WO2020201305A1

WO2020201305A1 - 4-(2,4-bis(2-hydroxyphenyl)-1h-imidazol-1-yl)benzoic acid derivatives as novel iron chelators

Info

Publication number: WO2020201305A1
Application number: PCT/EP2020/059166
Authority: WO
Inventors: Wilm Buhr; Michael Burgert; Franz DÜRRENBERGER; Aris Kalogerakis; Vania Manolova; Naja NYFFENEGGER; Klaus-Daniel UMLAND
Original assignee: Vifor (International) Ag
Priority date: 2019-04-01
Filing date: 2020-03-31
Publication date: 2020-10-08
Also published as: AR118557A1; TW202102478A

Abstract

The invention relates to novel compounds of the general formula (I) pharmaceutical compositions comprising them and the use thereof as medicaments, in particular for the use as iron chelators, more particularly for the use in the prophylaxis and/or treatment of diseases related to or caused by excess or increased iron levels, increased iron absorption or iron overload in a mammal, such as in particular thalassemia, hemochromatosis and ineffective erythropoiesis, or related to or caused by blood transfusions.

Description

4-(2,4-BIS(2-HYDROXYPHENYL)-1 H-IMIDAZOL-1-YL)BENZOIC ACID DERIVATIVES AS NOVEL IRON CHELATORS

DESCRIPTION

INTRODUCTION

The invention relates to novel compounds of the general formula (I), pharmaceutical compositions comprising them and the use thereof as medicaments, in particular for the use as iron chelators, more particularly for the use in the prophylaxis and/or treatment of diseases related to or caused by excess or increased iron levels, increased iron absorption or iron overload in a mammal, such as in particular thalassemia, hemochromatosis and ineffective erythropoiesis, or related to or caused by blood transfusions.

BACKGROUND AND PRIOR ART

Biophvsioloqical Background

Iron is an essential trace element for almost all organisms and is relevant in particular with respect to growth and the formation of blood. The balance of the iron metabolism is in this case primarily regulated on the level of iron recovery from haemoglobin of ageing erythrocytes and the duodenal absorption of dietary iron. The released iron is taken up via the intestine, in particular via specific transport systems (DMT-1 , ferroportin), transferred into the blood circulation and thereby conveyed to the appropriate tissues and organs (transferrin, transferrin receptors).

In the human body, the element iron is of great importance, inter alia for oxygen transport, oxygen uptake, cell functions such as mitochondrial electron transport, cognitive functions, etc. and ultimately for the entire energy metabolism.

On average, the human body contains 4 to 5 g iron, with it being present in enzymes, in haemoglobin and myoglobin, as well as depot or reserve iron in the form of ferritin and hemosiderin. Approximately half of this iron, about 2 g, is present as heme iron, bound in the haemoglobin of the erythrocytes. Since these erythrocytes have only a limited lifespan (75-150 days), new ones have to be formed continuously and old ones degraded (over 2 million erythrocytes are being formed per second). This high regeneration capacity is achieved by macrophages phagocytizing the ageing erythrocytes, lysing them and recycling the iron for maintenanace of iron metabolism. The majority of the iron required for erythropoiesis, about 25 mg per day, is provided in this way.

The daily iron requirement of a human adult is between 0.5 to 1.5 mg per day, infants and women during pregnancy require 2 to 5 mg of iron per day. The daily iron loss, e.g. by desquamation of skin and epithelial cells, is low. Increased iron loss occurs, for example, during menstrual hemorrhage in women. In a healthy human adult, the normal daily loss of iron of about 1 mg is usually replaced via the daily food intake thus rebalancing the daily iron requirement to the adequate level.

The iron level is regulated by absorption, with the absorption rate of the iron present in food being between 6 and 12 %, and up to 25 % in the case of iron deficiency. The absorption rate is regulated by the organism depending on the iron requirement and the size of the iron store. In the process, the human organism utilizes both divalent as well as trivalent iron ions. Usually, iron(lll) compounds are dissolved in the stomach at a sufficiently acid pH value and thus made available for absorption. The absorption of the iron is carried out in the upper small intestine by mucosal cells. In the process, trivalent non-heme iron is first reduced in the intestinal cell membrane to Fe(ll) for absorption, for example by ferric reductase (membrane-bound duodenal cytochrome b), so that it can then be transported into the intestinal cells by means of the transport protein DMT1 (divalent metal transporter 1). In contrast, heme iron enters the enterocytes through the cell membrane without any change. In the enterocytes, iron is either stored in ferritin as depot iron, or released into the blood by the transport protein ferroportin.

Hepcidin and ferroportin both play a central role in the process of iron transport and absorption regulation. The divalent iron transported into the blood by ferroportin is converted into trivalent iron by oxidases (ceruloplasmin, hephaestin), the trivalent iron then being transported to the relevant places in the organism by transferrin (see for example "Balancing acts: molecular control of mammalian iron metabolism". M.W. Hentze, Cell 117, 2004, 285-297).

Mammalian organisms are unable to actively discharge iron. The iron metabolism is substantially controlled by hepcidin via the cellular release of iron from macrophages, hepatocytes and enterocytes. Hepcidin is a peptide hormone produced in the liver. The predominant active form has 25 amino acids (see for example:“Hepcidin, a key regulator of iron metabolism and mediator of anaemia of inflammation”. T. Ganz, Blood, 102, 2003, 783-8), although two forms which are shortened at the amino end, hepcidin-22 and hepcidin-20, have been found. Hepcidin acts on the absorption of iron via the intestine and via the placenta and on the release of iron from the reticuloendothelial system. In the body, hepcidin is synthesized in the liver from what is known as pro-hepcidin, pro-hepcidin being coded by the gene known as the HAMP gene. The formation of hepcidin is regulated in direct correlation to the organisms iron level, i.e. if the organism is supplied with sufficient iron and oxygen, more hepcidin is formed, if iron and oxygen levels are low, or in case of increased erythropoiesis less hepcidin is formed. In the small intestinal mucosal cells and in the macrophages hepcidin binds with the transport protein ferroportin, which conventionally transports the phagocytotically recycled iron from the interior of the cell into the blood.

The transport protein ferroportin is a transmembrane protein consisting of 571 amino acids which is expressed in the liver, spleen, kidneys, heart, intestine and placenta. In particular, ferroportin is localized in the basolateral membrane of intestinal epithelial cells. Ferroportin exports Fe²⁺ into the blood. Hepcidin binds to ferroportin and triggers ferroportin internalization and degradation which inhibits iron transport to blood. If the ferroportin is inactivated, for example by hepcidin, so that it is unable to export the iron which is stored in the mucosal cells, the stored iron is lost with the natural shedding of cells via the stools. The absorption of iron in the intestine is therefore reduced, when ferroportin is inactivated or inhibited, for example by hepcidin. In addition, ferroportin is markedly localized in the mononuclear phagocyte system, to which the macrophages belong. Hepcidin plays an important role here when iron metabolism is impaired by chronic inflammation. In case of inflammation, in particular interleukin-6 is increased, triggering an increase in hepcidin levels. As a result, hepcidin binds to ferroportin of the macrophages, thus blocking the release of stored iron, which ultimately leads to anemia of inflammation (ACD or Al). On the other hand, if the serum iron level decreases, hepcidin production in the hepatocytes of the liver is reduced so that less hepcidin is released and accordingly less ferroportin is inactivated, allowing a larger amount of stored iron to be transported into the serum.

The hepcidin-ferroportin system directly regulates the iron metabolism, and in principle the hepcidin-ferroportin regulation mechanism acts via the two following opposite principles:

On the one hand, an increase of hepcidin leads to inactivation of ferroportin, thus blocking the release of stored iron from the cells into the serum, thus decreasing the serum iron level. In pathological cases a decreased serum iron level leads to a reduced hemoglobin level, reduced erythrocyte production and thus to iron deficiency anemia.

