and the like are discussed in more detail below.

Zusätzlich können die Zusammensetzungen der vorliegenden Erfindung in einer Dosierungsform mit verzögerter Freisetzung formuliert werden, um die geschwindigkeits-gesteuerte Freisetzung einer oder mehrerer Verbindungen gemäß allgemeiner Formel (I) zu ermöglichen und deren therapeutische Wirkung zu optimieren. Geeignete Dosierungsformen für eine verzögerte Freisetzung schließen Schichttabletten ein, die Schichten mit variierenden Abbaugeschwindigkeiten oder polymere Matrizen mit gesteuerter Freisetzung enthalten, die mit den aktiven Komponenten imprägniert sind, und in Tablettenform oder Kapseln gestaltet sind, die derartige imprägnierte oder verkapselte, poröse polymere Matrizen beinhalten.In addition, the compositions of the present invention may be formulated in a sustained release dosage form to facilitate the rate controlled release of one or more compounds of general formula (I) and to optimize their therapeutic effect. Suitable sustained-release dosage forms include coated tablets containing varying-rate films or controlled-release polymeric matrices impregnated with the active components and shaped into tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.

Präparationen in flüssiger Form schließen Lösungen, Suspensionen und Emulsionen ein. Als ein Beispiel können Wasser oder Wasser-Propylenglycol-Lösungen für parenterale Injektionen oder der Zusatz von Süßstoffen und Trübungsmitteln für orale Lösungen, Suspensionen und Emulsionen erwähnt werden. Präparationen in flüssiger Form können ferner Lösungen für intranasale Verabreichung einschließen.Preparations in liquid form include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injections or the addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Preparations in liquid form may further include solutions for intranasal administration.

Zur Inhalation geeignete Aerosol-Präparationen können Lösungen und Feststoffe in Pulverform einschließen, die mit einem pharmazeutisch verträglichen Träger, wie ein komprimiertes Inertgas, z. B. Stickstoff, in Kombination sein können.Aerosol preparations suitable for inhalation may include solutions and solids in powder form which are contacted with a pharmaceutically acceptable carrier, such as a compressed inert gas, e.g. As nitrogen, may be in combination.

Für die Zubereitung von Suppositorien wird zuerst ein niedrig schmelzendes Wachs, wie z. B. eine Mischung von Fettsäureglyceriden, wie z. B. Kakaobutter, geschmolzen und der aktive Bestandteil wird darin durch Rühren oder ähnliches Vermischen homogen dispergiert. Die geschmolzene homogene Mischung wird dann in passend bemessene Formen gegossen, man lässt abkühlen und dadurch verfestigen.For the preparation of suppositories, first a low-melting wax, such. B. a mixture of fatty acid glycerides, such as. Cocoa butter, is melted and the active ingredient is homogeneously dispersed therein by stirring or similar mixing. The molten homogeneous mixture is then poured into appropriately sized molds, allowed to cool and thereby solidified.

Ferner eingeschlossen sind Präparationen in fester Form, die kurz vor der Verwendung zu Präparationen in flüssiger Form für entweder orale oder parenterale Verabreichung umgewandelt werden sollen. Solche flüssigen Formen schließen Lösungen, Suspensionen und Emulsionen ein.Also included are preparations in solid form intended to be converted shortly before use to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

Die Verbindungen der vorliegenden Erfindung können ferner transdermal verabreichbar sein. Die transdermalen Zusammensetzungen können die Form von Cremes, Lotionen, Aerosolen und/oder Emulsionen annehmen und können in einen transdermalen Aufkleber des Matrix- oder Reservoir-Typs eingeschlossen werden, wie sie in der Technik für diesen Zweck gebräuchlich sind.The compounds of the present invention may also be transdermally administrable. The transdermal compositions may take the form of creams, lotions, aerosols and / or emulsions and may be included in a transdermal label of the matrix or reservoir type as commonly used in the art for this purpose.

Der Ausdruck Kapsel bezieht sich auf einen speziellen Behälter oder Gehäuse, das aus Methylzellulose, Polyvinylalkoholen oder denaturierten Gelatinen oder Stärke hergestellt ist, zum Halten oder Beinhalten von Zusammensetzungen, die die aktiven Bestandteile umfassen. Hartmantelkapseln sind typischerweise aus Mischungen von Knochen und Schweinehautgelatinen relativ hoher Gelstärke hergestellt. Die Kapsel selbst kann kleine Mengen von Farbstoffen, Trübungsmitteln, Weichmachern und Konservierungsstoffen enthalten.The term capsule refers to a particular container or housing made of methyl cellulose, polyvinyl alcohols or denatured gelatins or starch for holding or containing compositions comprising the active ingredients. Hard shell capsules are typically made from blends of bone and porcine gelatin of relatively high gel strength. The capsule itself may contain small amounts of dyes, opacifiers, emollients, and preservatives.

Tablette bedeutet komprimierte oder gegossene feste Dosierungsform, die die aktiven Bestandteile mit geeigneten Verdünnern enthält. Die Tablette kann durch Komprimieren von Mischungen oder Granulaten hergestellt werden, die durch Nassgranulierung, Trockengranulierung oder durch Kompaktierung erhalten wurden, die einem Fachmann bekannt sind.Tablet means compressed or poured solid dosage form containing the active ingredients with suitable diluents. The tablet may be prepared by compressing mixtures or granules obtained by wet granulation, dry granulation or compaction known to one skilled in the art.

Orale Gele beziehen sich auf die aktiven Bestandteile, die in einer hydrophilen halbfesten Matrix dispergiert oder solubilisiert sind.Oral gels refer to the active ingredients that are dispersed or solubilized in a hydrophilic semi-solid matrix.

Pulver für Zusammensetzungen beziehen sich auf Pulvermischungen, die die aktiven Bestandteile und geeignete Verdünner beinhalten, die in Wasser oder Säften suspendiert werden können.Powders for compositions refer to powder mixtures that include the active ingredients and suitable diluents that can be suspended in water or juices.

Geeignete Verdünner sind Substanzen, die für gewöhnlich den Großteil der Zusammensetzung oder Dosierungsform ausmachen. Geeignete Verdünner schließen Zucker, wie Lactose, Sucrose, Mannitol und Sorbitol, von Weizen, Mais, Reis und Kartoffeln abgeleitete Stärken, und Zellulosen, wie mikrokristalline Zellulose ein. Die Menge an Verdünnern in der Zusammensetzung kann sich von etwa 5 bis etwa 95 Gew.-% der gesamten Zusammensetzung, bevorzugt von etwa 25 bis etwa 75 Gew.-% und weiter bevorzugt von etwa 30 bis etwa 60 Gew.-% erstrecken.Suitable diluents are substances that usually make up the majority of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol, starches derived from wheat, corn, rice and potatoes, and celluloses such as microcrystalline cellulose. The amount of diluents in the composition can range from about 5 to about 95 weight percent of the total composition, preferably from about 25 to about 75 weight percent, and more preferably from about 30 to about 60 weight percent.

Der Ausdruck Sprengmittel bezieht sich auf Materialien, die der Zusammensetzung hinzugefügt wurden, um sie beim Aufbrechen (Zersprengen) und Freigeben der Medikamente zu unterstützen. Geeignete Sprengmittel schließen Stärkere, ”Kaltwasser-lösliche” modifizierte Stärken, wie Natrium-Carboxymethylstärke, natürliche und synthetische Gummis, wie Johannisbrotkernmehl, Karaya, Guar, Tragacanth und Agar, Cellulosederivate, wie Methylcellulose und Natrium-Carboxymethylcellulose, mikrokristalline Cellulosen und quervernetzte mikrokristalline Cellulosen, wie Natrium-Croscarmellose, Alginate, wie Alginsäure und Natriumalginat, Tonerden, wie Bentonite, und schäumende Mischungen. Die Menge an Sprengmittel in der Zusammensetzung kann sich von etwa 2 bis 20 Gew.-% der Zusammensetzung und weiter bevorzugt von etwa 5 bis etwa 10 Gew.-% erstrecken.The term disintegrants refers to materials that have been added to the composition to aid in breaking up and releasing the drugs. Suitable disintegrants include stronger, "cold water-soluble" modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean gum, karaya, guar, tragacanth and agar, cellulose derivatives such as methyl cellulose and sodium carboxymethyl cellulose, microcrystalline celluloses and cross-linked microcrystalline celluloses. such as sodium croscarmellose, alginates such as alginic acid and sodium alginate, clays such as bentonites, and effervescent mixtures. The amount of disintegrant in the composition can range from about 2 to 20 weight percent of the composition, and more preferably from about 5 to about 10 weight percent.

Bindemittel charakterisieren Substanzen, die Pulver miteinander binden oder ”verkleben” und sie durch Bildung von Granulaten bindig machen und somit als der ”Kleber” in der Formulierung dienen. Bindemittel fügen eine Kohäsionsstärke hinzu, die in den Verdünnern oder dem Aufgehmittel bereits verfügbar ist. Geeignete Bindemittel schließen Zucker, wie Sucrose, von Weizen, Mais, Reis und Kartoffeln abgeleitete Stärken, natürliche Gummis, wie Akaziengummi, Gelatine und Tragacanth, Derivate von Seetang, wie Alginsäure, Natriumalginat und Ammonium-Calcium-Alginat, Zellulosematerialien, wie Methylcellulose und Natrium-Carboxymethylcellulose und Hydroxypropyl-methylcellulose, Polyvinylpyrrolidon und anorganische Verbindungen, wie Magnesium-Aluminium-Silicat ein. Die Menge der Bindemittel in der Zusammensetzung kann sich von etwa 2 bis etwa 20 Gew.-% der Zusammensetzung, weiter bevorzugt von etwa 3 bis etwa 10 Gew.-% und noch weiter bevorzugt von etwa 3 bis etwa 6 Gew.-% erstrecken.Binders characterize substances that bind or "stick together" powders and make them coagulate through the formation of granules and thus serve as the "glue" in the formulation. Binders add a cohesive strength that is already available in the thinners or the grafting agent. Suitable binders include sugars such as sucrose, starches derived from wheat, corn, rice and potatoes, natural gums such as acacia, gelatin and tragacanth, derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate, cellulosic materials such as methylcellulose and sodium Carboxymethyl cellulose and hydroxypropyl methyl cellulose, polyvinyl pyrrolidone and inorganic compounds such as magnesium aluminum silicate. The amount of binder in the composition can range from about 2 to about 20 weight percent of the composition, more preferably from about 3 to about 10 weight percent, and even more preferably from about 3 to about 6 weight percent.

Gleitmittel bezieht sich auf eine der Dosierungsform hinzugefügte Substanz, um zu ermöglichen, dass die Tablette, Granulat usw., nachdem sie komprimiert wurde, aus der Gießform oder Pressform durch Verringern der Friktion oder Reibung freigegeben werden. Geeignete Gleitmittel schließen metallische Stearate, wie Magnesiumstearat, Calciumstearat oder Kaliumstearat, Stearinsäure, Wachse mit hohem Schmelzpunkt, und wasserlösliche Gleitmittel, wie Natriumchlorid, Natriumbenzoat, Natriumacetat, Natriumoleat, Polyethylenglycole und D,L-Leucin ein. Gleitmittel werden gewöhnlich bei dem letzten Schritt vor dem Komprimieren hinzugefügt, da sie auf den Oberflächen der Granulate und zwischen ihnen und den Teilen der Tablettenpresse vorhanden sein müssen. Die Menge an Gleitmittel in der Zusammensetzung kann sich von etwa 0,2 bis etwa 5 Gew.-% der Zusammensetzung, bevorzugt von etwa 0,5 bis etwa 2 Gew.-% und weiter bevorzugt von etwa 0,3 bis etwa 1,5 Gew.-% erstrecken.Lubricant refers to a substance added to the dosage form to enable the tablet, granules, etc., after it has been compressed, to be released from the mold or die by reducing friction or friction. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate, stearic acid, high melting waxes, and water-soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D, L-leucine. Lubricants are usually added at the last step before compression because they must be present on the surfaces of the granules and between them and the parts of the tablet press. The amount of lubricant in the composition can range from about 0.2 to about 5 weight percent of the composition, preferably from about 0.5 to about 2 weight percent, and more preferably from about 0.3 to about 1.5 Wt .-% extend.

Gleitmittel sind Materialien, die eine Anbackung verhindern und die Fließcharakteristika von Granulaten verbessern, so dass der Fluss glatt und einheitlich ist. Geeignete Gleitmittel schließen Siliziumdioxid und Talkum ein. Die Menge von Gleitmittel in der Zusammensetzung kann sich von 0,1 bis etwa 5 Gew.% der gesamten Zusammensetzung und bevorzugt von etwa 0,5 bis etwa 2 Gew.-% erstrecken. Lubricants are materials that prevent caking and improve the flow characteristics of granules so that the flow is smooth and uniform. Suitable lubricants include silica and talc. The amount of lubricant in the composition may range from 0.1 to about 5 weight percent of the total composition, and preferably from about 0.5 to about 2 weight percent.

Färbemittel sind Hilfsstoffe, die der Zusammensetzung oder der Dosierungsform eine Färbung bereitstellen. Derartige Hilfsstoffe können Farbstoffe mit Lebensmittelqualität einschließen, die auf einem geeigneten Adsorptionsmittel, wie Tonerde oder Aluminiumoxid adsorbiert sind. Die Menge des Färbemittels kann von etwa 0,1 bis etwa 5 Gew.-% der Zusammensetzung und bevorzugt von etwa 0,1 bis etwa 1 Gew.-% variieren.Colorants are adjuvants that provide color to the composition or dosage form. Such adjuvants may include food grade dyes adsorbed on a suitable adsorbent such as alumina or alumina. The amount of colorant may vary from about 0.1 to about 5 weight percent of the composition, and preferably from about 0.1 to about 1 weight percent.

Wie hierin verwendet ist eine ”pharmazeutisch wirksame Menge” eines Inhibitors eine Menge, die wirksam ist, um das erwünschte physiologische Ergebnis entweder in in vitro behandelten Zellen oder in einem in vivo behandelten Patienten zu erreichen. Spezifisch ist eine pharmazeutisch wirksame Menge eine Menge, die ausreichend ist, um für eine gewisse Zeitspanne ein oder mehrere der klinisch definierten pathologischen Prozesse, die mit GSK-3 assoziiert sind, zu inhibieren und/oder zu aktivieren. Die wirksame Menge kann in Abhängigkeit des spezifischen Inhibitors variieren und ist ferner von einer Vielfalt von Faktoren und Zuständen abhängig, die mit dem zu behandelnden Subjekt und der Schwere der Erkrankung in Beziehung stehen. Wenn zum Beispiel ein Inhibitor in vivo verabreicht werden soll, dann wären Faktoren, wie das Alter, Gewicht und die Gesundheit des Patienten als auch Dosisreaktionskurven und Toxizitätsdaten, die aus vorklinischen Arbeiten erhalten wurden, unter den berücksichtigten Faktoren. Falls der Inhibitor mit den Zellen in vivo in Kontakt gebracht werden soll, würde man ferner eine Vielfalt von vorklinischen in vitro Studien entwerfen, um solche Parameter, wie Aufnahme, biologische Halbwertszeit, Dosis, Toxizität, usw. zu bestimmen. Die Bestimmung einer pharmazeutisch wirksamen Menge für einen gegebenen pharmazeutisch aktiven Wirkstoff liegt völlig in der Fähigkeit eines Fachmanns.As used herein, a "pharmaceutically effective amount" of an inhibitor is an amount effective to achieve the desired physiological result in either in vitro treated cells or in an in vivo treated patient. Specifically, a pharmaceutically effective amount is an amount sufficient to inhibit and / or activate one or more of the clinically defined pathological processes associated with GSK-3 for a period of time. The effective amount may vary depending on the specific inhibitor and is further dependent on a variety of factors and conditions related to the subject to be treated and the severity of the disease. For example, if an inhibitor is to be administered in vivo, then factors such as age, weight and health of the patient as well as dose response curves and toxicity data obtained from preclinical work would be among the factors considered. In addition, if the inhibitor is to be contacted with the cells in vivo, one would design a variety of preclinical in vitro studies to determine such parameters as uptake, biological half-life, dose, toxicity, and so on. The determination of a pharmaceutically effective amount for a given pharmaceutically active agent is entirely within the ability of one skilled in the art.

Es ist für einen Fachmann leicht ersichtlich, dass andere geeignete Modifikationen und Adaptationen der hierin beschriebenen Zusammensetzungen offensichtlich sind und ohne Abweichung von dem hierin offenbarten Schutzumfang der Erfindung oder den Ausführungsformen vorgenommen werden können. Folgenden Verbindungen der allgemeinen Formel (I) wurden synthetisiert: Verbindung Nomenklatur 1 4'-[5-(3R-Methoxymethyl-2,3-dihydrobenzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-ylfsulfanylmethyl]-biphenyl-2-carbonitril 2 5-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-thiol 3 3-[5-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-benzonitril 4 2-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-5-(3-methoxybenzylsulfanyl)-[1,3,4]oxadiazol 5 2-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-5-(3-nitrobenzylsulfanyl)-[1,3,4]oxadiazol 6 4'-[5-(2-Phenylbenzooxazol-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-biphenyl-3-carbonitril 7 2-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-5-(4-bromobenzysulfanyl)-[1,3,4]oxadiazol 8 4-[5-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-benzonitril 9 4'-{5-[2-(3-Methoxypropylamino)-benzothiazol-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-biphenyl-3-carbonitril 10 4-[5-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-benzoesäuremethylester 11 4'-[5-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-biphenyl-2-carbonitril 12 2-(Biphenyl-4-ylmethylsulfanyl)-5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol 13 4'-[5-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-biphenyl-3-carbonitril 14 4'-[5-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-4-methoxy-biphenyl-2-carbonitril 15 4'-[5-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-4-fluoro-biphenyl-2-carbonitril 16 4'-[5-(3S-Methoxymethyl-2,3-dihydrobenzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-biphenyl-2-carbonitril 17 2-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-5-(4'-methoxybiphenyl-4-ylmethylsulfanyl)-[1,3,4]oxadiazol 18 4'-[5-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-biphenyl-4-carbonitril 19 2-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-5-(3',5'-difluorobiphenyl-4-ylmethylsulfanyl)-[1,3,4]oxadiazol 20 2-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-5-(3'-nitrobiphenyl-4-ylmethylsulfanyl)-[1,3,4]oxadiazol 21 5-(3-Methoxymethyl-2,3-dihydrobenzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-thiol 22 4'-[5-(3-Methoxymethyl-2,3-dihydrobenzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-biphenyl-2-carbonitril 23 4'-[5-(3-Hydroxymethyl-2,3-dihydrobenzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-biphenyl-2-carbonitril 24 5-(3R-Methoxymethyl-2,3-dihydrobenzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-thiol 25 2-Benzo[1,3]dioxol-5-yl-5-(biphenyl-4-ylmethylsulfanyl)-[1,3,4]oxadiazol 26 4'-(5-Benzo[1,3]dioxol-5-yl-[1,3,4]oxadiazol-2-ylsulfanylmethyl)-4-fluorobiphenyl-2-carbonitril 27 4-(5-Benzo[1,3]dioxol-5-yl-[1,3,4]oxadiazol-2-ylsulfanylmethyl)-benzoesäuremethylester 28 2-Benzo[1,3]dioxol-5-yl-5-(biphenyl-3-ylmethylsulfanyl)-[1,3,4]oxadiazol 29 4'-(5-Benzo[1,3]dioxol-5-yl-[1,3,4]oxadiazol-2-ylsulfanylmethyl)-biphenyl-3-carbonitril 30 4'-(5-Benzo[1,3]dioxol-5-yl-[1,3,4]oxadiazol-2-ylsulfanylmethyl)-4-methoxybiphenyl-2-carbonitril 31 2-Benzo[1,3]dioxol-5-yl-5-(2'-nitrobiphenyl-4-ylmethylsulfanyl)-[1,3,4]oxadiazol 32 2-Benzo[1,3]dioxol-5-yl-5-(4'-methoxybiphenyl-4-ylmethylsulfanyl)-[1,3,4]oxadiazol 33 4'-(5-Benzo[1,3]dioxol-5-yl-[1,3,4]oxadiazol-2-ylsulfanylmethyl)-biphenyl-4-carbonitril 34 2-Benzo[1,3]dioxol-5-yl-5-(3',5'-difluorobiphenyl-4-ylmethylsulfanyl)-[1,3,4]oxadiazol 35 2-Benzo[1,3]dioxol-5-yl-5-(3'-nitrobiphenyl-4-ylmethylsulfanyl)-[1,3,4]oxadiazol 36 5-Pyridin-4-yl-[1,3,4]oxadiazol-2-thiol 37 4-(5-Benzylsulfanyl-[1,3,4]oxadiazol-2-yl)-pyridin 38 4-[5-(4-Bromobenzylsulfanyl)-[1,3,4]oxadiazol-2-yl]-pyridin 39 4-(5-Pyridin-4-yl-[1,3,4]oxadiazol-2-ylsulfanylmethyl)-benzonitril 40 3-(5-Pyridin-4-yl-[1,3,4]oxadiazol-2-ylsulfanylmethyl)-benzonitril 41 4-[5-(3-Nitrobenzylsulfanyl)-[1,3,4]oxadiazol-2-yl]-pyridin 42 4-[5-(3-Methoxybenzylsulfanyl)-[1,3,4]oxadiazol-2-yl]-pyridin 43 4'-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-ylsulfanylmethyl)-biphenyl-2-carbonitril 44 4-[5-(4-tert-Butylbenzylsulfanyl)-[1,3,4]oxadiazol-2-yl]-pyridin 45 4-(5-Pyridin-4-yl-[1,3,4]oxadiazol-2-ylsulfanylmethyl)-benzoesäuremethylester 46 4-[5-(Biphenyl-3-ylmethylsulfanyl)-[1,3,4]oxadiazol-2-yl]-pyridin 47 4-Fluoro-4'-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-ylsulfanylmethyl)-biphenyl-2-carbonitril 48 4-[5-(4'-Methoxybiphenyl-4-ylmethylsulfanyl)-[1,3,4]oxadiazol-2-yl]-pyridin 49 4-[5-(Biphenyl4-ylmethylsulfanyl)-[1,3,4]oxadiazol-2-yl]-pyridin 50 4'-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-ylsulfanylmethyl)-biphenyl-3-carbonitril 51 4'-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-ylsulfanylmethyl)-biphenyl-4-carbonitril 52 N-[4-(5-Mercapto-[1,3,4]oxadiazol-2-yl)-pyridin-2-yl]-acetamid 53 N-{4-[5-(2'-Cyanobephenyl-4-ylmethylsulfanyl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-acetamid 54 N-{4-[5-(3-Methoxybenzylsulfanyl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-acetamid 55 N-{4-[5-(3-Cyanobenzylsulfanyl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-acetamid 56 N-[4-(5-Benzylsulfanyl)-[1,3,4]oxadiazol-2-yl)-pyridin-2-yl]-acetamid 57 4-[5-(3-Methoxybenzylsulfanyl)-[1,3,4]oxadiazol-2-yl]-benzonitril 58 2-(3-Methoxybenzylsulfanyl)-5-(4-nitrophenyl)-[1,3,4]oxadiazol 59 3-[5-(4-Cyanophenyl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-benzonitril 60 2-[5-(4-Cyanophenyl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-benzonitril 61 4-(5-Benzylsulfanyl-[1,3,4]oxadiazol-2-yl)-benzonitril 62 3-[5-(4-Nitrophenyl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-benzonitril 63 4'-[5-(4-Nitrophenyl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-biphenyl-2-carbonitril 64 2-Benzylsulfanyl-5-(4-nitrophenyl)-[1,3,4]oxadiazol 65 4'-[5-(4-Methoxyphenyl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-biphenyl-2-carbonitril 66 4'-(5-Phenyl-[1,3,4]oxadiazol-2-ylsulfanylmethyl)-biphenyl-2-carbonitril 67 3-(5-Phenyl-[1,3,4]oxadiazol-2-ylsulfanylmethyl)-benzonitril 68 2-(3-Methoxybenzylsulfanyl)-5-phenyl-[1,3,4]oxadiazol 69 2-Benzylsulfanyl-5-phenyl-[1,3,4]oxadiazol 70 3-[5-(4-Methoxyphenyl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-benzonitril 71 2-(3-Methoxybenzylsulfanyl)-5-(4-methoxyphenyl)-[1,3,4]oxadiazol 72 2-Benzylsulfanyl-5-(4-methoxyphenyl)-[1,3,4]oxadiazol 73 4-(5-Benzo[1,3]dioxol-5-yl-[1,3,4]oxadiazol-2-ylsulfanylmethyl)-benzoesäure 74 4-[5-(2,3-Dihydrobenzo[1,4}dioxin-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-benzoesäure 75 4-(5-Benzo[1,3]dioxol-5-yl-[1,3,4]oxadiazol-2-ylsulfanylmethyl)-N-isobutylbenzamid 76 4-(5-Benzo[1,3]dioxol-5-yl-[1,3,4]oxadiazol-2-ylsulfanylmethyl)-N-(2,2-dimethoxyethyl)-benzamid 77 4-[5-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-N-(2,2-dimethoxyethyl)-benzamid 78 4-[5-(2,3-Dehydrobenzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-N-isobutylbenzamid 79 5-{4-[5-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-phenyl-1H-tetrazol 80 3-(5-Benzo[1,3]dioxol-5-yl-[1,3,4]oxadiazol-2-ylsulfanylmethyl)-benzonitril 81 5-[4-(5-Benzo[1,3]dioxol-5-yl-[1,3,4]oxadiazol-2-ylsulfanylmethyl)]-phenyl]-1H-tetrazol 82 4'-(5-{3-[(2,2-Demethoxyethylamino)-methyl]-2,3-dihydrobenzo[1,4]dioxin-6-yl}-[1,3,4]oxadiazol-2-ylsulfanylmethyl)-biphenyl-2-carbonitril 83 Methansulfonsäure-7-[5-(2'-cyanobiphenyl-4-ylmethylsulfanyl)-[1,3,4]oxadiazol-2-yl]-2,3-dihydrobenzo[1,4]dioxin-2-ylmethylester 84 5-{3-[5-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-phenyl)-1H-tetrazol 85 4'-[5-(3R-Hydroxymethyl-2,3-dihydrobenzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-biphenyl-2-carbonitril 86 N-{6-[5-(2'-Cyanobiphenyl-4-ylmethylsulfanyl)-[1,3,4]oxadiazol-2-yl]-benzothiazol-2-yl)-acetamid 87 5-Benzo[1,3]dioxol-5-yl-[1,3,4]oxadiazol-2-thiol 88 2-Benzo[1,3]dioxol-5-yl-5-(4-bromobenzylsulfanyl)-[1,3,4]oxadiazol 89 2-Benzo[1,3]dioxol-5-yl-5-(3-methoxybenzylsulfanyl)-[1,3,4]oxadiazol 90 4-(5-Benzo[1,3]dioxol-5-yl-[1,3,4]oxadiazol-2-ylsulfanylmethyl)-benzonitril 91 2-Benzo[1,3]dioxol-5-yl-5-(3-nitrobenzylsulfanyl)-[1,3,4]oxadiazol 92 4'-(5-Benzo[1,3]dioxol-5-yl-[1,3,4]oxadiazol-2-ylsulfanylmethyl)-biphenyl-2-carbonitril 93 N-Benzyl-4-[5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-benzamid 94 4'-{5-[2-(3-Methoxybenzylamino)-benzothiazol-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-biphenyl-3-carbonitril 95 4'-[5-(2-Benzylbenzooxazol-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-biphenyl-3-carbonitril 96 4'-[5-(2-Benzyloxymethylbenzooxazol-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-biphenyl-3-carbonitril 97 4'-[5-(2-Benzyloxymethylbenzooxazol-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-biphenyl-2-carbonitril 98 4'-[5-(2-Hydroxymethylbenzooxazol-6-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-biphenyl-2-carbonitril 99 4'-[5-(2-Phenyl-3H-benzoimidazol-5-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-biphenyl-3-carbonitril 100 4'-[5-(8-Nitrodibenzofuran-2-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-biphenyl-3-carbonitril It will be readily apparent to one skilled in the art that other suitable modifications and adaptations of the compositions described herein will be apparent and may be made without departing from the scope of the invention or the embodiments disclosed herein. The following compounds of the general formula (I) were synthesized: connection nomenclature 1 4 '- [5- (3R-methoxymethyl-2,3-dihydrobenzo [1,4] dioxin-6-yl) - [1,3,4] oxadiazol-2-ylfsulfanylmethyl] -biphenyl-2-carbonitrile 2 5- (2,3-dihydrobenzo [1,4] dioxin-6-yl) - [1,3,4] oxadiazol-2-thiol 3 3- [5- (2,3-dihydrobenzo [1,4] dioxin-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -benzonitrile 4 2- (2,3-dihydrobenzo [1,4] dioxin-6-yl) -5- (3-methoxy-benzylsulfanyl) - [1,3,4] oxadiazole 5 2- (2,3-dihydrobenzo [1,4] dioxin-6-yl) -5- (3-nitrobenzylsulfanyl) - [1,3,4] oxadiazole 6 4 '- [5- (2-Phenylbenzooxazol-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -biphenyl-3-carbonitrile 7 2- (2,3-dihydrobenzo [1,4] dioxin-6-yl) -5- (4-bromobenzysulfanyl) - [1,3,4] oxadiazole 8th 4- [5- (2,3-dihydrobenzo [1,4] dioxin-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -benzonitrile 9 4 '- {5- [2- (3-methoxypropylamino) -benzothiazol-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -biphenyl-3-carbonitrile 10 4- [5- (2,3-dihydrobenzo [1,4] dioxin-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -benzoic acid methyl ester 11 4 '- [5- (2,3-dihydrobenzo [1,4] dioxin-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -biphenyl-2-carbonitrile 12 2- (biphenyl-4-ylmethylsulfanyl) -5- (2,3-dihydrobenzo [1,4] dioxin-6-yl) - [1,3,4] oxadiazole 13 4 '- [5- (2,3-dihydrobenzo [1,4] dioxin-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -biphenyl-3-carbonitrile 14 4 '- [5- (2,3-dihydrobenzo [1,4] dioxin-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -4-methoxy-biphenyl-2-carbonitrile 15 4 '- [5- (2,3-dihydrobenzo [1,4] dioxin-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -4-fluoro-biphenyl-2-carbonitrile 16 4 '- [5- (3S-methoxymethyl-2,3-dihydrobenzo [1,4] dioxin-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -biphenyl-2-carbonitrile 17 2- (2,3-dihydrobenzo [1,4] dioxin-6-yl) -5- (4'-methoxy-biphenyl-4-ylmethylsulfanyl) - [1,3,4] oxadiazole 18 4 '- [5- (2,3-dihydrobenzo [1,4] dioxin-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -biphenyl-4-carbonitrile 19 2- (2,3-dihydrobenzo [1,4] dioxin-6-yl) -5- (3 ', 5'-difluorobiphenyl-4-ylmethylsulfanyl) - [1,3,4] oxadiazole 20 2- (2,3-dihydrobenzo [1,4] dioxin-6-yl) -5- (3'-nitro-biphenyl-4-ylmethylsulfanyl) - [1,3,4] oxadiazole 21 5- (3-methoxymethyl-2,3-dihydrobenzo [1,4] dioxin-6-yl) - [1,3,4] oxadiazol-2-thiol 22 4 '- [5- (3-methoxymethyl-2,3-dihydrobenzo [1,4] dioxin-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -biphenyl-2-carbonitrile 23 4 '- [5- (3-hydroxymethyl-2,3-dihydrobenzo [1,4] dioxin-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -biphenyl-2-carbonitrile 24 5- (3R-methoxymethyl-2,3-dihydrobenzo [1,4] dioxin-6-yl) - [1,3,4] oxadiazol-2-thiol 25 2-Benzo [1,3] dioxol-5-yl-5- (biphenyl-4-ylmethylsulfanyl) - [1,3,4] oxadiazole 26 4 '- (5-Benzo [1,3] dioxol-5-yl- [1,3,4] oxadiazol-2-ylsulfanylmethyl) -4-fluorobiphenyl-2-carbonitrile 27 4- (5-Benzo [1,3] dioxol-5-yl- [1,3,4] oxadiazol-2-ylsulfanylmethyl) -benzoic acid methyl ester 28 2-Benzo [1,3] dioxol-5-yl-5- (biphenyl-3-ylmethylsulfanyl) - [1,3,4] oxadiazole 29 4 '- (5-Benzo [1,3] dioxol-5-yl- [1,3,4] oxadiazol-2-ylsulfanylmethyl) -biphenyl-3-carbonitrile 30 4 '- (5-Benzo [1,3] dioxol-5-yl- [1,3,4] oxadiazol-2-ylsulfanylmethyl) -4-methoxy-biphenyl-2-carbonitrile 31 2-Benzo [1,3] dioxol-5-yl-5- (2'-nitrobiphenyl-4-ylmethylsulfanyl) - [1,3,4] oxadiazole 32 2-Benzo [1,3] dioxol-5-yl-5- (4'-methoxy-biphenyl-4-ylmethylsulfanyl) - [1,3,4] oxadiazole 33 4 '- (5-Benzo [1,3] dioxol-5-yl- [1,3,4] oxadiazol-2-ylsulfanylmethyl) -biphenyl-4-carbonitrile 34 2-Benzo [1,3] dioxol-5-yl-5- (3 ', 5'-difluorobiphenyl-4-ylmethylsulfanyl) - [1,3,4] oxadiazole 35 2-Benzo [1,3] dioxol-5-yl-5- (3'-nitro-biphenyl-4-ylmethylsulfanyl) - [1,3,4] oxadiazole 36 5-Pyridin-4-yl- [1,3,4] oxadiazol-2-thiol 37 4- (5-Benzylsulfanyl- [1,3,4] oxadiazol-2-yl) -pyridine 38 4- [5- (4-Bromobenzylsulfanyl) - [1,3,4] oxadiazol-2-yl] -pyridine 39 4- (5-Pyridin-4-yl- [1,3,4] oxadiazol-2-ylsulfanylmethyl) -benzonitrile 40 3- (5-pyridin-4-yl- [1,3,4] oxadiazol-2-ylsulfanylmethyl) -benzonitrile 41 4- [5- (3-Nitrobenzylsulfanyl) - [1,3,4] oxadiazol-2-yl] -pyridine 42 4- [5- (3-Methoxybenzylsulfanyl) - [1,3,4] oxadiazol-2-yl] -pyridine 43 4 '- (5-pyridin-4-yl- [1,3,4] oxadiazol-2-ylsulfanylmethyl) -biphenyl-2-carbonitrile 44 4- [5- (4-tert-Butylbenzylsulfanyl) - [1,3,4] oxadiazol-2-yl] -pyridine 45 4- (5-Pyridin-4-yl- [1,3,4] oxadiazol-2-ylsulfanylmethyl) -benzoic acid methyl ester 46 4- [5- (Biphenyl-3-ylmethylsulfanyl) - [1,3,4] oxadiazol-2-yl] -pyridine 47 4-Fluoro-4 '- (5-pyridin-4-yl- [1,3,4] oxadiazol-2-ylsulfanylmethyl) -biphenyl-2-carbonitrile 48 4- [5- (4'-Methoxy-biphenyl-4-ylmethylsulfanyl) - [1,3,4] oxadiazol-2-yl] -pyridine 49 4- [5- (biphenyl-4 ylmethylsulfanyl) - [1,3,4] oxadiazol-2-yl] -pyridine 50 4 '- (5-pyridin-4-yl- [1,3,4] oxadiazol-2-ylsulfanylmethyl) -biphenyl-3-carbonitrile 51 4 '- (5-pyridin-4-yl- [1,3,4] oxadiazol-2-ylsulfanylmethyl) -biphenyl-4-carbonitrile 52 N- [4- (5-mercapto [1,3,4] oxadiazol-2-yl) -pyridin-2-yl] -acetamide 53 N- {4- [5- (2'-Cyanobephenyl-4-ylmethylsulfanyl) - [1,3,4] oxadiazol-2-yl] -pyridin-2-yl} -acetamide 54 N- {4- [5- (3-Methoxybenzylsulfanyl) - [1,3,4] oxadiazol-2-yl] -pyridin-2-yl} -acetamide 55 N- {4- [5- (3-Cyanobenzylsulfanyl) - [1,3,4] oxadiazol-2-yl] -pyridin-2-yl} -acetamide 56 N- [4- (5-benzylsulfanyl) - [1,3,4] oxadiazol-2-yl) -pyridin-2-yl] -acetamide 57 4- [5- (3-Methoxybenzylsulfanyl) - [1,3,4] oxadiazol-2-yl] -benzonitrile 58 2- (3-Methoxybenzylsulfanyl) -5- (4-nitrophenyl) - [1,3,4] oxadiazole 59 3- [5- (4-cyanophenyl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -benzonitrile 60 2- [5- (4-cyanophenyl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -benzonitrile 61 4- (5-Benzylsulfanyl- [1,3,4] oxadiazol-2-yl) -benzonitrile 62 3- [5- (4-nitrophenyl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -benzonitrile 63 4 '- [5- (4-nitrophenyl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -biphenyl-2-carbonitrile 64 2-Benzylsulfanyl-5- (4-nitrophenyl) - [1,3,4] oxadiazole 65 4 '- [5- (4-Methoxyphenyl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -biphenyl-2-carbonitrile 66 4 '- (5-phenyl- [1,3,4] oxadiazol-2-ylsulfanylmethyl) -biphenyl-2-carbonitrile 67 3- (5-phenyl- [1,3,4] oxadiazol-2-ylsulfanylmethyl) -benzonitrile 68 2- (3-Methoxybenzylsulfanyl) -5-phenyl- [1,3,4] oxadiazole 69 2-Benzylsulfanyl-5-phenyl- [1,3,4] oxadiazole 70 3- [5- (4-Methoxyphenyl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -benzonitrile 71 2- (3-Methoxybenzylsulfanyl) -5- (4-methoxyphenyl) - [1,3,4] oxadiazole 72 2-Benzylsulfanyl-5- (4-methoxyphenyl) - [1,3,4] oxadiazole 73 4- (5-Benzo [1,3] dioxol-5-yl- [1,3,4] oxadiazol-2-ylsulfanylmethyl) benzoic acid 74 4- [5- (2,3-dihydrobenzo [1,4} dioxin-6-yl) - benzoic acid [1,3,4] oxadiazol-2-ylsulfanylmethyl] 75 4- (5-Benzo [1,3] dioxol-5-yl- [1,3,4] oxadiazol-2-ylsulfanylmethyl) -N-isobutylbenzamid 76 4- (5-Benzo [1,3] dioxol-5-yl- [1,3,4] oxadiazol-2-ylsulfanylmethyl) -N- (2,2-dimethoxyethyl) benzamide 77 4- [5- (2,3-dihydrobenzo [1,4] dioxin-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -N- (2,2-dimethoxyethyl) benzamide 78 4- [5- (2,3-dehydrobenzo [1,4] dioxin-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -N-isobutylbenzamid 79 5- {4- [5- (2,3-dihydrobenzo [1,4] dioxin-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -phenyl-1H-tetrazole 80 3- (5-Benzo [1,3] dioxol-5-yl- [1,3,4] oxadiazol-2-ylsulfanylmethyl) -benzonitrile 81 5- [4- (5-Benzo [1,3] dioxol-5-yl- [1,3,4] oxadiazol-2-ylsulfanylmethyl)] - phenyl] -1H-tetrazole 82 4 '- (5- {3 - [(2,2-Demethoxyethylamino) methyl] -2,3-dihydrobenzo [1,4] dioxin-6-yl} - [1,3,4] oxadiazol-2-ylsulfanylmethyl ) biphenyl-2-carbonitrile 83 Methanesulfonic acid 7- [5- (2'-cyanobiphenyl-4-ylmethylsulfanyl) - [1,3,4] oxadiazol-2-yl] -2,3-dihydrobenzo [1,4] dioxin-2-ylmethyl ester 84 5- {3- [5- (2,3-dihydrobenzo [1,4] dioxin-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -phenyl) -1H-tetrazole 85 4 '- [5- (3R-hydroxymethyl-2,3-dihydrobenzo [1,4] dioxin-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -biphenyl-2-carbonitrile 86 N- {6- [5- (2'-cyanobiphenyl-4-ylmethylsulfanyl) - [1,3,4] oxadiazol-2-yl] -benzothiazol-2-yl) -acetamide 87 5-Benzo [1,3] dioxol-5-yl- [1,3,4] oxadiazol-2-thiol 88 2-Benzo [1,3] dioxol-5-yl-5- (4-bromobenzylsulfanyl) - [1,3,4] oxadiazole 89 2-Benzo [1,3] dioxol-5-yl-5- (3-methoxy-benzylsulfanyl) - [1,3,4] oxadiazole 90 4- (5-Benzo [1,3] dioxol-5-yl- [1,3,4] oxadiazol-2-ylsulfanylmethyl) -benzonitrile 91 2-Benzo [1,3] dioxol-5-yl-5- (3-nitrobenzylsulfanyl) - [1,3,4] oxadiazole 92 4 '- (5-Benzo [1,3] dioxol-5-yl- [1,3,4] oxadiazol-2-ylsulfanylmethyl) -biphenyl-2-carbonitrile 93 N-benzyl-4- [5- (2,3-dihydrobenzo [1,4] dioxin-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -benzamide 94 4 '- {5- [2- (3-methoxy-benzylamino) -benzothiazol-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -biphenyl-3-carbonitrile 95 4 '- [5- (2-Benzylbenzooxazol-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -biphenyl-3-carbonitrile 96 4 '- [5- (2-Benzyloxymethylbenzooxazol-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -biphenyl-3-carbonitrile 97 4 '- [5- (2-Benzyloxymethylbenzooxazol-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -biphenyl-2-carbonitrile 98 4 '- [5- (2-Hydroxymethylbenzooxazol-6-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -biphenyl-2-carbonitrile 99 4 '- [5- (2-phenyl-3H-benzoimidazol-5-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -biphenyl-3-carbonitrile 100 4 '- [5- (8-nitrodibenzofurane-2-yl) - [1,3,4] oxadiazol-2-ylsulfanylmethyl] -biphenyl-3-carbonitrile