On the other hand, a decrease of hepcidin results in an increase of active ferroportin, thus allowing an enhanced release of stored iron and an enhanced iron uptake e.g. from the food, thus increasing the serum iron level. In pathological cases an increased iron level leads to organ iron overload.

Iron Overload Conditions and Diseases

Iron overload states and diseases are characterized by excess iron levels in organs. Therein, the problems arise from excess serum iron levels which lead to non-transferrin bound iron (NTBI). The NTBI is rapidly taken up unspecifically by the organs, leading to an accumulation of iron in tissue and organs. Iron overload causes many diseases and undesired medical conditions, including cardiac, kidney, liver and endocrine damage. Further, iron accumulation in brain has been observed in patients suffering from neurodegenerative diseases such as for example Alzheimer’s disease and Parkinson’s disease. As a particular detrimental aspect of excess free iron the undesired formation of radicals must be mentioned. In particular iron(ll) ions catalyze the formation (inter alia via Fenton reaction) of reactive oxygen species (ROS). These ROS cause damage to DNA, lipids, proteins and carbohydrates which has far- reaching effects in cells, tissue and organs. The formation of ROS is well known and described in the literature to cause the so-called oxidative stress.

Iron overload may occur, for example, due to a genetic defect, such as in the iron overload disease haemochromatosis. Flemochromatosis is a disease of iron overload caused by mutations in genes that control hepcidin synthesis or in the hepcidin gene itself, or mutations in ferroportin leading to severe iron overload, which causes cardiac, kidney, liver and endocrine damages.

In the known iron overload disease beta-thalassemia mutations in the beta globin gene cause a reduction in hemoglobin production and ineffective erythropoiesis, the inability to produce adequate numbers of red cells because of damage to and death of developing red cells in the bone marrow. This causes upregulation of the rate of erythropoiesis and a reduction in hepcidin level to make more iron available for increased erythropoietic activity. This maladaptive response results in iron overload. Red cells in thalassemia have a shortened half-life because of the toxicity of an imbalanced ratio of alpha- and beta- hemoglobin-subunits.

Further known iron overload related diseases are diseases associated with ineffective erythropoiesis such as the myelodysplastic syndromes (also known as MDS or myelodysplasia), polycythemia vera, etc.

Further, mutations in genes involved in sensing the systemic iron stores, such as hepcidin (Hampl), hemochromatosis protein (HFE), hemojuvelin (HJV) and transferrin receptor 2 (TFR2) cause iron overload in mice and men. Accordingly, diseases related to FIFE and gene mutations, chronic hemolysis associated diseases, sickle cell diseases, red cell membrane disorders, as well as Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency), erythrpoietic porphyria and Friedrich^'s Ataxia can be mentioned. Further, subgroups of iron overload comprise transfusional iron overload, iron intoxication, pulmonary hemosiderosis, osteopenia, insulin resistense, African iron overload, Flallervordan Spatz disease, hyperferritinemia, ceruloplasmin deficiency, neonatal hemochromatosis and red blood cell disorders comprising beta thalassemia, alpha thalassemia, thalassemia major and intermedia, sickle cell disease and myelodyplastic syndrome are included.

Further disease and/or disorders and/or diseased conditions associated with elevated iron levels include, but are not limited to, diseases with elevated iron level, comprising ataxia, Friedrich's ataxia, age-related macular degeneration, age-related cataract, age-related retinal diseases and neurodegenrative disease, whereby such neurodegenrative disease comprises Alzheimer's disease, Parkinson's disease, pantothenate kinase-associated neurodegeneration, restless leg syndrom and Huntington's disease.

Also blood transfusions may lead to iron overload, e.g. in some of the diseases mentioned herein that are treated with blood transfusions, e.g. transfusion-depedent thalassemia, myelodysplastic syndromes (MDS, myelodysplasia).

Iron Overload Therapies of the Prior Art

Modern approaches of treating excess iron are based on the above described hepcidin- ferroportin regulation mechanism and provide hepcidin agonists or hepcidin mimetics, ferroportin inhibitors or compounds having an inhibiting or controlling effect on the biochemical regulatory pathways in the iron metabolism. This therapeutic approach is based on a direct involvement into the disturbed iron metabolism pathway by directly acting via the primary regulator hepcidin by providing a kind of hepcidin substitute or supply or by inhibiting ferroportin to block excessive iron absorption.

For example, known hepcidin mimetics comprise the so-called minihepcidins as described for example in WO 2013/086143. Minihepcidins are small-sized synthetic peptide analogues of the hepcidin N-terminus which is crucial for hepcidin interaction with ferroportin. Minihepcidins have been developed on the basis that the first 9 amino acids of hepcidin (DTHFPICIF) which are sufficient for in vitro activity (measured as ferroportin-GFP degradation). Minihepcidins have a modified hepcidin-9 amino acid sequence to exhibit improved resistance to proteolysis and enhanced biophysical interaction with ferroportin. Minihepcidins are described to be useful for the treatment of human iron overload conditions caused by hepcidin deficiency.

WO 2015/069660 describes methods for increasing hepcidin expression for treating iron overload disorders by decreasing non-transferrin bound iron (NTBI) by administering a modified iron binding/releasing transferrin.

Many of the described compounds which act as hepcidin agonists or hepcidin mimetics are relatively high molecular weight compounds, in particular those which are obtainable predominantly by genetic engineering. Various further approaches on the basis of biomolecular interactions and biomolecules have been described. The disadvantage is the complex preparation and high sensitivity of such biomolecular compounds. At least one therapeutic Fpn antibody was reported to be efficacious in humans:“LY2928057 bound ferroportin and blocked interactions with hepcidin, allowing iron efflux, leading to increased serum iron and transferrin saturation (TSat) levels and increased hepcidin in monkeys and humans. In CKD patients, LY2928057 led to slower hemoglobin decline and reduction in ferritin (compared to placebo).” See Sheetz 2019 BrJCIinPharmacol.

Low molecular weight compounds which play a part in iron metabolism and can have an inhibiting or promoting effect are known, e.g. from WO2008/151288, W02008/1 18790, W02008/115999, and W02008/109840, relating to compounds acting as divalent metal transporter-1 (DMT1) inhibitors; from W02008/123093 relating to an agent for prevention or treatment of iron overload disorders, comprising 22 beta-methoxyolean-12-ene-3 beta, 24(4 beta)-diol; from EP1074254 and EP1072265 relating to the use of catechic- and flavonoid- structure plant polyphenols for treating iron overload.

WO2017/068089 (and its corresponding US equivalent US2018/0319783) and WO2017/068090 as well as WO2018/192973 describe novel low molecular weight compounds acting as ferroportin inhibitors in the treatment of excess iron conditions and iron overload diseases and further mention a possible combination therapy with conventional iron chelator drugs like Deferasirox.

A well-established hitherto existing method for directly treating iron overload is based on the concept to reduce the amount of iron in the serum by increased removal of the iron from the body. The eldest known and still routine treatment method in an otherwise-healthy person consists of regularly scheduled phlebotomies (bloodletting). When first diagnosed, the phlebotomies are usually scheduled fairly frequent, e.g. once a week, until iron levels are brought to within normal range, followed by phlebotomies which are then scheduled once a month or every three months depending upon the patient's rate of iron loading.

For patients unable to tolerate routine blood draws, chelating agents are frequently used to remove excess iron amounts from the serum.

Well known and established drugs used in iron chelation therapy comprise, for example, deferoxamine (also known as desferrioxamine B, N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4- [(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl} amino)pentyl]-N-hydroxysuccinamide or Desferal®), which is a bacterial siderophore. Deferoxamine binds iron in the bloodstream as a chelator and enhances its elimination via urine and faeces. Typical treatment of chronic iron overload requires subcutaneous injection over a period of 8 - 12 hours daily. Parenterally injectable compositions of desferrioxamine-B salts are described for example in WO 1998/25887.