Bevorzugte erfindungsgemäße Ausführungen sind nachfolgend erläutert, wobei die Erfindung alle nachfolgend aufgeführten bevorzugten Ausführungsformen einzeln und in Kombination umfasst.Preferred embodiments according to the invention are explained below, wherein the invention comprises all the preferred embodiments listed below individually and in combination.

Figurenbeschreibungfigure description

1: zeigt beispielhafte Verbindungen der allgemeinen Formel (I) 1 : shows exemplary compounds of general formula (I)

2: zeigt 2 weitere beispielhafte Verbindungen der allgemeinen Formel (I) 2 Figure 2 shows further exemplary compounds of the general formula (I)

3: Effekte am wt-Zebrafisch-Embryo durch die Verbindungen 92, 11 und 43. 3 : Effects on the wt Zebrafish Embryo by Compounds 92, 11 and 43.

Die Embryos werden gesammelt und in 24-Wellplatten platziert, zehn Embryos pro Well und in E2-Medium bei 28°C. Die Verbindungen werden bei 5 hpf (50% Epibolie) zugegeben, und die Embryos in einer Lösung aus E2-Medium und zu testender Verbindung bis zu 2 Tagen inkubiert. Die Phänotypen werden mittels Axio Scope. A1 Mikroskop von Carl Zeiss nach ca. 44–48 hpf untersucht;2–4 A, E: Kopf- und Schwanzform des Kontroll-Embryos inkubiert mit 2% DMSO; B, F: Kopf- und Schwanzform eines Zebrafischembryos inkubiert mit 92. Diese Verbindung verursacht bei 0,5 μM einen Phänotyp ohne Augen und bei 1,0 μM einen gebogenen bzw. entstellten Schwanz; C, G: Kopf- und Schwanzform eines Zebrafischembryos inkubiert mit 11, welche bei 2,5 μM einen Phänotyp mit einer undefinierten Augenpigmentierung und einen gebogenen bzw. entstellten Schwanz verursacht; D, H: Kopf- und Schwanzform eines Zebrafischembryos inkubiert mit 43. Diese Verbindung verursacht bei 20 μM einen Phänotyp ohne Augen und mit gebogenem Schwanz.The embryos are collected and placed in 24-well plates, ten embryos per well and in E2 medium at 28 ° C. The compounds are added at 5 hpf (50% epibole) and the embryos are incubated in a solution of E2 medium and compound to be tested for up to 2 days. The phenotypes are analyzed using Axio Scope. A1 microscope from Carl Zeiss examined after approx. 44-48 hpf; 2-4 A, E: Head and tail of the control embryo incubated with 2% DMSO; B, F: Head and tail shape of a zebrafish embryo incubated with 92. This compound causes a phenotype without eyes at 0.5 μM and a bent tail at 1.0 μM; C, G: head and tail shape of a zebrafish embryo incubated with 11, which at 2.5 μM causes a phenotype with undefined eye pigmentation and a bent tail; D, H: Head and tail shape of a zebrafish embryo incubated with 43. This compound causes a phenotype without eyes and with a bent tail at 20 μM.

Beispiele Examples

Beispiel 1: Synthese der Verbindung 1Example 1: Synthesis of Compound 1

Schritt 1:Step 1:

Benzo[d][1,3]dioxol-5-carbonsäure (1,66 g, 10 mmol, 1 eq) wird in 20 mL MeOH gegeben und auf 0°C gekühlt. Bei 0°C wird SOCl2 (1,45 mL, 20 mmol, 2 eq) zugetropft. Nach erfolgter Zugabe wird die Mischung bei 50°C über Nacht weitergerührt. Es werden ca. 25 mL Wasser zugegeben und das MeOH wird abrotiert. Die wässrige Phase wird mit gesättigter NaHCO3-Lösung auf pH 6 eingestellt und anschließend gegen Essigsäureethylester ausgeschüttelt. Die organische Phase wird gegen gesättigte NaClaq ausgeschüttelt und über MgSO4 getrocknet. Ausbeute: 1,6 g (89%), weißer Feststoff.Benzo [d] [1,3] dioxole-5-carboxylic acid (1.66 g, 10 mmol, 1 eq) is added to 20 mL MeOH and cooled to 0 ° C. At 0 ° C, SOCl 2 (1.45 mL, 20 mmol, 2 eq) is added dropwise. After the addition, the mixture is stirred at 50 ° C overnight. About 25 mL of water are added and the MeOH is removed by rotary evaporation. The aqueous phase is adjusted to pH 6 with saturated NaHCO 3 solution and then extracted by shaking with ethyl acetate. The organic phase is extracted by shaking with saturated NaCl aq and dried over MgSO 4 . Yield: 1.6 g (89%), white solid.

Schritt 2:Step 2:

Methylbenzo[d]dioxol-5-carboxylat (1,08 g, 6,0 mmol, 1 eq) wird in 30 mL Ethanol gegeben, mit Hydrazinmonohydrat (2,91 mL, 60 mmol, 10 eq) versetzt und unter Rückfluss 2 Tage gerührt. Der ausgefallene Feststoff wird abfiltriert und mit Wasser und Ethanol gewaschen. Ausbeute: 0,72 g (67%), weißer Feststoff.Methyl benzo [d] dioxole-5-carboxylate (1.08 g, 6.0 mmol, 1 eq) is added to 30 mL ethanol, hydrazine monohydrate (2.91 mL, 60 mmol, 10 eq) added and refluxed for 2 days touched. The precipitated solid is filtered off and washed with water and ethanol. Yield: 0.72 g (67%), white solid.

Schritt 3:Step 3:

Benzo[d][1,3]dioxol-5-carbohydrazid (535 mg, 3.00 mmol, 1 eq) wird in 5 mL Ethanol gegeben, mit CS2 (397 μL, 6,60 mmol, 2 eq) und NEt3 (469 μL, 3,30 mmol, 1,1 eq) versetzt und über Nacht unter Rückfluss gerührt. Die Reaktionsmischung wird mit Essigsäureethylester versetzt und gegen 0,1 N HCl ausgeschüttelt. Anschließend wird gegen NaClaq ausgeschüttelt und über Na2SO4 getrocknet. Die organische Phase wird einrotiert und der Feststoff in Cyclohexan/Essigsäureethylester umkristallisiert. Ausbeute: 521 mg (79%) hellgelber Feststoff.Benzo [d] [1,3] dioxole-5-carbohydrazide (535 mg, 3.00 mmol, 1 eq) is added in 5 mL ethanol, with CS 2 (397 μL, 6.60 mmol, 2 eq) and NEt 3 ( 469 μL, 3.30 mmol, 1.1 eq) and stirred under reflux overnight. The reaction mixture is mixed with ethyl acetate and shaken out against 0.1 N HCl. It is then shaken out against NaCl aq and dried over Na 2 SO 4 . The organic phase is concentrated by rotary evaporation and the solid is recrystallized in cyclohexane / ethyl acetate. Yield: 521 mg (79%) of a light yellow solid.

Schritt 4:Step 4:

5-(benzo[d][1,3]dioxol-5-yl)-1,3,4-oxadiazol-2-thiol (55 mg, 0,25 mmol, 1 eq) wird in 1 mL DMF (Dimethylformamid) gegeben. Es werden 250 μL 1 N NaOH zugegeben und die Lösung kurze Zeit bei Raumtmperatur gerührt. Anschließend wird 4'-(bromomethyl)biphenyl-2-carbonitril (103 mg, 0,38 mmol, 1,5 eq) zugegeben und die Lösung 5 h bei Raumtemperatur gerührt. Der ausgefallene Feststoff wird abfiltriert und einmal mit wenig DMF und mehrfach mit Ethanol gewaschen. Ausbeute: 73 mg (71%), brauner Feststoff: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.31 (2H, m), 4.34 (2H, m), 4.65 (2H, s), 7.05 (1H, d, J = 8.4 Hz), 7.41 (1H, d, J = 2.0 Hz), 7.44 (1H, dd, J = 2.0 Hz, J = 8.4 Hz), 7.55-7.65 (6H, m, br), 7.79 (1H, td, J = 1.2 Hz, J = 7.7 Hz), 7.95 (1H, dd, J = 0.9 Hz, J = 7.7 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.9, 64.4, 64.8, 110.5, 115.4, 116.3, 118.5, 118.8, 120.3, 128.6, 129.3, 129.7, 130.5, 133.8, 134.2, 137.5, 137.8, 144.1, 144.3, 147.1, 163.0, 165.3; MS: Molekülpeak: m/z = 427; rel. Häufigkeit 40% Basispeak: m/z = 192; HPLC: 8.39 Minuten5- (benzo [d] [1,3] dioxol-5-yl) -1,3,4-oxadiazole-2-thiol (55 mg, 0.25 mmol, 1 eq) is dissolved in 1 mL of DMF (dimethylformamide). given. 250 μL of 1N NaOH are added and the solution is stirred for a short time at room temperature. Subsequently, 4 '- (bromomethyl) biphenyl-2-carbonitrile (103 mg, 0.38 mmol, 1.5 eq) is added and the solution is stirred for 5 h at room temperature. The precipitated solid is filtered off and washed once with a little DMF and several times with ethanol. Yield: 73 mg (71%), brown solid: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.31 (2H, m), 4.34 (2H, m), 4.65 (2H, s ), 7.05 (1H, d, J = 8.4 Hz), 7.41 (1H, d, J = 2.0 Hz), 7.44 (1H, dd, J = 2.0 Hz, J = 8.4 Hz), 7.55-7.65 (6H, m , br), 7.79 (1H, td, J = 1.2 Hz, J = 7.7 Hz), 7.95 (1H, dd, J = 0.9 Hz, J = 7.7 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.9, 64.4, 64.8, 110.5, 115.4, 116.3, 118.5, 118.8, 120.3, 128.6, 129.3, 129.7, 130.5, 133.8, 134.2, 137.5 , 137.8, 144.1, 144.3, 147.1, 163.0, 165.3; MS: Molecular peak: m / z = 427; rel. Frequency 40% base peak: m / z = 192; HPLC: 8.39 minutes

Analog wurden die Verbindungen 2–5, 7, 8, 10–15, 17–72, 80, 86 ab Stufe 4 und Verbindung 87 bis Stufe 4 synthetisiert.Analogously, compounds 2-5, 7, 8, 10-15, 17-72, 80, 86 from stage 4 and compound 87 to stage 4 were synthesized.

Verbindung 2: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.32 (2H, m), 4.34 (2H, m), 7.05 (1H, d, J = 8.46 Hz), 7.30 (1H, d, J = 2.0 Hz), 7.36 (1H, dd, J = 8.4 Hz, J = 2.0 Hz), 14.2 (1H, s, br); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 64.4, 64.8, 115.0, 115.7, 118.6, 120.0, 144.2, 147.3, 160.6, 177.6 MS: Molekülpeak: m/z = 236; rel. Häufigkeit 100% HPLC: 5.93 MinutenCompound 2: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.32 (2H, m), 4.34 (2H, m), 7.05 (1H, d, J = 8.46 Hz), 7.30 ( 1H, d, J = 2.0 Hz), 7.36 (1H, dd, J = 8.4 Hz, J = 2.0 Hz), 14.2 (1H, s, br); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 64.4, 64.8, 115.0, 115.7, 118.6, 120.0, 144.2, 147.3, 160.6, 177.6 MS: Molecular peak: m / z = 236; rel. Frequency 100% HPLC: 5.93 minutes

Verbindung 3: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.31 (2H, m), 4.34 (2H, m), 4.61 (2H, s), 7.05 (1H, d, J = 8.4 Hz), 7.39 (1H, d, J = 2.0 Hz), 7.42 (1H, dd, J = 2.1 Hz, J = 8.4 Hz), 7.57 (1H, t, J = 7.8 Hz), 7.77 (1H, dt, J = 1.3 Hz, J = 7.8 Hz), 7.84 (1H, m), 7.96 (1H, t, J = 1.5 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.2, 64.5, 64.7, 111.8, 115.5, 116.3, 118.5, 118.9, 120.4, 130.1, 131.8, 133.0, 134.4, 139.3, 144.2, 147.1, 162.7, 165.5; MS: Molekülpeak: m/z = 351; rel. Häufigkeit 80% Basispeak: m/z = 163; HPLC: 7.53 MinutenCompound 3: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.31 (2H, m), 4.34 (2H, m), 4.61 (2H, s), 7.05 (1H, d, J = 8.4 Hz), 7.39 (1H, d, J = 2.0 Hz), 7.42 (1H, dd, J = 2.1 Hz, J = 8.4 Hz), 7.57 (1H, t, J = 7.8 Hz), 7.77 (1H, dt, J = 1.3 Hz, J = 7.8 Hz), 7.84 (1H, m), 7.96 (1H, t, J = 1.5 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.2, 64.5, 64.7, 111.8, 115.5, 116.3, 118.5, 118.9, 120.4, 130.1, 131.8, 133.0, 134.4, 139.3, 144.2, 147.1 , 162.7, 165.5; MS: Molecular peak: m / z = 351; rel. Frequency 80% base peak: m / z = 163; HPLC: 7.53 minutes

Verbindung 4: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 3.51 (3H, s), 4.10 (2H, m), 4.12 (2H, m), 4.31 (2H, s), 6.64 (1H, m), 6.82 (3H, m), 7.04 (1H, t, J = 7.84 Hz), 7.19 (1H, d, J = 2.0 Hz), 7.23 (1H, dd, J = 2.0 Hz, J = 8.4 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 36.2, 55.4, 64.4, 64.8, 113.6, 114.9, 115.3, 116.3, 118.5, 120.2, 121.5, 130.0, 138.4, 144.1, 147.0, 159.5, 162.8, 165.2; MS: Molekülpeak: m/z = 356; rel. Häufigkeit 58% Basispeak: m/z = 163; HPLC: 7.85 MinutenCompound 4: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 3.51 (3H, s), 4.10 (2H, m), 4.12 (2H, m), 4.31 (2H, s), 6.64 (1H, m), 6.82 (3H, m), 7.04 (1H, t, J = 7.84 Hz), 7.19 (1H, d, J = 2.0 Hz), 7.23 (1H, dd, J = 2.0 Hz, J = 8.4 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 36.2, 55.4, 64.4, 64.8, 113.6, 114.9, 115.3, 116.3, 118.5, 120.2, 121.5, 130.0, 138.4, 144.1, 147.0, 159.5 , 162.8, 165.2; MS: Molecular peak: m / z = 356; rel. Frequency 58% base peak: m / z = 163; HPLC: 7.85 minutes

Verbindung 5: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.30 (2H, m), 4.34 (2H, m), 4.70 (2H, s), 7.04 (1H, d, J = 8.4 Hz), 7.37 (1H, d, J = 2.0 Hz), 7.41 (1H, dd, J = 2.1 Hz, J = 8.4 Hz), 7.65 (1H, t, J = 7.9 Hz), 7.95 (1H, d, J = 7.7 Hz), 8.14 (1H, m), 8.39 (1H, t, J = 1.9 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.1, 64.4, 64.8, 115.4, 116.2, 118.5, 120.3, 123.0, 124.1, 130.4, 136.1, 139.9, 144.1, 147.1, 148.0, 162.6, 165.4; MS: Molekülpeak: m/z = 371; rel. Häufigkeit 45% Basispeak: m/z = 163; HPLC: 7.63 Minuten Compound 5: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.30 (2H, m), 4.34 (2H, m), 4.70 (2H, s), 7.04 (1H, d, J = 8.4 Hz), 7.37 (1H, d, J = 2.0 Hz), 7.41 (1H, dd, J = 2.1 Hz, J = 8.4 Hz), 7.65 (1H, t, J = 7.9 Hz), 7.95 (1H, d, J = 7.7 Hz), 8.14 (1H, m), 8.39 (1H, t, J = 1.9 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.1, 64.4, 64.8, 115.4, 116.2, 118.5, 120.3, 123.0, 124.1, 130.4, 136.1, 139.9, 144.1, 147.1, 148.0, 162.6 , 165.4; MS: Molecular peak: m / z = 371; rel. Frequency 45% base peak: m / z = 163; HPLC: 7.63 minutes

Verbindung 7: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.31 (2H, m), 4.34 (2H, m), 4.53 (2H, s), 7.05 (1H, d, J = 8.4 Hz), 7.39 (1H, d, J = 2.0 Hz), 7.43 (3H, m), 7.54 (2H, m); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.1, 64.0, 64.4, 115.0, 115.9, 118.2, 120.0, 120.9, 131.2, 131.4, 136.4, 143.8, 146.8, 162.4, 165.0; MS: Molekülpeak: m/z = 404/406; rel. Häufigkeit 20/22% Basispeak: m/z = 161; HPLC: 8.54 MinutenCompound 7: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.31 (2H, m), 4.34 (2H, m), 4.53 (2H, s), 7.05 (1H, d, J = 8.4 Hz), 7.39 (1H, d, J = 2.0 Hz), 7.43 (3H, m), 7.54 (2H, m); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.1, 64.0, 64.4, 115.0, 115.9, 118.2, 120.0, 120.9, 131.2, 131.4, 136.4, 143.8, 146.8, 162.4, 165.0; MS: Molecular peak: m / z = 404/406; rel. Frequency 20/22% base peak: m / z = 161; HPLC: 8.54 minutes

Verbindung 8: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.31 (2H, m), 4.34 (2H, m), 4.63 (2H, s), 7.05 (1H, d, J = 8.4 Hz), 7.37 (1H, d, J = 2.0 Hz), 7.41 (1H, dd, J = 8.4 Hz, J = 2.0 Hz), 7.67 (2H, d, J = 8.3 Hz), 7.81 (2H, d, J = 8.3 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.3, 64.0, 64.4, 110.4, 115.0, 115.8, 118.2, 118.6, 119.9, 130.0, 132.4, 142.8, 143.8, 146.7, 162.2, 165.0; MS: Molekülpeak: m/z = 351; rel. Häufigkeit 48% Basispeak: m/z = 163; HPLC: 7.49 MinutenCompound 8: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.31 (2H, m), 4.34 (2H, m), 4.63 (2H, s), 7.05 (1H, d, J = 8.4 Hz), 7.37 (1H, d, J = 2.0 Hz), 7.41 (1H, dd, J = 8.4 Hz, J = 2.0 Hz), 7.67 (2H, d, J = 8.3 Hz), 7.81 (2H, d, J = 8.3 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.3, 64.0, 64.4, 110.4, 115.0, 115.8, 118.2, 118.6, 119.9, 130.0, 132.4, 142.8, 143.8, 146.7, 162.2, 165.0 ; MS: Molecular peak: m / z = 351; rel. Frequency 48% base peak: m / z = 163; HPLC: 7.49 minutes

Verbindung 10: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 3.89 (3H, s), 4.36 (2H, m), 4.39 (2H, m), 4.67 (2H, s), 7.10 (1H, d, J = 8.4 Hz), 7.42 (1H, d, J = 2.0 Hz), 7.47 (1H, dd, J = 8.4 Hz, J = 2.0 Hz), 7.67 (2H, d, J = 8.3 Hz), 7.97 (2H, d, J = 8.3 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.4, 52.1, 64.0, 64.4, 115.0, 115.8, 118.1, 120.0, 128.9, 129.4, 142.4, 143.8, 146.7, 162.3, 165.0, 165.8; MS: Molekülpeak: m/z = 384; rel. Häufigkeit 58% Basispeak: m/z = 161; HPLC: 7.66 MinutenCompound 10: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 3.89 (3H, s), 4.36 (2H, m), 4.39 (2H, m), 4.67 (2H, s), 7.10 (1H, d, J = 8.4 Hz), 7.42 (1H, d, J = 2.0 Hz), 7.47 (1H, dd, J = 8.4 Hz, J = 2.0 Hz), 7.67 (2H, d, J = 8.3 Hz), 7.97 (2H, d, J = 8.3 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.4, 52.1, 64.0, 64.4, 115.0, 115.8, 118.1, 120.0, 128.9, 129.4, 142.4, 143.8, 146.7, 162.3, 165.0, 165.8 ; MS: Molecular peak: m / z = 384; rel. Frequency 58% base peak: m / z = 161; HPLC: 7.66 minutes

Verbindung 11: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.31 (2H, m), 4.34 (2H, m), 4.65 (2H, s), 7.05 (1H, d, J = 8.4 Hz), 7.41 (1H, d, J = 2.0 Hz), 7.44 (1H, dd, J = 2.0 Hz, J = 8.4 Hz), 7.55-7.65 (6H, m, br), 7.79 (1H, td, J = 1.2 Hz, J = 7.7 Hz), 7.95 (1H, dd, J = 0.9 Hz, J = 7.7 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.9, 64.4, 64.8, 110.5, 115.4, 116.3, 118.5, 118.8, 120.3, 128.6, 129.3, 129.7, 130.5, 133.8, 134.2, 137.5, 137.8, 144.1, 144.3, 147.1, 163.0, 165.3; MS: Molekülpeak: m/z = 427; rel. Häufigkeit 40% Basispeak: m/z = 192; HPLC: 8.39 MinutenCompound 11: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.31 (2H, m), 4.34 (2H, m), 4.65 (2H, s), 7.05 (1H, d, J = 8.4 Hz), 7.41 (1H, d, J = 2.0 Hz), 7.44 (1H, dd, J = 2.0 Hz, J = 8.4 Hz), 7.55-7.65 (6H, m, br), 7.79 (1H, td , J = 1.2 Hz, J = 7.7 Hz), 7.95 (1H, dd, J = 0.9 Hz, J = 7.7 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.9, 64.4, 64.8, 110.5, 115.4, 116.3, 118.5, 118.8, 120.3, 128.6, 129.3, 129.7, 130.5, 133.8, 134.2, 137.5 , 137.8, 144.1, 144.3, 147.1, 163.0, 165.3; MS: Molecular peak: m / z = 427; rel. Frequency 40% base peak: m / z = 192; HPLC: 8.39 minutes

Verbindung 12: 1H-NMR (DMSO-d6, 300 MHz): δ [ppm] = 4.31 (4H, m), 4.60 (2H, s), 7.03 (1H, d, J = 8.4 Hz), 7.5 (11H, m); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 36.1, 64.5, 64.9, 115.5, 116.4, 118.6, 120.4, 127.1, 127.3, 127.5, 128.0, 129.4, 130.1, 136.4, 140.1, 144.3, 147.2, 163.1, 165.4; MS: Molekülpeak: m/z = 402; rel. Häufigkeit 1%; Basispeak: m/z = 43; HPLC: 9.1 Minuten Compound 12: 1 H-NMR (DMSO-d 6 , 300 MHz): δ [ppm] = 4.31 (4H, m), 4.60 (2H, s), 7.03 (1H, d, J = 8.4 Hz), 7.5 ( 11H, m); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 36.1, 64.5, 64.9, 115.5, 116.4, 118.6, 120.4, 127.1, 127.3, 127.5, 128.0, 129.4, 130.1, 136.4, 140.1, 144.3 , 147.2, 163.1, 165.4; MS: Molecular peak: m / z = 402; rel. Frequency 1%; Base peak: m / z = 43; HPLC: 9.1 minutes

Verbindung 13: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.3 (4H, m), 4.62 (2H, s), 7.05 (1H, d, J = 8.5 Hz), 7.39 (1H, d, J = 2.1 Hz), 7.44 (1H, dd, J = 8.5 Hz, J = 2.1 Hz), 7.59 (2H, d, J = 8.3 Hz), 7.66 (1H, m), 7.74 (2H, d, J = 8.3 Hz), 7.82 (1H, td, J = 6.6 Hz, J = 1.3 Hz), 8.02 (1H, d, J = 8.0 Hz), 8.14 (1H, s); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 36.0, 64.5, 64.9, 112.6, 115.5, 116.4, 118.6, 119.2, 120.4, 127.6, 130.2, 130.6, 130.7, 131.6, 131.9, 137.6, 137.8, 141.1, 144.3, 147.2, 163.0, 165.4; MS: Molekülpeak: m/z = 427; rel. Häufigkeit 34% Basispeak: m/z = 192; HPLC: 8.8 MinutenCompound 13: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.3 (4H, m), 4.62 (2H, s), 7.05 (1H, d, J = 8.5 Hz), 7.39 ( 1H, d, J = 2.1 Hz), 7.44 (1H, dd, J = 8.5 Hz, J = 2.1 Hz), 7.59 (2H, d, J = 8.3 Hz), 7.66 (1H, m), 7.74 (2H, d, J = 8.3 Hz), 7.82 (1H, td, J = 6.6 Hz, J = 1.3 Hz), 8.02 (1H, d, J = 8.0 Hz), 8.14 (1H, s); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 36.0, 64.5, 64.9, 112.6, 115.5, 116.4, 118.6, 119.2, 120.4, 127.6, 130.2, 130.6, 130.7, 131.6, 131.9, 137.6 , 137.8, 141.1, 144.3, 147.2, 163.0, 165.4; MS: Molecular peak: m / z = 427; rel. Frequency 34% base peak: m / z = 192; HPLC: 8.8 minutes

Verbindung 14: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 3.85 (3H, s), 4.33 (4H, m), 4.64 (2H, s), 7.05 (1H, d, J = 8.4 Hz), 7.35 (1H, dd; J = 8.7 Hz, J = 2.8 Hz), 7.41 (1H, d, J = 2.0 Hz), 7.44 (1H, dd, J = 8.4 Hz, J = 2.1 Hz), 7.53 (4H, m), 7.61 (2H, d, J = 8.3 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 36.0, 56.4, 64.5, 64.9, 111.3, 115.5, 116.4, 118.5, 118.6, 118.8, 120.4, 120.6, 129.3, 129.8, 131.9, 137.0, 137.4, 144.3, 147.2, 159.0, 163.1, 165.4; MS: Molekülpeak: m/z = 457; rel. Häufigkeit 16% Basispeak: m/z = 222; HPLC: 8.8 MinutenCompound 14: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 3.85 (3H, s), 4.33 (4H, m), 4.64 (2H, s), 7.05 (1H, d, J = 8.4 Hz), 7.35 (1H, dd, J = 8.7 Hz, J = 2.8 Hz), 7.41 (1H, d, J = 2.0 Hz), 7.44 (1H, dd, J = 8.4 Hz, J = 2.1 Hz) , 7.53 (4H, m), 7.61 (2H, d, J = 8.3 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 36.0, 56.4, 64.5, 64.9, 111.3, 115.5, 116.4, 118.5, 118.6, 118.8, 120.4, 120.6, 129.3, 129.8, 131.9, 137.0 , 137.4, 144.3, 147.2, 159.0, 163.1, 165.4; MS: Molecular peak: m / z = 457; rel. Frequency 16% base peak: m / z = 222; HPLC: 8.8 minutes

Verbindung 15: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 7.97 (1H, dd, J = 9.0 Hz, J = 1.9 Hz), 7.68 (2H, m), 7.63 (2H, m) 7.56 (2H, d, J = 8.3 Hz), 7.45 (1H, dd, J = 8.4 Hz, J = 2.1 Hz), 7.40 (1H, d, J = 2.1 Hz), 7.05 (1H, d, J = 8.5 Hz), 4.65 (2H, s), 4.32 (4H, m), MS: Molekülpeak: m/z = 445; rel. Häufigkeit 32% Basispeak: m/z = 210; HPLC: 8.8 MinutenCompound 15: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 7.97 (1H, dd, J = 9.0 Hz, J = 1.9 Hz), 7.68 (2H, m), 7.63 (2H, m) 7.56 (2H, d, J = 8.3 Hz), 7.45 (1H, dd, J = 8.4 Hz, J = 2.1 Hz), 7.40 (1H, d, J = 2.1 Hz), 7.05 (1H, d, J = 8.5 Hz), 4.65 (2H, s), 4.32 (4H, m), MS: Molecular peak: m / z = 445; rel. Frequency 32% base peak: m / z = 210; HPLC: 8.8 minutes