Two further established iron chelating drugs approved for use in patients receiving regular blood transfusions to treat thalassemia, resulting in the development of iron overload, are deferasirox and deferiprone. Deferasirox (Exjade®, 4-(3,5-bis(2-hydroxyphenyl)-1 H-1 ,2,4-triazol-

1-yl)benzoic acid), being described for example in WO 1997/49395 or in the scientific paper of Heinz et al. “4-[3,5-Bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoid Acid: A novel Efficient and Selective Iron(lll) Complexing Agent”; Angewandte Chemie, Int. Edt., Vol. 38, No. 17, pages 2568 - 2570, 1999, and deferiprone (Ferriprox®, 3-hydroxy-1 ,2-dimethylpyridin-4(1 H)-one) are similarly acting as an iron chelating agent, thus being suitable as a drug for iron chelation therapy. Jezwski et al. “Optical Behaviour of Substituted 4-(2’-Hydroxyphenyl)imidazoles”; J. Phys. Chem. Part B, Vol. 119, No. 6, pages 2507 - 2514, 2015 and DE 4320802 A1 provide general technical background information with respect to 2-hydroxyphenly-substituted imidazoles without being further relevant for the specific technical field of the present application.

Further compounds acting as iron chelator for use in the treatment of iron overload have been described for example in WO2013/142258 relating to encapsulated particles of diethylenetriaminepentaacetate (DTPA) and a zinc salt; in W02003/041709 relating to 4-hydroxy-

2-alkylquniolines such as 4-hydroxy-2-nonylqunioline as an iron chelator; in W01998/09626 relating to chelating agents for treating iron overload states on the basis of dithiocarbamate- containing compositions; in WO2015/077655 relating to desferrithiocin derivatives for the use in the treatment of iron overload diseases acting as iron chelating agents; or in W02005/051411 relating to novel antibiotics or antimycotics on the basis of oxachelin and derivatives, which are described to act as an iron chelator and to be used in the treatment of iron overload diseases.

The treatment of excess iron or iron overload by chelation therapy is well established and provides an easy and direct possibility to quickly remove excess iron in chelated form from the body and thus rapidly counterbalance iron overload when it occurs, e.g. upon blood transfusions. However, the established drugs for iron chelation therapy are known to exhibit several disadvantages. Deferoxamine (desferrioxamine B) only has low, inadequate activity on oral administration and requires parenteral administration, e.g. by subcutaneous infusion. This, however, demands the use of medicinal equipment such as infusion syringes and equipment, infusion devices and electrical drives etc. Further, infusions or injections always bear the risk of microbiological contamination of the puncture with possible infections or inflammations. Parenteral administration ways are further much more cost intensive and require medical attencance and visits in a hospital or at a doctor, which further increases treatment costs and may negatively affect patient compliance. In contrast oral administration routes are much cheaper and beneficial with respect to patient compliance and are thus preferred.

Established oral iron chelators such as deferasirox (Exjade®) and deferiprone (Ferriprox®) are further known to exhibit an undesired toxic potential and undesired adverse effects. The European Medicines Agency (EMA) issued a warning that deferasirox's toxicity is likely to increase when the maximum recommended dose increases from 30 to 40 mg/kg per day. The FDA reports 4-week oral toxicity study results in Rats for deferasirox (Exjade^®) with significant toxicological effects and observed mortality rates (see e.g. Tamal K. Chakraborti, NDA No. 21 - 882, pages 420 to 424). The prescribing information of deferasirox includes a warning with respect to renal, hepatic failure and/or gastrointestinal hemorrhage. Exjade may cause renal impairment, including failure, hepatic impairment, including failure, gastrointestinal hemorrhage. In some reported cases, these reactions were fatal. These reactions were more frequently observed in patients with advanced age, high risk myelodysplastic syndromes (MDS), underlying renal or hepatic impairment or low platelet counts (<50 x 10⁹/L). Exjade therapy requires close patient monitoring, including laboratory tests of renal and hepatic function.

OBJECT

The object of the present invention was to provide new iron chelating compounds. In particular, the new iron chelators should be therapeutically effective and safe compounds that can be used as medicaments, particularly for the treatment of diseases or conditions related to or caused by excess or increased iron levels, increased iron absorption or iron overload in a mammal. The new iron chelators should in particular be therapeutically effective in treating iron overload diseases such as thalassemia and hemochromatosis or be suitable to reduce excess iron related to or caused by blood transfusions. A further object of the present invention was to provide new iron chelating compounds having a high iron binding affinity. Further, the new iron chelating compounds should exhibit a sufficient complex stability to safely remove bound iron from the body. In a further object of the present invention the new iron chelating compounds should exhibit a high selectivity to iron. It was in particular desired to provide new iron chelating compounds with an optimized balance between iron binding capacity or complex stability, iron release from the complex and/or selectivity. A high selectivity and an optimized balance of iron binding and release is particularly important to avoid uncontrolled binding of all iron from the body, tissues and cells. A further object of the invention was to provide new therapeutically effective and safe iron chelating compounds with low or compared to known chelators reduced adverse effects and good compatibility. A further object of the invention was to provide new therapeutically effective and safe iron chelating compounds with low or compared to known chelators reduced toxicity, which is particularly important in long-term applications. In particular iron overload usually needs a continued treatment over the whole lifetime and thus requires medicaments with long-term compatibility and safety. A further object of the invention was to provide new therapeutically effective and safe iron chelating compounds with good or compared to known chelators improved solubility. A further object of the invention was to provide new therapeutically effective and safe iron chelating compounds for oral administration. In a further object the new compounds should have a defined structure (stoichiometry) and should be preparable by simple synthesis processes as compared to biomolecular compounds.

This goal was achieved by the development of the novel compounds according to the formulae as defined herein, such as in particular according to formula (I), which have been found to act as improved iron chelators, thus being suitable for the use in the prophylaxis and/or treatment of diseases or conditions related to or caused by excess or increased iron levels, increased iron absorption or iron overload in a mammal or in reducing excess iron caused by blood transfusions.

DESCRIPTION OF THE INVENTION

The inventors have surprisingly found that novel compounds having the general structural formula (I) as defined herein, act as iron chelators with low toxicity, high affinity and selectivity, having sufficient stability and good solubility properties, being particularly suitable as therapeutically effective and safe iron chelators for the use as medicaments, in particular for the use in the prophylaxis and/or treatment of diseases or conditions related to or caused by excess or increased iron levels, increased iron absorption or iron overload in a mammal, such as in particular thalassemia and hemochromatosis or for reducing excess iron caused by blood transfusions. The reduced toxicity of the novel compounds is in particular for long-term administration in the treatment of iron overload advantageous. The novel compounds further turned out as suitable iron chelators for oral administration, which is the preferred administration route due to lower costs and medicinal effort and increased patient compliance and safety.

Accordingly, in a first aspect the present invention relates to novel compounds of general formula (I)

wherein the group -COR¹ represents a group -(C=0)-R\ wherein

R¹ is selected from the group consisting of

- -OH,

- Ci-C4-alkoxy,

- Ci-C4-halogenoalkyl having 1 to 3 halogen atoms,

Ci-C4-halogenoalkoxy having 1 to 3 halogen atoms, and

- a deprotonated group -O^Q or a salt form thereof;

R² represents one or more substituents independently selected from the group consisting of

- hydrogen,

- halogen,

- -OH,

- linear or branched CrC₆-alkyl which may carry 1 , 2 or 3 substituents,

- C3-C6-cycloalkyl which may carry 1 , 2 or 3 substituents, and

Ci-C₆-alkoxy which may carry 1 , 2 or 3 substituents,

wherein the substituents of alkyl, cycloalkyl and alkoxy may be the same or different and may independently be selected from the group consisting halogen, CrCi-alkyl, Ci-C3-alkoxy, wherein the alkyl- and alkoxy-substituent each may carry 1 , 2 or 3 further substituents independently selected from halogen, CrC3-alkyl and Ci-C3-alkoxy;

R³ is selected from the group consisting of

hydrogen,

- linear or branched Ci-C4-alkyl which may carry 1 , 2 or 3 substituents, and

- C3-C6-cycloalkyl which may carry 1 , 2 or 3 substituents,

wherein the substituents of alkyl and cycloalkyl may be the same or different and may independently be selected from the group consisting of halogen, Ci-C3-alkyl and CrC3-alkoxy, wherein the alkyl- and alkoxy-substituent each may carry 1 , 2 or 3 further substituents independently selected from halogen, CrC3-alkyl and CrC3-alkoxy;

R⁴ and R⁵ each represent one or more substituents independently selected from the group consisting of

- hydrogen,

- halogen,

- -OH,

- linear or branched CrC₆-alkyl which may carry 1 , 2 or 3 substituents,

- C3-C6-cycloalkyl which may carry 1 , 2 or 3 substituents, and

- Ci-C₆-alkoxy which may carry 1 , 2 or 3 substituents,

wherein the substituents of alkyl, cycloalkyl and alkoxy may be the same or different and may independently be selected from the group consisting of halogen, cyano, Ci-C3-alkyl and C1-C3- alkoxy, wherein the alkyl- and alkoxy-substituent each may carry 1 , 2 or 3 further substituents independently selected from Ci-C3-alkyl and CrC3-alkoxy; R⁶ and R⁶ each represent one or more substituents independently selected from the group consisting of

- hydrogen,

- a negative chargee, or a salt form thereof; and pharmaceutically acceptable salts thereof.

Definitions

The term“substituted” means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.

The term“optionally substituted” means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Commonly, it is possible for the number of optional substituents, when present, to be 1 , 2, 3, 4 or 5, in particular 1 , 2 or 3, unless indicated otherwise.

As used herein, the term“one or more”, e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention, means“1 , 2, 3, 4 or 5, particularly 1 ,

2, 3 or 4, more particularly 1 , 2 or 3, even more particularly 1 or 2”.

Further, if used herein, the position via which a respective subsituent is connected to the rest of the molecule may in a drawn structure be depicted by a hash sign (#) or a dashed line in said substituent.

The term “comprising” or“including” when used in the present specification includes “consisting of”.

If within the present specification any item is referred to as “as mentioned herein”, it means that it may be mentioned anywhere in the present specification.

The term“mammal” includes humans and animals, with humans being preferred.

Further, the terms as mentioned in the present specification or claims have the following meanings:

The term“halogen” or“halogen atom” means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom, more preferably fluorine or chlorine, with fluorine being most preferred.

The term “alkyl” generally includes a linear or branched, saturated, monovalent hydrocarbon group preferably containing 1 to 6, particularly preferably 1 to 4, even more preferred 1 , 2 or 3 carbon atoms. In particular, the term“Ci-C₆-alkyl” means a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5 or 6 carbon atoms. The term “Ci-C4-alkyl” means a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2,

3, or 4 carbon atoms. Particularly, said group has 1 , 2 or 3 carbon atoms (“Ci-C3-alkyl”). Examples include a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group or a tert- butyl group, an n-pentyl group, an i-pentyl group, a sec- pentyl group, a t-pentyl group, a 2-methylbutyl group, an n-hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 1-ethylbutyl group, a 2- ethylbutyl group, a 3-ethylbutyl group, a 1 , 1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-dimethylbutyl group, a 1-ethyl-1-methylpropyl group, or an isomer thereof. Preferred are a methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, sec-butyl, and t-butyl group. C₁-C₃ alkyl, in particular, methyl, ethyl and i-propyl are more preferred. More preferred are Ci and C₂ alkyl, such as methyl and ethyl. Most preferred is a methyl group.

The term “cycloalkyl” generally relates to a saturated, monovalent, monocyclic hydrocarbon ring containing 3 to 8 carbon atoms, preferably containing 3 to 6 carbon atoms. In particular, the term“C3-C6-cycloalkyl” means a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms. Said C3-C6-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, with a cyclopropyl group being particularly preferred.

The term“alkoxy” generally relates to a linear or branched, saturated, monovalent alkyl- O- group, in which the term “alkyl” has the meaning as defined supra. In particular, the term “CrC₆-alkoxy” or “CrC4-alkoxy” or “CrC3-alkoxy” refers to a group of the formula (Ci-C₆-alkyl)-0-, (Ci-C₄-alkyl)-0- or (Ci-C₃-alkyl)-0-, respectively, wherein in each case “Ci-C₆-alkyl”, “Ci-C4-alkyl” and “Ci-C3-alkyl” have the meaning as defined supra. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or ferf- butoxy, or an isomer thereof. Preferred are methoxy and ethoxy, with methoxy being most preferred.

The alkyl, cycloalkyl and/or alkoxy groups as defined herein may carry one or more substituents, such as in particular 1 , 2 or 3 substituents.

Preferred substituents of alkyl, cycloalkyl and/or alkoxy groups as defined herein may independently be selected from group comprising halogen, cyano, an alkyl group or an alkoxy group, each as defined herein. Particularly preferred substituents of alkyl, cycloalkyl and/or alkoxy groups as defined herein are selected from halogen, CrC3-alkyl and Ci-C3-alkoxy. Therein, also the alkyl- and alkoxy-substituent itself may carry 1 , 2 or 3 further substituents independently selected from halogen, CrC3-alkyl and Ci-C3-alkoxy.

In particular, an alkyl-group as defined herein being substituted with one or more halogen atoms may also be designated by the term “halogenoalkyl”, such as in particular “Ci-C₆-halogenoalkyl” or“Ci-C4-halogenoalkyl”, which means a linear or branched, saturated, monovalent hydrocarbon group in which the term “alkyl”, “Ci-C₆-alkyl” or “Ci-C4-alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a chlorine and/or fluorine atom, preferably a fluorine atom. More particularly, all said halogen atoms are fluorine atoms (e.g. “Ci-C4-fluoroalkyl”). Examples of a Ci-C4-halogenoalkyl group comprise a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, a trichloromethyl group, a bromomethyl group, a dibromomethyl group, a tribromomethyl group, a 1 -fluoroethyl group, a 1-chloroethyl group, a 1-bromoethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a difluoroethyl group such as a 1 ,2-difluoroethyl group, a 1 ,2-dichloroethyl group, a 1 ,2-dibromoethyl group, a 2,2-difluoroethyl group, a 2,2- dichloroethyl group, a 2,2-dibromoethyl group a 2,2,2-trifluoroethyl group, a heptafluoroethyl group, a 1 -fluoropropyl group, a 1-chloropropyl group, a 1 -bromopropyl group, a 2-fluoropropyl group, a 2-chloropropyl group, a 2-bromopropyl group, a 3-fluoropropyl group, a 3-chloropropyl group, a 3-bromopropyl group, a 1 ,2-difluoropropyl group, a 1 ,2-dichloropropyl group, a 1 ,2- dibromopropyl group, a 2,3-difluoropropyl group, a 2,3-dichloropropyl group, a 2,3-dibromopropyl group, a 3,3,3-trifluoropropyl group, a 2,2,3,3,3-pentafluoropropyl group, a 2-fluorobutyl group, a 2-chlorobutyl group, a 2-bromobutyl group, a 4-fluorobutyl group, a 4-chlorobutyl group, a 4- bromobutyl group, a 4,4,4-trifluorobutyl group, a 2,2,3,3,4,4,4-heptafluorobutyl group, a perfluorobutyl group, etc.. A trifluorom ethyl group is particularly preferred.