Verbindung 17: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 3.87 (3H, s), 4.31 (4H, m), 4.58, (2H, s), 7.01 (2H, d, J = 8.8 Hz), 7.04 (1H, d, J = 8.3 Hz), 7.43 (2H, m), 7.51 (2H, m), 7.58 (4H, m); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 36.2, 55.6, 64.5, 64.9, 114.8, 115.5, 116.4, 118.6, 120.4 126.6 128.2, 130.0, 132.4, 135.5, 139.7, 144.3, 147.1, 159.4, 163.1, 165.4; MS: Molekülpeak: m/z = 432; rel. Häufigkeit 9% Basispeak: m/z = 197; HPLC: 9.05 MinutenCompound 17: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 3.87 (3H, s), 4.31 (4H, m), 4.58, (2H, s), 7.01 (2H, d, J = 8.8 Hz), 7.04 (1H, d, J = 8.3 Hz), 7.43 (2H, m), 7.51 (2H, m), 7.58 (4H, m); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 36.2, 55.6, 64.5, 64.9, 114.8, 115.5, 116.4, 118.6, 120.4, 126.6, 128.2, 130.0, 132.4, 135.5, 139.7, 144.3, 147.1 , 159.4, 163.1, 165.4; MS: Molecular peak: m / z = 432; rel. Frequency 9% base peak: m / z = 197; HPLC: 9.05 minutes

Verbindung 18: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.33 (4H, m), 4.62 (2H, s), 7.05 (1H, d, J = 8.3 Hz), 7.39 (1H, d, J = 2.1 Hz), 7.44 (1H, dd, J = 8.5 Hz, J = 2.1 Hz), 7.61 (2H, d, J = 8.5 Hz), 7.74 (2H, d, J = 8.5 Hz), 7.90 (4H, m); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 36.0, 64.5, 64.9, 110.6, 115.5, 116.4, 118.6, 119.3, 120.4, 127.7, 128.0, 130.3, 133.3, 138.0, 138.1, 144.3, 144.5, 147.2, 163.0, 165.4; MS: Molekülpeak: m/z = 427; rel. Häufigkeit 2% Basispeak: m/z = 192; HPLC: 8.80 Minuten Compound 18: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.33 (4H, m), 4.62 (2H, s), 7.05 (1H, d, J = 8.3 Hz), 7.39 ( 1H, d, J = 2.1 Hz), 7.44 (1H, dd, J = 8.5 Hz, J = 2.1 Hz), 7.61 (2H, d, J = 8.5 Hz), 7.74 (2H, d, J = 8.5 Hz) , 7.90 (4H, m); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 36.0, 64.5, 64.9, 110.6, 115.5, 116.4, 118.6, 119.3, 120.4, 127.7, 128.0, 130.3, 133.3, 138.0, 138.1, 144.3 , 144.5, 147.2, 163.0, 165.4; MS: Molecular peak: m / z = 427; rel. Frequency 2% base peak: m / z = 192; HPLC: 8.80 minutes

Verbindung 19: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.33 (4H, m), 4.61 (2H, s), 7.05 (1H, d, J = 8.5 Hz), 7.22 (1H, m), 7.38 (1H, d, J = 2.1 Hz), 7.43 (3H, m), 7.57 (2H, d, J = 8.2 Hz), 7.73 (2H, d, J = 8.2 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 36.0, 64.5, 64.9, 103.2, 110.1, 110.3, 115.5, 116.4, 118.6, 120.4, 127.5, 130.2, 137.4, 137.9, 143.7, 144.3, 147.2, 162.4, 163.0, 164.3, 165.4; MS: Molekülpeak: m/z = 438; rel. Häufigkeit 29% Basispeak: m/z = 203; HPLC: 9.19 MinutenCompound 19: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.33 (4H, m), 4.61 (2H, s), 7.05 (1H, d, J = 8.5 Hz), 7.22 ( 1H, m), 7.38 (1H, d, J = 2.1 Hz), 7.43 (3H, m), 7.57 (2H, d, J = 8.2 Hz), 7.73 (2H, d, J = 8.2 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 36.0, 64.5, 64.9, 103.2, 110.1, 110.3, 115.5, 116.4, 118.6, 120.4, 127.5, 130.2, 137.4, 137.9, 143.7, 144.3 , 147.2, 162.4, 163.0, 164.3, 165.4; MS: Molecular peak: m / z = 438; rel. Frequency 29% base peak: m / z = 203; HPLC: 9.19 minutes

Verbindung 20: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.32 (4H, m), 4.63 (2H, s), 7.05 (1H, d, J = 8.1 Hz), 7.39 (1H, d, J = 2.1 Hz), 7.44 (1H, dd, J = 8.4 Hz, J = 2.1 Hz), 7.62 (2H, d, J = 8.5 Hz), 7.77 (3H, m), 8.13 (1H, m), 8.21 (1H, m), 8.42 (1H, m); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 36.0, 64.5, 64.9, 115.5, 116.4, 118.6, 120.4, 121.5, 122.7, 127.7, 130.3, 130.9, 133.7, 137.6, 137.8, 141.7, 144.3, 147.2, 148.9, 163.0, 165.5; MS: Molekülpeak: m/z = 447; rel. Häufigkeit 40% Basispeak: m/z = 212; HPLC: 9.10 MinutenCompound 20: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.32 (4H, m), 4.63 (2H, s), 7.05 (1H, d, J = 8.1 Hz), 7.39 ( 1H, d, J = 2.1 Hz), 7.44 (1H, dd, J = 8.4 Hz, J = 2.1 Hz), 7.62 (2H, d, J = 8.5 Hz), 7.77 (3H, m), 8.13 (1H, m), 8.21 (1H, m), 8.42 (1H, m); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 36.0, 64.5, 64.9, 115.5, 116.4, 118.6, 120.4, 121.5, 122.7, 127.7, 130.3, 130.9, 133.7, 137.6, 137.8, 141.7 , 144.3, 147.2, 148.9, 163.0, 165.5; MS: Molecular peak: m / z = 447; rel. Frequency 40% base peak: m / z = 212; HPLC: 9.10 minutes

Verbindung 21: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 3.32 (3H, s), 3.61 (2H, m), 4.10 (1H, m), 4.43 (2H, m), 7.07 (1H, m), 7.32 (1H, m), 7.37 (1H, m), 14.60 (1H, s); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 58.7, 65.3, 70.3, 72.1, 114.6, 118.0, 119.7, 143.4, 146.4, 160.1, 177.4; MS: Molekülpeak: m/z = 280; rel. Häufigkeit 100%, HPLC: 5.45 MinutenCompound 21: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 3.32 (3H, s), 3.61 (2H, m), 4.10 (1H, m), 4.43 (2H, m), 7.07 (1H, m), 7.32 (1H, m), 7.37 (1H, m), 14.60 (1H, s); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 58.7, 65.3, 70.3, 72.1, 114.6, 118.0, 119.7, 143.4, 146.4, 160.1, 177.4; MS: Molecular peak: m / z = 280; rel. Frequency 100%, HPLC: 5.45 minutes

Verbindung 22: 1H-NMR (DMSO-d6, 500 MHz): mδ [ppm] = 3.33 (3H, s), 3.61 (2H, m), 4.10 (1H, m), 4.44 (2H, m), 4.66 (2H, s), 7.07 (1H, m), 7.45 (2H, m), 7.57 (3H, m), 7.63 (3H, m), 7.78 (1H, td, J = 7.6 Hz, J = 1.2 Hz), 7.95 (1H, dd, J = 7.7 Hz, J = 1.1 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.4, 58.7, 65.2, 70.3, 72.0, 110.1, 115.1, 116.2, 118.0, 118.5, 119.9, 128.2, 128.8, 129.4, 130.1, 133.5, 133.8, 137.1, 137.4, 143.3, 143.9, 146.2, 162.6, 164.9; MS: Molekülpeak: m/z = 471; rel. Häufigkeit 45% Basispeak: m/z = 192; HPLC: 8.59 MinutenCompound 22: 1 H-NMR (DMSO-d 6 , 500 MHz): mδ [ppm] = 3.33 (3H, s), 3.61 (2H, m), 4.10 (1H, m), 4.44 (2H, m), 4.66 (2H, s), 7.07 (1H, m), 7.45 (2H, m), 7.57 (3H, m), 7.63 (3H, m), 7.78 (1H, td, J = 7.6 Hz, J = 1.2 Hz ), 7.95 (1H, dd, J = 7.7 Hz, J = 1.1 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.4, 58.7, 65.2, 70.3, 72.0, 110.1, 115.1, 116.2, 118.0, 118.5, 119.9, 128.2, 128.8, 129.4, 130.1, 133.5 , 133.8, 137.1, 137.4, 143.3, 143.9, 146.2, 162.6, 164.9; MS: Molecular peak: m / z = 471; rel. Frequency 45% base peak: m / z = 192; HPLC: 8.59 minutes

Verbindung 23: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 3.64 (2H, m), 3.68 (1H, s, br), 4.10 (1H, m), 4.24 (1H, m), 4.42 (1H, dd, J = 11.5 Hz, J = 2.2 Hz), 4.65 (2H, s) 7.06 (1H, d, J = 8.3 Hz), 7.43 (2H, m), 7.60 (6H, m), 7.78 (1H, td, J = 7.7 Hz, J = 1.2 Hz), 7.94 (1H, dd, J = 7.7 Hz, J = 1.0 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.4, 59.6, 65.4, 73.7, 110.1, 115.1, 116.1, 117.9, 118.5, 119.8, 128.2, 128.8, 129.4, 130.1, 133.4, 133.8, 137.1, 137.4, 143.5, 144.0, 146.2, 162.6, 165.0; MS: Molekülpeak: m/z = 471; rel. Häufigkeit 35% Basispeak: m/z = 192; HPLC: 7.51 Minuten Compound 23: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 3.64 (2H, m), 3.68 (1H, s, br), 4.10 (1H, m), 4.24 (1H, m ), 4.42 (1H, dd, J = 11.5 Hz, J = 2.2 Hz), 4.65 (2H, s) 7.06 (1H, d, J = 8.3 Hz), 7.43 (2H, m), 7.60 (6H, m) , 7.78 (1H, td, J = 7.7 Hz, J = 1.2 Hz), 7.94 (1H, dd, J = 7.7 Hz, J = 1.0 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.4, 59.6, 65.4, 73.7, 110.1, 115.1, 116.1, 117.9, 118.5, 119.8, 128.2, 128.8, 129.4, 130.1, 133.4, 133.8 , 137.1, 137.4, 143.5, 144.0, 146.2, 162.6, 165.0; MS: Molecular peak: m / z = 471; rel. Frequency 35% base peak: m / z = 192; HPLC: 7.51 minutes

Verbindung 24: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 3.33 (3H, s), 3.61 (2H, m), 4.10 (1H, m), 4.42 (2H, m), 7.07 (1H, m), 7.31 (1H, m), 7.37 (1H, m), 14.62 (1H, s); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 58.8, 65.3, 70.2, 72.1, 114.6, 118.0, 119.7, 143.3, 146.4, 160.1, 177.2; MS: Molekülpeak: m/z = 280; el. Häufigkeit 100%; HPLC: 5.49 MinutenCompound 24: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 3.33 (3H, s), 3.61 (2H, m), 4.10 (1H, m), 4.42 (2H, m), 7.07 (1H, m), 7.31 (1H, m), 7.37 (1H, m), 14.62 (1H, s); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 58.8, 65.3, 70.2, 72.1, 114.6, 118.0, 119.7, 143.3, 146.4, 160.1, 177.2; MS: Molecular peak: m / z = 280; el. frequency 100%; HPLC: 5.49 minutes

Verbindung 25: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.55 (2H, s), 6.08 (2H, s), 7.04 (1H, d, J = 8.1 Hz), 7.28 (1H, m), 7.38 (3H, m), 7.45 (1H, dd, J = 8.1 Hz J = 1.7 Hz), 7.48 (2H, d, J = 8.3 Hz), 7.58 (4H, m); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.6, 102.1, 106.2, 109.1, 116.6, 121.7, 126.6, 126.8, 127.6, 128.9, 129.7, 135.8, 139.6, 148.1, 150.5, 162.6, 165.1; MS: Molekülpeak: m/z = 388; rel. Häufigkeit 23% Basispeak: m/z = 167; HPLC: 9.12 MinutenCompound 25: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.55 (2H, s), 6.08 (2H, s), 7.04 (1H, d, J = 8.1 Hz), 7.28 ( 1H, m), 7.38 (3H, m), 7.45 (1H, dd, J = 8.1 Hz J = 1.7 Hz), 7.48 (2H, d, J = 8.3 Hz), 7.58 (4H, m); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.6, 102.1, 106.2, 109.1, 116.6, 121.7, 126.6, 126.8, 127.6, 128.9, 129.7, 135.8, 139.6, 148.1, 150.5, 162.6 , 165.1; MS: Molecular peak: m / z = 388; rel. Frequency 23% base peak: m / z = 167; HPLC: 9.12 minutes

Verbindung 26: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.66 (2H, s), 6.16 (2H, s), 7.11 (1H, d, J = 8.1 Hz), 7.45 (1H, d, J = 1.7 HZ), 7.51 (1H, dd, J = 8.1 Hz, J = 1.7 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.65 (4H, m), 7.96 (1H, dd, J = 8.5 Hz, J = 2.3 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.4, 102.1, 106.1, 109.2, 111.6, 116.6, 117.4, 120.5, 121.1, 121.7, 129.2, 132.4, 136.2, 137.6, 140.8, 148.1, 150.4, 159.8, 161.8, 162.6, 165.1; MS: Molekülpeak: m/z = 431; rel. Häufigkeit 34% Basispeak: m/z = 210; HPLC: 8.77 MinutenCompound 26: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.66 (2H, s), 6.16 (2H, s), 7.11 (1H, d, J = 8.1 Hz), 7.45 ( 1H, d, J = 1.7 HZ), 7.51 (1H, dd, J = 8.1 Hz, J = 1.7 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.65 (4H, m), 7.96 (1H, dd, J = 8.5 Hz, J = 2.3 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.4, 102.1, 106.1, 109.2, 111.6, 116.6, 117.4, 120.5, 121.1, 121.7, 129.2, 132.4, 136.2, 137.6, 140.8, 148.1 , 150.4, 159.8, 161.8, 162.6, 165.1; MS: Molecular peak: m / z = 431; rel. Frequency 34% base peak: m / z = 210; HPLC: 8.77 minutes

Verbindung 27: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 3.82 (3H, s), 4.63 (2H, s), 6.15 (2H, s), 7.10 (1H, d, J = 8.1 Hz), 7.41 (1H, d, J = 1.7 Hz), 7.48 (1H, dd, J = 8.1 Hz, J = 1.7 Hz), 7.62 (2H, d, J = 8.4 Hz), 7.92 (2H, d, J = 8.4 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.4, 52.2, 102.2, 106.1, 109.2, 116.6, 121.7, 128.8, 129.4, 142.4, 148.1, 150.4, 162.3, 165.1, 165.9; MS: Molekülpeak: m/z = 370; rel. Häufigkeit 34% Basispeak: m/z = 149; HPLC: 7.61 MinutenCompound 27: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 3.82 (3H, s), 4.63 (2H, s), 6.15 (2H, s), 7.10 (1H, d, J = 8.1 Hz), 7.41 (1H, d, J = 1.7 Hz), 7.48 (1H, dd, J = 8.1 Hz, J = 1.7 Hz), 7.62 (2H, d, J = 8.4 Hz), 7.92 (2H, d, J = 8.4 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.4, 52.2, 102.2, 106.1, 109.2, 116.6, 121.7, 128.8, 129.4, 142.4, 148.1, 150.4, 162.3, 165.1, 165.9; MS: Molecular peak: m / z = 370; rel. Frequency 34% base peak: m / z = 149; HPLC: 7.61 minutes

Verbindung 28: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.63 (2H, s), 6.15 (2H, s), 7.06 (1H, d, J = 8.1 Hz), 7.37 (1H, m), 7.46 (6H, m), 7.60 (3H, m), 7.77 (1H, s); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.9, 102.1, 106.1, 109.1, 116.6, 121.7, 126.1, 126.6, 127.4, 127.6, 128.1, 128.8, 129.2, 137.5, 139.7, 140.3, 148.1, 150.4, 162.6, 165.1; MS: Molekülpeak: m/z = 388; rel. Häufigkeit 47% Basispeak: m/z = 167; HPLC: 9.06 Minuten Compound 28: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.63 (2H, s), 6.15 (2H, s), 7.06 (1H, d, J = 8.1 Hz), 7.37 ( 1H, m), 7.46 (6H, m), 7.60 (3H, m), 7.77 (1H, s); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.9, 102.1, 106.1, 109.1, 116.6, 121.7, 126.1, 126.6, 127.4, 127.6, 128.1, 128.8, 129.2, 137.5, 139.7, 140.3 , 148.1, 150.4, 162.6, 165.1; MS: Molecular peak: m / z = 388; rel. Frequency 47% Base peak: m / z = 167; HPLC: 9.06 minutes

Verbindung 29: 1H NMR (500 MHz, CDCl3): δ [ppm] = 4.714 (2H, s), 7.601 (4H, m), 7.680 (2H, d, J = 8.24 Hz), 7.786 (1H, dt, J = 7.72 Hz, 1.27 Hz), 7.948 (1H, dd, J = 7.72 Hz, J = 0.94 Hz), 8.227 (2H, m), 8.413 (2H, m); 13C-NMR (125 MHz, CDCl3): δ [ppm] = 35.96, 110.57, 118.99, 125.08, 128.25, 128.76, 129.00, 129.42, 129.93, 130.55, 134.01, 134.33, 137.71, 137.77, 144.44, 149.60, 164.46, 165.24; MS: Molekülpeak = 414; rel. Häufigkeit 10%; Basispeak = 192; HPLC: 9.0 MinutenCompound 29: 1 H NMR (500 MHz, CDCl 3): δ [ppm] = 4.714 (2H, s), 7.601 (4H, m), 7.680 (2H, d, J = 24.8 Hz), 7,786 (1H, dt , J = 7.72 Hz, 1.27 Hz), 7,948 (1H, dd, J = 7.72 Hz, J = 0.94 Hz), 8,227 (2H, m), 8,413 (2H, m); 13 C-NMR (125 MHz, CDCl 3): δ [ppm] = 35.96, 110.57, 118.99, 125.08, 128.25, 128.76, 129.00, 129.42, 129.93, 130.55, 134.01, 134.33, 137.71, 137.77, 144.44, 149.60, 164.46 , 165.24; MS: Molecular peak = 414; rel. Frequency 10%; Base peak = 192; HPLC: 9.0 minutes

Verbindung 30: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 3.86 (3H, s), 4.64 (2H, s), 6.16 (2H, s), 7.11 (1H, d, J = 8.2 Hz), 7.35 (1H, dd, J = 8.7 Hz, J = 2.8 Hz), 7.45 (1H, d, J = 1.7 Hz), 7.52 (5H, m), 7.61 (2H, d, J = 8.3 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.9, 56.3, 102.6, 106.6, 109.6, 111.3, 117.1, 118.5, 118.8, 120.6, 122.2, 129.3, 129.8, 131.9, 137.0, 137.3, 137.4, 148.6, 150.9, 159.0, 163.1, 165.6; MS: Molekülpeak: m/z = 443 ; rel. Häufigkeit 21% Basispeak: m/z = 222; HPLC: 8.8 MinutenCompound 30: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 3.86 (3H, s), 4.64 (2H, s), 6.16 (2H, s), 7.11 (1H, d, J = 8.2 Hz), 7.35 (1H, dd, J = 8.7 Hz, J = 2.8 Hz), 7.45 (1H, d, J = 1.7 Hz), 7.52 (5H, m), 7.61 (2H, d, J = 8.3 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.9, 56.3, 102.6, 106.6, 109.6, 111.3, 117.1, 118.5, 118.8, 120.6, 122.2, 129.3, 129.8, 131.9, 137.0, 137.3 , 137.4, 148.6, 150.9, 159.0, 163.1, 165.6; MS: Molecular peak: m / z = 443; rel. Frequency 21% base peak: m / z = 222; HPLC: 8.8 minutes

Verbindung 31: 1H-NMR (DMSO-d6, 300 MHz): δ [ppm] = 4.62 (2H, s), 6.15 (2H, s), 7.11 (1H, d, J = 8.13 Hz), 7.32 (2H, d, J = 6.4 HZ), 7.53 (6H, m), 7.75 (1H, td, J = 7.6 Hz, J = 1.3 Hz), 7.97 (1H, dd, J = 8.0 Hz, J = 1.2 Hz); 13C-NMR (DMSO-d6, 125 MHz) δ [ppm] = 36.0, 102.6, 106.6, 109.6, 117.1, 122.2, 124.5, 128.5, 129.4, 129.9, 132.3, 133.4, 135.0, 136.8, 137.3, 148.6, 149.3, 150.9, 163.1, 165.6; MS: Molekülpeak: m/z = 433; rel. Häufigkeit 42.6% Basispeak: m/z = 212; HPLC: 8.8 MinutenCompound 31: 1 H-NMR (DMSO-d 6 , 300 MHz): δ [ppm] = 4.62 (2H, s), 6.15 (2H, s), 7.11 (1H, d, J = 8.13 Hz), 7.32 ( 2H, d, J = 6.4 HZ), 7.53 (6H, m), 7.75 (1H, td, J = 7.6 Hz, J = 1.3 Hz), 7.97 (1H, dd, J = 8.0 Hz, J = 1.2 Hz) ; 13 C-NMR (DMSO-d 6 , 125 MHz) δ [ppm] = 36.0, 102.6, 106.6, 109.6, 117.1, 122.2, 124.5, 128.5, 129.4, 129.9, 132.3, 133.4, 135.0, 136.8, 137.3, 148.6, 149.3, 150.9, 163.1, 165.6; MS: Molecular peak: m / z = 433; rel. Frequency 42.6% Base peak: m / z = 212; HPLC: 8.8 minutes

Verbindung 32: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 3.79 (3H, s), 4.60 (2H, s), 6.16 (2H, s), 7.01 (2H, dd, J = 2.1 Hz, J = 8.8 Hz), 7.11 (1H, d, J = 8.2 Hz), 7.44 (1H, d, J = 1.8 Hz), 7.52 (3H, m), 7.59 (4H, m); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 36.2, 53.6, 102.6, 106.6, 109.6, 114.8, 117.1, 122.2, 126.7, 128.2, 130.0, 132.4, 135.5, 139.7, 148.6, 150.9, 159.4, 163.1, 165.5; MS: Molekülpeak: m/z = 418; rel. Häufigkeit 3% Basispeak: m/z = 197; HPLC: 9.03 MinutenCompound 32: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 3.79 (3H, s), 4.60 (2H, s), 6.16 (2H, s), 7.01 (2H, dd, J = 2.1 Hz, J = 8.8 Hz), 7.11 (1H, d, J = 8.2 Hz), 7.44 (1H, d, J = 1.8 Hz), 7.52 (3H, m), 7.59 (4H, m); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 36.2, 53.6, 102.6, 106.6, 109.6, 114.8, 117.1, 122.2, 126.7, 128.2, 130.0, 132.4, 135.5, 139.7, 148.6, 150.9 , 159.4, 163.1, 165.5; MS: Molecular peak: m / z = 418; rel. Frequency 3% base peak: m / z = 197; HPLC: 9.03 minutes

Verbindung 33: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.63 (2H, s), 6.15 (2H, s), 7.10 (1H, d, J = 8.9 Hz), 7.43 (1 H, d, J = 2.0 Hz),7.51 (1H, dd, J = 8.4 Hz, J = 2.0 Hz), 7.61 (2H, d, J = 8.0 Hz), 7.73 (2H, m), 7.89 (4H, m); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.9, 102.6, 106.6, 109.6, 110.6, 117.1, 119.3, 122.2, 127.7, 128.0, 130.3, 133.3, 138.0, 138.1, 144.5, 148.6, 150.9, 163.0, 165.5; MS: Molekülpeak: m/z = 413; rel. Häufigkeit 24% Basispeak: m/z = 192; HPLC: 8.77 MinutenCompound 33: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.63 (2H, s), 6.15 (2H, s), 7.10 (1H, d, J = 8.9 Hz), 7.43 ( 1 H, d, J = 2.0 Hz), 7.51 (1H, dd, J = 8.4 Hz, J = 2.0 Hz), 7.61 (2H, d, J = 8.0 Hz), 7.73 (2H, m), 7.89 (4H , m); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.9, 102.6, 106.6, 109.6, 110.6, 117.1, 119.3, 122.2, 127.7, 128.0, 130.3, 133.3, 138.0, 138.1, 144.5, 148.6 , 150.9, 163.0, 165.5; MS: Molecular peak: m / z = 413; rel. Frequency 24% base peak: m / z = 192; HPLC: 8.77 minutes

Verbindung 34: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.62 (2H, s), 6.16 (2H, s), 7.11 (1H, d, J = 8.1 Hz), 7.22 (1H, m), 7,44 (3H, m), 7,52 (1H, dd, J = 8.1 Hz, J = 1.8 Hz), 7.58 (2H, d, J = 8.3 Hz), 7.73 (2H, d, J = 8.3 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.9, 102.6, 103.2, 106.6, 109.6, 110.1, 110.3, 117.1, 122.2, 127.5, 130.2, 137.4, 137.9, 143.7, 148.6, 150.9, 162.3, 163.0, 164.2, 165.6; MS: Molekülpeak: m/z = 424; rel. Häufigkeit 24% Basispeak: m/z = 203; HPLC: 9.15 MinutenCompound 34: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.62 (2H, s), 6.16 (2H, s), 7.11 (1H, d, J = 8.1 Hz), 7.22 ( 1H, m), 7.44 (3H, m), 7.52 (1H, dd, J = 8.1 Hz, J = 1.8 Hz), 7.58 (2H, d, J = 8.3 Hz), 7.73 (2H, d , J = 8.3 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.9, 102.6, 103.2, 106.6, 109.6, 110.1, 110.3, 117.1, 122.2, 127.5, 130.2, 137.4, 137.9, 143.7, 148.6, 150.9 , 162.3, 163.0, 164.2, 165.6; MS: Molecular peak: m / z = 424; rel. Frequency 24% base peak: m / z = 203; HPLC: 9.15 minutes

Verbindung 35: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.64 (2H, s), 6.16 (2H, s), 7.11 (1H, d, J = 8.6 Hz), 7.44 (1H, d, J = 1.7 Hz), 7.52 (1H, dd, J = 8.1 Hz, J = 1.6 Hz), 7.63 (2H, d, J = 8.4 Hz), 7.77 (3H, m), 8.14 (1H, m), 8.22 (1H, m), 8.43 (1H, m); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 36.0, 102.6, 106.6, 109.6, 117.1, 121.5, 122.2, 122.7, 127.7, 130.4, 131.0, 133.7, 137.6, 137.8, 141.4, 148.6, 148.9, 150.9, 163.0, 165.6; MS: Molekülpeak: m/z = 433; rel. Häufigkeit 32% Basispeak: m/z = 212; HPLC: 9.05 MinutenCompound 35: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.64 (2H, s), 6.16 (2H, s), 7.11 (1H, d, J = 8.6 Hz), 7.44 ( 1H, d, J = 1.7 Hz), 7.52 (1H, dd, J = 8.1 Hz, J = 1.6 Hz), 7.63 (2H, d, J = 8.4 Hz), 7.77 (3H, m), 8.14 (1H, m), 8.22 (1H, m), 8.43 (1H, m); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 36.0, 102.6, 106.6, 109.6, 117.1, 121.5, 122.2, 122.7, 127.7, 130.4, 131.0, 133.7, 137.6, 137.8, 141.4, 148.6 , 148.9, 150.9, 163.0, 165.6; MS: Molecular peak: m / z = 433; rel. Frequency 32% base peak: m / z = 212; HPLC: 9.05 minutes

Verbindung 36: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 7.81 (2H, dd, J = 4.4 Hz, J = 1.6 Hz), 8.81 (2H, dd, J = 4.4 Hz, J = 1.6 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 119.6, 129.7, 150.8, 158.7, 177.8; MS: Molekülpeak: m/z = 179; rel. Häufigkeit 100% Basispeak: m/z = 179, HPLC: 1.20 MinutenCompound 36: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 7.81 (2H, dd, J = 4.4 Hz, J = 1.6 Hz), 8.81 (2H, dd, J = 4.4 Hz, J = 1.6 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 119.6, 129.7, 150.8, 158.7, 177.8; MS: Molecular peak: m / z = 179; rel. Frequency 100% base peak: m / z = 179, HPLC: 1.20 minutes

Verbindung 37: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.62 (2H, s), 7.30 (1H, m), 7.36 (2H, m), 7.50 (2H, m), 7.90 (2H, dd, J = 4.4 Hz, J = 1.6 Hz), 8.82 (2H, dd, J = 4.4 Hz, 1.6 Hz); 13C-NMR (DMSO-d6, 125 MHz):_δ [ppm] = 35.8, 120.0, 127.8, 128.6, 129.1, 130.0, 136.4, 150.8, 163.6, 164.7; MS: Molekülpeak: m/z = 269; rel. Häufigkeit 8% Basispeak: m/z = 91; HPLC: 4.89 MinutenCompound 37: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.62 (2H, s), 7.30 (1H, m), 7.36 (2H, m), 7.50 (2H, m), 7.90 (2H, dd, J = 4.4 Hz, J = 1.6 Hz), 8.82 (2H, dd, J = 4.4 Hz, 1.6 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): _ δ [ppm] = 35.8, 120.0, 127.8, 128.6, 129.1, 130.0, 136.4, 150.8, 163.6, 164.7; MS: Molecular peak: m / z = 269; rel. Frequency 8% base peak: m / z = 91; HPLC: 4.89 minutes

Verbindung 38: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.65 (2H, s), 7.49 (2H, d, J = 8.4 Hz), 7.69 (2H, d, J = 8.4 Hz), 8.63 (2H, d, J = 6.9 Hz), 9.37 (2H, d, J = 6.9 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.0, 123.0, 124.5, 131.5, 132.2, 136.0, 137.3, 146.2, 162.0, 166.9; MS: Molekülpeak: m/z = 347/349; rel. Häufigkeit 8/9% Basispeak: m/z = 169; HPLC: 6.77 MinutenCompound 38: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.65 (2H, s), 7.49 (2H, d, J = 8.4 Hz), 7.69 (2H, d, J = 8.4 Hz), 8.63 (2H, d, J = 6.9 Hz), 9.37 (2H, d, J = 6.9 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.0, 123.0, 124.5, 131.5, 132.2, 136.0, 137.3, 146.2, 162.0, 166.9; MS: Molecular peak: m / z = 347/349; rel. Frequency 8/9% base peak: m / z = 169; HPLC: 6.77 minutes

Verbindung 39: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.69 (2H, s), 7.71 (2H, d, J = 8.2 Hz), 7.83 (2H, d, J = 8.2 Hz), 7.88 (2H, dd, J = 4.4 Hz, J = 1.6 Hz), 8.82 (2H, dd, J = 4.5 Hz, J = 1.5 Hz) ; 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.2, 110.5, 118.6, 120.0, 130.0, 130.1, 132.4, 142.6, 150.8, 163.9, 164.4; MS: Molekülpeak: m/z = 294; rel. Häufigkeit 51% Basispeak: m/z = 116; HPLC: 4.51 MinutenCompound 39: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.69 (2H, s), 7.71 (2H, d, J = 8.2 Hz), 7.83 (2H, d, J = 8.2 Hz), 7.88 (2H, dd, J = 4.4 Hz, J = 1.6 Hz), 8.82 (2H, dd, J = 4.5 Hz, J = 1.5 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.2, 110.5, 118.6, 120.0, 130.0, 130.1, 132.4, 142.6, 150.8, 163.9, 164.4; MS: Molecular peak: m / z = 294; rel. Frequency 51% base peak: m / z = 116; HPLC: 4.51 minutes

Verbindung 40; 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.66 (2H, s), 7.58 (1H, t, J = 7.8 Hz), 7.78 (1H, dt, J = 7.7 Hz, J = 1.3 Hz), 7.86 (1H, m), 7.88 (2H, dd, J = 4.4 Hz, J = 1.6 Hz), 7.99 (1H, t, J = 1.4 Hz),8.82 (2H, dd, J = 4.4 Hz, J = 1.6 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 34.8, 111.4, 118.5, 120.0, 129.8, 130.0, 131.5, 132.7, 134.0, 138.6, 150.9, 163.8, 164.4; MS: Molekülpeak: m/z = 294; rel. Häufigkeit 100% Basispeak: m/z = 294; HPLC: 4.51 MinutenCompound 40; 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.66 (2H, s), 7.58 (1H, t, J = 7.8 Hz), 7.78 (1H, dt, J = 7.7 Hz, J = 1.3 Hz), 7.86 (1H, m), 7.88 (2H, dd, J = 4.4 Hz, J = 1.6 Hz), 7.99 (1H, t, J = 1.4 Hz), 8.82 (2H, dd, J = 4.4 Hz, J = 1.6 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 34.8, 111.4, 118.5, 120.0, 129.8, 130.0, 131.5, 132.7, 134.0, 138.6, 150.9, 163.8, 164.4; MS: Molecular peak: m / z = 294; rel. Frequency 100% base peak: m / z = 294; HPLC: 4.51 minutes

Verbindung 41: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.75 (2H, s), 7.66 (1H, t, J = 7.9 Hz), 7.87 (2H, dd, J = 4.4 Hz, J = 1.6 Hz), 7.98 (1H, d, J = 7.8 Hz), 8.15 (1H, m), 8.43 (1H, t, J = 1.9 Hz), 8.81 (2H, dd, J = 4.4 Hz, J = 1.6 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 34.7, 120.0, 122.6, 123.8, 129.9, 130.1, 135.8, 139.4, 147.7, 150.9, 163.8, 164,5; MS: Molekülpeak: m/z = 314; rel. Häufigkeit 90% Basispeak: m/z = 177; HPLC: 5.15 MinutenCompound 41: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.75 (2H, s), 7.66 (1H, t, J = 7.9 Hz), 7.87 (2H, dd, J = 4.4 Hz, J = 1.6 Hz), 7.98 (1H, d, J = 7.8 Hz), 8.15 (1H, m), 8.43 (1H, t, J = 1.9 Hz), 8.81 (2H, dd, J = 4.4 Hz, J = 1.6 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 34.7, 120.0, 122.6, 123.8, 129.9, 130.1, 135.8, 139.4, 147.7, 150.9, 163.8, 164.5; MS: Molecular peak: m / z = 314; rel. Frequency 90% base peak: m / z = 177; HPLC: 5.15 minutes

Verbindung 42: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 3.79 (3H, s), 4.64 (2H, s), 6.92 (1H, dd, J = 8.1 Hz, J = 2.3 Hz), 7.13 (2H, m), 7.32 (1H, t, J = 7.8 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.8, 55.0, 113.2, 114.7, 120.0, 121.2, 129.7, 130.0, 137.8, 151.0, 159.2, 163.7, 164.8; MS: Molekülpeak: m/z = 299; rel. Häufigkeit 29% Basispeak: m/z = 121; HPLC: 5.08 MinutenCompound 42: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 3.79 (3H, s), 4.64 (2H, s), 6.92 (1H, dd, J = 8.1 Hz, J = 2.3 Hz), 7.13 (2H, m), 7.32 (1H, t, J = 7.8 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.8, 55.0, 113.2, 114.7, 120.0, 121.2, 129.7, 130.0, 137.8, 151.0, 159.2, 163.7, 164.8; MS: Molecular peak: m / z = 299; rel. Frequency 29% base peak: m / z = 121; HPLC: 5.08 minutes

Verbindung 43: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.71 (1H, s), 7.58 (3H, m), 7.62 (1H, d, J = 7.7 Hz), 7.68 (2H, d, J = 8.1 Hz), 7.78 (1H, t, J = 7.7 Hz), 7.91 (2H, d, J = 4.1 Hz), 7.95 (1H, d, J = 7.5 Hz), 8.85 (2H, s, br); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.4, 110.1, 118.5, 120.1, 128.2, 128.9, 129.4, 130.0, 130.1, 133.5, 133.7, 137.2, 137.3, 143.9, 150.8, 163.8, 164.8; MS: Molekülpeak: m/z = 370; rel. Häufigkeit 13% Basispeak: m/z = 192; HPLC: 6.63 MinutenCompound 43: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.71 (1H, s), 7.58 (3H, m), 7.62 (1H, d, J = 7.7 Hz), 7.68 ( 2H, d, J = 8.1 Hz), 7.78 (1H, t, J = 7.7 Hz), 7.91 (2H, d, J = 4.1 Hz), 7.95 (1H, d, J = 7.5 Hz), 8.85 (2H, s, br); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.4, 110.1, 118.5, 120.1, 128.2, 128.9, 129.4, 130.0, 130.1, 133.5, 133.7, 137.2, 137.3, 143.9, 150.8, 163.8 , 164.8; MS: Molecular peak: m / z = 370; rel. Frequency 13% base peak: m / z = 192; HPLC: 6.63 minutes

Verbindung 44: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 1.24 (9H, s), 4.58 (2H, s), 7.40 (4H, m), 7.88 (2H, m), 8.81 (2H, m); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 31.0, 34.3, 35.6, 120.0, 125.4, 128.9, 130.1, 133.3, 150.2, 151.0, 163.7, 164.8; MS: Molekülpeak: m/z = 325; rel. Häufigkeit 20% Basispeak: m/z = 147; HPLC: 7.24 MinutenCompound 44: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 1.24 (9H, s), 4.58 (2H, s), 7.40 (4H, m), 7.88 (2H, m), 8.81 (2H, m); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 31.0, 34.3, 35.6, 120.0, 125.4, 128.9, 130.1, 133.3, 150.2, 151.0, 163.7, 164.8; MS: Molecular peak: m / z = 325; rel. Frequency 20% base peak: m / z = 147; HPLC: 7.24 minutes

Verbindung 45: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 3.82 (3H, s), 4.67 (2H, s), 7.64 (2H, d, J = 8.2 Hz), 7.86 (2H, m), 7.92 (2H, d, J = 8.2 Hz), 8.88 (2H, m); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.3, 52.1, 120.0, 128.9, 129.5, 130.1, 142.3, 151.0, 163.8, 164.5, 165.91 MS: Molekülpeak: m/z = 327; rel. Häufigkeit 31% Basispeak: m/z = 149; HPLC: 4.86 MinutenCompound 45: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 3.82 (3H, s), 4.67 (2H, s), 7.64 (2H, d, J = 8.2 Hz), 7.86 ( 2H, m), 7.92 (2H, d, J = 8.2 Hz), 8.88 (2H, m); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.3, 52.1, 120.0, 128.9, 129.5, 130.1, 142.3, 151.0, 163.8, 164.5, 165.91 MS: Molecular peak: m / z = 327; rel. Frequency 31% base peak: m / z = 149; HPLC: 4.86 minutes

Verbindung 46: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.68 (2H, s), 7.46 (3H, m), 7.51 (2H, m), 7.59 (1H, m), 7.63 (2H, m), 7.81 (1H, m), 7.88 (2H, dd, J = 4.4 Hz, J = 1.6 Hz), 8.78 (2H, dd, J = 4.4 Hz, J = 1.6 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.8, 120.0, 126.1, 126.6, 126.9, 127.6, 128.1, 128.9, 129.3, 130.0, 137.3, 139.7, 140.3, 150.9, 163.7, 164.6; MS: Molekülpeak: m/z = 345; rel. Häufigkeit 31% Basispeak: m/z = 167; HPLC: 7.30 MinutenCompound 46: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.68 (2H, s), 7.46 (3H, m), 7.51 (2H, m), 7.59 (1H, m), 7.63 (2H, m), 7.81 (1H, m), 7.88 (2H, dd, J = 4.4Hz, J = 1.6Hz), 8.78 (2H, dd, J = 4.4Hz, J = 1.6Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.8, 120.0, 126.1, 126.6, 126.9, 127.6, 128.1, 128.9, 129.3, 130.0, 137.3, 139.7, 140.3, 150.9, 163.7, 164.6 ; MS: Molecular peak: m / z = 345; rel. Frequency 31% base peak: m / z = 167; HPLC: 7.30 minutes

Verbindung 47: 1H-NMR (DMSO-d6, 300 MHz): δ [ppm] = 4.71 (2H, s), 7.57 (2H, d, J = 1.8 Hz), 7.67 (4H, m), 7.90 (2H, dd, J = 4.4 Hz, J = 1.7 Hz), 7.97 (1H, m), 8.82 (2H, dd, J = 4.4 Hz, J = 1.7 Hz); 13C-NMR (DMSO-d6, 125 MHz) δ [ppm] = 35.9, 112.1, 117.9, 120.5, 121.0, 121.5, 129.5, 129.9, 130.5, 132.9, 136.8, 137.8, 141.3, 151.4, 164.3, 165.3; MS: Molekülpeak: m/z = 388; rel. Häufigkeit 16% Basispeak: m/z = 210; HPLC: 7.0 MinutenCompound 47: 1 H-NMR (DMSO-d 6 , 300 MHz): δ [ppm] = 4.71 (2H, s), 7.57 (2H, d, J = 1.8 Hz), 7.67 (4H, m), 7.90 ( 2H, dd, J = 4.4 Hz, J = 1.7 Hz), 7.97 (1H, m), 8.82 (2H, dd, J = 4.4 Hz, J = 1.7 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz) δ [ppm] = 35.9, 112.1, 117.9, 120.5, 121.0, 121.5, 129.5, 129.9, 130.5, 132.9, 136.8, 137.8, 141.3, 151.4, 164.3, 165.3; MS: Molecular peak: m / z = 388; rel. Frequency 16% base peak: m / z = 210; HPLC: 7.0 minutes

Verbindung 49: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.67 (2H, s), 7.36 (1H, m), 7.46 (2H, m), 7.6 (2H, d, J = 8.3 Hz), 7.7 (4H, m), 7.9 (2H, dd, J = 4.5 Hz, J = 1.7 Hz); 13C-NMR (DMSO-d6, 125 MHz) δ [ppm] = 36.1, 120.5, 127.1, 127.3, 128.0, 129.4, 130.2, 130.5, 136.2, 140.0, 140.1, 151.4, 164.1, 165.3; MS: Molekülpeak: m/z = 345; rel. Häufigkeit 11% Basispeak: m/z = 167; HPLC: 7.3 MinutenCompound 49: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.67 (2H, s), 7.36 (1H, m), 7.46 (2H, m), 7.6 (2H, d, J = 8.3 Hz), 7.7 (4H, m), 7.9 (2H, dd, J = 4.5 Hz, J = 1.7 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz) δ [ppm] = 36.1, 120.5, 127.1, 127.3, 128.0, 129.4, 130.2, 130.5, 136.2, 140.0, 140.1, 151.4, 164.1, 165.3; MS: Molecular peak: m / z = 345; rel. Frequency 11% base peak: m / z = 167; HPLC: 7.3 minutes

Verbindung 48: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 3.79 (3H, s), 4.66 (2H, s), 7.01 (2H, d, J = 8.6 Hz), 7.55 (2H, d, J = 8.2 Hz), 7.60 (4H, m), 7.90 (2H, d, J = 5.8 Hz), 8.82 (2H, d, J = 5.8 Hz), 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 36.1, 55.6, 114.8, 120.4, 126.8, 128.2, 130.1, 130.5, 132.4, 135.3, 139.8, 151.4, 159.5, 164.2, 165.3; MS: Molekülpeak: m/z = 375; rel. Häufigkeit 6% Basispeak: m/z = 197; HPLC: 7.32 MinutenCompound 48: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 3.79 (3H, s), 4.66 (2H, s), 7.01 (2H, d, J = 8.6 Hz), 7.55 ( 2H, d, J = 8.2 Hz), 7.60 (4H, m), 7.90 (2H, d, J = 5.8 Hz), 8.82 (2H, d, J = 5.8 Hz), 13 C-NMR (DMSO) d 6 , 125 MHz): δ [ppm] = 36.1, 55.6, 114.8, 120.4, 126.8, 128.2, 130.1, 130.5, 132.4, 135.3, 139.8, 151.4, 159.5, 164.2, 165.3; MS: Molecular peak: m / z = 375; rel. Frequency 6% base peak: m / z = 197; HPLC: 7.32 minutes

Verbindung 50: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.68 (2H, s), 7.64 (3H, m), 7.74 (2H, d), 7.82 (1H, dt, J = 7.7 Hz, J = 1.3 Hz), 7.90 (2H, dd, J = 4.5 Hz, J = 1.7 Hz), 8.01 (1H, m), 8.15 (1H, m), 8.82 (2H, dd, J = 4.5 Hz, J = 1.7 Hz); 13C-NMR (DMSO-d6, 125 MHz) δ [ppm] = 36.0, 112.6, 119.2, 120.4, 127.6, 130.3, 130.5, 130.6, 130.7, 131.6, 131.9, 137.3, 137.9, 141.1, 151.4, 164.2, 165.2; MS: Molekülpeak: m/z = 370; rel. Häufigkeit 13% Basispeak: m/z = 192; HPLC: 7.0 MinutenCompound 50: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.68 (2H, s), 7.64 (3H, m), 7.74 (2H, d), 7.82 (1H, dt, J = 7.7 Hz, J = 1.3 Hz), 7.90 (2H, dd, J = 4.5 Hz, J = 1.7 Hz), 8.01 (1H, m), 8.15 (1H, m), 8.82 (2H, dd, J = 4.5 Hz, J = 1.7 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz) δ [ppm] = 36.0, 112.6, 119.2, 120.4, 127.6, 130.3, 130.5, 130.6, 130.7, 131.6, 131.9, 137.3, 137.9, 141.1, 151.4, 164.2, 165.2; MS: Molecular peak: m / z = 370; rel. Frequency 13% base peak: m / z = 192; HPLC: 7.0 minutes

Verbindung 51: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.69 (2H, s), 7.64 (2H, d, J = 8.1 Hz), 7.75 (2H, d, J = 8.1 Hz), 7.90 (6H, m), 8.82 (2H, m); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.9, 110.6, 119.3, 120.4, 127.8, 128.0, 130.4, 130.5, 133.3, 137.8, 138,1, 144.5, 151.4, 165.2, 164.3; MS: Molekülpeak: m/z = 370; rel. Häufigkeit 16% Basispeak: m/z = 192; HPLC: 6.99 MinutenCompound 51: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.69 (2H, s), 7.64 (2H, d, J = 8.1 Hz), 7.75 (2H, d, J = 8.1 Hz), 7.90 (6H, m), 8.82 (2H, m); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.9, 110.6, 119.3, 120.4, 127.8, 128.0, 130.4, 130.5, 133.3, 137.8, 138.1, 144.5, 151.4, 165.2, 164.3 ; MS: Molecular peak: m / z = 370; rel. Frequency 16% base peak: m / z = 192; HPLC: 6.99 minutes

Verbindung 52: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 2.14 (3H, s), 7.49 (1H, dd, J = 5.1 Hz, J = 1.5 Hz), 8.53 (1H, dd, J = 5.1 Hz, J = 0.7 Hz), 8.54 (1H, s), 10.82 (1H, s), 14.90 (1H, s); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 23.9, 108.8, 114.9, 131.4, 149.4, 153.0, 158.8, 169.8, 177.7; MS: Molekülpeak: m/z = 236; rel. Häufigkeit 100%; HPLC: 1.95 MinutenCompound 52: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 2.14 (3H, s), 7.49 (1H, dd, J = 5.1 Hz, J = 1.5 Hz), 8.53 (1H, dd, J = 5.1 Hz, J = 0.7 Hz), 8.54 (1H, s), 10.82 (1H, s), 14.90 (1H, s); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 23.9, 108.8, 114.9, 131.4, 149.4, 153.0, 158.8, 169.8, 177.7; MS: Molecular peak: m / z = 236; rel. Frequency 100%; HPLC: 1.95 minutes

Verbindung 53: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 2.14 (3H, s), 4.70 (2H, s), 7.58 (5H, m), 7.68 (2H, d, J = 8.2 Hz), 7.78 (1H, td, J = 7.6 Hz, J = 1.3 Hz), 7.94 (1H, dd, J = 7.6 Hz, J = 1.1 Hz), 8.52 (1H, dd, J = 5.1 Hz, J = 0.7 Hz), 8.64 (1H, s), 10.80 (1H, s); 13C-NMR (DMSO-d6, 125 MHz): nδ [ppm] = 23.9, 35.5, 109.3, 110.1, 115.4, 118.5, 128.3, 128.9, 129.4, 130.1, 131.8, 133.5, 133.9, 137.2, 144.0, 149.5, 153.1, 163.9, 164.7, 169.8; MS: Molekülpeak: m/z = 427; rel. Häufigkeit 10% Basispeak: m/z = 192; HPLC: 7.00 MinutenCompound 53: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 2.14 (3H, s), 4.70 (2H, s), 7.58 (5H, m), 7.68 (2H, d, J = 8.2 Hz), 7.78 (1H, td, J = 7.6 Hz, J = 1.3 Hz), 7.94 (1H, dd, J = 7.6 Hz, J = 1.1 Hz), 8.52 (1H, dd, J = 5.1 Hz, J = 0.7 Hz), 8.64 (1H, s), 10.80 (1H, s); 13 C-NMR (DMSO-d 6 , 125 MHz): n δ [ppm] = 23.9, 35.5, 109.3, 110.1, 115.4, 118.5, 128.3, 128.9, 129.4, 130.1, 131.8, 133.5, 133.9, 137.2, 144.0, 149.5 , 153.1, 163.9, 164.7, 169.8; MS: Molecular peak: m / z = 427; rel. Frequency 10% base peak: m / z = 192; HPLC: 7.00 minutes

Verbindung 54: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 2.14 (3H, s), 3.73 (3H, s), 4.58 (2H, s), 6.86 (1H, m), 7.07 (2H, m), 7.27 (1H, m), 7.58 (1H, dd, J = 5.1 Hz, J = 1.5 Hz), 8.52 (1H, dd, J = 5.1 Hz, J = 0.7 Hz), 8.63 (1H, s), 10.80 (1H, s); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 24.0, 35.9, 55.0, 109.2, 113.3, 114.6, 115.4, 121.2, 129.7, 131.8, 137.8, 149.4, 153.0, 159.3, 163.8, 164.7, 169.8; MS: Molekülpeak: m/z = 356; rel. Häufigkeit 33% Basispeak: m/z = 121; HPLC: 5.82 MinutenCompound 54: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 2.14 (3H, s), 3.73 (3H, s), 4.58 (2H, s), 6.86 (1H, m), 7.07 (2H, m), 7.27 (1H, m), 7.58 (1H, dd, J = 5.1 Hz, J = 1.5 Hz), 8.52 (1H, dd, J = 5.1 Hz, J = 0.7 Hz), 8.63 ( 1H, s), 10.80 (1H, s); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 24.0, 35.9, 55.0, 109.2, 113.3, 114.6, 115.4, 121.2, 129.7, 131.8, 137.8, 149.4, 153.0, 159.3, 163.8, 164.7 , 169.8; MS: Molecular peak: m / z = 356; rel. Frequency 33% base peak: m / z = 121; HPLC: 5.82 minutes

Verbindung 55: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 2.14 (3H, s), 4.64 (2H, s), 7.57 (2H, m), 7.77 (1H, d, J = 7.8 Hz), 7.87 (1H, d, J = 7.8 Hz), 7.97 (1H, s), 8.51 (1H, d, J = 5.1 Hz), 8.61 (1H, s), 10.81 (1H, s); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 23.9, 34.8, 109.2, 111.4, 115.4, 118.5, 129.8, 131.5, 131.8, 132.6, 134.1, 138.6, 149.5, 153.0, 163.9, 164.4, 169.8; MS: Molekülpeak: m/z = 351; rel. Häufigkeit 35% Basispeak: m/z = 32; HPLC: 5.32 MinutenCompound 55: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 2.14 (3H, s), 4.64 (2H, s), 7.57 (2H, m), 7.77 (1H, d, J = 7.8 Hz), 7.87 (1H, d, J = 7.8 Hz), 7.97 (1H, s), 8.51 (1H, d, J = 5.1 Hz), 8.61 (1H, s), 10.81 (1H, s); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 23.9, 34.8, 109.2, 111.4, 115.4, 118.5, 129.8, 131.5, 131.8, 132.6, 134.1, 138.6, 149.5, 153.0, 163.9, 164.4 , 169.8; MS: Molecular peak: m / z = 351; rel. Frequency 35% base peak: m / z = 32; HPLC: 5.32 minutes

Verbindung 56: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 2.15 (3H, s), 4.61 (2H, s), 7.30 (1H, m), 7.36 (2H, m), 7.51 (2H, m), 7.58 (1H, dd, J = 5.1 Hz, J = 1.5 Hz), 8.52 (1H, dd, J = 5.1 Hz, J = 0.8 Hz), 8.63 (1H, s), 10.80 (1H, s); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 24.0, 35.9, 109.2, 115.4, 127.8, 128.6, 129.1, 131.7, 136.4, 149.4, 153.0, 163.8, 164.4, 169.8; MS: Molekülpeak: m/z = 326; rel. Häufigkeit 30% Basispeak: m/z = 91; HPLC: 5.73 MinutenCompound 56: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 2.15 (3H, s), 4.61 (2H, s), 7.30 (1H, m), 7.36 (2H, m), 7.51 (2H, m), 7.58 (1H, dd, J = 5.1 Hz, J = 1.5 Hz), 8.52 (1H, dd, J = 5.1 Hz, J = 0.8 Hz), 8.63 (1H, s), 10.80 ( 1H, s); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 24.0, 35.9, 109.2, 115.4, 127.8, 128.6, 129.1, 131.7, 136.4, 149.4, 153.0, 163.8, 164.4, 169.8; MS: Molecular peak: m / z = 326; rel. Frequency 30% base peak: m / z = 91; HPLC: 5.73 minutes

Verbindung 57: 1H-NMR (500 MHz, CDCl3, DMSO-d6): δ [ppm] = 8.09-8.05 (m, 2H), 7.79-7.71 (m, 2H), 7.23 (t, J = 7.9 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.98-6.95 (m, 1H), 6.82 (dd, J = 8.3, 2.0 Hz, 1H), 4.49 (s, 2H), 3.77 (s, 3H); 13C-NMR (125 MHz, DMSO): δ [ppm] = 165.39, 164.31, 159.94, 136.78, 132.91, 129.97, 127.50, 127.13, 121.43, 117.92, 115.14, 114.78, 113.83, 55.35, 36.92; MS: Molekülpeak = 323; rel. Häufigkeit 25% Basispeak = 121; HPLC: 7.80 MinutenCompound 57: 1 H-NMR (500 MHz, CDCl 3, DMSO-d 6): δ [ppm] = 8:09 to 8:05 (m, 2H), 7.79-7.71 (m, 2H), 7.23 (t, J = 7.9 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.98-6.95 (m, 1H), 6.82 (dd, J = 8.3, 2.0 Hz, 1H), 4.49 (s, 2H), 3.77 (s , 3H); 13 C-NMR (125 MHz, DMSO): δ [ppm] = 165.39, 164.31, 159.94, 136.78, 132.91, 129.97, 127.50, 127.13, 121.43, 117.92, 115.14, 114.78, 113.83, 55.35, 36.92; MS: molecular peak = 323; rel. Frequency 25% base peak = 121; HPLC: 7.80 minutes

Verbindung 58: 1H-NMR (500 MHz, DMSO-d6): δ [ppm] = 8.43-8.38 (m, 2H), 8.26-8.18 (m, 2H), 7.27 (t, J = 7.9 Hz, 1H), 7.07 (m, 2H), 6.88-6.85 (m, 1H), 4.59 (s, 2H), 3.73 (s, 3H); 13C-NMR (126 MHz, DMSO): δ [ppm] = 164.74, 163.89, 159.27, 149.13, 137.86, 129.69, 128.49, 127.74, 124.58, 121.20, 114.68, 113.30, 55.04, 35.87; MS: Molekülpeak = 343; rel. Häufigkeit 23% Basispeak = 121; HPLC: 8.22 MinutenCompound 58: 1 H NMR (500 MHz, DMSO-d 6 ): δ [ppm] = 8.43-8.38 (m, 2H), 8.26-8.18 (m, 2H), 7.27 (t, J = 7.9 Hz, 1H ), 7.07 (m, 2H), 6.88-6.85 (m, 1H), 4.59 (s, 2H), 3.73 (s, 3H); 13 C-NMR (126 MHz, DMSO): δ [ppm] = 164.74, 163.89, 159.27, 149.13, 137.86, 129.69, 128.49, 127.74, 124.58, 121.20, 114.68, 113.30, 55.04, 35.87; MS: Molecular peak = 343; rel. Frequency 23% base peak = 121; HPLC: 8.22 minutes

Verbindung 59: 1H NMR (300 MHz, DMSO-d6): δ [ppm] = 8.03 (dt, J = 6.8, J = 0.9 Hz, 2H), 7.76-7.64 (m, 4H), 7.56-7.48 (m, 1H), 7.40 (t, J = 7.8 Hz, 1H), 4.47 (s, 2H); 13C-NMR (75 MHz, DMSO): δ [ppm] = 163.90, 163.85, 136.84, 133.00, 132.25, 131.93, 131.11, 129.02, 126.59, 126.45, 117.62, 117.14, 114.57, 112.29, 34.93; MS: Molekülpeak = 318; rel. Häufigkeit 49% Basispeak = 116: HPLC: 7.40 MinutenCompound 59: 1 H NMR (300 MHz, DMSO-d 6): δ [ppm] = 8:03 (dt, J = 6.8, J = 0.9 Hz, 2H), 7.76-7.64 (m, 4H), 7:56 to 7:48 ( m, 1H), 7.40 (t, J = 7.8 Hz, 1H), 4.47 (s, 2H); 13 C-NMR (75 MHz, DMSO): δ [ppm] = 163.90, 163.85, 136.84, 133.00, 132.25, 131.93, 131.11, 129.02, 126.59, 126.45, 117.62, 117.14, 114.57, 112.29, 34.93; MS: molecular peak = 318; rel. Frequency 49% Base peak = 116: HPLC: 7.40 minutes

Verbindung 60: 1H NMR (500 MHz, CDCl3): δ [ppm] = 4.728 (2H, s), 7.481 (1H, m), 7.513 (1H, m), 7.573 (2H, m), 7.626 (2H, m), 7.671 (1H, dt, J = 7.71 Hz, J = 1.35 Hz), 7.793 (1H, dd, J = 7.79 Hz, 0.96 Hz), 7.819 (2H, m), 8.138 (2H, m); 13C-NMR (125 MHz, CDCl3): δ [ppm] = 36.43, 111.23, 115.14, 117.85, 118.57, 127.10, 127.42, 127.81, 129.25, 129.55, 129.98, 132.87, 132.90, 133.81, 136.06, 138.07, 144.69, 164.39, 165.14; MS: Molekülpeak = 394; rel. Häufigkeit 15% Basispeak = 192; HPLC: 8.6 Minuten. Compound 60: 1 H NMR (500 MHz, CDCl 3): δ [ppm] = 4.728 (2H, s), 7,481 (1H, m), 7.513 (1H, m), 7.573 (2H, m), 7.626 (2H , m), 7,671 (1H, dt, J = 7.71 Hz, J = 1.35 Hz), 7,793 (1H, dd, J = 7.79 Hz, 0.96 Hz), 7,819 (2H, m), 8,138 (2H, m); 13 C-NMR (125 MHz, CDCl 3): δ [ppm] = 36.43, 111.23, 115.14, 117.85, 118.57, 127.10, 127.42, 127.81, 129.25, 129.55, 129.98, 132.87, 132.90, 133.81, 136.06, 138.07, 144.69 , 164.39, 165.14; MS: Molecular peak = 394; rel. Frequency 15% base peak = 192; HPLC: 8.6 minutes.

Verbindung 61: 1H NMR (300 MHz, DMSO-d6): δ [ppm] = 8.09 (td, J = 8.2, J = 0.9 Hz, 4H), 7.49 (d, J = 7.3 Hz, 2H), 7.31 (m, 3H), 4.61 (s, 2H); 13C-NMR (75 MHz, DMSO): δ [ppm] = 164.45, 164.07, 136.42, 133.33, 129.02, 128.56, 127.78, 127.06, 126.91, 118.02, 114.06, 35.88; MS: Molekülpeak = 293; rel. Häufigkeit 18% Basispeak = 91; HPLC: 7.76 MinutenCompound 61: 1 H NMR (300 MHz, DMSO-d 6 ): δ [ppm] = 8.09 (td, J = 8.2, J = 0.9 Hz, 4H), 7.49 (d, J = 7.3 Hz, 2H), 7.31 (m, 3H), 4.61 (s, 2H); 13 C-NMR (75 MHz, DMSO): δ [ppm] = 164.45, 164.07, 136.42, 133.33, 129.02, 128.56, 127.78, 127.06, 126.91, 118.02, 114.06, 35.88; MS: Molecular peak = 293; rel. Frequency 18% base peak = 91; HPLC: 7.76 minutes

Verbindung 62: 1H NMR (300 MHz, DMSO-d6): δ [ppm] = 8.45-8.36 (m, 2H), 8.25-8.16 (m, 2H), 7.99 (dd, J = 2.3, J = 1.1 Hz, 1H), 7.90-7.82 (m, 1H), 7.81-7.72 (m, 1H), 7.58 (t, J = 7.8 Hz, 1H), 4.66 (s, 2H); 13C-NMR (75 MHz, DMSO): δ [ppm] = 164.40, 164.01, 149.12, 138.63, 134.00, 132.64, 131.47, 129.79, 128.46, 127.73, 124.54, 118.47, 111.39, 34.79; MS: Molekülpeak = 338; rel. Häufigkeit 45% Basispeak = 116; HPLC: 7.85 MinutenCompound 62: 1 H NMR (300 MHz, DMSO-d 6): δ [ppm] = 8:45 to 8:36 (m, 2H), 8:25 to 8:16 (m, 2H), 7.99 (dd, J = 2.3, J = 1.1 Hz, 1H), 7.90-7.82 (m, 1H), 7.81-7.72 (m, 1H), 7.58 (t, J = 7.8Hz, 1H), 4.66 (s, 2H); 13 C-NMR (75 MHz, DMSO): δ [ppm] = 164.40, 164.01, 149.12, 138.63, 134.00, 132.64, 131.47, 129.79, 128.46, 127.73, 124.54, 118.47, 111.39, 34.79; MS: Molecular peak = 338; rel. Frequency 45% base peak = 116; HPLC: 7.85 minutes

Verbindung 64: 1H NMR (300 MHz, DMSO-d6): δ [ppm] = 8.48-8.35 (m, 2H), 8.28-8.16 (m, 2H), 7.56-7.44 (m, 2H), 7.43-7.22 (m, 3H), 4.62 (s, 2H); 13C-NMR (75 MHz, DMSO): δ [ppm] = 164.71, 163.86, 149.11, 136.39, 129.03, 128.57, 128.47, 127.79, 127.72, 124.56, 35.89; MS: Molekülpeak = 313; rel. Häufigkeit 15% Basispeak = 91; HPLC: 8.21 MinutenCompound 64: 1 H NMR (300 MHz, DMSO-d 6): δ [ppm] = 8:48 to 8:35 (m, 2H), 8:28 to 8:16 (m, 2H), 7:56 to 7:44 (m, 2H), 7.43- 7.22 (m, 3H), 4.62 (s, 2H); 13 C-NMR (75 MHz, DMSO): δ [ppm] = 164.71, 163.86, 149.11, 136.39, 129.03, 128.57, 128.47, 127.79, 127.72, 124.56, 35.89; MS: molecular peak = 313; rel. Frequency 15% base peak = 91; HPLC: 8.21 minutes

Verbindung 65: 1HNMR (300 MHz, DMSO-d6): δ [ppm] = 8.48-8.35 (m, 2H), 8.28-8.16 (m, 2H), 7.56-7.44 (m, 2H), 7.43-7.22 (m, 3H), 4.62 (s, 2H); 13C-NMR (75 MHz, DMSO): δ [ppm] = 164.71, 163.86, 149.11, 136.39, 129.03, 128.57, 128.47, 127.79, 127.72, 124.56, 35.89; MS: Molekülpeak = 399; rel. Häufigkeit 45% Basispeak = 192; HPLC: 8.64 MinutenCompound 65: 1H NMR (300 MHz, DMSO-d 6 ): δ [ppm] = 8.48-8.35 (m, 2H), 8.28-8.16 (m, 2H), 7.56-7.44 (m, 2H), 7.43-7.22 (m, 3H), 4.62 (s, 2H); 13 C-NMR (75 MHz, DMSO): δ [ppm] = 164.71, 163.86, 149.11, 136.39, 129.03, 128.57, 128.47, 127.79, 127.72, 124.56, 35.89; MS: molecular peak = 399; rel. Frequency 45% base peak = 192; HPLC: 8.64 minutes

Verbindung 66: 1H NMR (300 MHz, DMSO-d6): δ [ppm] = 8.00-7.91 (m, 3H), 7.78 (td, J = 7.7, 1.4 Hz, 1H), 7.69-7.53 (m, 9H), 4.68 (s, 2H); 13C-NMR (75 MHz, DMSO): δ [ppm] = 165.28, 163.25, 143.95, 137.36, 137.16, 133.81, 133.48, 131.98, 130.05, 129.38, 128.89, 128.23, 126.37, 122.97, 118.46, 110.08, 35.49; MS: Molekülpeak = 369; rel. Häufigkeit 21% Basispeak = 192; HPLC: 8.67 MinutenCompound 66: 1 H NMR (300 MHz, DMSO-d 6 ): δ [ppm] = 8.00-7.91 (m, 3H), 7.78 (td, J = 7.7, 1.4 Hz, 1H), 7.69-7.53 (m, 9H), 4.68 (s, 2H); 13 C-NMR (75 MHz, DMSO): δ [ppm] = 165.28, 163.25, 143.95, 137.36, 137.16, 133.81, 133.48, 131.98, 130.05, 129.38, 128.89, 128.23, 126.37, 122.97, 118.46, 110.08, 35.49; MS: Molecular peak = 369; rel. Frequency 21% base peak = 192; HPLC: 8.67 minutes

Verbindung 67: 1H NMR (500 MHz, DMSO-d6): δ [ppm] = 7.98 (s, 1H), 7.96-7.92 (m, 2H), 7.85 (d, J = 7.9 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.66-7.55 (m, 4H), 4.63 (s, 2H); 13C-NMR (126 MHz, DMSO): δ [ppm] = 165.34, 162.94, 138.80, 133.98, 132.64, 132.03, 131.43, 129.79, 129.39, 126.36, 122.92, 118.48, 111.37, 34.81; MS: Molekülpeak = 293; rel. Häufigkeit 84% Basispeak = 157; HPLC: 7.41 MinutenCompound 67: 1 H NMR (500 MHz, DMSO-d 6 ): δ [ppm] = 7.98 (s, 1H), 7.96-7.92 (m, 2H), 7.85 (d, J = 7.9 Hz, 1H), 7.77 (d, J = 7.7Hz, 1H), 7.66-7.55 (m, 4H), 4.63 (s, 2H); 13 C-NMR (126 MHz, DMSO): δ [ppm] = 165.34, 162.94, 138.80, 133.98, 132.64, 132.03, 131.43, 129.79, 129.39, 126.36, 122.92, 118.48, 111.37, 34.81; MS: Molecular peak = 293; rel. Frequency 84% base peak = 157; HPLC: 7.41 minutes

Verbindung 68: 1H NMR (500 MHz, DMSO-d6): δ [ppm] = 8.01-7.92 (m, 2H), 7.68-7.55 (m, 3H), 7.26 (t, J = 7.8 Hz, 1H), 7.05 (m, 2H), 6.88-6.82 (m, 1H), 4.55 (s, 2H), 3.72 (s, 3H); 13C NMR (126 MHz, DMSO): δ [ppm] = 165.21, 163.25, 159.25, 138.02, 132.01, 129.66, 129.40, 126.36, 122.97, 121.15, 114.64, 113.24, 55.01, 35.90; MS: Molekülpeak = 298; rel. Häufigkeit 45% Basispeak = 121; HPLC: 7.81 MinutenCompound 68: 1 H NMR (500 MHz, DMSO-d 6 ): δ [ppm] = 8.01-7.92 (m, 2H), 7.68-7.55 (m, 3H), 7.26 (t, J = 7.8 Hz, 1H) , 7.05 (m, 2H), 6.88-6.82 (m, 1H), 4.55 (s, 2H), 3.72 (s, 3H); 13 C NMR (126 MHz, DMSO): δ [ppm] = 165.21, 163.25, 159.25, 138.02, 132.01, 129.66, 129.40, 126.36, 122.97, 121.15, 114.64, 113.24, 55.01, 35.90; MS: molecular peak = 298; rel. Frequency 45% base peak = 121; HPLC: 7.81 minutes

Verbindung 69: 1H NMR (500 MHz, DMSO-d6): δ [ppm] = 7.99-7.92 (m, 2H), 7.65-7.56 (m, 3H), 7.51-7.46 (m, 2H), 7.37-7.32 (m, 2H), 7.31-7.26 (m, 1H), 4.59 (s, 2H; 13C NMR (126 MHz, DMSO): δ [ppm] = 165.20, 163.25, 136.55, 132.00, 129.41, 129.00, 128.56, 127.74, 126.35, 122.97, 35.91; MS: Molekülpeak = 268 rel. Häufigkeit 30% Basispeak = 91: HPLC: 7.79 MinutenCompound 69: 1 H NMR (500 MHz, DMSO-d 6 ): δ [ppm] = 7.99-7.92 (m, 2H), 7.65-7.56 (m, 3H), 7.51-7.46 (m, 2H), 7.37- 7.32 (m, 2H), 7.31-7.26 (m, 1H), 4.59 (s, 2H, 13 C NMR (126 MHz, DMSO): δ [ppm] = 165.20, 163.25, 136.55, 132.00, 129.41, 129.00, 128.56 , 127.74, 126.35, 122.97, 35.91; MS: molecular peak = 268 rel. Frequency 30% base peak = 91: HPLC: 7.79 minutes