In particular, an alkoxy-group as defined herein being substituted with one or more halogen atoms may also be designated by the term “halogenoalkoxy”, such as in particular “Ci-C₆-halogenoalkoxy” or“Ci-C4-halogenoalkoxy”, which means a linear or branched, saturated, monovalent hydrocarbon group in which the term“alkoxy”,“Ci-C₆-alkoxy” or“Ci-C4-alkoxy” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a chlorine and/or fluorine atom, preferably a fluorine atom. More particularly, all said halogen atoms are fluorine atoms (e.g.“Ci-C4-fluoroalkoxy”). Examples of a Ci-C4-halogenoalkoxy group comprise fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy, with a trifluoromethoxy group being particularly preferred.

The term “C1-C4”, as used in the present text, e.g. in the context of the definition of “Ci-C4-alkyl”,“Ci-C4-halogenoalkyl”,“Ci-C4-alkoxy” or“Ci-C4-halogenoalkoxy” means an alkyl- or alkoxy- group having a finite number of carbon atoms of 1 to 4, i.e. 1 , 2, 3 or 4 carbon atoms.

Further, as used herein, the term“C3-Cs”, as used in the present text, e.g. in the context of the definition of “C3-Cs-cycloalkyl” means a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms.

When a range of values is given, said range encompasses each value and sub-range within said range. For example:

"C1-C6" encompasses C 1 , C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2- C4, C2-C3, C3-C6, C3-C5, and C3-C4;

"C1-C4" encompasses Ci, C2, C3, C4, C1-C4, C1-C3, C1-C2, C2-C4, C2-C3, and C3-C4;

"C1-C3" encompasses Ci , C2, C3, C1-C3, C1-C2, and C2-C3;

"C3-C6" encompasses C3, 0₄, C5, C6, C3-C6, C3-C5, C3-C₄, C₄-C6, C₄-C5, and C5-G6.

According to the present invention a group -COR represents a carbonyl group -(C=0)-R. Therein, it is preferred that the group R represents an -OH group to form a carboxylic acid group -(=0)-OH. Such carbonyl- or carboxylic acid group may also be present in deprotonated form — (C— 0)-O^q or in any salt form thereof.

In a second aspect the present invention relates to novel compounds of general formula (II)

wherein

the group -COOR^1# represents a group -(C=0)-0-R^1#, wherein

R^1# is selected from the group consisting of

- hydrogen,

- linear or branched CrC4-alkyl,

- Ci-C4-halogenoalkyl having 1 to 3 halogen atoms, and

a negative charge© or a salt form thereof;

- hydrogen,

- halogen,

- -OH,

- linear or branched CrC₆-alkyl which may carry 1 , 2 or 3 substituents,

- C3-C6-cycloalkyl which may carry 1 , 2 or 3 substituents, and

- Ci-C₆-alkoxy which may carry 1 , 2 or 3 substituents,

wherein the substituents of alkyl, cycloalkyl and alkoxy may be the same or different and may independently be selected from the group consisting of halogen, Ci-C3-alkyl and Ci-C3-alkoxy, wherein the alkyl- and alkoxy-substituent each may carry 1 , 2 or 3 further substituents independently selected from halogen, CrC3-alkyl and CrC3-alkoxy;

R³ is selected from the group consisting of

- hydrogen,

linear or branched CrC4-alkyl which may carry 1 , 2 or 3 substituents, and

- C3-C6-cycloalkyl which may carry 1 , 2 or 3 substituents,

wherein the substituents of alkyl, cycloalkyl and alkoxy may be the same or different and may independently be selected from the group consisting of halogen, Ci-C3-alkyl and CrC3-alkoxy, wherein each of the alkyl- and alkoxy-substituent may carry 1 , 2 or 3 further substituents independently selected from halogen, CrC3-alkyl and CrC3-alkoxy;

hydrogen,

- halogen,

- -OH,

- linear or branched CrC₆-alkyl which may carry 1 , 2 or 3 substituents,

- C3-C6-cycloalkyl which may carry 1 , 2 or 3 substituents, and

- Ci-C₆-alkoxy which may carry 1 , 2 or 3 substituents,

wherein the substituents of alkyl, cycloalkyl and alkoxy may be the same or different and may independently be selected from the group consisting of halogen, Ci-C3-alkyl and Ci-C3-alkoxy, wherein each of the alkyl- and alkoxy-substituent may carry 1 , 2 or 3 further substituents independently selected from Ci-C3-alkyl and CrC3-alkoxy; and pharmaceutically acceptable salts thereof. In a third aspect the present invention relates to novel compounds of general formula (I) or (II) supra, wherein

- hydrogen,

- halogen,

- -OH,

- linear or branched CrC₆-alkyl which may carry 1 , 2 or 3 substituents,

- C3-C6-cycloalkyl which may carry 1 , 2 or 3 substituents, and

- Ci-C₆-alkoxy which may carry 1 , 2 or 3 substituents,

wherein the substituents of alkyl, cycloalkyl and alkoxy may be the same or different and may independently be selected from the group consisting of halogen, Ci-C3-alkyl and Ci-C3-alkoxy, wherein the alkyl- and the alkoxy-substituent each may carry 1 , 2 or 3 further substituents independently selected from halogen and CrC3-alkoxy;

R³ is selected from the group consisting of

- hydrogen,

- linear or branched CrC4-alkyl which may carry 1 , 2 or 3 substituents, and

- C3-C6-cycloalkyl which may carry 1 , 2 or 3 substituents,

wherein the substituents of alkyl, cycloalkyl and alkoxy are selected from Ci-C3-alkyl;

- hydrogen,

- halogen,

- -OH,

- linear or branched CrC₆-alkyl which may carry 1 , 2 or 3 substituents,

- C3-C6-cycloalkyl which may carry 1 , 2 or 3 substituents, and

- Ci-C₆-alkoxy which may carry 1 , 2 or 3 substituents,

wherein the substituents of alkyl, cycloalkyl and alkoxy may be the same or different and may independently be selected from the group consisting of halogen, Ci-C3-alkyl and Ci-C3-alkoxy, wherein the alkyl- and alkoxy-substituent each may carry 1 , 2 or 3 further substituents selected from Ci-C3-alkoxy; and pharmaceutically acceptable salts thereof.

In a fourth aspect the present invention relates to novel compounds of general formula (I) or (II) supra, wherein

- hydrogen,

- halogen,

- linear or branched CrC4-alkyl which may carry 1 , 2 or 3 substituents, and

- Ci-C4-alkoxy which may carry 1 , 2 or 3 substituents, wherein the substituents of alkyl and alkoxy may be the same or different and may independently be selected from the group consisting of halogen, Ci-C3-alkyl, and CrC3-alkoxy, wherein the alkyl- and the alkoxy-substituent each may carry 1 , 2 or 3 further substituents independently selected from halogen and CrC3-alkoxy;

R³ is selected from the group consisting of

- hydrogen,

linear or branched CrC4-alkyl which may carry 1 , 2 or 3 substituents, and

- C3-C6-cycloalkyl which may carry 1 , 2 or 3 substituents,

wherein the substituents of alkyl and cycloalkyl are selected from CrC3-alkyl;

- hydrogen,

- -OH,

- linear or branched Ci-C3-alkyl, and

- Ci-C4-alkoxy; and pharmaceutically acceptable salts thereof.

In a further aspect of the present invention the substituents of the general formula (I) or (II) supra, independently have the following preferred meaning:

1) R¹ is -OH and R^1# is hydrogen, respectively.

2) R² is selected from the group consisting of

hydrogen,

halogen, such as preferably fluorine,

Ci-C3-alkyl which may be substituted with 1 , 2 of 3 halogen atoms, such as preferably trifluoromethyl,

CrC3-alkoxy, such as preferably methoxy,

- CrC3-alkoxy which may be substituted with 1 or 2 alkoxy groups, such as preferably a methoxy-substituted ethoxy group, or an ethoxy group substituted with a methoxy- substituted ethoxy group.