Verbindung 70: 1H NMR (500 MHz, DMSO-d6): δ [ppm] = 7.96 (t, J = 1.5 Hz, 1H), 7.91-7.86 (m, 2H), 7.85-7.81 (m, 1H), 7.76 (dt, J = 7.7, J = 1.3 Hz, 1H), 7.57 (t, J = 7.8 Hz, 2H), 7.16-7.09 (m, 2H), 4.60 (s, 1H), 3.84 (s, 3H); 13C NMR (126 MHz, DMSO): δ [ppm] = 165.31, 162.06, 138.85, 133.97, 132.62, 131.41, 129.78, 128.25, 118.49, 115.26, 114.85, 111.36, 55.51, 34.84; MS: Molekülpeak = 323; rel. Häufigkeit 68% Basispeak = 135; HPLC: 7.47 Minuten Compound 70: 1 H NMR (500 MHz, DMSO-d 6): δ [ppm] = 7.96 (t, J = 1.5 Hz, 1H), 7.91-7.86 (m, 2H), 7.85-7.81 (m, 1H) , 7.76 (dt, J = 7.7, J = 1.3 Hz, 1H), 7.57 (t, J = 7.8 Hz, 2H), 7.16-7.09 (m, 2H), 4.60 (s, 1H), 3.84 (s, 3H ); 13 C NMR (126 MHz, DMSO): δ [ppm] = 165.31, 162.06, 138.85, 133.97, 132.62, 131.41, 129.78, 128.25, 118.49, 115.26, 114.85, 111.36, 55.51, 34.84; MS: molecular peak = 323; rel. Frequency 68% base peak = 135; HPLC: 7.47 minutes

Verbindung 71: 1H NMR (500 MHz, DMSO-d6): δ [ppm] = 7.93-7.87 (m, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.16-7.10 (m, 2H), 7.03 (t, J = 5.0 Hz, 2H), 6.88-6.82 (m, 1H), 4.53 (s, 2H), 3.85 (s, 3H), 3.72 (s, 3H); 13C NMR (126 MHz, DMSO): δ [ppm] = 165.17, 162.40, 162.05, 159.24, 138.09, 129.64, 128.24, 121.14, 115.32, 114.86, 114.61, 113.22, 55.52, 55.01, 35.92; MS: Molekülpeak = 328; rel. Häufigkeit 55% Basispeak = 121; HPLC: 7.83 MinutenCompound 71: 1 H NMR (500 MHz, DMSO-d 6): δ [ppm] = 7.93-7.87 (m, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7:16 to 7:10 (m, 2H) , 7.03 (t, J = 5.0 Hz, 2H), 6.88-6.82 (m, 1H), 4.53 (s, 2H), 3.85 (s, 3H), 3.72 (s, 3H); 13 C NMR (126 MHz, DMSO): δ [ppm] = 165.17, 162.40, 162.05, 159.24, 138.09, 129.64, 128.24, 121.14, 115.32, 114.86, 114.61, 113.22, 55.52, 55.01, 35.92; MS: molecular peak = 328; rel. Frequency 55% base peak = 121; HPLC: 7.83 minutes

Verbindung 72: 1H NMR (500 MHz, DMSO-d6): δ [ppm] = 7.92-7.86 (m, 2H), 7.49-7.45 (m, 2H), 7.38-7.32 (m, 2H), 7.31-7.25 (m, 1H), 7.16-7.10 (m, 2H), 4.56 (s, 2H), 3.85 (s, 3H); 13C NMR (126 MHz, DMSO): δ [ppm] = 165.16, 162.39, 162.04, 136.61, 128.98, 128.54, 128.22, 127.71, 115.31, 114.86, 55.51, 35.93; MS: Molekülpeak = 298; rel. Häufigkeit 50% Basispeak = 133; HPLC: 7.83 Minuten Compound 72: 1 H NMR (500 MHz, DMSO-d 6): δ [ppm] = 7.92-7.86 (m, 2H), 7:49 to 7:45 (m, 2H), 7:38 to 7:32 (m, 2H), 7.31- 7.25 (m, 1H), 7.16-7.10 (m, 2H), 4.56 (s, 2H), 3.85 (s, 3H); 13 C NMR (126 MHz, DMSO): δ [ppm] = 165.16, 162.39, 162.04, 136.61, 128.98, 128.54, 128.22, 127.71, 115.31, 114.86, 55.51, 35.93; MS: molecular peak = 298; rel. Frequency 50% base peak = 133; HPLC: 7.83 minutes

Beispiel 2: Synthese der Verbindung 73Example 2: Synthesis of the compound 73

Schritt 1:Step 1:

Methyl-4-((5-(benzo[d][1,3]dioxol-5-yl)-1,3,4-oxadiazol-2-ylthio)methylbenzoat (Verbindung 27) (300 mg, 0,81 mmol, 1 eq) wird in 5 mL einer 2 N Lithiumhydroxidtetrahydrofuran-Lösung gegeben. Die Mischung wird bei 60°C über Nacht unter Argonatmosphäre gerührt. Die Reaktionsmischung wird mit Wasser versetzt und mit 1N HCl neutralisiert. Anschließend wird gegen Essigsäureethylester ausgeschüttelt, und die organische Phase gegen NaClaq ausgeschüttelt und über MgSO4 getrocknet. Die Lösung wird einrotiert. Ausbeute: 239 mg (83%), rosafarbener Feststoff: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.56 (2H, s), 6.08 (2H, s), 7.04 (1H, d, J = 8.1 Hz), 7.35 (1H, d, J = 1.6 Hz), 7.43 (1H, dd, J = 8.1 Hz, J 1.7 Hz), 7.53 (2H, d, J = 8.2 Hz), 7.84 (2H, d, J = 8.2 Hz), 12.8 (1H, s, br); 13C-NMR (DMSO-d6, 125 MHz) 6 [ppm] = 35.4, 102.1, 106.1, 109.1, 116.6, 121.7, 129.1, 129.5, 130.4, 141.7, 148.1, 150.4, 162.4, 165.1, 166.9; MS: Molekülpeak: m/z = 356; rel. Häufigkeit 48% Basispeak: m/z = 149 HPLC: 6.15 MinutenMethyl 4 - ((5- (benzo [d] [1,3] dioxol-5-yl) -1,3,4-oxadiazol-2-ylthio) methyl benzoate (Compound 27) (300 mg, 0.81 mmol 1 eq) is added to 5 mL of a 2 N lithium hydroxide tetrahydrofuran solution, the mixture is stirred overnight at 60 ° C. under an argon atmosphere, the reaction mixture is mixed with water and neutralized with 1N HCl, then partitioned between ethyl acetate and ethyl acetate Partitioned out against NaCl aq and dried over MgSO 4. The solution is concentrated in a rotary evaporator Yield: 239 mg (83%), pink solid: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.56 (2H , s), 6.08 (2H, s), 7.04 (1H, d, J = 8.1 Hz), 7.35 (1H, d, J = 1.6 Hz), 7.43 (1H, dd, J = 8.1 Hz, J 1.7 Hz) , 7.53 (2H, d, J = 8.2 Hz), 7.84 (2H, d, J = 8.2 Hz), 12.8 (1H, s, br); 13 C-NMR (DMSO-d 6 , 125 MHz) 6 [ppm ] = 35.4, 102.1, 106.1, 109.1, 116.6, 121.7, 129.1, 129.5, 130.4, 141.7, 148.1, 150.4, 162.4, 165.1, 166.9, MS: Molecular peak: m / z = 356, rel frequency 48% Base peak: m / z = 149 HPLC: 6.15 minutes

Analog wurde die Verbindung 74 synthetisiert. Edukt zu Verbindung 74 war Verbindung 10: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.31 (2H, m), 4.34 (2H, m), 4.62 (2H, s), 7.05 (1H, d, J = 8.4 Hz), 7.38 (1H, d, J = 2.0 Hz), 7.43 (1H, dd, J = 8.4 Hz, J = 2.1 Hz), 7.59 (2H, d, J = 8.3 Hz), 7.91 (2H, d, J = 8.3 Hz), 12.95 (1H, s, br); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.4, 64.1, 64.4, 115.1, 115.7, 118.2, 119.8, 129.3, 129.5, 130.1, 141.9, 143.8, 146.7, 162.4, 165.0, 166.8; MS: Molekülpeak: m/z = 370; rel. Häufigkeit 54% Basispeak: m/z = 163; HPLC: 6.22 MinutenAnalogously, compound 74 was synthesized. Starting material to compound 74 was compound 10: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.31 (2H, m), 4.34 (2H, m), 4.62 (2H, s), 7.05 ( 1H, d, J = 8.4 Hz), 7.38 (1H, d, J = 2.0 Hz), 7.43 (1H, dd, J = 8.4 Hz, J = 2.1 Hz), 7.59 (2H, d, J = 8.3 Hz) , 7.91 (2H, d, J = 8.3 Hz), 12.95 (1H, s, br); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.4, 64.1, 64.4, 115.1, 115.7, 118.2, 119.8, 129.3, 129.5, 130.1, 141.9, 143.8, 146.7, 162.4, 165.0, 166.8 ; MS: Molecular peak: m / z = 370; rel. Frequency 54% base peak: m / z = 163; HPLC: 6.22 minutes

Beispiel 3: Synthese der Verbindung 75Example 3: Synthesis of Compound 75

Schritt 1:Step 1:

Eine Mischung aus 4-((5-(benzo[d][1,3]dioxol-5-yl)-1,3,4-oxadiazol-2-ylthio)methyl)-benzoesäure (Verbindung 73) (100 mg, 0,28 mmol, 1 eq) und SOCl2 (30,5 μL, 0,42 mmol, 1,5 eq) wird unter Rückfluss in 1 mL trockenem Toluol für 2 h gerührt. Anschließend wird der Überschuss an SOCl2 mehrmals mit trockenem Toluol abrotiert. 2-methylpropan-1-amin (27,8 μL, 0,28 mmol, 1 eq) und K2CO3 (38 mg, 0,28 mmol, 1 eq) werden in trockenes Aceton gegeben und bei 0°C für 30 Minuten gerührt. Das Säurechlorid wird anschließend in Aceton gelöst und tropfenweise der Lösung zugegeben. Sobald die Umsetzung vollständig ist wird die Mischung mit Wasser versetzt und gegen Essigsäureethylester ausgeschüttelt. Anschließend wird die organische Phase gegen NaClaq ausgeschüttelt und über MgSO4 getrocknet. Die Lösung wird einrotiert und der Feststoff in Ethanol umkristallisiert. Ausbeute: 90 mg (81%), beiger Feststoff: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 0.85 (3H, s), 0.87 (3H, s), 1.81 (1H, m), 3.05 (2H, m), 4.60 (2H, s), 6.16 (2H, s), 7.10 (1H, d, J = 8.1 Hz), 7.43 (1H, d, J = 1.6 Hz), 7.50 (1H, dd, J = 8.1 Hz, J = 1.7 Hz), 7.54 (2H, d, J = 8.2 Hz), 7.78 (2H, d, J = 8.3 Hz), 8.42 (1H, t, J = 5.7 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 20.2, 28.0, 35.4, 46.6, 102.1, 106.1, 109.2, 116.6, 121.8, 127.5, 128.8, 134.1, 139.8, 148.1, 150.5, 162.4, 165.1, 165.8; MS: Molekülpeak: m/z = 411; rel. Häufigkeit 43% Basispeak: m/z = 149; HPLC: 7.11 MinutenA mixture of 4 - ((5- (benzo [d] [1,3] dioxol-5-yl) -1,3,4-oxadiazol-2-ylthio) methyl) benzoic acid (Compound 73) (100 mg, 0.28 mmol, 1 eq) and SOCl 2 (30.5 μL, 0.42 mmol, 1.5 eq) is stirred under reflux in 1 mL of dry toluene for 2 h. Subsequently, the excess of SOCl 2 is repeatedly removed by rotary evaporation with dry toluene. 2-methylpropan-1-amine (27.8 μL, 0.28 mmol, 1 eq) and K 2 CO 3 (38 mg, 0.28 mmol, 1 eq) are placed in dry acetone and incubated at 0 ° C for 30 Stirred for minutes. The acid chloride is then dissolved in acetone and added dropwise to the solution. Once the reaction is complete, water is added to the mixture and shaken out against ethyl acetate. The organic phase is then extracted by shaking against NaCl aq and dried over MgSO 4 . The solution is concentrated by rotary evaporation and the solid is recrystallised in ethanol. Yield: 90 mg (81%), beige solid: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 0.85 (3H, s), 0.87 (3H, s), 1.81 (1H, m ), 3.05 (2H, m), 4.60 (2H, s), 6.16 (2H, s), 7.10 (1H, d, J = 8.1 Hz), 7.43 (1H, d, J = 1.6 Hz), 7.50 (1H , dd, J = 8.1 Hz, J = 1.7 Hz), 7.54 (2H, d, J = 8.2 Hz), 7.78 (2H, d, J = 8.3 Hz), 8.42 (1H, t, J = 5.7 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 20.2, 28.0, 35.4, 46.6, 102.1, 106.1, 109.2, 116.6, 121.8, 127.5, 128.8, 134.1, 139.8, 148.1, 150.5, 162.4 , 165.1, 165.8; MS: Molecular peak: m / z = 411; rel. Frequency 43% base peak: m / z = 149; HPLC: 7.11 minutes

Analog wurden die Verbindungen 93 und 76–78 synthetisiert. Edukt zu Verbindung 76 war Verbindung 74.Analogously, compounds 93 and 76-78 were synthesized. Starting material to compound 76 was compound 74.

Verbindung 76: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 3.27 (6H, s), 3.33 (2H, br, liegt unter dem Wassersignal), 4.48 (1H, t, J = 5.6 Hz), 4.61 (2H, s), 6.16 (2H, s), 7.11 (1H, d, J = 8.1 Hz), 7.44 (1H, d, J = 1.7 Hz), 7.50 (1H, dd, J = 8.1 Hz, J = 1.7 Hz), 7.55 (2H, d, J = 8.1 Hz), 7.80 (2H, d, J = 8.1 Hz), 8.52 (1H, t, J = 5.7 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.4, 41.1, 53.2, 101.8, 102.2, 106.2, 109.2, 116.6, 121.7, 127.5, 128.9, 133.5, 140.1, 148.1, 150.4, 162.4, 165.1, 166.0; MS: Molekülpeak: m/z = 443; rel. Häufigkeit 2% Basispeak: m/z = 149; HPLC: 6.07 MinutenCompound 76: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 3.27 (6H, s), 3.33 (2H, br, is below the water signal), 4.48 (1H, t, J = 5.6 Hz), 4.61 (2H, s), 6.16 (2H, s), 7.11 (1H, d, J = 8.1 Hz), 7.44 (1H, d, J = 1.7 Hz), 7.50 (1H, dd, J = 8.1 Hz, J = 1.7 Hz), 7.55 (2H, d, J = 8.1 Hz), 7.80 (2H, d, J = 8.1 Hz), 8.52 (1H, t, J = 5.7 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.4, 41.1, 53.2, 101.8, 102.2, 106.2, 109.2, 116.6, 121.7, 127.5, 128.9, 133.5, 140.1, 148.1, 150.4, 162.4 , 165.1, 166.0; MS: Molecular peak: m / z = 443; rel. Frequency 2% base peak: m / z = 149; HPLC: 6.07 minutes

Verbindung 77: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 3.28 (6H, s), 3.35 (2H, d, J = 5.7 Hz), 4.32 (4H, m), 4.50 (1H, t, J = 5.6 Hz), 4.61 (2H, s), 7.05 (1H, d, J = 8.3 Hz), 7.40 (1H, d, J = 2.0 Hz), 7.43 (1H, dd, J = 8.3 Hz, J = 2.0 Hz), 7.55 (2H, d, J = 8.2 Hz), 7.81 (2H, d, J = 8.2 Hz), 8.52 (1H, t, J = 5.8 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.4, 41.1, 53.2, 64.0, 64.4, 101.8, 115.0, 105.8, 108.2, 119.9, 127.4, 128.8, 133.5, 140.0, 143.8, 146.7, 162.4, 164.9, 165.9; MS: Molekülpeak: m/z = 457; rel. Häufigkeit 4% Basispeak: m/z = 161; HPLC: 6.13 MinutenCompound 77: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 3.28 (6H, s), 3.35 (2H, d, J = 5.7 Hz), 4.32 (4H, m), 4.50 ( 1H, t, J = 5.6Hz), 4.61 (2H, s), 7.05 (1H, d, J = 8.3Hz), 7.40 (1H, d, J = 2.0Hz), 7.43 (1H, dd, J = 8.3 Hz, J = 2.0 Hz), 7.55 (2H, d, J = 8.2 Hz), 7.81 (2H, d, J = 8.2 Hz), 8.52 (1H, t, J = 5.8 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.4, 41.1, 53.2, 64.0, 64.4, 101.8, 115.0, 105.8, 108.2, 119.9, 127.4, 128.8, 133.5, 140.0, 143.8, 146.7, 162.4, 164.9, 165.9; MS: Molecular peak: m / z = 457; rel. Frequency 4% base peak: m / z = 161; HPLC: 6.13 minutes

Verbindung 78: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 0.92 (3H, s), 0.94 (3H, s), 1.87 (1H, m), 3.12 (2H, m), 4.37 (4H, m), 4.66 (2H, s), 7.10 (1H, d, J = 8.4 Hz), 7.45 (1H, d, J = 2.0 Hz), 7.48 (1H, dd, J = 8.4 Hz, J = 2.0 Hz), 7.60 (2H, d, J = 8.2 Hz), 7.85 (2H, d, J = 8.2 Hz), 8.46 (1H, t, J = 5.7 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 20.2, 28.1, 35.4, 46.6, 64.1, 64.4, 115.0, 115.8, 118.1, 119.9, 127.4, 128.8, 134.1, 139.7, 143.8, 146.7, 162.4, 164.9, 165.8; MS: Molekülpeak: m/z = 425; rel. Häufigkeit 37% Basispeak: m/z = 161; HPLC: 7.16 MinutenCompound 78: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 0.92 (3H, s), 0.94 (3H, s), 1.87 (1H, m), 3.12 (2H, m), 4.37 (4H, m), 4.66 (2H, s), 7.10 (1H, d, J = 8.4 Hz), 7.45 (1H, d, J = 2.0 Hz), 7.48 (1H, dd, J = 8.4 Hz, J = 2.0 Hz), 7.60 (2H, d, J = 8.2 Hz), 7.85 (2H, d, J = 8.2 Hz), 8.46 (1H, t, J = 5.7 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 20.2, 28.1, 35.4, 46.6, 64.1, 64.4, 115.0, 115.8, 118.1, 119.9, 127.4, 128.8, 134.1, 139.7, 143.8, 146.7 , 162.4, 164.9, 165.8; MS: Molecular peak: m / z = 425; rel. Frequency 37% base peak: m / z = 161; HPLC: 7.16 minutes

Beispiel 4: Synthese der Verbindung 79Example 4: Synthesis of Compound 79

Schritt 1:Step 1:

4-((5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,3,4-oxadiazol-2ylthio)methyl)benzonitril (34 mg, 0,10 mmol, 1 eq), NaN3 (78 mg, 1,20 mmol, 12 eq) und NH4Cl (64 mg, 1,20 mmol, 12 eq) werden in 1 mL DMF gegeben und für 5 h bei 100°C in einer Synthese-Mikrowelle erhitzt. Nach Abkühlen auf Raumtemperatur wird der Mischung etwas Wasser zugegeben und mit 2 N HCl angesäuert. Die wässrige Phase wird gegen Essigsäureethylester ausgeschüttelt. Anschließend wird die organische Phase gegen NaClaq ausgeschüttelt und über NaSO4 getrocknet. Ausbeute: 27 mg (79%), braunroter Feststoff: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.35 (2H, m), 4.38 (2H, m), 4.70 (2H, s), 7.10 (1H, d, J = 8.4 Hz), 7.43 (1H, d, J = 2.0 Hz), 7.47 (1H, dd, J = 8.4 Hz, J = 2.1 Hz), 7.75 (2H, d, J = 8.3 Hz), 8.05 (2H, d, J = 8.3 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.5, 64.0, 64.4, 115.0, 115.8, 118.2, 119.9, 123.6, 127.1, 130.0, 140.1, 143.8, 146.7, 162.4, 165.1; MS: Molekülpeak: m/z = 394; rel. Häufigkeit 8% Basispeak: m/z = 163; HPLC: 6.01 Minuten4 - ((5- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -1,3,4-oxadiazol-2-thio) methyl) benzonitrile (34 mg, 0.10 mmol, 1 eq), NaN 3 (78 mg, 1.20 mmol, 12 eq) and NH 4 Cl (64 mg, 1.20 mmol, 12 eq) are added to 1 mL DMF and 5 h at 100 ° C in a synthesis Microwave heated. After cooling to room temperature, a little water is added to the mixture and acidified with 2N HCl. The aqueous phase is shaken out against ethyl acetate. The organic phase is then shaken out against NaCl aq and dried over NaSO 4 . Yield: 27 mg (79%), tan solid: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.35 (2H, m), 4.38 (2H, m), 4.70 (2H, s ), 7.10 (1H, d, J = 8.4 Hz), 7.43 (1H, d, J = 2.0 Hz), 7.47 (1H, dd, J = 8.4 Hz, J = 2.1 Hz), 7.75 (2H, d, J = 8.3 Hz), 8.05 (2H, d, J = 8.3 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.5, 64.0, 64.4, 115.0, 115.8, 118.2, 119.9, 123.6, 127.1, 130.0, 140.1, 143.8, 146.7, 162.4, 165.1; MS: Molecular peak: m / z = 394; rel. Frequency 8% base peak: m / z = 163; HPLC: 6.01 minutes

Analog wurde die Verbindung 84 synthetisiert: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.30 (2H, m), 4.34 (2H, m), 4.67 (2H, s), 7.02 (1H, d, J = 8.4 Hz), 7.36 (1H, d, J = 2.0), 7.41 (1H, dd, J = 8.3 Hz, J = 2.0 Hz), 7.58 (1H, t, J = 7.7 Hz), 7.70 (1H, d, J = 7.8 Hz), 7.95 (1H, d, J = 7.8 Hz), 8.21 (1H, s); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.5, 64.0, 64.4, 115.0, 115.8, 118.1, 119.9, 126.2, 127.5, 129.6, 131.8, 138.4, 143.8, 146.7, 162.4, 165.0; MS: Molekülpeak: m/z = 394; rel. Häufigkeit 16% Basispeak: m/z = 163; HPLC: 5.91 MinutenAnalogously, compound 84 was synthesized: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.30 (2H, m), 4.34 (2H, m), 4.67 (2H, s), 7.02 (1H , d, J = 8.4 Hz), 7.36 (1H, d, J = 2.0), 7.41 (1H, dd, J = 8.3 Hz, J = 2.0 Hz), 7.58 (1H, t, J = 7.7 Hz), 7.70 (1H, d, J = 7.8 Hz), 7.95 (1H, d, J = 7.8 Hz), 8.21 (1H, s); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.5, 64.0, 64.4, 115.0, 115.8, 118.1, 119.9, 126.2, 127.5, 129.6, 131.8, 138.4, 143.8, 146.7, 162.4, 165.0 ; MS: Molecular peak: m / z = 394; rel. Frequency 16% base peak: m / z = 163; HPLC: 5.91 minutes

Ebenfalls analog wurde die Verbindung 81 synthetisiert.Likewise, compound 81 was synthesized.

Beispiel 5: Synthese der Verbindung 23Example 5: Synthesis of compound 23

Schritt 1:Step 1:

4'-((5-(3-(methoxymethyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,3,4-oxadiazol-2-ylthio)-methyl)-biphenyl-2-carbonitril (Verbindung 22) (400 mg, 0,85 mmol, 1 eq) wird in 10 mL Dichlormethan geben und mit einer Trockeneis/Aceton-Mischung auf –78°C gekühlt. Anschließend wird unter Argonatmosphäre bei –78°C eine 1 N Bortribromid-Lösung in Hexan (850 μL, 0,85 mmol, 1 eq) zugetropft. Die Mischung wird anschließend über Nacht bei Raumtemperatur gerührt. Danach mit gesättigter NaHCO3-Lösung neutralisieren und die Reaktionsmischung auf Wasser geben und gegen Essigsäureethylester ausschütteln. Die organischen Phasen werden vereinigt, gegen NaClaq ausgeschüttelt und über MgSO4 getrocknet. Anschließend wird die Mischung einrotiert und mittels Säulenchromatographie gereinigt (Cyclohexan-Essigsäureethylester = 1:2). Ausbeute: 283 mg (73%), hellgelber Feststoff: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.61 (2H, s), 6.16 (2H, s), 7.10 (1H, d, J = 8.1 Hz), 7.41 (1H, d, J = 1.4 Hz), 7.47 (1H, dd, J = 8.1 Hz, J = 1.5 Hz), 7.57 (1H, t, J = 7.7 Hz), 7.76 (1H, d, J = 7.7 Hz), 7.84 (1H, d, J = 7.8 Hz), 7.96 (1H, s); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 34.7, 102.1, 106.1, 109.1, 111.4, 116.6, 118.5, 121.7, 129.8, 131.4, 132.6, 133.9, 138.8, 148.1, 150.4, 162.2, 165.2; MS: Molekülpeak: m/z = 337; rel. Häufigkeit 65% Basispeak: m/z = 149; HPLC: 7.21 Minuten4 '- ((5- (3- (methoxymethyl) -2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -1,3,4-oxadiazol-2-ylthio) methyl) - Biphenyl-2-carbonitrile (Compound 22) (400 mg, 0.85 mmol, 1 eq) is added to 10 mL dichloromethane and cooled to -78 ° C with a dry ice / acetone mixture. Then, under argon atmosphere at -78 ° C, a 1 N boron tribromide solution in hexane (850 μL, 0.85 mmol, 1 eq) was added dropwise. The mixture is then stirred overnight at room temperature. Then neutralize with saturated NaHCO 3 solution and add the reaction mixture to water and shake out with ethyl acetate. The organic phases are combined, shaken out against NaCl aq and dried over MgSO 4 . The mixture is then concentrated by rotary evaporation and purified by column chromatography (cyclohexane-ethyl acetate = 1: 2). Yield: 283 mg (73%), light yellow solid: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.61 (2H, s), 6.16 (2H, s), 7.10 (1H, d , J = 8.1 Hz), 7.41 (1H, d, J = 1.4 Hz), 7.47 (1H, dd, J = 8.1 Hz, J = 1.5 Hz), 7.57 (1H, t, J = 7.7 Hz), 7.76 ( 1H, d, J = 7.7 Hz), 7.84 (1H, d, J = 7.8 Hz), 7.96 (1H, s); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 34.7, 102.1, 106.1, 109.1, 111.4, 116.6, 118.5, 121.7, 129.8, 131.4, 132.6, 133.9, 138.8, 148.1, 150.4, 162.2 , 165.2; MS: Molecular peak: m / z = 337; rel. Frequency 65% base peak: m / z = 149; HPLC: 7.21 minutes

Analog wurde die Verbindung 85 synthetisiert: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.65 (2H, s), 6.15 (2H, s), 7.11 (1H, d, J = 8.1 Hz), 7.15 (1H, s, br), 7.43 (1H, d, J = 1.6 Hz)' 7.50 (1H, dd, J = 8.1 Hz, J = 1.7 Hz), 7.71 (2H, d, J = 8.3 Hz), 8.00 (2H, d, J = 8.3 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.4, 102.1, 105.0, 106.2, 108.9, 109.1, 116.6, 119.7, 121.7, 127.1, 130.0, 148.1, 150.4, 162.4, 165.1; MS: Molekülpeak: m/z = 380; rel. Häufigkeit 23% Basispeak: m/z = 147; HPLC: 5.92 MinutenAnalogously, compound 85 was synthesized: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.65 (2H, s), 6.15 (2H, s), 7.11 (1H, d, J = 8.1 Hz ), 7.15 (1H, s, br), 7.43 (1H, d, J = 1.6 Hz) ' 7.50 (1H, dd, J = 8.1 Hz, J = 1.7 Hz), 7.71 (2H, d, J = 8.3 Hz ), 8.00 (2H, d, J = 8.3 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.4, 102.1, 105.0, 106.2, 108.9, 109.1, 116.6, 119.7, 121.7, 127.1, 130.0, 148.1, 150.4, 162.4, 165.1; MS: Molecular peak: m / z = 380; rel. Frequency 23% base peak: m / z = 147; HPLC: 5.92 minutes

Beispiel 6: Synthese der Verbindung 82 Example 6: Synthesis of Compound 82

Schritt 1:Step 1:

4'-((5-(3-hydroxymethyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,3,4-oxadiazol-2-ylthio)methyl)-biphenyl-2-carbonitril (238 mg, 0,52 mmol, 1 eq) wird in 10 mL Dichlormethan geben und auf 0°C gekühlt. Anschließend wird Et3N (0,72 mL, 5,2 mmol, 10 eq) und Methansulfonylchlorid (402 μL, 5,2 mmol, 10 eq) zugetropft und die Mischung 1 h bei 0°C und weitere 4 h bei Raumtemperatur gerührt. Die Reaktionsmischung wird mit gesättigter NaHCO3-Lösung neutralisiert und gegen Dichlormethan ausgeschüttelt. Die organischen Phasen werden vereinigt, gegen NaClaq ausgeschüttelt und über MgSO4 getrocknet. Anschließend wird die Mischung einrotiert und mittels Säulenchromatographie gereinigt (Cyclohexan-Essigsäureethylester = 1:1). Ausbeute: 273 mg (98%), gelbes Öl (Verbindung 83): 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 3.26 (3H, s), 4.17 (1H, m), 4.45 (1H, m), 4.50 (1H, dd, J = 11.6 Hz, J = 2.4 Hz), 4.55 (1H, dd, J = 11.6 Hz, J = 3.3 Hz), 4.62 (1H, m), 4.67 (2H, s), 7.11 (1H, d, J = 8.1 Hz), 7.48 (2H, m), 7.61 (6H, m), 7.77 (1H, td, J = 7.6 Hz, J = 1.3 Hz), 7.95 (1H, d, J = 7.7 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.4, 36.8, 64.3, 67.8, 70.9, 110.1, 115.2, 116.4, 118.2, 118.5, 120.3, 128.2, 128.8, 129.4, 130.1, 133.5, 133.8, 137.1, 137.4, 142.7, 143.9, 145.9, 162.7, 164.9; MS: Molekülpeak: m/z = 535; rel. Häufigkeit 18% Basispeak: m/z = 192; HPLC: 8.49 Minuten4 '- ((5- (3-hydroxymethyl) -2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -1,3,4-oxadiazol-2-ylthio) methyl) -biphenyl- Add 2-carbonitrile (238 mg, 0.52 mmol, 1 eq) in 10 mL dichloromethane and cool to 0 ° C. Subsequently, Et 3 N (0.72 mL, 5.2 mmol, 10 eq) and methanesulfonyl chloride (402 μL, 5.2 mmol, 10 eq) are added dropwise and the mixture for 1 h at 0 ° C and stirred for a further 4 h at room temperature , The reaction mixture is neutralized with saturated NaHCO 3 solution and shaken out against dichloromethane. The organic phases are combined, shaken out against NaCl aq and dried over MgSO 4 . The mixture is then concentrated by rotary evaporation and purified by column chromatography (cyclohexane-ethyl acetate = 1: 1). Yield: 273 mg (98%), yellow oil (Compound 83): 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 3.26 (3H, s), 4.17 (1H, m), 4.45 (1H, m), 4.50 (1H, dd, J = 11.6 Hz, J = 2.4 Hz), 4.55 (1H, dd, J = 11.6 Hz, J = 3.3 Hz), 4.62 (1H, m), 4.67 (2H , s), 7.11 (1H, d, J = 8.1 Hz), 7.48 (2H, m), 7.61 (6H, m), 7.77 (1H, td, J = 7.6 Hz, J = 1.3 Hz), 7.95 (1H , d, J = 7.7 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.4, 36.8, 64.3, 67.8, 70.9, 110.1, 115.2, 116.4, 118.2, 118.5, 120.3, 128.2, 128.8, 129.4, 130.1, 133.5 , 133.8, 137.1, 137.4, 142.7, 143.9, 145.9, 162.7, 164.9; MS: Molecular peak: m / z = 535; rel. Frequency 18% base peak: m / z = 192; HPLC: 8.49 minutes

Schritt 2:Step 2:

Zu einer Lösung aus (S)-(7-(5-((2'-cyanobiphenyl-4-yl)methylthio)-1,3,4-oxadiazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl methanesulfonate (Verbindung 83) (69 mg, 0,13 mmol, 1 eq) in 2 mL THF wird bei 0°C 2,2-Dimethoxyethylamine (140 μL, 1,3 mmol, 10 eq) und NEt3 (180 μL, 1,3 mmol, 10 eq) zugegeben. Die Reaktionsmischung wird 5 Tage bei Raumtemperatur gerührt. Anschließend wird die Reaktionsmischung auf Wasser gegeben und gegen Essigsäureethylester ausgeschüttelt. Die organischen Phasen werden vereinigt, gegen NaClaq ausgeschüttelt und über MgSO4 getrocknet. Anschließend wird die Mischung einrotiert und mittels Säulenchromatographie gereinigt (MeOH-Essigsäureethylester = 1:10). Ausbeute: 58 mg (83%), dunkelgelbes Öl: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 1.91 (1H, m), 2.61 (2H, dd, J = 5.4 Hz, J = 0.7 Hz), 2.78 (1H, m), 2.85 (1H, m), 3.18 (3H, s), 3.19 (3H, s), 4.00 (1H, m), 4.17 (1H, m), 4.30 (2H, m), 4.54 (2H, s), 6.87 (1H, m), 7.32 (1H, m), 7.46 (4H, m), 7.52 (2H, m), 7.64 (1H, td, J = 7.8 Hz, J = 1.3 Hz), 7.74 (1H, m); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 36.7, 50.2, 52.1, 53.8, 53.9, 67.7, 74.1, 104.9, 111.8, 116.5, 117.8, 118.7, 119.1, 120.8, 129.0, 130.0, 130.4, 131.1, 134.1, 134.7, 138.4, 138.8, 144.7, 145.4, 147.6, 163.7, 166.3; MS: Molekülpeak: m/z = 544; rel. Häufigkeit 1% Basispeak: m/z = 75; HPLC: 6.34 MinutenTo a solution of (S) - (7- (5 - ((2'-cyanobiphenyl-4-yl) methylthio) -1,3,4-oxadiazol-2-yl) -2,3-dihydrobenzo [b] [ 1,4] dioxin-2-yl) methyl methanesulfonate (Compound 83) (69 mg, 0.13 mmol, 1 eq) in 2 mL THF at 0 ° C 2,2-dimethoxyethylamine (140 μL, 1.3 mmol , 10 eq) and NEt 3 (180 μL, 1.3 mmol, 10 eq) were added. The reaction mixture is stirred for 5 days at room temperature. The reaction mixture is then added to water and shaken out against ethyl acetate. The organic phases are combined, shaken out against NaCl aq and dried over MgSO 4 . The mixture is then concentrated by rotary evaporation and purified by column chromatography (MeOH-ethyl acetate = 1:10). Yield: 58 mg (83%), dark yellow oil: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 1.91 (1H, m), 2.61 (2H, dd, J = 5.4 Hz, J = 0.7 Hz), 2.78 (1H, m), 2.85 (1H, m), 3.18 (3H, s), 3.19 (3H, s), 4.00 (1H, m), 4.17 (1H, m), 4.30 (2H , m), 4.54 (2H, s), 6.87 (1H, m), 7.32 (1H, m), 7.46 (4H, m), 7.52 (2H, m), 7.64 (1H, td, J = 7.8 Hz, J = 1.3 Hz), 7.74 (1H, m); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 36.7, 50.2, 52.1, 53.8, 53.9, 67.7, 74.1, 104.9, 111.8, 116.5, 117.8, 118.7, 119.1, 120.8, 129.0, 130.0 , 130.4, 131.1, 134.1, 134.7, 138.4, 138.8, 144.7, 145.4, 147.6, 163.7, 166.3; MS: Molecular peak: m / z = 544; rel. Frequency 1% base peak: m / z = 75; HPLC: 6.34 minutes

Beispiel 7: Synthese der Vorstufe von Verbindung 86Example 7: Synthesis of the precursor of Compound 86

Schritt 1:Step 1:

4-Aminobenzoesäure (3,4 g, 24.5 mmol, 1 eq) wird in 30 mL Ethanol gegeben und tropfenweise mit 2,4 mL konzentrierter H2SO4 versetzt. Nach kompletter Zugabe wird die Mischung 6 h unter Rückfluss gerührt. Die Reaktionsmischung wird anschließend unter Kühlung auf 200 mL Wasser gegeben und mit konzentrierter NH4OH auf pH 7 gestellt. Das Fällungsprodukt wird abfiltriert und mit Wasser gewaschen. Ausbeute: 2,63 g (71%), farbloser Feststoff.4-aminobenzoic acid (3.4 g, 24.5 mmol, 1 eq) is added to 30 mL of ethanol and treated dropwise with 2.4 mL of concentrated H 2 SO 4 . After complete addition, the mixture is stirred for 6 h under reflux. The reaction mixture is then added with cooling to 200 ml of water and adjusted to pH 7 with concentrated NH 4 OH. The precipitate is filtered off and washed with water. Yield: 2.63 g (71%), colorless solid.