3) R³ is selected from the group consisting of

hydrogen,

Ci-C4-alkyl, such as preferably methyl, ethyl or iso-butyl,

CrC3-alkyl which may be substituted with an alkoxy group, such as preferably a methoxy-substituted methyl group,

C3-C6-cycloalkyl, such as preferably cyclopropyl.

4) R⁴ is selected from the group consisting of

hydrogen,

halogen, such as preferably fluorine,

CrC3-alkoxy, such as preferably methoxy. 5) R⁵ is selected from the group consisting of

hydrogen,

halogen, such as preferably fluorine,

- CrC3-alkoxy, such as preferably methoxy.

6) R^s and R^6’ each are hydrogen.

The invention encompasses also combinations of the embodiments according to the various aspects described above.

For the suitability as an iron chelator it is of particular importance that the compounds of the present invention form sufficiently stable and highly selective complexes with iron. Therefore, in further aspect the potential of the novel compounds to act as an efficient and safe iron chelator can be concluded from their affinity to chelate iron and form iron complexes. The affinity to bind iron can also be designated as the complex activity, which in principle corresponds to their dissociation or equilibrium constants.

However, not only a high affinity but also a certain complex stability is important. It is crucial that sufficient iron is bound with sufficient complex stability to safely remove the chelated iron from the body but also the affinity must not be too high to extract all biophysiologically iron from tissue and cells.

Further, a high selectivity to primarily bind iron instead of other metals such as e g. Cu²⁺, Zn²⁺, Ni²⁺, Mg²⁺ or Ca²⁺ is desired.

The affinity or complex activity of the compounds of the present invention with respect to iron and the selectivity over various metals can be defined by the so-called pM/pFe value, wherein “M” indicates“metal” (pM) such as particularly iron (pFe). Said pM/pFe value can be determined according to the potentiometric titration method described in detail in the Methods A) and B) in the examples below, wherein Method A) is preferred. Therein, potentiometric titrations are performed in water/DMSO solution mixtures for the determination of the equilibrium constants of the complex formation.

Accordingly, in a further aspect the present invention relates to novel compounds of general formula (I), (II) or (III) as defined anywhere herein, which are further characterized by a complex activity or selectivity represented by a pFe value of at least (³) 19, preferably at least (³) 20. Further, the pFe value preferably does not exceed 27. The pFe value of the novel compounds of the present invention is preferably in the range of 19 to 27, more preferably in the range of 20 to 27, even more preferably in the range of 20 to 25. As explained above, the pFe value characterizes the affinity of the chelator (ligand) to the iron and reflects the binding activity and thus the strength or stability of the iron complex as well as its selectivity to iron.

If the pFe value is below 19 the affinity to stably and selectively bind iron is not sufficient. Although a complex formation with iron may occur the stability of the complex until the complexed iron is removed from the body may suffer and the complex may dissociate anywhere on its way through the body and release the complexed iron again. Further, compounds having a pFe value below 19 may not be sufficiently selective to chelate iron instead of other metals as explained below in context with preferred pM values.

If the pFe value is above 27 the affinity may be too high and uncontrolled iron binding may occur leading to uncontrolled and undesired extraction of iron from tissue and cells instead of chelating only the excess iron resulting from the iron overload conditions. The pFe values defined herein can be determined with the potentiometric titration method as described in detail in the Methods A) and B) in the Examples below, among which Method A) is preferred.

In a further aspect the present invention relates to novel compounds of general formula (I), (II) or (III) as defined anywhere herein, which are further characterized by a selectivity to one or more of the metals Cu²⁺, Zn²⁺, Ni²⁺, Mg²⁺ or Ca²⁺, represented by the following pM values:

Metal element pM value

< 15

< 8

The compounds of the present invention may be characterized by one or more of the above defined pM values and in any combination thereof.

Therein, the pM value characterizes the selectivity of the compounds of the present invention to bind to the respective metals Cu²⁺, Zn²⁺, Ni²⁺, Mg²⁺ or Ca²⁺.

If the pM values of the respective metals exceed the defined upper value, the affinity to the respective metal becomes too high and the affinity to the target metal iron (Fe³⁺) may be reduced. Therefore, the pM values for the metal elements Cu²⁺, Zn²⁺, Ni²⁺, Mg²⁺ or Ca²⁺ should generally be lower than the pFe value.

A particularly preferred embodiment relates to the novel compounds of general formula (I), (II) or (III) as defined anywhere herein, which are further characterized by a selectivity to Zn, represented by a pM value (pZn value) of < 8.

In a further embodiment the novel compounds are characterized by a selectivity to Zn, represented by a pM value (pZn value) of < 8 and by at least one of the further pM values indicated above.

The pM values defined herein can be determined with the same potentio metric titration method as the pFe value and as described in detail in the Method in the Examples below (Methods A) and B).

As explained above, the pM/pFe values characterize the affinity of the compounds of the present invention to the respective metal element and thus reflect the binding activity to the respective metal elements. The pM/pFe values represent log-values.

In a further aspect the present invention relates to novel compounds of general formula (I), (II) or (III) as defined anywhere herein, which are characterized by a good solubility in water, physiological media or aqueous solutions.

It is particularly preferred that the novel compounds are characterized by one or more of the aforesaid properties of pFe value, pM value of one or more of the indicated metals and/or solubility.

Particularly preferably the compounds according to the present invention are selected from the compounds as shown in the following Table 1 :

or pharmaceutically acceptable salts thereof.

In a particularly preferred aspect the present invention relates to novel compounds of general formula (I) or (II) supra, which are represented by the formula (III) according to Example 40:

and pharmaceutically acceptable salts thereof.

Pharmaceutically acceptable salts of the compounds according to the invention include, for example, salts with suitable pharmaceutically acceptable bases, such as, for example, salts with alkaline or alkaline-earth hydroxides, such as NaOH, KOH, Ca(OH)₂, Mg(OH)₂

The novel compounds of the present invention can be present in an amorphous, crystalline or partially crystalline form or they may also be present exist as hydrates.

Medical Use

The novel compounds according to formula (I) and its further embodiments, as defined above, have surprisingly been found to act as iron chelators with improved therapeutic efficacy and improved characteristics for pharmaceutical administration forms, making them particularly suitable for the use as a medicament, such as in particular for the use as iron chelators in vivo.

As mentioned above, as important characteristics which determine suitability as therapeutical iron chelator toxicity, affinity, selectivity, complex stability and solubility can be mentioned besides its efficacy to reduce iron overload in tissue (e.g. in liver).

The suitability and superiority of the novel compounds according to the present invention is shown in the Examples below in more detail.

Due to the particular suitability of the compounds as defined herein as therapeutically effective and safe iron chelators, the compounds of the present invention are particularly suitable for the use in the prophylaxis and/or treatment of conditions or diseases related to, accompanied by or caused by increased iron levels, increased iron absorption, iron overload or ineffective erythropoiesis in mammals.

The novel compounds of the present invention are further particularly suitable for the use as an iron chelator in vivo in conditions of increased iron levels, increased iron absorption or iron overload in a mammal caused by blood transfusions, in particular in blood transfusions given in the conditions or diseases described herein (e g. thalassemia, myelodysplastic syndromes (MDS, myelodysplasia). Diseases or conditions being associated with, being related to, being caused by or leading to increased or excess iron levels, increased iron absorption, iron overload (e.g. serum or tissue iron overload) or ineffective erythropoiesis comprise in particular thalassemia, including alpha-thalassemia, beta-thalassemia and delta-thalassemia.

Diseases or conditions being associated with, being related to, being caused by or leading to increased or excess iron levels, increased iron absorption, iron overload (e.g. serum or tissue iron overload) or ineffective erythropoiesis further comprise hemoglobinopathy, such as hemoglobin E disease (HbE), hemoglobin H disease (HbH), haemochromatosis, hemolytic anemia, such as sickle cell anemia (sickle cell disease) and congenital dyserythropoietic anemia.

Diseases or conditions being associated with, being related to, being caused by or leading to increased or excess iron levels, increased iron absorption, iron overload (e.g. tissue iron overload) further comprise neurodegenerative diseases, such as for example Alzheimer’s disease and Parkinson’s disease, wherein the compounds are considered to be effective by limiting the deposition or increase of iron in tissue or cells.

The novel compounds of the present invention are further suitable for the use in the prophylaxis and/or treatment of formation of radicals, reactive oxygen species (ROS) and oxidative stress caused by excess iron or iron overload as well as in the prophylaxis and/or treatment of cardiac, kidney, liver and endocrine damage caused by excess iron or iron overload, and further in the prophylaxis and/or treatment of inflammation triggered by excess iron or iron overload.

Diseases associated with ineffective erythropoiesis comprise in particular thalassemia, myelodysplastic syndromes (MDS, myelodysplasia) and polycythemia vera as well as congenital dyserythropoietic anemia.

Further diseases, disorders and/or diseased conditions, which may be treated with the novel compounds of the present invention, comprise excess iron or iron overload caused by mutations in genes involved in sensing the systemic iron stores, such as hepcidin (Hampl), hemochromatosis protein (HFE), hemojuvelin (HJV) and transferrin receptor 2 (TFR2), such as in particular diseases related to HFE and HJV gene mutations, mutations in ferroportin, chronic hemolysis associated diseases, sickle cell diseases, red cell membrane disorders, Glucose-e- phosphate dehydrogenase deficiency (G6PD deficiency), erythrpoietic porphyria, Friedrich^'s Ataxia, as well as subgroups of iron overload such as transfusional iron overload, iron intoxication, pulmonary hemosiderosis, osteopenia, insulin resistense, African iron overload, Hallervordan Spatz disease, hyperferritinemia, ceruloplasmin deficiency, neonatal hemochromatosis and red blood cell disorders comprising thalassemia, including alpha thalassemia, beta thalassemia and delta thalassemia, thalassemia intermedia, sickle cell disease and myelodyplastic syndrome.

Further diseases and/or disorders and/or diseased conditions associated with elevated iron levels, which may be treated with the novel compounds of the present invention, include, but are not limited to, diseases with elevated iron level, comprising ataxia, Friedrich's ataxia, age- related macular degeneration, age-related cataract, age-related retinal diseases and

neurodegenrative disease, such as pantothenate kinase-associated neurodegeneration, restless leg syndrom and Huntington's disease.

Dosage Forms In view thereof a further object of the present invention relates to a medicament containing one or more of the novel compounds as defined above, such as in particular a medicament for the prophylaxis and/or treatment in any of the indications, conditions, states, disorders or diseases as defined above.

A further aspect of the present invention relates to pharmaceutical compositions and medicaments comprising one or more of the novel compounds according to the invention as defined above and optionally one or more pharmacologically acceptable carriers and/or auxiliary substances and/or solvents.

A further aspect of the present invention relates to pharmaceutical compositions and medicaments comprising one or more of the novel compounds according to the invention as defined above and optionally one or more further pharmaceutically effective compounds or co drugs.

The said pharmaceutical compositions contain, for example up to 99 weight-% or up to 90 weight-% or up to 80 weight-% or or up to 70 weight-% of the compounds of the invention, the remainder being each formed by pharmacologically acceptable carriers and/or auxiliaries and/or solvents and/or optionally further pharmaceutically active compounds.

Pharmaceutically acceptable carriers, auxiliary substances or solvents are common pharmaceutical carriers, auxiliary substances or solvents, including various organic or inorganic carrier and/or auxiliary materials as they are customarily used for pharmaceutical purposes, in particular for solid medicament formulations. Examples include excipients, such as saccharose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talcum, calcium phosphate, calcium carbonate; binding agents, such as cellulose, methylcellulose, hydroxypropylcellulose, polypropyl pyrrolidone, gelatine, gum arabic, polyethylene glycol, saccharose, starch; disintegrating agents, such as starch, hydrolyzed starch, carboxymethylcellulose, calcium salt of

carboxymethylcellulose, hydroxypropyl starch, sodium glycol starch, sodium bicarbonate, calcium phosphate, calcium citrate; lubricants, such as magnesium stearate, talcum, sodium laurylsulfate; flavorants, such as citric acid, menthol, glycin, orange powder; preserving agents, such as sodium benzoate, sodium bisulfite, paraben (for example methylparaben, ethylparaben, propylparaben, butylparaben); stabilizers, such as citric acid, sodium citrate, acetic acid and multicarboxylic acids from the titriplex series, such as, for example,

diethylenetriaminepentaacetic acid (DTPA); suspending agents, such as methycellulose, polyvinyl pyrrolidone, aluminum stearate; dispersing agents; diluting agents, such as water, organic solvents; waxes, fats and oils, such as beeswax, cocoa butter; polyethylene glycol; white petrolatum; etc..

Liquid medicament formulations, such as solutions, suspensions and gels usually contain liquid carrier, such as water and/or pharmaceutically acceptable organic solvents. Furthermore, such liquid formulations can also contain pH-adjusting agents, emulsifiers or dispersing agents, buffering agents, preserving agents, wetting agents, gelatinizing agents (for example

methylcellulose), dyes and/or flavouring agents, for example as defined above. The compositions may be isotonic, that is, they can have the same osmotic pressure as blood. The isotonicity of the composition can be adjusted by using sodium chloride and other pharmaceutically acceptable agents, such as, for example, dextrose, maltose, boric acid, sodium tartrate, propylene glycol and other inorganic or organic soluble substances. The viscosity of the liquid compositions can be adjusted by means of a pharmaceutically acceptable thickening agent, such as methylcellulose. Other suitable thickening agents include, for example, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, carbomer and the like. The preferred concentration of the thickening agent will depend on the agent selected.

Pharmaceutically acceptable preserving agents can be used in order to increase the storage life of the liquid composition. Benzyl alcohol can be suitable, even though a plurality of preserving agents including, for example, paraben, thimerosal, chlorobutanol and benzalkonium chloride can also be used.

The above-mentioned pharmaceutical compositions are in principle suitable, for example, for intravenous, intraperitoneal, intramuscular, intravaginal, intrabuccal, percutaneous, subcutaneous, mucocutaneous, oral, rectal, transdermal, topical, intradermal, intragasteral or intracutaneous application and can be provided, for example, in the form of pills, tablets, enteric- coated tablets, film tablets, layer tablets, sustained release formulations for oral, subcutaneous or cutaneous administration (in particular as a plaster), depot formulations, dragees, suppositories, gels, salves, syrup, granulates, suppositories, emulsions, dispersions, microcapsules, microformulations, nanoformulations, liposomal formulations, capsules, enteric-coated capsules, powders, inhalation powders, microcrystalline formulations, inhalation sprays, epipastics, drops, nose drops, nose sprays, aerosols, ampoules, solutions, juices, suspensions, infusion solutions or injection solutions etc..

However, oral administration and accordingly oral administration forms such as pills, tablets, enteric-coated tablets, film tablets, layer tablets, sustained release formulations for oral administration, dragees, syrup, granulates, microcapsules, capsules, enteric-coated capsules, powders, drops, ampoules, solutions, juices and suspensions are preferred.

A further object of the present invention relates to medicaments or combined preparations containing one or more of the novel compounds as defined above and at least one further pharmaceutically active compound or co-drug, such as in particular a compound for the prophylaxis and treatment of iron overload and the associated symptoms.

Preferably the at least one further pharmaceutically active compound or co-drug is a compound for the prophylaxis and treatment of any of the states, disorders or diseases as defined above, such as in particular a pharmaceutically active compound for the prophylaxis and treatment of thalassemia, haemochromatosis, neurodegenerative diseases (such as Alzheimer’s disease or Parkinson’s disease) and the associated symptoms.