Schritt 2:Step 2:

Methyl-4-aminobenzoat (2 g, 12,1 mmol, 1 eq) wird in 16 mL konzentrierter Essigsäure gegeben und mit KSCN (4,67 g, 0,048 mmol, 4 eq) versetzt. Die Mischung wird 1 h bei Raumtemperatur gerührt. Anschließend wird Brom (616 μL, 0,012 mmol, 1 eq) in 8 mL Essigsäure gelöst und diese Mischung der Reaktionslösung über 1 h zugetropft. Die Mischung wird über Nacht bei Raumtemperatur gerührt. Die Reaktionslösung wird auf Wasser gegeben und mit konzentrierter NH4OH auf pH 7 eingestellt. Das Fällungsprodukt wird abfiltriert und mit Wasser gewaschen. Ausbeute: 1,49 g (56%), gelber Feststoff.Add methyl 4-aminobenzoate (2 g, 12.1 mmol, 1 eq) in 16 mL concentrated acetic acid and add KSCN (4.67 g, 0.048 mmol, 4 eq). The mixture is stirred for 1 h at room temperature. Subsequently, bromine (616 μL, 0.012 mmol, 1 eq) is dissolved in 8 mL of acetic acid and this mixture is added dropwise to the reaction solution over 1 h. The mixture is stirred overnight at room temperature. The reaction solution is added to water and adjusted to pH 7 with concentrated NH 4 OH. The precipitate is filtered off and washed with water. Yield: 1.49 g (56%), yellow solid.

Schritt 3:Step 3:

Siehe Beispiel 9 Stufe 1. Ausbeute: 1,15 g (73%), leicht gelblicher Feststoff.See Example 9 Step 1. Yield: 1.15 g (73%), slightly yellowish solid.

Schritt 4: Step 4:

Ethyl-2-acetamidobenzo[d]thiazol-6-carboxylat (1,1 g, 4,16 mmol, 1 eq) wird in 10 mL MeOH gegeben und mit 2 mL 1 N NaOH versetzt. Die Mischung wird 4 h bei Raumtemperatur gerührt. Anschließend wird die Reaktionslösung auf Wasser gegeben und mit 1 N HCl auf pH 2 eingestellt. Die Mischung wird über Nacht in den Kühlschrank gestellt und es bildet sich ein Feststoff. Der Feststoff wird abfiltriert und mit Wasser gewaschen. Ausbeute: 914 mg (93%), leicht gelblicher Feststoff.Ethyl 2-acetamidobenzo [d] thiazole-6-carboxylate (1.1 g, 4.16 mmol, 1 eq) is added to 10 mL MeOH and 2 mL 1 N NaOH are added. The mixture is stirred for 4 h at room temperature. Subsequently, the reaction solution is added to water and adjusted to pH 2 with 1N HCl. The mixture is placed in the refrigerator overnight and a solid forms. The solid is filtered off and washed with water. Yield: 914 mg (93%), slightly yellowish solid.

Schritt 5:Step 5:

In 5 mL trockenem DMF werden 2-Acetamidobenzo[d]thiazol-6-carbonsäure (200 mg, 0,85 mmol, 1 eq), tert-Butylcarbazid (123,5 mg, 0,94 mmol, 1.1 eq) und EDCl (Ethylendichlorid) (195,5 mg, 1,02 mmol, 1.2 eq) gegeben und kurz gerührt. Anschließend wird HOBt·H2O zugegeben und über Nacht bei Raumtemperatur gerührt. Danach wird die Reaktionsmischung auf Wasser geben und gegen Essigsäureethylester ausgeschüttelt. Die organischen Phasen werden vereinigt, gegen NaClaq ausgeschüttelt und über MgSO4 getrocknet. Anschließend wird die Mischung einrotiert und in Essigsäureethylester umkristallisiert. Ausbeute: 250 mg (84%), farbloser Feststoff.In 5 mL dry DMF are added 2-acetamidobenzo [d] thiazole-6-carboxylic acid (200 mg, 0.85 mmol, 1 eq), tert-butyl carbazide (123.5 mg, 0.94 mmol, 1.1 eq) and EDCI ( Ethylene dichloride) (195.5 mg, 1.02 mmol, 1.2 eq) and stirred briefly. Then HOBt · H 2 O is added and stirred overnight at room temperature. Thereafter, the reaction mixture is added to water and shaken out against ethyl acetate. The organic phases are combined, shaken out against NaCl aq and dried over MgSO 4 . The mixture is then concentrated by rotary evaporation and recrystallized in ethyl acetate. Yield: 250 mg (84%), colorless solid.

Schritt 6:Step 6:

Eine Lösung aus tert-Butyl2-(2-acetamidobenzo[d]thiazol-6-carbonyl)hydrazincarboxylat (100 mg, 0,28 mmol, 1 eq) in 1 mL Trifluoressigsäure wird 1 h bei Raumtemperatur gerührt. Anschließend wird die Trifluoressigsäure abrotiert und der Feststoff in Ethanol umkristallisiert. Ausbeute: 65 mg (94%), farbloser Feststoff.A solution of tert-butyl 2- (2-acetamidobenzo [d] thiazole-6-carbonyl) hydrazinecarboxylate (100 mg, 0.28 mmol, 1 eq) in 1 mL trifluoroacetic acid is stirred for 1 h at room temperature. Subsequently, the trifluoroacetic acid is spun off and the solid recrystallized in ethanol. Yield: 65 mg (94%), colorless solid.

Beispiel 8: Synthese der Vorstufen für die Verbindung 23 und 85Example 8: Synthesis of Precursors for Compound 23 and 85

Schritt 1:Step 1:

Zu einer Lösung aus 3,4-Dihydroxybenzoesäure (2,0 g, 13 mmol, 1 eq) in 25 mL MeOH wird tropfenweise SOCl2 (1,88 mL, 26 mmol, 2 eq) über 1 h bei 0°C zugegeben. Die Lösung wird 12 h bei 50°C gerührt. Es werden 30 mL Wasser zugegeben und das MeOH wird abrotiert. Die wässrige Phase wird mit gesättigter NaHCO3-Lösung auf pH 6 gestellt und anschließend gegen Essigsäureethylester ausgeschüttelt. Die organische Phase wird gegen NaClaq ausgeschüttelt und über MgSO4 getrocknet. Ausbeute: 2,1 g (97%), weißer FeststoffTo a solution of 3,4-dihydroxybenzoic acid (2.0 g, 13 mmol, 1 eq) in 25 mL MeOH is added dropwise SOCl 2 (1.88 mL, 26 mmol, 2 eq) over 1 h at 0 ° C. The solution is stirred for 12 h at 50.degree. 30 mL of water are added and the MeOH is removed by rotary evaporation. The aqueous phase is adjusted to pH 6 with saturated NaHCO 3 solution and then extracted by shaking with ethyl acetate. The organic phase is shaken out against NaCl aq and dried over MgSO 4 . Yield: 2.1 g (97%), white solid

Schritt 2:Step 2:

Methyl-3,4-dihydroxybenzoat (0,8 g, 4,75 mmol, 1 eq) und K2CO3 (0,65 g, 4,75 mmol, 1 eq) werden in trockenes Aceton gegeben und 15 Minuten bei Raumtemperatur gerührt. Anschließend wird die Lösung mit Epibromohydrin (0,40 mL, 4,75 mmol, 1 eq) versetzt und über Nacht bei 70°C gerührt. Es werden 20 mL Wasser zugegeben und die wässrige Phase gegen Essigsäureethylester ausgeschüttelt. Die organische Phase wird gegen NaClaq ausgeschüttelt und über Na2SO4 getrocknet. Anschließend wird die Mischung einrotiert und mittels Säulenchromatographie gereinigt (Dichlormethan-Essigsäureethylester = 4:1). Ausbeute: 1.01 g (95%), farbloses Öl.Methyl 3,4-dihydroxybenzoate (0.8 g, 4.75 mmol, 1 eq) and K 2 CO 3 (0.65 g, 4.75 mmol, 1 eq) are added to dry acetone and stirred for 15 minutes at room temperature touched. Subsequently, the solution is mixed with epibromohydrin (0.40 mL, 4.75 mmol, 1 eq) and stirred overnight at 70.degree. 20 mL of water are added and the aqueous phase is extracted by shaking with ethyl acetate. The organic phase is shaken out against NaCl aq and dried over Na 2 SO 4 . The mixture is then concentrated by rotary evaporation and purified by column chromatography (dichloromethane-ethyl acetate = 4: 1). Yield: 1.01 g (95%), colorless oil.

Schritt 2 bei einer enantiomerenreinen Verbindung:Step 2 for an enantiomerically pure compound:

Methyl-3,4-dihydroxybenzoat (1,0 g, 6 mmol, 1 eq), (2S)-(+)-Glycidyl-tosylat (1,37 g, 6 mmol, 1 eq) und K2CO3 (0,99 g, 7,2 mmol, 1,2 eq) werden in 15 mL DMF gegeben. Die Mischung wird für 5 h unter Argonatmosphäre bei 60°C gerührt. Es werden 30 mL Wasser zugegeben und die wässrige Phase gegen Essigsäureethylester ausgeschüttelt. Die organische Phase wird gegen NaClaq ausgeschüttelt und über Na2SO4 getrocknet. Anschließend wird die Mischung einrotiert und mittels Säulenchromatographie gereinigt (Dichlormethan-Essigsäureethylester = 4:1). Ausbeute: 1,25 g (93%), farbloses Öl.Methyl 3,4-dihydroxybenzoate (1.0 g, 6 mmol, 1 eq), (2S) - (+) - glycidyl tosylate (1.37 g, 6 mmol, 1 eq) and K 2 CO 3 (0 , 99 g, 7.2 mmol, 1.2 eq) are placed in 15 mL DMF. The mixture is stirred for 5 h under argon atmosphere at 60 ° C. 30 mL of water are added and the aqueous phase is extracted by shaking with ethyl acetate. The organic Phase is shaken out against NaCl aq and dried over Na 2 SO 4 . The mixture is then concentrated by rotary evaporation and purified by column chromatography (dichloromethane-ethyl acetate = 4: 1). Yield: 1.25 g (93%), colorless oil.

Schritt 3:Step 3:

Zu einer Suspension aus NaH (115 mg, 4,81 mmol, 1,2 eq) in 5 mL trockenem Tetrahydrofuran wird bei 0°C Methyl-3-(hydroxymethyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-carboxylat (900 mg, 4,01 mmol, 1 eq) zugegeben. Die Mischung wird 30 Minuten bei Raumtemperatur gerührt und anschließend mit Mel (374 μL, 6,01 mmol, 1,5 eq) versetzt. Die Reaktionsmischung wird 48 h bei Raumtemperatur gerührt und anschließend mit 10 mL Wasser versetzt. Die wässrige Phase wird gegen Essigsäureethylester ausgeschüttelt. Die organische Phase wird gegen NaClaq ausgeschüttelt und über MgSO4 getrocknet. Anschließend wird die Mischung einrotiert und mittels Säulenchromatographie gereinigt (Dichlormethan-Essigsäureethylester = 20:1). Ausbeute: 678 mg (71%), farbloses Öl.To a suspension of NaH (115 mg, 4.81 mmol, 1.2 eq) in 5 mL dry tetrahydrofuran at 0 ° C is added methyl 3- (hydroxymethyl) -2,3-dihydrobenzo [b] [1,4] dioxin-6-carboxylate (900 mg, 4.01 mmol, 1 eq). The mixture is stirred for 30 minutes at room temperature and then treated with Mel (374 μL, 6.01 mmol, 1.5 eq). The reaction mixture is stirred for 48 h at room temperature and then treated with 10 mL of water. The aqueous phase is shaken out against ethyl acetate. The organic phase is shaken out against NaCl aq and dried over MgSO 4 . The mixture is then concentrated by rotary evaporation and purified by column chromatography (dichloromethane-ethyl acetate = 20: 1). Yield: 678 mg (71%), colorless oil.

Beispiel 9 Synthese der Vorstufen für die Verbindungen 52–56 und der Verbindung 86Example 9 Synthesis of Precursors for Compounds 52-56 and Compound 86

Schritt 1:Step 1:

Methyl 2-aminoisonicotinat (0,200 g, 1,31 mmol, 1 eq) wird in 2 mL Essigsäureanhydrid bei 105°C für 1–2 h gerührt. Die Mischung wird auf Raumtemperatur abgekühlt und der sich absetzende Feststoff abfiltriert und mit Wasser gewaschen. Der Feststoff wurde ein weiteres Mal in Wasser umkristallisiert. Ausbeute: 226 mg (89%), gelber Feststoff.Methyl 2-aminoisonicotinate (0.200 g, 1.31 mmol, 1 eq) is stirred in 2 mL acetic anhydride at 105 ° C for 1-2 h. The mixture is cooled to room temperature and the settling solid is filtered off and washed with water. The solid was recrystallized once more in water. Yield: 226 mg (89%), yellow solid.

Beispiel 10: Synthese nicht kommerzieller BiphenyleExample 10: Synthesis of non-commercial biphenyls

Schritt 1: Kupplung des aromatischen Rings mittels Suzuki-ReaktionStep 1: Coupling of the aromatic ring by Suzuki reaction

Zu einer Losung aus Brombenzol (785 mg, 5 mmol, 1 eq) in 15 mL Toluol/Ethanol (1:1) wird Pd(PPh3)4 (0,17 g, 0,14 mmol, 0,03 eq) zugegeben und die Mischung unter Argonatmosphäre gerührt. Anschließend werden 7,5 mL 2 N Na2CO3-Lösung und p-Tolylboronsäure (0,80 g, 6 mmol, 1,2 eq) zugegeben. Die Mischung wird 1–2 Tage bei 80°C gerührt. Anschließend wird sie mit Wasser versetzt. Die wässrige Phase wird gegen Essigsäureethylester ausgeschüttelt. Die organische Phase wird gegen NaClaq ausgeschüttelt und über MgSO4 getrocknet. Anschließend wird die Mischung einrotiert und mittels Säulenchromatographie gereinigt (Cyclohexan-Essigsäureethylester). Ausbeute: wurde nicht bestimmt. Substanz wurde direkt weiter umgesetzt.To a solution of bromobenzene (785 mg, 5 mmol, 1 eq) in 15 mL toluene / ethanol (1: 1) is added Pd (PPh 3 ) 4 (0.17 g, 0.14 mmol, 0.03 eq) and the mixture stirred under argon atmosphere. Subsequently, 7.5 ml of 2N Na 2 CO 3 solution and p-tolylboronic acid (0.80 g, 6 mmol, 1.2 eq) are added. The mixture is stirred for 1-2 days at 80 ° C. Then it is mixed with water. The aqueous phase is shaken out against ethyl acetate. The organic phase is shaken out against NaCl aq and dried over MgSO 4 . The mixture is then concentrated by rotary evaporation and purified by column chromatography (cyclohexane-ethyl acetate). Yield: was not determined. Substance was directly further reacted.

Schritt 2: Bromierung an der benzylischen PositionStep 2: Bromination at the benzylic position

Zu einer Lösung aus 4-Methylbiphenyl (201 mg, 1,2 mmol, 1 eq) in 12 mL CCl4 werden NBS (N-Bromsuccinimid) (202 mg, 1,14 mmol, 0,95 eq) und AIBN [Azo-bis-(isobutyronitril)] (6 mg, 0,037 mmol, 0,03 eq) zugegeben. Die Mischung wird unter Rückfluss bei 80°C für 2 Tage gerührt. Anschließend wird die Reaktionsmischung mit Wasser versetzt. Die wässrige Phase wird gegen Essigsäureethylester ausgeschüttelt. Die organische Phase wird gegen NaClaq ausgeschüttelt und über MgSO4 getrocknet. Anschließend wird die Mischung einrotiert und mittels Säulenchromatographie gereinigt (Cyclohexan-Essigsäureethylester). Ausbeute: wurde nicht bestimmt. Substanz wurde direkt weiter umgesetzt.To a solution of 4-methylbiphenyl (201 mg, 1.2 mmol, 1 eq) in 12 mL CCl 4 are added NBS (N-bromosuccinimide) (202 mg, 1.14 mmol, 0.95 eq) and AIBN [azo] bis (isobutyronitrile)] (6 mg, 0.037 mmol, 0.03 eq). The mixture is stirred at reflux at 80 ° C for 2 days. Subsequently, the reaction mixture is mixed with water. The aqueous phase is shaken out against ethyl acetate. The organic phase is shaken out against NaCl aq and dried over MgSO 4 . The mixture is then concentrated by rotary evaporation and purified by column chromatography (cyclohexane-ethyl acetate). Yield: was not determined. Substance was directly further reacted.

Verbindung 85 wurde gemäß Beispiel 5 hergestellt.Compound 85 was prepared according to Example 5.

Verbindung 85: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 3.40 (1H, s, br), 3.59 (2H, m), 4.04 (1H, m), 4.15 (1H, m), 4.34 (1H, dd, J = 11.5 Hz, J = 2.3 Hz), 4.57 (2H, s) 6.98 (1H, d, J = 8.3 Hz), 7.35 (2H, m), 7.53 (6H, m), 7.70 (1H, td, J = 7.7 Hz, J = 1.3 Hz), 7.85 (1H, dd, J = 7.7 Hz, J = 0.9 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.4, 59.6, 65.4, 73.7, 110.1, 115.0, 116.1, 117.9, 118.5, 119.8, 128.2, 128.8, 129.3, 130.1, 133.4, 133.8, 137.1, 137.4, 143.5, 144.0, 146.2, 162.5, 164.9; MS: Molekülpeak: m/z = 457, rel. Häufigkeit 38% Basispeak: m/z = 192; HPLC: 7.48 MinutenCompound 85: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 3.40 (1H, s, br), 3.59 (2H, m), 4.04 (1H, m), 4.15 (1H, m ), 4.34 (1H, dd, J = 11.5 Hz, J = 2.3 Hz), 4.57 (2H, s) 6.98 (1H, d, J = 8.3 Hz), 7.35 (2H, m), 7.53 (6H, m) , 7.70 (1H, td, J = 7.7 Hz, J = 1.3 Hz), 7.85 (1H, dd, J = 7.7 Hz, J = 0.9 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.4, 59.6, 65.4, 73.7, 110.1, 115.0, 116.1, 117.9, 118.5, 119.8, 128.2, 128.8, 129.3, 130.1, 133.4, 133.8 , 137.1, 137.4, 143.5, 144.0, 146.2, 162.5, 164.9; MS: Molecular peak: m / z = 457, rel. Frequency 38% base peak: m / z = 192; HPLC: 7.48 minutes

Verbindung 86 wurde bis Stufe 4 gemäß Beispiel 1 hergestellt.Compound 86 was prepared to Stage 4 of Example 1.

Verbindung 86: 1H NMR (500 MHz, DMSO-d6): δ [ppm] = 12.56 (s, 1H), 8.64 (d, J = 1.5 Hz, 1H), 8.01 (dd, J = 8.5, 1.8 Hz, 1H), 7.94 (dd, J = 7.8, J = 1.1 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.78 (td, J = 7.7, 1.4 Hz, 1H), 7.67 (d, J = 8.3 Hz, 2H), 7.63-7.55 (m, 4H), 4.69 (s, 2H), 2.23 (s, 3H); 13C NMR (126 MHz, DMSO): δ [ppm] = 169.77, 165.44, 162.91, 160.79, 151.12, 143.97, 137.37, 137.18, 133.83, 133.50, 132.43, 130.07, 129.41, 128.93, 128.25, 124.39, 121.08, 120.66, 118.49, 117.83, 110.09, 35.55, 22.78; MS: Molekülpeak = 483; rel. Häufigkeit 30% Basispeak = 192; HPLC: 7.76 MinutenCompound 86: 1 H NMR (500 MHz, DMSO-d 6 ): δ [ppm] = 12.56 (s, 1H), 8.64 (d, J = 1.5 Hz, 1H), 8.01 (dd, J = 8.5, 1.8 Hz , 1H), 7.94 (dd, J = 7.8, J = 1.1 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.78 (td, J = 7.7, 1.4 Hz, 1H), 7.67 (d, J = 8.3Hz, 2H), 7.63-7.55 (m, 4H), 4.69 (s, 2H), 2.23 (s, 3H); 13 C NMR (126 MHz, DMSO): δ [ppm] = 169.77, 165.44, 162.91, 160.79, 151.12, 143.97, 137.37, 137.18, 133.83, 133.50, 132.43, 130.07, 129.41, 128.93, 128.25, 124.39, 121.08, 120.66 , 118.49, 117.83, 110.09, 35.55, 22.78; MS: molecular peak = 483; rel. Frequency 30% base peak = 192; HPLC: 7.76 minutes

Verbindung 87 wurde bis Stufe 3 gemäß Beispiel 1 hergestellt.Compound 87 was prepared to Stage 3 according to Example 1.

Verbindung 87: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 6.14 (2H, s), 7.10 (1H, d, J = 8.1 Hz), 7.33 (1H, d, J = 1.6 Hz), 7.42 (1H, dd, J = 8.1 Hz, J = 1.6 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 102.1, 105.6, 109.1, 116.1, 121.5, 148.1, 150.6, 160.3, 177.2; MS: Molekülpeak: m/z = 222; rel. Häufigkeit 100% Basispeak: m/z 222; HPLC: 4.90 MinutenCompound 87: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 6.14 (2H, s), 7.10 (1H, d, J = 8.1 Hz), 7.33 (1H, d, J = 1.6 Hz), 7.42 (1H, dd, J = 8.1 Hz, J = 1.6 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 102.1, 105.6, 109.1, 116.1, 121.5, 148.1, 150.6, 160.3, 177.2; MS: Molecular peak: m / z = 222; rel. Frequency 100% base peak: m / z 222; HPLC: 4.90 minutes

Verbindungen 88 bis 92 wurden gemäß Beispiel 1 hergestellt. Compounds 88 to 92 were prepared according to Example 1.

Verbindung 88: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.54 (2H, s), 6.16 (2H, s), 7.10 (1H, d, J = 8.1 Hz), 7.43 (3H, m), 7.50 (1H, dd, J = 8.1 Hz, J = 1.8 Hz), 7.54 (2H, m); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.1, 102.1, 106.1, 109.1, 116.6, 120.8, 121.7, 131.2, 131.4, 136.4, 148.1, 150.5, 162.4, 165.1; MS: Molekülpeak: m/z = 390/392; rel. Häufigkeit 20/22% Basispeak: m/z = 147; HPLC: 8.11 Minuten Compound 88: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.54 (2H, s), 6.16 (2H, s), 7.10 (1H, d, J = 8.1 Hz), 7.43 ( 3H, m), 7.50 (1H, dd, J = 8.1 Hz, J = 1.8 Hz), 7.54 (2H, m); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.1, 102.1, 106.1, 109.1, 116.6, 120.8, 121.7, 131.2, 131.4, 136.4, 148.1, 150.5, 162.4, 165.1; MS: Molecular peak: m / z = 390/392; rel. Frequency 20/22% Base peak: m / z = 147; HPLC: 8.11 minutes

Verbindung 89: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 3.73 (3H, s), 4.53 (2H, s), 6.16 (2H, s), 6.86 (1H, m), 7.04 (2H, m), 7.12 (1H, d, J = 8.1 Hz), 7.26 (1H, t, J = 7.8 Hz), 7.44 (1H, d, J = 1.6 Hz), 7.52 (1H, dd, J = 8.1 Hz, J = 1.7 Hz); 13C-NMR (DMSO-d6, 125 MHz):_δ [ppm] = 35.8, 55.0, 102.0, 106.2, 109.1, 113.2, 114.6, 116.6, 121.1, 121.7, 129.6, 138.1, 148.1, 150.4, 159.2, 162.6, 165.0; MS: Molekülpeak: m/z = 342; rel. Häufigkeit 51% Basispeak: m/z = 121; HPLC: 7.52 MinutenCompound 89: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 3.73 (3H, s), 4.53 (2H, s), 6.16 (2H, s), 6.86 (1H, m), 7.04 (2H, m), 7.12 (1H, d, J = 8.1 Hz), 7.26 (1H, t, J = 7.8 Hz), 7.44 (1H, d, J = 1.6 Hz), 7.52 (1H, dd, J = 8.1 Hz, J = 1.7 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.8, 55.0, 102.0, 106.2, 109.1, 113.2, 114.6, 116.6, 121.1, 121.7, 129.6, 138.1, 148.1, 150.4, 159.2, 162.6 , 165.0; MS: Molecular peak: m / z = 342; rel. Frequency 51% base peak: m / z = 121; HPLC: 7.52 minutes

Verbindung 90: 1 H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.64 (2H, s), 6.16 (2H, s), 7.11 (1H, d, J = 8.1 Hz), 7.42 (1H, d, J = 1.6 Hz), 7.48 (1H, dd, J = 8.1 Hz, J = 1.7 Hz) 7.68 (2H, d, J = 8.3 Hz), 7.82 (2H, d, J = 8.3 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.2, 102.1, 106.1, 109.1, 110.4, 116.5, 118.6,,121.7, 130.0, 132.4, 142.8, 148.1, 150.5, 162.2, 165.2; MS: Molekülpeak: m/z = 337; rel. Häufigkeit 55% Basispeak: m/z = 149; HPLC: 7.09 MinutenCompound 90: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.64 (2H, s), 6.16 (2H, s), 7.11 (1H, d, J = 8.1 Hz), 7.42 ( 1H, d, J = 1.6 Hz), 7.48 (1H, dd, J = 8.1 Hz, J = 1.7 Hz) 7.68 (2H, d, J = 8.3 Hz), 7.82 (2H, d, J = 8.3 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.2, 102.1, 106.1, 109.1, 110.4, 116.5, 118.6,, 121.7, 130.0, 132.4, 142.8, 148.1, 150.5, 162.2, 165.2; MS: Molecular peak: m / z = 337; rel. Frequency 55% base peak: m / z = 149; HPLC: 7.09 minutes

Verbindung 91; 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.71 (2H, s), 6.16 (2H, s), 7.10 (1H, d, J = 8.1 Hz), 7.42 (1H, d, J = 1.6 Hz), 7.49 (1H, dd, J = 8.1 Hz, J = 1.6 Hz), 7.65 (1H, t, J = 7.9 Hz), 7.96 (1H, d, J = 7.9 Hz), 8.15 (1H, dd, J = 8.2 Hz, J = 2.2 Hz), 8.40 (1H, t, J = 1.9 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 34.7, 102.1, 106.1, 109.1, 116.5, 121.6, 122.6, 123.7, 130.0, 135.7, 139.6, 147.6, 148.1, 150.4, 162.2, 165.2; MS: Molekülpeak: m/z = 357; rel. Häufigkeit 60% Basispeak: m/z = 149; HPLC: 7.54 MinutenCompound 91; 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.71 (2H, s), 6.16 (2H, s), 7.10 (1H, d, J = 8.1 Hz), 7.42 (1H, d , J = 1.6 Hz), 7.49 (1H, dd, J = 8.1 Hz, J = 1.6 Hz), 7.65 (1H, t, J = 7.9 Hz), 7.96 (1H, d, J = 7.9 Hz), 8.15 ( 1H, dd, J = 8.2 Hz, J = 2.2 Hz), 8.40 (1H, t, J = 1.9 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 34.7, 102.1, 106.1, 109.1, 116.5, 121.6, 122.6, 123.7, 130.0, 135.7, 139.6, 147.6, 148.1, 150.4, 162.2, 165.2 ; MS: Molecular peak: m / z = 357; rel. Frequency 60% base peak: m / z = 149; HPLC: 7.54 minutes

Verbindung 92; 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.66 (2H, s), 6.15 (2H, s), 7.11 (1H, d, J = 8.1 Hz), 7.45 (1H, d, J = 1.6 Hz), 7.51 (1H, dd, J = 8.1 Hz, J = 1.7 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.61 (2H, m), 7.64 (2H, d, J = 8.2 Hz), 7.78 (1H, m), 7.95 (1H, d, J = 7.6 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.5, 102.1, 106.1, 109.1, 110.1, 116.6, 118.5, 121.7, 128.3, 128.9, 129.4, 130.1, 133.5, 133.8, 137.2, 137.4, 144.0, 148.1, 150.4, 162.6, 165.1; MS: Molekülpeak: m/z = 413; rel. Häufigkeit 40% Basispeak: m/z = 192; HPLC: 8.36 MinutenConnection 92; 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.66 (2H, s), 6.15 (2H, s), 7.11 (1H, d, J = 8.1 Hz), 7.45 (1H, d , J = 1.6 Hz), 7.51 (1H, dd, J = 8.1 Hz, J = 1.7 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.61 (2H, m), 7.64 (2H, d, J = 8.2 Hz), 7.78 (1H, m), 7.95 (1H, d, J = 7.6 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.5, 102.1, 106.1, 109.1, 110.1, 116.6, 118.5, 121.7, 128.3, 128.9, 129.4, 130.1, 133.5, 133.8, 137.2, 137.4 , 144.0, 148.1, 150.4, 162.6, 165.1; MS: Molecular peak: m / z = 413; rel. Frequency 40% base peak: m / z = 192; HPLC: 8.36 minutes

Verbindung 93 wurde gemäß Beispiel 2 hergestellt.Compound 93 was prepared according to Example 2.

Verbindung 93: 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.31 (2H, m), 4.34 (2H, m), 4.47 (2H, d, J = 5.9 Hz), 4.62 (2H, s), 7.05 (1H, d, J = 8.4 Hz), 7.23 (1H, m), 7.32 (4H, m), 7.40 (1H, d, J = 2.0 Hz), 7.43 (1H, dd, J = 8.3 Hz, J = 2.0 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.86 (2H, d, J = 8.2 Hz), 9.01 (1H, t, J = 5.9 Hz); 13C-NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.4, 42.6, 64.1, 64.4, 115.1, 115.8, 118.3, 119.8, 126.7, 127.3, 127.5, 128.4, 128.8, 133.7, 139.6, 140.1, 143.8, 146.7, 162.4, 165.0, 165.8; MS: Molekülpeak: m/z = 459; rel. Häufigkeit 43% Basispeak: m/z = 161; HPLC: 7.66 MinutenCompound 93: 1 H-NMR (DMSO-d 6 , 500 MHz): δ [ppm] = 4.31 (2H, m), 4.34 (2H, m), 4.47 (2H, d, J = 5.9 Hz), 4.62 ( 2H, s), 7.05 (1H, d, J = 8.4 Hz), 7.23 (1H, m), 7.32 (4H, m), 7.40 (1H, d, J = 2.0 Hz), 7.43 (1H, dd, J = 8.3 Hz, J = 2.0 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.86 (2H, d, J = 8.2 Hz), 9.01 (1H, t, J = 5.9 Hz); 13 C-NMR (DMSO-d 6 , 125 MHz): δ [ppm] = 35.4, 42.6, 64.1, 64.4, 115.1, 115.8, 118.3, 119.8, 126.7, 127.3, 127.5, 128.4, 128.8, 133.7, 139.6, 140.1 , 143.8, 146.7, 162.4, 165.0, 165.8; MS: Molecular peak: m / z = 459; rel. Frequency 43% base peak: m / z = 161; HPLC: 7.66 minutes

Beispiel 11: GSK-3β in vitro AssayExample 11: GSK-3β in vitro assay

Gereinigte GSK-3β (0.5 μg) wird in einer Reaktionsmischung aus 50 mM Tris pH 7.3, 10 mM MgAc2, 0.01% β-mercaptoethanol, 32P[γ-ATP] (100 μM, 0.5 μCi/Assay) und 100 μM Peptidsubstrat pIRS-1 (RREGGMSRPAS(p)VDG) inkubiert. Die erfindungsgemäßen Verbindungen der allgemeinen Formel (I) werden bei verschiedenen Konzentrationen zugegeben (1, 10 und 100 μM), und die Reaktionsmischung für 15 min bei 30°C inkubiert. Die Reaktion wird gestoppt, auf p81 Papier (Whathman) gespottet, mit 10 mM Phosphorsäure gewaschen, und mittels Strahlungsdetektor vermessen. Die GSK-3β-Aktivität wird errechnet aus dem prozentualen Anteil der GSK-3β-Aktivität in Anwesenheit des Inhibitors, im Verhältnis zur GSK-3β-Aktivität in Abwesenheit eines Inhibitors, welche auf 100% festgelegt wird. Die Tabelle 1 zeigt die hierbei errechneten IC50 Werte für verschieden Verbindungen der allgemeinen Formel (I). Tabelle 1: Ergebnis des GSK-3β in vitro Assay IC50 in μM/(GSK 3) Verbindung > 5 4 ≤ 5 3, 8, 10, 45, 46, 54, 75 und 89 ≤ 1 5, 11, 25, 27, 43, 52, 53, 55, 56, 80, 91, 92 Purified GSK-3β (0.5 μg) is dissolved in a reaction mixture of 50 mM Tris pH 7.3, 10 mM MgAc 2 , 0.01% β-mercaptoethanol, 32 P [γ-ATP] (100 μM, 0.5 μCi / assay) and 100 μM peptide substrate pIRS-1 (RREGGMSRPAS (p) VDG). The compounds of the general formula (I) according to the invention are added at different concentrations (1, 10 and 100 μM) and the reaction mixture is incubated for 15 min at 30 ° C. The reaction is stopped, spotted on p81 paper (Whathman), washed with 10 mM phosphoric acid, and measured by means of a radiation detector. GSK-3β activity is calculated as the percentage of GSK-3β activity in the presence of the inhibitor relative to GSK-3β activity in the absence of inhibitor set at 100%. Table 1 shows the IC 50 values calculated here for various compounds of the general formula (I). Table 1: Result of the GSK-3β in vitro assay IC 50 in μM / (GSK 3) connection > 5 4 ≤ 5 3, 8, 10, 45, 46, 54, 75 and 89 ≤ 1 5, 11, 25, 27, 43, 52, 53, 55, 56, 80, 91, 92

Beispiel 12: In Vivo Aktivität in Zebrafisch-Embryos.Example 12: In vivo activity in zebrafish embryos.

Für die Evaluation der Verbindungen 92, 11 und 43 in vivo wurde der wt-Zebrafisch verwendet. Die Embryos werden gesammelt und in 24-Wellplatten platziert, zehn Embryos pro Well und in E2-Medium bei 28°C inkubiert. Die Verbindungen werden bei 5 hpf (50% Epibolie) zugegeben, und die Embryos in einer Lösung aus E2-Medium und zu testender Verbindung bis zu 2 Tagen inkubiert. Die Phänotypen werden mittels Axio Scope. A1 Mikroskop von Carl Zeiss 44–48 hpf untersucht. Die Ergebnisse zeigt Abbildung 3. Die Verbindung 92 verursacht bei einer Konzentration von 0,5 μM einen Phänotyp ohne Augen und bei 1,0 μM einen gebogenen bzw. entstellten Schwanz. Die Verbindung 11 verursacht in einer Konzentration von 2,5 μM einen Phänotyp mit einer undefinierten Augenpigmentierung und einen gebogenen bzw. entstellten Schwanz. Verbindung 43 verursacht bei einer Konzentration von 20 μM einen Phänotyp ohne Augen und einen gebogenen Schwanz.For the evaluation of compounds 92, 11 and 43 in vivo, the wt zebrafish was used. The embryos are collected and placed in 24-well plates, ten embryos per well and incubated in E2 medium at 28 ° C. The compounds are added at 5 hpf (50% epibole) and the embryos are incubated in a solution of E2 medium and compound to be tested for up to 2 days. The phenotypes are analyzed using Axio Scope. A1 microscope from Carl Zeiss 44-48 hpf examined. The results are shown in Figure 3. Compound 92 causes a phenotype without eyes at 0.5 μM and a bent or dislocated tail at 1.0 μM. Compound 11 at a concentration of 2.5 μM causes a phenotype with undefined eye pigmentation and a bent tail. Compound 43 causes a phenotype without eyes and a curved tail at a concentration of 20 μM.

Der Zebrafisch ist ein mittlerweile weitverbreiteter Modelorganismus. Zebrafisch-Embryos sind optisch transparent und machen es somit möglich funktionelle und morphologische Änderungen zu erkennen ohne das Versuchstier zu präparieren bzw. zu täten. Seine morphologische und physiologische Ähnlichkeit zu Säugern und die erleichterte Analyse von phänotypischen Merkmalen sind nur zwei von vielen nennenswerten Vorteilen. Desweiteren kann man durch die hohe Fertilität des Zebrafischs schnell und kostengünstig potentielle Verbindungen untersuchen und validieren.1 The zebrafish is a meanwhile widespread model organism. Zebrafish embryos are optically transparent and thus make it possible to detect functional and morphological changes without preparing or doing the experimental animal. Its morphological and physiological similarity to mammals and the ease of analysis of phenotypic traits are just two of many noteworthy advantages. Furthermore, the high fertility of the zebrafish allows quick and cost-effective investigation and validation of potential compounds. 1

Die ersten Schritte einer sich entwickelnden Tautopathie führen zu tau-Phosphorylierung und anschließender Aggregation. Diese frühen Krankheitsstadien verlaufen zumeist sehr langsam. Die frühen Stadien dieser Erkrankungen sind daher in transgenen Mäusen nur sehr schwer zu untersuchen, da es nicht möglich ist Bilder von Zellen über die langen Zeiträume der ersten Stadien zu vergleichen. Darüber hinaus sind Wirbeltiere als in-vivo-Modelle für schnelle Hochdurchsatz-Screenings für Inhibitoren einer tau-Pathologie nicht verfügbar. Daher wurde der Zebrafisch als Modellorganismus für die Untersuchung von Tautopathien und insbesondere zur Evaluierung möglicher Medikamente etabliert.The first steps of a developing tautopathy lead to tau phosphorylation and subsequent aggregation. These early disease stages are usually very slow. The early stages of these diseases are therefore very difficult to study in transgenic mice, as it is not possible to compare images of cells over the long periods of the first stages. In addition, vertebrates are not available as in vivo models for rapid high-throughput screenings for tau pathology inhibitors. Therefore, the zebrafish has been established as a model organism for the study of tautopathies and in particular for the evaluation of possible drugs.

GSK-3 ist eine Komponente des Wnt-Signalwegs, welcher eine wichtige Rolle in der Entwicklung von Wirbeltier-Embryonen spielt. Eine Störung dieses Signalwegs durch eine Inhibition der GSK-3 führt zu charakteristischen Merkmalen (Phänotypen) in der Entwicklung des Zebrafischs. Diese Entwicklungsstörung kann beim Zebrafisch-Embryo z. B. zu einem augenlosen Phänotyp, zu einem verkrümmten Rücken oder zu multipler Ohrenbildung führen.3–4 Sofern diese Phänotypen beobachtet werden können, deutet dies auf eine wahrscheinliche Verwendung der Verbindungen als Therapeutikum hin, da sich daraus ableiten lässt, dass eine Inhibition von GSK-3 in vivo stattfindet und die Substanzen zellpermeabel und bioverfügbar sind. Die in vivo Effekte der Verbindung 92 wurden bereits bei 0.5 μM beobachtet. Im Vergleich zu anderen Publikationen ist dies eine geringe Konzentration eines GSK-3 Inhibitors. Daraus lässt sich schließen, dass Verbindung 92 ein sehr potenter Inhibitor für GSK-3 ist und zudem sehr gut bioverfügbar und zellpermeabel ist.GSK-3 is a component of the Wnt signaling pathway that plays an important role in the development of vertebrate embryos. Disruption of the GSK-3 pathway leads to characteristic features (phenotypes) in the development of the zebrafish. This developmental disorder can zebrafish embryo z. B. lead to an eyeless phenotype, a crooked back or multiple ear formation. 3-4 Insofar as these phenotypes can be observed, this indicates a probable use of the compounds as a therapeutic, since it can be deduced that GSK-3 is inhibited in vivo and the substances are cell-permeable and bioavailable. The in vivo effects of Compound 92 were already observed at 0.5 μM. Compared to other publications, this is a low concentration of a GSK-3 inhibitor. It can be concluded that compound 92 is a very potent inhibitor of GSK-3 and is also very bioavailable and cell-permeable.

Eventuelle Nebenwirkungen durch die Beeinflussung der embryonalen Entwicklung, können zunächst vernachlässigt werden, da dies nur die Zulassung eines Wirkstoffs zu einer Behandlung einer Patientin während einer Schwangerschaft betrifft. Insbesondere Tautopathien betreffen jedoch vor allem ältere Menschen. Zudem sind diese Erkrankungen so schwerwiegend, dass allgemein eine Behandlung dieser Erkrankung Vorrang haben sollte.Possible side effects of influencing embryonic development can be neglected at first as this only concerns the authorization of a drug for treatment of a patient during pregnancy. Tautopathies, however, mainly affect the elderly. In addition, these diseases are so severe that generally treatment of this disease should prevail.

Claims (6)

Verbindungen der allgemeinen Formel (I)
Figure 00680001
worin R1 für einen der folgenden Reste steht:
Figure 00680002
Figure 00690001
Figure 00700001
Figure 00710001
Figure 00720001
Figure 00730001
Figure 00740001
R2 für einen der folgenden Reste steht -X15,
Figure 00750001
Figure 00760001
Figure 00770001
Figure 00780001
Figure 00790001
Figure 00800001
R3, R4, R5, R6, R7, R10, R11, R12, R13 unabhängig voneinander folgende Reste bedeuten: -R14, -R15, -R16, -R17, -R18, -R19, -R20, -(CH2)n-R14, -(CH2)n-R15, -(CH2)n-R16, -(CH2)n-R17, -(CH2)n-R18, -(CH2)n-R19, -(CH2)n-R20;
Figure 00800002
Figure 00810001
-H, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, cyclo-C6H11, cyclo-C7H13, cyclo-C8H15, -Ph, -CH2-Ph, -CH2-CH2-Ph, -CH2-CH2-CH2-Ph, -CH=CH-Ph, -C≡C-Ph, -CPh3, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -C5H11, -CH(CH3)-C3H7, -CH2-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2, -C(CH3)2-C2H5, -CH2-C(CH3)3, -CH(C2H5)2, -C2H4-CH(CH3)2, -C6H13, -C7H15, -C8H17, -C3H6-CH(CH3)2, -C2H4-CH(CH3)-C2H5, -CH(CH3)-C4H9, -CH2-CH(CH3)-C3H7, -CH(CH3)-CH2-CH(CH3)2, -CH(CH3)-CH(CH3)-C2H5, -CH2-CH(CH3)-CH(CH3)2, -CH2-C(CH3)2-C2H5, -C(CH3)2-C3H7, -C(CH3)2-CH(CH3)2, -C2H4-C(CH3)3, -CH(CH3)-C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C2H4-CH=CH2, -CH2-CH=CH-CH3, -CH=CH-C2H5, -CH2-C(CH3)=CH2, -CH(CH3)-CH=CH, -CH=C(CH3)2, -C(CH3)=CH-CH3, -CH=CH-CH=CH2, -C3H6-CH=CH2, -C2H4-CH=CH-CH3, -CH2-CH=CH-C2H5, -CH=CH-C3H7, -CH2-CH=CH-CH=CH2, CH=CH-CH=CH-CH3, -CH=CH-CH2-CH=CH2, -C(CH3)=CH-CH=CH2, -CH=C(CH3)-CH=CH2, -CH=CH-C(CH3)=CH2, -C2H4-C(CH3)=CH2, -CH2-CH(CH3)-CH=CH2, -CH(CH3)-CH2-CH=CH2, -CH2-CH=C(CH3)2, -CH2-C(CH3)=CH-CH3, -CH(CH3)-CH=CH-CH3, -CH=CH-CH(CH3)2, -CH=C(CH3)-C2H5, -C(CH3)=CH-C2H5, -C(CH3)=C(CH3)2, -C(CH3)2-CH=CH2, -CH(CH3)-C(CH3)=CH2, -C(CH3)=CH-CH=CH2, -CH=C(CH3)CH=CH2, -CH=CH-C(CH3)=CH2, -C4H8-CH=CH2, -C3H6-CH=CH-CH3, -C2H4-CH=CH-C2H5, -CH2-CH=CH-C3H7, -CH=CH-C4H9, -C3H6-C(CH3)=CH2, -C2H4-CH(CH3)-CH=CH2, -CH2-CH(CH3)-CH2-CH=CH2, -CH(CH3)-C2H4-CH=CH2, -C2H4-CH=C(CH3)2, -C2H4-C(CH3)=CH-CH3, -CH2-CH(CH3)-CH=CH-CH3, -CH(CH3)-CH2-CH=CH-CH3, -CH2-CH=CH-CH(CH3)2, -CH2-CH=C(CH3)-C2H5, -CH2-C(CH3)=CH-C2H5, -CH(CH3)-CH=CH-C2H5, -CH=CH-CH2-CH(CH3)2, -CH=CH-CH(CH3)-C2H5, -CH=C(CH3)-C3H7, -C(CH3)=CH-C3H7, -CH2-CH(CH3)-C(CH3)=CH2, -CH(CH3)-CH2-C(CH3)=CH2, -CH(CH3)-CH(CH3)-CH=CH2, -CH2-C(CH3)2-CH=CH2, -C(CH3)2-CH2-CH=CH2, -CH2-C(CH3)=C(CH3)2, -CH(CH3)-CH=C(CH3)2, -C(CH3)2-CH=CH-CH3, -CH(CH3)-C(CH3)=CH-CH3, -CH=C(CH3)-CH(CH3)2, -C(CH3)=CH-CH(CH3)2, -C(CH3)=C(CH3)-C2H5, -CH=CH-C(CH3)3, -C(CH3)2-C(CH3)=CH2, -CH(C2H5)-C(CH3)=CH2, -C(CH3)(C2H5)-CH=CH2, -CH(CH3)-C(C2H5)=CH2, -CH2-C(C3H7)=CH2, -CH2-C(C2H5)=CH-CH3, -CH(C2H5)-CH=CH-CH3, -C(C4H9)=CH2, -C(C3H7)=CH-CH3, -C(C2H5)=CH-C2H5, -C(C2H5)=C(CH3)2, -C[C(CH3)3]=CH2, -C[CH(CH3)(C2H5)]=CH2, -C[CH2-CH(CH3)2]=CH2, -C2H4-CH=CH-CH=CH2, -CH2-CH=CH-CH2-CH=CH2, -CH=CH-C2H4-CH=CH2, -CH2-CH=CH-CH=CH-CH3, -CH=CH-CH2-CH=CH-CH3, -CH=CH-CH=CH-C2H5, -CH2-CH=CH-C(CH3)=CH2, -CH2-CH=C(CH3)-CH=CH2, -CH2-C(CH3)=CH-CH=CH2, -CH(CH3)-CH=CH-CH=CH2, -CH=CH-CH2-C(CH3)=CH2, -CH=CH-CH(CH3)-CH=CH2, -CH=C(CH3)-CH2-CH=CH2, -C(CH3)=CH-CH2-CH=CH2, -CH=CH-CH=C(CH3)2, -CH=CH-C(CH3)=CH-CH3, -CH=C(CH3)-CH=CH-CH3, -C(CH3)=CH-CH=CH-CH3, -CH-C(CH3)-C(CH3)=CH2, -C(CH3)=CH-C(CH3)=CH2, -C(CH3)=C(CH3)-CH=CH2, -CH=CH-CH=CH-CH=CH2, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -C2H4-C≡CH -CH2-C≡C-CH3, -C≡C-C2H5, -C3H6-C≡CH, -C2H4-C≡C-CH3, -CH2-C≡C-C2H5, -C≡C-C3H7, -CH(CH3)-C≡CH, -CH2-CH(CH3)-C≡CH, -CH(CH3)-CH2-C≡CH, -CH(CH3)-C≡C-CH3, -C4H8-C≡CH, -C3H6-C≡C-CH3, -C2H4-C≡C-C2H5, -CH2-C≡C-C3H7, -C≡C-C4H9, -C2H4-CH(CH3)-C≡CH, -CH2-CH(CH3)-CH2-C≡CH, -CH(CH3)-C2H4-C≡CH, -CH2-CH(CH3)-C≡C-CH3, -CH(CH3)-CH2-C≡C-CH3, -CH(CH3)-C≡C-C2H5, -CH2-C≡C-CH(CH3)2, -C≡C-CH(CH3)-C2H5, -C≡C-CH2-CH(CH3)2, -C≡C-C(CH3)3, -CH(C2H5)-C≡C-CH3, -C(CH3)2-C≡C-CH3, -CH(C2H5)-CH2-C≡CH, -CH2-CH(C2H5)-C≡CH, -C(CH3)2-CH2-C≡CH, -CH2-C(CH3)2-C≡CH, -CH(CH3)-CH(CH3)-C≡CH, -CH(C3H7)-C≡CH, -C(CH3)(C2H5)-C≡CH, -C≡C-C≡CH, -CH2-C≡C-C≡CH, -C≡C-C≡C-CH3, -CH(C≡CH)2, -C2H4-C≡C-C≡CH, -CH2-C≡C-CH2-C≡CH, -C≡C-C2H4-C≡CH, -CH2-C≡C-C≡C-CH3, -C≡C-CH2-C≡C-CH3, -C≡C-C≡C-C2H5, -C≡C-CH(CH3)-C-CH, -CH(CH3)-C≡C-C≡CH, -CH(C≡CH)-CH2-C≡CH, -C(C≡CH)2-CH3, -CH2-CH(C≡CH)2, -CH(C≡CH)-C≡C-CH3, -O-CH2-CH(OCH3)2, -O-CH2-CH(OC2H5)2, -O-C2H4-CH(OCH3)2, -O-C2H4-CH(OC2H5)2, -NH-CH2-CH(OCH3)2, -NH-CH2-CH(OC2H5)2, -NH-C2H4-CH(OCH3)2, -NH-C2H4-CH(OC2H5)2, -CH2-CH(OCH3)2 oder -CH2-CH(OC2H5)2;
Figure 00830001
R14, R15, R16, R17, R18, R19, R20, R21, R22, R24, R25, R27 unabhängig voneinander folgende Reste bedeuten: -H, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, cyclo-C6H11, cyclo-C7H13, cyclo-C8H15, -Ph, -CH2-Ph, -CH2-CH2-Ph, -CH2-CH2-CH2-Ph, -CH=CH-Ph, -C≡C-Ph, -CPh3, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -C5H11, -CH(CH3}-C3H7, -CH2-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2, -C(CH3)2-C2H5, -CH2-C(CH3)3, -CH(C2H5)2, -C2H4-CH(CH3)2, -C6H13, -C7H15, -C8H17, -C3H6-CH(CH3)2, -C2H4-CH(CH3)-C2H5, -CH(CH3)-C4H9, -CH2-CH(CH3)-C3H7, -CH(CH3)-CH2-CH(CH3)2, -CH(CH3)-CH(CH3)-C2H5, -CH2-CH(CH3)-CH(CH3)2, -CH2-C(CH3)2-C2H5, -C(CH3)2-C3H7, -C(CH3)2-CH(CH3)2, -C2H4-C(CH3)3, -CH(CH3)-C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C2H4-CH=CH2, -CH2-CH=CH-CH3, -CH=CH-C2H5, -CH2-C(CH3)=CH2, -CH(CH3)-CH=CH, -CH=C(CH3)2, -C(CH3)=CH-CH3, -CH=CH-CH=CH2, -C3H6-CH=CH2, -C2H4-CH=CH-CH3, -CH2-CH=CH-C2H5, -CH=CH-C3H7, -CH2-CH=CH-CH=CH2, -CH=CH-CH=CH-CH3, -CH=CH-CH2-CH=CH2, -C(CH3)=CH-CH=CH2, -CH=C(CH3)-CH=CH2, -CH=CH-C(CH3)=CH2, -C2H4-C(CH3)=CH2, -CH2-CH(CH3)-CH=CH2, -CH(CH3)-CH2-CH=CH2, -CH2-CH=C(CH3)2, -CH2-C(CH3)=CH-CH3, -CH(CH3)-CH=CH-CH3, -CH=CH-CH(CH3)2, -CH=C(CH3)-C2H5, -C(CH3)=CH-C2H5, -C(CH3)=C(CH3)2, -C(CH3)2-CH=CH2, -CH(CH3)-C(CH3)=CH2, -C(CH3)=CH-CH=CH2, -CH=C(CH3)-CH=CH2, -CH=CH-C(CH3)=CH2, -C4H8-CH=CH2, -C3H6-CH=CH-CH3, -C2H4-CH=CH-C2H5, -CH2-CH=CH-C3H7, -CH=CH-C4H9, -C3H6-C(CH3)=CH2, -C2H4-CH(CH3)-CH=CH2, -CH2-CH(CH3)-CH2-CH=CH2, -CH(CH3)-C2H4-CH=CH2, -C2H4-CH=C(CH3)2, -C2H4-C(CH3)=CH-CH3, -CH2-CH(CH3)-CH=CH-CH3, -CH(CH3)-CH2-CH=CH-CH3, -CH2-CH=CH-CH(CH3)2, -CH2-CH=C(CH3)-C2H5, -CH2-C(CH3)=CH-C2H5, -CH(CH3)-CH=CH-C2H5, -CH=CH-CH2-CH(CH3)2, -CH=CH-CH(CH3)-C2H5, -CH=C(CH3)-C3H7, -C(CH3)=CH-C3H7, -CH2-CH(CH3)-C(CH3)=CH2, -CH(CH3)-CH2-C(CH3)=CH2, -CH(CH3)-CH(CH3)-CH=CH2, -CH2-C(CH3)2-CH=CH2, -C(CH3)2-CH2-CH=CH2, -CH2-C(CH3)=C(CH3)2, -CH(CH3)-CH=C(CH3)2, -C(CH3)2-CH=CH-CH3, -CH(CH3)-C(CH3)=CH-CH3, -CH=C(CH3)-CH(CH3)2, -C(CH3)=CH-CH(CH3)2, -C(CH3)=C(CH3)-C2H5, -CH=CH-C(CH3)3, -C(CH3)2-C(CH3)=CH2, -CH(C2H5)-C(CH3)=CH2, -C(CH3)(C2H5)-CH=CH2, -CH(CH3)-C(C2H5)=CH2, -CH2-C(C3H7)=CH2, -CH2-C(C2H5)=CH-CH3, -CH(C2H5)-CH=CH-CH3, -C(C4H9)=CH2, -C(C3H7)=CH-CH3, -C(C2H5)=CH-C2H5, -C(C2H5)=C(CH3)2, -C[C(CH3)3]=CH2, -C[CH(CH3)(C2H5)]=CH2, -C[CH2-CH(CH3)2]=CH2, -C2H4-CH=CH-CH=CH2, -CH2-CH=CH-CH2-CH=CH2, -CH=CH-C2H4-CH=CH2, -CH2-CH=CH-CH=CH-CH3, -CH=CH-CH2-CH=CH-CH3, -CH=CH-CH=CH-C2H5, -CH2-CH=CH-C(CH3)=CH2, -CH2-CH=C(CH3)-CH=CH2, -CH2-C(CH3)=CH-CH=CH2, -CH(CH3)-CH=CH-CH=CH2, -CH=CH-CH2-C(CH3)=CH2, -CH=CH-CH(CH3)-CH=CH2, -CH=C(CH3)-CH2-CH=CH2, -C(CH3)=CH-CH2-CH=CH2, -CH=CH-CH=C(CH3)2, -CH=CH-C(CH3)=CH-CH3, -CH=C(CH3)-CH=CH-CH3, -C(CH3)=CH-CH=CH-CH3, -CH=C(CH3)-C(CH3)=CH2, -C(CH3)=CH-C(CH3)=CH2, -C(CH3)=C(CH3)-CH=CH2, -CH=CH-CH=CH-CH=CH2, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -C2H4-C≡CH, -CH2-C≡C-CH3, -C≡C-C2H5, -C3H6-C≡CH, -C2H4-C≡C-CH3, -CH2-C≡C-C2H5, -C≡C-C3H7, -CH(CH3)-C≡CH, -CH2-CH(CH3)-C≡CH, -CH(CH3)-CH2-C≡CH, -CH(CH3)-C≡C-CH3, -C4H8-C≡CH, -C3H6-C≡C-CH3, -C2H4-C≡C-C2H5, -CH2-C≡C-C3H7, -C≡C-C4H9, -C2H4-CH(CH3)-C≡CH, -CH2-CH(CH3)-CH2-C≡CH, -CH(CH3)-C2H4-C≡CH, -CH2-CH(CH3)-C≡C-CH3, -CH(CH3)-CH2-C≡C-CH3, -CH(CH3)-C≡C-C2H5, -CH2-C≡C-CH(CH3)2, -C≡C-CH(CH3)-C2H5, -C≡C-CH2-CH(CH3)2, -C≡C-C(CH3)3, -CH(C2H5)-C≡C-CH3, -C(CH3)2-C≡C-CH3, -CH(C2H5)-CH2-C≡CH, -CH2-CH(C2H5)-C≡CH, -C(CH3)2-CH2-C≡CH, -CH2-C(CH3)2-C≡CH, -CH(CH3)-CH(CH3)-C≡CH, -CH(C3H7)-C≡CH, -C(CH3)(C2H5)-C≡CH, -C≡C-C≡CH, -CH2-C≡C-C≡CH, -C≡C-C≡-CH3, -CH(C≡CH)2, -C2H4-C≡C-C≡CH, -CH2-C≡C-CH2-C≡CH, -C≡C-C2H4-C≡CH, -CH2-C≡C-C≡C-CH3, -C≡C-CH2-C≡C-CH3, -C≡C-C≡C-C2H5, -C≡C-CH(CH3)-C≡CH, -CH(CH3)-C≡C-C≡CH, -CH(C≡CH)-CH2-C≡CH, -C(C≡CH)2-CH3, -CH2-CH(C≡CH)2, -CH(C≡CH)-C≡C-CH3, -OH, -OCH3, -OC2H5, -OC3H7, -O-cyclo-C3H5, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OPh, -OCH2-Ph, -OCPh3, -SH, -NO2, -SCH3, -SC2H5, -SC3H7, -S-cyclo-C3H5, -SCH(CH3)2, -SC(CH3)3, -F, -Cl, -Br, -I, -P(O)(OH)2, -P(O)(OCH3)2, -P(O)(OC2H5)2, -P(O)(OCH(CH3)2)2, -C(OH)[P(O)(OH)2]2, -Si(CH3)2(C(CH3)3), -Si(C2H5)3, -Si(CH3)3, -N3, -CN, -OCN, -NCO, -SCN, -NCS, -CHO, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -COCN, -COOCH3, -COOC2H5, -COOC3H7, -COO-cyclo-C3H5, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-C2H5, -OOC-C3H7, -OOC-cyclo-C3H5, -OOC-CH(CH3)2, -OOC-C(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-C3H5, -CONH[CH(CH3)2], -CONH[C(CH3)3], -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON(cyclo-C3H5)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -NHCOCH3, -NHCOC2H5, -NHCOC3H7, -NHCO-cyclo-C3H5, -NHCO-CH(CH3)2, -NHCO-C(CH3)3, -NHCO-OCH3, -NHCO-OC2H5, -NHCO-OC3H7, -NHCO-O-cyclo-C3H5, -NHCO-OCH(CH3)2, -NHCO-OC(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NH-cyclo-C3H5, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N(cyclo-C3H5)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -SOCH3, -SOC2H5, -SOC3H7, -SO-cyclo-C3H5, -SOCH(CH3)2, -SOC(CH3)3, -SO2CH3, -SO2C2H5, -SO2C3H7, -SO2-cyclo-C3H5, -SO2CH(CH3)2, -SO2C(CH3)3, -SO3H, -SO3CH3, -SO3C2H5, -SO3C3H7, -SO3-cyclo-C3H5, -SO3CH(CH3)2, -SO3C(CH3)3, -O-SO2CH3, -O-SO2C2H5, -O-SO2C3H7, -O-SO2-cyclo-C3H5, -O-SO2CH(CH3)2, -O-SO2C(CH3)3, -SO2NH2, -OCF3, -OC2F5, -O-COOCH3, -O-COOC2H5, -O-COOC3H7, -O-COO-cyclo-C3H5, -O-COOCH(CH3)2, -O-COOC(CH3)3, -NH-CO-NH2, -NH-CO-NHCH3, -NH-CO-NHC2H5, -NH-CO-NHC3H7, -NH-CO-NH-cyclo-C3H5, -NH-CO-NH[CH(CH3)2], -NH-CO-NH[C(CH3)3], -NH-CO-N(CH3)2, -NH-CO-N(C2H5)2, -NH-CO-N(C3H7)2, -NH-CO-N(cyclo-C3H5)2, -NH-CO-N[CH(CH3)2]2, -NH-CO-N[C(CH3)3]2, -NH-CS-NH2, -NH-CS-NHCH3, -NH-CS-NHC2H5, -NH-CS-NHC3H7, -NH-CS-NH-cyclo-C3H5, -NH-CS-NH[CH(CH3)2], -NH-CS-NH[C(CH3)3], -NH-CS-N(CH3)2, -NH-CS-N(C2H5)2, -NH-CS-N(C3H7)2, -NH-CS-N(cyclo-C3H5)2, -NH-CS-N[CH(CH3)2]2, -NH-CS-N[C(CH3)3]2, -NH-C(=NH)-NH2, -NH-C(=NH)-NHCH3, -NH-C(=NH)-NHC2H5, -NH-C(=NH)-NHC3H7, -NH-C(=NH)-NH-cyclo-C3H5, -NH-C(=NH)-NH[CH(CH3)2], -NH-C(=NH)-NH[C(CH3)3], -NH-C(=NH)-N(CH3)2, -NH-C(=NH)-N(C2H5)2, -NH-C(=NH)-N(C3H7)2, -NH-C(=NH)-N(cyclo-C3H5)2, -O-CO-NH2, -NH-C(=NH)-N[CH(CH3)2]2, -NH-C(=NH)-N[C(CH3)3]2, -O-CO-NHCH3, -O-CO-NHC2H5, -O-CO-NHC3H7, -O-CO-NH-cyclo-C3H5, -O-CO-NH[CH(CH3)2], -O-CO-NH[C(CH3)3], -O-CO-N(CH3)2, -O-CO-N(C2H5)2, -O-CO-N(C3H7)2, -O-CO-N(cyclo-C3H5)2, -O-CO-N[CH(CH3)2]2, -O-CO-N[C(CH3)3]2, -O-CO-OCH3, -O-CO-OC2H5, -O-CO-OC3H7, -O-CO-O-cyclo-C3H5, -O-CO-OCH(CH3)2, -O-CO-OC(CH3)3, -O-CH2-CH(OCH3)2, -O-CH2-CH(OC2H5)2, -O-C2H4-CH(OCH3)2, -O-C2H4-CH(OC2H5)2, -NH-CH2-CH(OCH3)2, -NH-CH2-CH(OC2H5)2, -NH-C2H4-CH(OCH3)2, -NH-C2H4-CH(OC2H5)2, -CH2-OPh, -CH2-O-CH2Ph, -NH-CH2-OH, -NH-C2H4-OH, -NH-C3H6-OH, -NH-C4H8-OH, -NH-C5H10-OH, -NH-CH2-OCH3, -NH-C2H4-OCH3, -NH-C3H6-OCH3, -NH-C4H8-OCH3, -NH-C5H10-OCH3, -NH-CH2-OC2H5, -NH-C2H4-OC2H5, -NH-C3H6-OC2H5, -NH-C4H8-OC2H5, -NH-C5H10-OC2H5, -CH2-OH, -C2H4-OH, -C3H6-OH, -C4H8-OH, -C5H10-OH, -CH2-CH(OCH3)2 oder -CH2-CH(OC2H5)2; X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13 und X14 unabhängig voneinander folgende Reste bedeuten: -H, -CF3, -CH3, -C2H5, -C3H7, -CH(CH3)2, -OH, -OCH3, -OC2H5, -OC3H7, -OPh, -NO2, -F, -Cl, -Br, -I, -CN, -COCH3, -COC2H5, -COC3H7, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -OCF3, -Ph, -CH2-Ph, Tetrazol; X15 für einen der folgenden Reste steht: -H, -CF3, -CH3, -C2H5, -C3H7, -CH(CH3)2, -OH, -OCH3, -OC2H5, -OC3H7, -OPh, -NO2, -F, -Cl, -Br, -I, -CN, -COCH3, -COC2H5, -COC3H7, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -OCF3, -CO-NH-R21, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5 , -C(CH3)3, -C5H11, -CH=CH2, -CH2-CH=CH2, -Ph, -CH2-Ph, -CH2-CH2-Ph, -CH2-CH2-CH2-Ph, -CH=CH-Ph, -NH-CO-R21; n ist eine ganze Zahl ausgewählt aus 1, 2, 3, 4 oder 5; sowie deren Metallkomplexe, Salze, Enantiomere, Enantiomerengemische, Diastereomere, Diastereomerengemische, Tautomere, Hydrate, Solvate, und Racemate der vorgenannten Verbindungen.Compounds of the general formula (I)
Figure 00680001
wherein R 1 represents one of the following radicals:
Figure 00680002
Figure 00690001
Figure 00700001
Figure 00710001
Figure 00720001
Figure 00730001
Figure 00740001
R 2 is one of the following radicals -X 15 ,
Figure 00750001
Figure 00760001
Figure 00770001
Figure 00780001
Figure 00790001
Figure 00800001
R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 independently represent the following radicals: -R 14 , -R 15 , -R 16 , -R 17 , -R 18 , -R 19 , -R 20 , - (CH 2 ) n -R 14 , - (CH 2 ) n -R 15 , - (CH 2 ) n -R 16 , - (CH 2 ) n -R 17 , - (CH 2 ) n -R 18 , - (CH 2 ) n -R 19 , - (CH 2 ) n -R 20 ;
Figure 00800002
Figure 00810001
-H, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 Cl, -CH 2 Br, -CH 2 I, -CH 2 -CH 2 F, -CH 2 -CHF 2 , -CH 2 - CF 3 , -CH 2 -CH 2 Cl, -CH 2 -CH 2 Br, -CH 2 -CH 2 I, cyclo-C 3 H 5 , cyclo-C 4 H 7 , cyclo-C 5 H 9 , cyclo- C 6 H 11 , cyclo-C 7 H 13 , cyclo-C 8 H 15 , -Ph, -CH 2 -Ph, -CH 2 -CH 2 -Ph, -CH 2 -CH 2 -CH 2 -Ph, CH = CH-Ph, -C≡C-Ph, -CPh 3 , -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH (CH 3 ) 2 , -C 4 H 9 , -CH 2 -CH (CH 3 ) 2 , -CH (CH 3 ) -C 2 H 5 , -C (CH 3 ) 3 , -C 5 H 11 , -CH (CH 3 ) -C 3 H 7 , -CH 2 - CH (CH 3 ) -C 2 H 5 , -CH (CH 3 ) -CH (CH 3 ) 2 , -C (CH 3 ) 2 -C 2 H 5 , -CH 2 -C (CH 3 ) 3 , - CH (C 2 H 5 ) 2 , -C 2 H 4 -CH (CH 3 ) 2 , -C 6 H 13 , -C 7 H 15 , -C 8 H 17 , -C 3 H 6 -CH (CH 3 ) 2 , -C 2 H 4 -CH (CH 3 ) -C 2 H 5 , -CH (CH 3 ) -C 4 H 9 , -CH 2 -CH (CH 3 ) -C 3 H 7 , -CH ( CH 3 ) -CH 2 -CH (CH 3 ) 2 , -CH (CH 3 ) -CH (CH 3 ) -C 2 H 5 , -CH 2 -CH (CH 3 ) -CH (CH 3 ) 2 , - CH 2 -C (CH 3 ) 2 -C 2 H 5 , -C (CH 3 ) 2 -C 3 H 7 , -C (CH 3 ) 2 -CH (CH 3 ) 2 , -C 2 H 4 -C (CH 3 ) 3 , -CH (CH 3 ) -C (CH 3 ) 3 , -CH = CH 2 , -CH 2 -CH = CH 2 , -C (CH 3 ) = CH 2 , -CH = CH-CH 3 , -C 2 H 4 -CH = CH 2 , -CH 2 -CH = CH-CH 3 , -CH = CH-C 2 H 5 , -CH 2 -C (CH 3 ) = CH 2 , -CH (CH 3 ) -CH = CH, -CH = C (CH 3 ) 2 , -C (CH 3 ) = CH-CH 3 , -CH = CH-CH = CH 2 , -C 3 H 6 -CH = CH 2 , -C 2 H 4 -CH = CH-CH 3 , -CH 2 -CH = CH-C 2 H 5 , -CH = CH-C 3 H 7 , -CH 2 -CH = CH-CH = CH 2 , CH = CH-CH = CH-CH 3 , -CH = CH-CH 2 -CH = CH 2 , -C (CH 3 ) = CH- CH = CH 2, -CH = C (CH 3) -CH = CH 2, -CH = CH-C (CH 3) = CH 2, -C 2 H 4 -C (CH 3) = CH 2, -CH 2 -CH (CH 3 ) -CH = CH 2 , -CH (CH 3 ) -CH 2 -CH = CH 2 , -CH 2 -CH = C (CH 3 ) 2 , -CH 2 -C (CH 3 ) = CH-CH 3, -CH (CH 3) -CH = CH-CH 3, -CH = CH-CH (CH 3) 2, -CH = C (CH 3) -C 2 H 5, -C (CH 3 ) = CH-C 2 H 5 , -C (CH 3 ) = C (CH 3 ) 2 , -C (CH 3 ) 2 -CH = CH 2 , -CH (CH 3 ) -C (CH 3 ) = CH 2 , -C (CH 3 ) = CH-CH = CH 2 , -CH = C (CH 3 ) CH = CH 2 , -CH = CH-C (CH 3 ) = CH 2 , -C 4 H 8 - CH = CH 2 , -C 3 H 6 -CH = CH-CH 3 , -C 2 H 4 -CH = CH-C 2 H 5 , -CH 2 -CH = CH-C 3 H 7 , -CH = CH -C 4 H 9 , -C 3 H 6 -C (CH 3 ) = CH 2 , -C 2 H 4 -CH (CH 3 ) -CH = CH 2 , -CH 2 -CH (CH 3 ) -CH 2 -CH = CH 2 , -CH (CH 3 ) -C 2 H 4 -CH = CH 2 , -C 2 H 4 -CH = C (CH 3) 2, -C 2 H 4 -C (CH 3) = CH-CH 3, -CH 2 -CH (CH 3) -CH = CH-CH 3, -CH (CH 3) -CH 2 -CH = CH-CH 3 , -CH 2 -CH = CH-CH (CH 3 ) 2 , -CH 2 -CH = C (CH 3 ) -C 2 H 5 , -CH 2 -C (CH 3 ) = CH-C 2 H 5 , -CH (CH 3 ) -CH = CH-C 2 H 5 , -CH = CH-CH 2 -CH (CH 3 ) 2 , -CH = CH-CH (CH 3 ) -C 2 H 5 , -CH = C (CH 3 ) -C 3 H 7 , -C (CH 3 ) = CH-C 3 H 7 , -CH 2 -CH (CH 3 ) -C (CH 3 ) = CH 2 , -CH (CH 3 ) -CH 2 -C (CH 3 ) = CH 2 , -CH (CH 3 ) -CH (CH 3 ) -CH = CH 2 , -CH 2 -C (CH 3 ) 2 -CH = CH 2 , -C (CH 3 ) 2 -CH 2 -CH = CH 2 , -CH 2 -C (CH 3 ) = C (CH 3 ) 2 , -CH (CH 3 ) -CH = C (CH 3 ) 2 , -C (CH 3 ) 2 -CH = CH-CH 3 , -CH (CH 3 ) -C (CH 3 ) = CH-CH 3 , -CH = C (CH 3 ) -CH ( CH 3 ) 2 , -C (CH 3 ) = CH-CH (CH 3 ) 2 , -C (CH 3 ) = C (CH 3 ) -C 2 H 5 , -CH = CH-C (CH 3 ) 3 , -C (CH 3 ) 2 -C (CH 3 ) = CH 2 , -CH (C 2 H 5 ) -C (CH 3 ) = CH 2 , -C (CH 3 ) (C 2 H 5 ) -CH = CH 2 , -CH (CH 3 ) -C (C 2 H 5 ) = CH 2 , -CH 2 -C (C 3 H 7 ) = CH 2 , -CH 2 -C (C 2 H 5 ) = CH -CH 3 , -CH (C 2 H 5 ) -CH = CH-CH 3 , -C (C 4 H 9 ) = CH 2 , -C (C 3 H 7 ) = CH-CH 3 , -C (C 2 H 5 ) = CH-C 2 H 5 , -C (C 2 H 5 ) = C (CH 3 ) 2 , -C [C (CH 3 ) 3 ] = CH 2 , -C [CH (CH 3 ) (C 2 H 5 )] = CH 2 , -C [CH 2 -CH (CH 3 ) 2 ] = CH 2 , -C 2 H 4 -CH = CH- CH = CH 2 , -CH 2 -CH = CH-CH 2 -CH = CH 2 , -CH = CH-C 2 H 4 -CH = CH 2 , -CH 2 -CH = CH-CH = CH-CH 3 , -CH = CH-CH 2 -CH = CH-CH 3 , -CH = CH-CH = CH-C 2 H 5 , -CH 2 -CH = CH-C (CH 3 ) = CH 2 , -CH 2 -CH = C (CH 3) -CH = CH 2, -CH 2 -C (CH 3) = CH-CH = CH 2, -CH (CH 3) -CH = CH-CH = CH 2, -CH = CH-CH 2 -C (CH 3 ) = CH 2 , -CH = CH-CH (CH 3 ) -CH = CH 2 , -CH = C (CH 3 ) -CH 2 -CH = CH 2 , -C ( CH 3 ) = CH-CH 2 -CH = CH 2 , -CH = CH-CH = C (CH 3 ) 2 , -CH = CH-C (CH 3 ) = CH-CH 3 , -CH = C (CH 3) -CH = CH-CH 3, -C (CH 3) = CH-CH = CH-CH 3, -CH-C (CH 3) -C (CH 3) = CH 2, -C (CH 3) = CH-C (CH 3 ) = CH 2 , -C (CH 3 ) = C (CH 3 ) -CH = CH 2 , -CH = CH-CH = CH-CH = CH 2 , -C≡CH, - C≡C-CH 3 , -CH 2 -C≡CH, -C 2 H 4 -C≡CH-CH 2 -C≡C-CH 3 , -C≡CC 2 H 5 , -C 3 H 6 -C ≡CH, -C 2 H 4 -C≡C-CH 3 , -CH 2 -C≡CC 2 H 5 , -C≡CC 3 H 7 , -CH (CH 3 ) -C≡CH, -CH 2 - CH (CH 3 ) -C≡CH, -CH (CH 3 ) -CH 2 -C≡CH, -CH (CH 3 ) -C≡C-CH 3 , -C 4 H 8 -C≡CH, -C 3 H 6 -C≡C-CH 3 , -C 2 H 4 -C≡CC 2 H 5 , -CH 2 - C≡CC 3 H 7 , -C≡CC 4 H 9 , -C 2 H 4 -CH (CH 3 ) -C≡CH, -CH 2 -CH (CH 3 ) -CH 2 -C≡CH, -CH (CH 3 ) - C 2 H 4 -C≡CH, -CH 2 -CH (CH 3 ) -C≡C-CH 3 , -CH (CH 3 ) -CH 2 -C≡C-CH 3 , -CH (CH 3 ) - C≡CC 2 H 5 , -CH 2 -C≡C-CH (CH 3 ) 2 , -C≡C-CH (CH 3 ) -C 2 H 5 , -C≡C-CH 2 -CH (CH 3 ) 2 , -C≡CC (CH 3 ) 3 , -CH (C 2 H 5 ) -C≡C-CH 3 , -C (CH 3 ) 2 -C≡C-CH 3 , -CH (C 2 H 5 ) -CH 2 -C≡CH, -CH 2 -CH (C 2 H 5 ) -C≡CH, -C (CH 3 ) 2 -CH 2 -C≡CH, -CH 2 -C (CH 3 ) 2 -C≡CH, -CH (CH 3 ) -CH (CH 3 ) -C≡CH, -CH (C 3 H 7 ) -C≡CH, -C (CH 3 ) (C 2 H 5 ) -C ≡CH, -C≡CC≡CH, -CH 2 -C≡CC≡CH, -C≡CC≡C-CH 3 , -CH (C≡CH) 2 , -C 2 H 4 -C≡CC≡CH , -CH 2 -C≡C-CH 2 -C≡CH, -C≡CC 2 H 4 -C≡CH, -CH 2 -C≡CC≡C-CH 3 , -C≡C-CH 2 -C ≡C-CH 3 , -C≡CC≡CC 2 H 5 , -C≡C-CH (CH 3 ) -C-CH, -CH (CH 3 ) -C≡CC≡CH, -CH (C≡CH ) -CH 2 -C≡CH, -C (C≡CH) 2 -CH 3 , -CH 2 -CH (C≡CH) 2 , -CH (C≡CH) -C≡C-CH 3 , -O -CH 2 -CH (OCH 3 ) 2 , -O-CH 2 -CH (OC 2 H 5 ) 2 , -OC 2 H 4 -CH (OCH 3 ) 2 , -OC 2 H 4 -CH (OC 2 H 5 ) 2 , -NH-CH 2 -CH (OCH 3 ) 2 , -NH-CH 2 -CH (OC 2 H 5 ) 2 , -NH-C 2 H 4 -CH (OCH 3 ) 2 , -NH- C 2 H 4 - CH (OC 2 H 5 ) 2 , -CH 2 -CH (OCH 3 ) 2 or -CH 2 -CH (OC 2 H 5 ) 2 ;
Figure 00830001
R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 24 , R 25 , R 27 independently represent the following radicals: -H, -CH 2 F, - CHF 2 , -CF 3 , -CH 2 Cl, -CH 2 Br, -CH 2 I, -CH 2 -CH 2 F, -CH 2 -CHF 2 , -CH 2 -CF 3 , -CH 2 -CH 2 Cl, -CH 2 -CH 2 Br, -CH 2 -CH 2 I, cyclo-C 3 H 5 , cyclo-C 4 H 7 , cyclo-C 5 H 9 , cyclo-C 6 H 11 , cyclo-C 7 H 13 , cyclo-C 8 H 15 , -Ph, -CH 2 -Ph, -CH 2 -CH 2 -Ph, -CH 2 -CH 2 -CH 2 -Ph, -CH = CH-Ph, -C≡ C-Ph, -CPh 3 , -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH (CH 3 ) 2 , -C 4 H 9 , -CH 2 -CH (CH 3 ) 2 , - CH (CH 3 ) -C 2 H 5 , -C (CH 3 ) 3 , -C 5 H 11 , -CH (CH 3 ) -C 3 H 7 , -CH 2 -CH (CH 3 ) -C 2 H 5 , -CH (CH 3 ) -CH (CH 3 ) 2 , -C (CH 3 ) 2 -C 2 H 5 , -CH 2 -C (CH 3 ) 3 , -CH (C 2 H 5 ) 2 , -C 2 H 4 -CH (CH 3 ) 2 , -C 6 H 13 , -C 7 H 15 , -C 8 H 17 , -C 3 H 6 -CH (CH 3 ) 2 , -C 2 H 4 - CH (CH 3 ) -C 2 H 5 , -CH (CH 3 ) -C 4 H 9 , -CH 2 -CH (CH 3 ) -C 3 H 7 , -CH (CH 3 ) -CH 2 -CH ( CH 3 ) 2 , -CH (CH 3 ) -CH (CH 3 ) -C 2 H 5 , -CH 2 -CH (CH 3 ) -CH (CH 3 ) 2 , -CH 2 -C (CH 3 ) 2 -C 2 H 5 , -C (CH 3 ) 2 -C 3 H 7 , -C (CH 3 ) 2 -CH (CH 3 ) 2 , -C 2 H 4 -C (CH 3 ) 3 , -CH (CH 3 ) -C (CH 3 ) 3 , -CH = CH 2 , -CH 2 -CH = CH 2 , -C (CH 3 ) = CH 2 , -CH = CH-CH 3 , -C 2 H 4 -CH = CH 2 , -CH 2 -CH = CH-CH 3 , -CH = CH-C 2 H 5 , -CH 2 -C (CH 3 ) = CH 2 , -CH (CH 3 ) -CH = CH, -CH = C (CH 3) 2, -C (CH 3) = CH-CH 3, -CH = CH-CH = CH 2, -C 3 H 6 -CH = CH 2, -C 2 H 4 -CH = CH -CH 3 , -CH 2 -CH = CH-C 2 H 5 , -CH = CH-C 3 H 7 , -CH 2 -CH = CH-CH = CH 2 , -CH = CH-CH = CH-CH 3 , -CH = CH-CH 2 -CH = CH 2 , -C (CH 3 ) = CH-CH = CH 2 , -CH = C (CH 3 ) -CH = CH 2 , -CH = CH-C ( CH 3 ) = CH 2 , -C 2 H 4 -C (CH 3 ) = CH 2 , -CH 2 -CH (CH 3 ) -CH = CH 2 , -CH (CH 3 ) -CH 2 -CH = CH 2 , -CH 2 -CH = C (CH 3 ) 2 , -CH 2 -C (CH 3 ) = CH-CH 3 , -CH (CH 3 ) -CH = CH-CH 3 , -CH = CH-CH (CH 3 ) 2 , -CH = C (CH 3 ) -C 2 H 5 , -C (CH 3 ) = CH-C 2 H 5 , -C (CH 3 ) = C (CH 3 ) 2 , -C (CH 3 ) 2 -CH = CH 2 , -CH (CH 3 ) -C (CH 3 ) = CH 2 , -C (CH 3 ) = CH-CH = CH 2 , -CH = C (CH 3 ) - CH = CH 2 , -CH = CH-C (CH 3 ) = CH 2 , -C 4 H 8 -CH = CH 2 , -C 3 H 6 -CH = CH-CH 3 , -C 2 H 4 -CH = CH-C 2 H 5 , -CH 2 -CH = CH-C 3 H 7 , -CH = CH-C 4 H 9 , -C 3 H 6 -C (CH 3 ) = CH 2 , -C 2 H 4 -CH (CH 3 ) -CH = CH 2 , -CH 2 -CH (CH 3 ) -CH 2 -CH = CH 2 , -CH (CH 3 ) -C 2 H 4 -CH = CH 2 , -C 2 H 4 -CH = C (CH 3 ) 2 , -C 2 H 4 -C (CH 3 ) = CH-CH 3 , -CH 2 -CH (CH 3 ) -CH = CH-CH 3 , -CH (CH 3 ) -CH 2 -CH = CH-CH 3 , -CH 2 -CH = CH-CH (CH 3 ) 2 , -CH 2 -CH = C (CH 3 ) -C 2 H 5 , -CH 2 -C (CH 3 ) = CH-C 2 H 5 , -CH (CH 3 ) -CH = CH-C 2 H 5 , -CH = CH-CH 2 -CH (CH 3 ) 2 , -CH = CH-CH (CH 3 ) -C 2 H 5 , -CH = C (CH 3 ) -C 3 H 7 , -C (CH 3 ) = CH-C 3 H 7 , -CH 2 -CH (CH 3 ) -C (CH 3 ) = CH 2 , -CH (CH 3 ) -CH 2 -C (CH 3 ) = CH 2 , -CH (CH 3 ) -CH (CH 3 ) -CH = CH 2 , -CH 2 -C (CH 3 ) 2 -CH = CH 2 , -C (CH 3 ) 2 -CH 2 -CH = CH 2 , -CH 2 -C (CH 3 ) = C (CH 3 ) 2 , -CH (CH 3 ) -CH = C (CH 3 ) 2 , -C (CH 3 ) 2 -CH = CH-CH 3 , -CH (CH 3 ) -C (CH 3 ) = CH-CH 3 , -CH = C (CH 3 ) -CH (CH 3 ) 2 , -C (CH 3 ) = CH-CH (CH 3 ) 2 , -C (CH 3 ) = C (CH 3 ) -C 2 H 5 , -CH = CH-C (CH 3 ) 3 , -C (CH 3 ) 2 -C (CH 3 ) = CH 2 , -CH (C 2 H 5 ) -C (CH 3 ) = CH 2 , -C (CH 3 ) (C 2 H 5 ) -CH = CH 2 , -CH (CH 3 ) -C (C 2 H 5 ) = CH 2 , -CH 2 -C (C 3 H 7 ) = CH 2 , -CH 2 -C (C 2 H 5 ) = CH-CH 3 , -CH ( C 2 H 5 ) -CH = CH-CH 3 , -C (C 4 H 9 ) = CH 2 , -C (C 3 H 7 ) = CH-CH 3 , -C (C 2 H 5 ) = CH- C 2 H 5 , -C (C 2 H 5 ) = C (CH 3 ) 2 , -C [C (CH 3 ) 3 ] = CH 2 , -C [CH (CH 3 ) (C 2 H 5 )] = CH 2 , -C [CH 2 -CH (CH 3 ) 2 ] = CH 2 , -C 2 H 4 -CH = CH-CH = CH 2 , -CH 2 -CH = CH-CH 2 -CH = CH 2 , -CH = CH-C 2 H 4 -CH = CH 2 , -CH 2 -CH = CH-CH = CH-CH 3 , -CH = CH-CH 2 -CH = CH-CH 3 , -CH = CH-CH = CH-C 2 H 5 , -CH 2 -CH = CH-C (CH 3 ) = CH 2 , -CH 2 -CH = C (CH 3 ) -CH = CH 2 , -CH 2 -C (CH 3 ) = CH-CH = CH 2 , -CH (CH 3 ) -CH = CH-CH = CH 2 , -CH = CH-CH 2 -C (CH 3 ) = CH 2 , -CH = CH- CH (CH 3 ) -CH = CH 2 , -CH = C (CH 3 ) -CH 2 -CH = CH 2 , -C (CH 3 ) = CH-CH 2 -CH = CH 2 , -CH = CH- CH = C (CH 3 ) 2 , -CH = CH-C (CH 3 ) = CH-CH 3 , -CH = C (CH 3 ) -CH = CH-CH 3 , -C (CH 3 ) = CH- CH = CH-CH 3, -CH = C (CH 3) -C (CH 3) = CH 2, -C (CH 3) = CH-C (CH 3) = CH 2, -C (CH 3) = C (CH 3 ) -CH = CH 2 , -CH = CH-CH = CH-CH = CH 2 , -C≡CH, -C≡C-CH 3 , -CH 2 -C≡CH, -C 2 H 4 -C≡CH, -CH 2 -C≡C-CH 3 , -C≡CC 2 H 5 , -C 3 H 6 -C≡CH, -C 2 H 4 -C≡C-CH 3 , -CH 2 -C≡CC 2 H 5 , -C≡CC 3 H 7 , -CH (CH 3 ) -C≡CH, -CH 2 -CH (CH 3 ) -C≡CH, -CH (CH 3 ) -CH 2 -C≡CH, -CH (CH 3 ) -C≡C-CH 3 , -C 4 H 8 -C≡CH, -C 3 H 6 -C≡C-CH 3 , -C 2 H 4 -C≡CC 2 H 5 , -CH 2 -C≡CC 3 H 7 , -C≡CC 4 H 9 , -C 2 H 4 -CH (CH 3 ) -C≡CH, -CH 2 -CH (CH 3 ) -CH 2 -C≡CH, -CH (CH 3 ) -C 2 H 4 -C≡CH, -CH 2 -CH (CH 3 ) -C ≡C-CH 3 , -CH (CH 3 ) -CH 2 -C≡C-CH 3 , -CH (CH 3 ) -C≡CC 2 H 5 , -CH 2 -C≡C-CH (CH 3 ) 2 , -C≡C-CH (CH 3 ) -C 2 H 5 , -C≡C-CH 2 -CH (CH 3 ) 2 , -C≡CC (CH 3 ) 3 , -CH (C 2 H 5 ) -C≡C-CH 3 , -C (CH 3 ) 2 -C≡C-CH 3 , -CH (C 2 H 5 ) -CH 2 -C≡CH, -CH 2 -CH (C 2 H 5 ) -C≡CH, -C (CH 3 ) 2 -CH 2 -C≡CH, -CH 2 -C (CH 3 ) 2 -C≡CH, -CH (CH 3 ) -CH (CH 3 ) -C ≡CH, -CH (C 3 H 7 ) -C≡CH, -C (CH 3 ) (C 2 H 5 ) -C≡CH, -C≡CC≡CH, -CH 2 -C≡CC≡CH, -C≡CC≡-CH 3 , -CH (C≡CH) 2 , -C 2 H 4 -C≡CC≡CH, -CH 2 -C≡C-CH 2 -C≡CH, -C≡CC 2 H 4 -C≡CH, -CH 2 -C≡CC≡C-CH 3 , -C≡C-CH 2 -C≡C-CH 3 , -C≡CC≡CC 2 H 5 , -C≡C- CH (CH 3 ) -C≡CH, -CH (CH 3 ) -C≡CC≡CH, -CH (C≡CH) -CH 2 -C≡CH, -C (C≡CH) 2 -CH 3 , -CH 2 -CH (C ≡CH) 2 , -CH (C≡CH) -C≡C-CH 3 , -OH, -OCH 3 , -OC 2 H 5 , -OC 3 H 7 , -O-cyclo-C 3 H 5 , - OCH (CH 3 ) 2 , -OC (CH 3 ) 3 , -OC 4 H 9 , -OPh, -OCH 2 -Ph, -OCPh 3 , -SH, -NO 2 , -SCH 3 , -SC 2 H 5 , -SC 3 H 7 , -S-cyclo-C 3 H 5 , -SCH (CH 3 ) 2 , -SC (CH 3 ) 3 , -F, -Cl, -Br, -I, -P (O) (OH) 2 , -P (O) (OCH 3 ) 2 , -P (O) (OC 2 H 5 ) 2 , -P (O) (OCH (CH 3 ) 2 ) 2 , -C (OH) [ P (O) (OH) 2 ] 2 , -Si (CH 3 ) 2 (C (CH 3 ) 3 ), -Si (C 2 H 5 ) 3 , -Si (CH 3 ) 3 , -N 3 , - CN, -OCN, -NCO, -SCN, -NCS, -CHO, -COCH 3 , -COC 2 H 5 , -COC 3 H 7 , -CO-cyclo-C 3 H 5 , -COCH (CH 3 ) 2 , -COC (CH 3 ) 3 , -COOH, -COCN, -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 7 , -COO-cyclo-C 3 H 5 , -COOCH (CH 3 ) 2 , - COOC (CH 3 ) 3 , -OOC-CH 3 , -OOC-C 2 H 5 , -OCO-C 3 H 7 , -OCO-cyclo-C 3 H 5 , -OCO-CH (CH 3 ) 2 , - OOC-C (CH 3 ) 3 , -CONH 2 , -CONHCH 3 , -CONHC 2 H 5 , -CONHC 3 H 7 , -CONH -cycloC 3 H 5 , -CONH [CH (CH 3 ) 2 ], -CONH [C (CH 3 ) 3 ], -CON (CH 3 ) 2 , -CON (C 2 H 5 ) 2 , -CON (C 3 H 7 ) 2 , -CON (cycloC 3 H 5 ) 2 , -CON [CH (CH 3 ) 2 ] 2 , - CON [C (CH 3 ) 3 ] 2 , -NHCOCH 3 , -NHCOC 2 H 5 , -NHCOC 3 H 7 , -NHCO-cyclo-C 3 H 5 , -NHCO-CH (CH 3 ) 2 , -NHCO- C (CH 3 ) 3 , -NHCO-OCH 3 , -NHCO-OC 2 H 5 , -NHCO-OC 3 H 7 , -NHCO-O-cyclo-C 3 H 5 , -NHCO-OCH (CH 3 ) 2 , -NHCO-OC (CH 3 ) 3 , -NH 2 , -NHCH 3 , -NHC 2 H 5 , -NHC 3 H 7 , -NH-cyclo-C 3 H 5 , -NHCH (CH 3 ) 2 , - NHC (CH 3 ) 3 , -N (CH 3 ) 2 , -N (C 2 H 5 ) 2 , -N (C 3 H 7 ) 2 , -N (cyclo-C 3 H 5 ) 2 , -N [ CH (CH 3 ) 2 ] 2 , -N [C (CH 3 ) 3 ] 2 , -SOCH 3 , -SOC 2 H 5 , -SOC 3 H 7 , -SO-cyclo-C 3 H 5 , -SOCH ( CH 3 ) 2 , -SOC (CH 3 ) 3 , -SO 2 CH 3 , -SO 2 C 2 H 5 , -SO 2 C 3 H 7 , -SO 2 -cyclo-C 3 H 5 , -SO 2 CH (CH 3 ) 2 , -SO 2 C (CH 3 ) 3 , -SO 3 H, -SO 3 CH 3 , -SO 3 C 2 H 5 , -SO 3 C 3 H 7 , -SO 3 -cyclo-C 3 H 5 , -SO 3 CH (CH 3 ) 2 , -SO 3 C (CH 3 ) 3 , -O-SO 2 CH 3 , -O-SO 2 C 2 H 5 , -O-SO 2 C 3 H 7 , -O-SO 2 -cyclo-C 3 H 5 , -O-SO 2 CH (CH 3 ) 2 , -O-SO 2 C (CH 3 ) 3 , -SO 2 NH 2 , -OCF 3 , -OC 2 F 5 , -O-COOCH 3 , -O-COOC 2 H 5 , -O-COOC 3 H 7 , -O-COO-cyclo-C 3 H 5 , -O-COOCH (CH 3 ) 2 , -O- COOC (CH 3 ) 3 , -NH-CO-NH 2 , -NH-CO-NHCH 3 , -NH-CO-NHC 2 H 5 , -NH-CO-NHC 3 H 7 , -NH-CO-NH- cyclo-C 3 H 5 , -NH-CO-NH [CH (CH 3 ) 2 ], -NH-CO-NH [C (CH 3 ) 3 ], -NH-CO-N (CH 3 ) 2 , NH-CO-N (C 2 H 5 ) 2 , -NH-CO-N (C 3 H 7 ) 2 , -NH-CO-N (cyclo-C 3 H 5 ) 2 , -NH-CO-N [ CH (CH 3 ) 2 ] 2 , -NH-CO-N [C (CH 3 ) 3 ] 2 , -NH-CS-NH 2 , -NH-CS-NHCH 3 , -NH-CS-NHC 2 H 5 , -NH-CS-NHC 3 H 7 , -NH-CS-NH-cyclo-C 3 H 5 , -NH-CS-NH [CH (CH 3 ) 2 ], -NH-CS-NH [C (CH 3 ) 3 ], -NH-CS-N (CH 3 ) 2 , -NH-CS-N (C 2 H 5 ) 2 , -NH-CS-N (C 3 H 7 ) 2 , -NH-CS- N (cyclo-C 3 H 5 ) 2 , -NH-CS-N [CH (CH 3 ) 2 ] 2 , -NH-CS-N [C (CH 3 ) 3 ] 2 , -NH-C (= NH ) -NH 2 , -NH-C (= NH) -NHCH 3 , -NH-C (= NH) -NHC 2 H 5 , -NH-C (= NH) -NHC 3 H 7 , -NH-C ( = NH) -NH-cyclo-C 3 H 5 , -NH-C (= NH) -NH [CH (CH 3 ) 2 ], -NH-C (= NH) -NH [C (CH 3 ) 3 ] , -NH-C (= NH) -N (CH 3 ) 2 , -NH-C (= NH) -N (C 2 H 5 ) 2 , -NH-C (= NH) -N (C 3 H 7 ) 2 , -NH-C (= NH) -N (cycloC 3 H 5 ) 2 , -O-CO-NH 2 , -NH-C (= NH) -N [CH (CH 3 ) 2 ] 2 , -NH-C (= NH) -N [C (CH 3 ) 3 ] 2 , -O-CO-NHCH 3 , -O-CO-NHC 2 H 5 , -O-CO-NHC 3 H 7 , -O-CO-NH-cyclo-C 3 H 5 , -O-CO-NH [CH (CH 3 ) 2 ], -O-CO-NH [C (CH 3 ) 3 ], -O-CO -N (CH 3 ) 2 , -O-CO-N (C 2 H 5 ) 2 , -O-CO-N (C 3 H 7 ) 2 , -O-CO-N (cyclo-C 3 H 5 ) 2 , -O-CO-N [CH (CH 3 ) 2 ] 2 , -O-CO-N [C (CH 3 ) 3 ] 2 , -O-CO-OCH 3 , -O-CO-OC 2 H 5 , -O-CO-OC 3 H 7 , -O-CO-O-cyclo-C 3 H 5 , -O-CO-OCH (CH 3 ) 2 , -O-CO-OC (CH 3 ) 3 , -O-CH 2 -CH (OCH 3 ) 2 , -O-CH 2 -CH (OC 2 H 5 ) 2 , -OC 2 H 4 -CH (OCH 3 ) 2 , -OC 2 H 4 -CH (OC 2 H 5 ) 2 , -NH-CH 2 -CH (OCH 3 ) 2 , -NH-CH 2 -CH (OC 2 H 5 ) 2 , -NH-C 2 H 4 -CH (OCH 3 ) 2 , - NH-C 2 H 4 -CH (OC 2 H 5 ) 2 , -CH 2 -OPh, -CH 2 -O-CH 2 Ph, -NH-CH 2 -OH, -NH-C 2 H 4 -OH, -NH-C 3 H 6 -OH, -NH-C 4 H 8 -OH, -NH-C 5 H 10 -OH, -NH-CH 2 -OCH 3 , -NH-C 2 H 4 -OCH 3 , -NH-C 3 H 6 -OCH 3 , -NH-C 4 H 8 -OCH 3 , -NH-C 5 H 10 -OCH 3 , -NH-CH 2 -OC 2 H 5 , -NH-C 2 H 4 -OC 2 H 5 , -NH-C 3 H 6 -OC 2 H 5 , -NH-C 4 H 8 -OC 2 H 5 , -NH-C 5 H 10 -OC 2 H 5 , -CH 2 - OH, -C 2 H 4 -OH, -C 3 H 6 -OH, -C 4 H 8 -OH, -C 5 H 10 -OH, -CH 2 -CH (OCH 3 ) 2 or -CH 2 -CH (OC 2 H 5 ) 2 ; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 are each independently of one another the following radicals: -H, -CF 3 , -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH (CH 3 ) 2 , -OH, -OCH 3 , -OC 2 H 5 , -OC 3 H 7 , -OPh, -NO 2 , -F, -Cl, -Br, -I, -CN, -COCH 3 , -COC 2 H 5 , -COC 3 H 7 , -COOH, -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 7 , -OCF 3 , -Ph, -CH 2 -Ph, tetrazole; X 15 is one of the following radicals: -H, -CF 3 , -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH (CH 3 ) 2 , -OH, -OCH 3 , -OC 2 H 5 , -OC 3 H 7 , -OPh, -NO 2 , -F, -Cl, -Br, -I, -CN, -COCH 3 , -COC 2 H 5 , -COC 3 H 7 , -COOH, -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 7 , -OCF 3 , -CO-NH-R 21 , -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH (CH 3 ) 2 , -C 4 H 9 , -CH 2 -CH (CH 3 ) 2 , -CH (CH 3 ) -C 2 H 5 , -C (CH 3 ) 3 , -C 5 H 11 , -CH = CH 2 , -CH 2 -CH = CH 2 , -Ph, -CH 2 -Ph, -CH 2 -CH 2 -Ph, -CH 2 -CH 2 -CH 2 -Ph, -CH = CH-Ph, -NH- CO-R 21 ; n is an integer selected from 1, 2, 3, 4 or 5; and their metal complexes, salts, enantiomers, enantiomer mixtures, diastereomers, diastereomer mixtures, tautomers, hydrates, solvates, and racemates of the abovementioned compounds. Verbindungen gemäß Anspruch 1 zur Verwendung in der Medizin.Compounds according to claim 1 for use in medicine. Verbindungen gemäß Anspruch 1 zur Verwendung als Inhibitor der GSK-3.Compounds according to claim 1 for use as inhibitors of GSK-3. Verwendung der Verbindungen gemäß Anspruch 1 zur Prophylaxe und Behandlung von Alzheimer-Krankheit und anderer Tauopathien, Asthma, bipolare affektive Störungen, Depression, Nervenzelltod und Schlaganfall, Parkinson, Huntington, Skelettmuskelatrophie, Kardioprotektion, Haarverlust, verringerte Spermienmotilität, Diabetes und damit in Zusammenhang stehende Folgeerkrankungen, wie Syndrom X und Adipositas, Erkrankungen, die durch einzellige Parasiten verursacht werden, transmissible spongiforme Enzephalopathie, Schizophrenie, Krankheiten des zirkadianen Rhythmus und Krebs.Use of the compounds according to claim 1 for the prophylaxis and treatment of Alzheimer's disease and other tauopathies, asthma, bipolar affective disorders, depression, neuronal death and stroke, Parkinson's, Huntington's, skeletal muscle atrophy, cardioprotection, hair loss, reduced sperm motility, diabetes and related sequelae , such as Syndrome X and obesity, diseases caused by unicellular parasites, transmissible spongiform encephalopathy, schizophrenia, circadian rhythm diseases and cancer. Pharmazeutische Zusammensetzung, enthaltend mindestens eine Verbindung gemäß Anspruch 1 und mindestens einen pharmakologisch verträglichen Hilfsstoff, Träger und/oder mindestens ein Lösungsmittel.Pharmaceutical composition containing at least one compound according to claim 1 and at least one pharmacologically acceptable excipient, carrier and / or at least one solvent. Pharmazeutische Zusammensetzung gemäß Anspruch 5 zur Prophylaxe und Behandlung von Alzheimer-Krankheit und andere tauopathien, Asthma, bipolare affektive Störungen, Depression, Nervenzelltod und Schlaganfall, Parkinson, Huntington, Skelettmuskelatrophie, Kardioprotektion, Haarverlust, verringerte Spermienmotilität, Diabetes und damit in Zusammenhang stehende Folgeerkrankungen, wie Syndrom X und Adipositas, Erkrankungen, die durch einzellige Parasiten verursacht werden, transmissible spongiforme Enzephalopathie, Schizophrenie, Krankheiten des zirkadianen Rhythmus und Krebs.A pharmaceutical composition according to claim 5 for the prophylaxis and treatment of Alzheimer's disease and other tauopathies, asthma, bipolar affective disorders, depression, neuronal death and stroke, Parkinson's, Huntington's, skeletal muscle atrophy, cardioprotection, hair loss, reduced sperm motility, diabetes and related sequelae, syndrome X and obesity, diseases caused by unicellular parasites, transmissible spongiform encephalopathy, schizophrenia, circadian rhythm diseases and cancer.
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