More preferably the at least one further pharmaceutically active compound or co-drug is also an iron-chelating compound, a hepcidin agonist or hepcidin mimetic, synthetic hepcidin or modified analogues thereof, including mini hepcidins, or a ferroportin inhibitor or a combination thereof.

Suitable iron-chelating co-drugs may be selected from deferoxamine (DFO; Desferal®; N'- [5-(Acetyl-hydroxy-amino)pentyl]-N-[5-[3-(5-aminopentyl-hydroxy-carbamoyl)

propanoylamino]pentyl]-N-hydroxy-butane diamide), deferasirox (Exjade®; 4-(3,5-bis(2- hydroxyphenyl)-1 H-1 ,2,4-triazol-1-yl)benzoic acid), deferiprone (DFP; Ferriprox®) and/or deferitrin. Oral iron-chelators as co-drugs, such as deferasirox and deferiprone are preferred.

Suitable ferroportin inhibitors may be selected from the compounds described in

WO2017/068089 and WO2017/068090 as well as WO2018/192973. In a preferred aspect of the invention the at least one further pharmaceutically active compound or co-drug is a ferroportin inhibitor according to the formula

or any pharmaceutically acceptable salt thereof, such as in particular a salt thereof as described in WO2018/192973, including in particular a 3HCI salt having the formula

1 : 1 sulfate salt having the formula

and polymorphs thereof.

The at least one further pharmaceutically active compound or co-drug for reducing excess iron or for treating iron overload may further be selected from Tmprss6 targeting ASO and siRNA, apotransferrin, curcumin, SSP-004184.

The at least one further pharmaceutically active compound or co-drug may further be selected from antioxidants, such as n-acetyl cysteine; anti-diabetics, such as GLP-1 receptor agonists; antibiotics, such as vancomycin (Van) or tobramycin; drugs for the treatment of malaria; anticancer agents; antifungal drugs; drugs for the treatment of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, comprising dopamine agonists such as Levodopa; anti-viral drugs, such as interferon-a or ribavirin; immunosuppressants, such as cyclosporine A or cyclosporine A derivatives; iron supplements; vitamin supplements; red cell production stimulators, including antagonists of TGFbeta superfamily members, such as

Luspatercept, antibodies, fragments of antibodies, non-antibody scaffold drugs or cells producing activin receptor ligand traps; EPO and ESA, HDAC inhibitors; anti-p-selectin Abs, HA (relevant for SCD), drugs targeting HbS aggregation; anti-inflammatory biologies; anti-thrombolytics;

statins; vasopressors; and inotropic compounds.

A very preferred combination of a novel iron chelator according to the present invention with a further pharmaceutically active compound or co-drug relates to the combination of a compound according to the formula (III)

or any pharmaceutically acceptable salts thereof, and a ferroportin inhibitor according to the formula

or any pharmaceutically acceptable salt thereof, such as in particular a 3HCI salt or a 1 : 1 sulfate salt.

A further object of the present invention relates to the use of the novel compounds as defined above per se, in a combination therapy (fixed dose or free dose combinations for sequential use) with one or two other active ingredients (drugs, co-drugs). Such combination therapy comprises co-administration of the novel compounds of the present invention with the at least one additional pharmaceutically active compound (co-drug).

Combination therapy in a fixed dose combination therapy comprises co-administration of the compounds of the present invention with the at least one additional pharmaceutically active compound in a fixed-dose formulation. Combination therapy in a free dose combination therapy comprises co-administration of the compounds of the present invention and the at least one additional pharmaceutically active compound in free doses of the respective compounds, either by simultaneous administration of the individual compounds or by sequential use of the individual compounds distributed over a time period. The at least one additional pharmaceutically active compound (co-drug) is preferably selected from the drugs defined above, preferably drugs for reducing iron overload such as the ferroportin inhibitors defined above or iron chelators as defined above, or antioxidants, anti-diabetics, antibiotics, drugs for the treatment of malaria, anticancer agents, antifungal drugs, drugs for the treatment of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, anti-viral drugs, immunosuppressents, iron supplements, vitamin supplements, red cell production stimulators, anti-inflammatory biologies, anti-thrombolytics, statins, vasopressors and inotropic compounds etc., each preferably as defined above.

A further object of the present invention relates to the use of the above combinations for the prophylaxis and/or treatment of conditions or diseases caused by excess iron or iron overload states such as in particular thalassemia and hemochromatosis and other disorders as described in the present application.

A further object of the present invention relates to the use of the compounds as defined herein per se or the hereinabove described combination therapies, in combination with blood transfusion.

The compounds, medicaments and or combined preparations according to the present invention may be administered orally, parentally, as well as intravenously, with oral administration being preferred. Regarding suitable administration forms reference is made to the description supra.

In a preferred embodiment of the invention the compounds are administered in the form of a tablet or capsule, as defined above. These may be present, for example, as acid resistant forms or with pH dependent coatings.

The compounds of the present invention as the active substance can be administered, for example, with a unit dose of 0.001 mg/kg to 500 mg/kg body weight, for example 1 to 4 times a day. However, the dose can be increased or reduced depending on the age, weight, condition of the patient, severity of the disease or type of administration.

Accordingly, a further object of the present invention relates to compounds, medicaments, compositions and combined preparations as defined above for the preparation of a medicament, particularly for the prophylaxis and treatment of any indication, state, disorder or disease as defined above, in particular for oral administration.

A further object of the present invention relates to a method for the prophylaxis and treatment as defined above, such as in particular for the prophylaxis and/or treatment of conditions, disorders or diseases being associated with, leading to or being caused by increased or excess iron levels and in particular iron overload, iron storage diseases being associated with or leading to increased iron levels, and diseases being associated with ineffective erythropoiesis, the method comprising administering, to a patient (human or animal) in need thereof, a compound, a medicament, a composition or a combined preparation as defined above.

Therein, diseases being associated with, being related to, being caused by or leading to increased iron levels or iron overload are as defined above.

A further object of the present invention relates to the use of the compounds as defined above for the preparation of a medicament, particularly for the prophylaxis and treatment and of any indication, state, disorder or disease as defined above.

Preparation Process and Syntheses Routes

The compounds according to the invention of general structural formula (I), (II) and (III) may basically be obtained by the processes described below and as shown in the following general procedures (General Schemes). Accordingly, a further object of the invention is a process for the production of the compounds of general formula (I), (II) and (III) as described herein.

The compounds according to the invention of general structural formula (I) were obtained by the synthesis methods described below in the following general procedures and general schemes. Therein, the substituents may have the meaning as described anywhere hierein:

General scheme 1 :

The synthesis was started with commercial available substituted anilines of common structure 51 , which were transformed with substituted nitriles 52 to benzimidamides with the common structure 53 under basic conditions by using sodium bis(trimethylsilyl)amide as base. It is also possible to use other bases like sodium hydride (Advanced Synthesis and Catalysis, 2016, vol. 358, 17, p. 2759 - 2766). Afterwards the addition of benzimidamides 53 with bromobenzyloxy arylalkylketones of common structure 54 yielded in triaryl halogen substituted imidazoles of common structure 55 (US5616601).

General scheme 1 a:

Preparation of benzimidates of common structure 62 having the carboxylic functional group already introduced, were synthesized by starting from benzo nitriles of common structure 59. Treatment of 59 with sodium benz(trimethylsilyl)amide was resulted in the imidamid 60 (Baumann M., Baxendale I. R., Bioorg. and Med. Chem. 2017, 25, 23, 6218 - 6223). Afterwards oxidative coupling with boronic acids of common structure 61 using copper(ll) acetate monohydrate as the catalyst under open flask conditions were resulted in the substituted benzimidates 62 (Li J.; Benard S., Neuville L; Zhu J. Org. Lett. 2012, 14, 23, 5980 - 5983).

General scheme 2:

57

The triaryl halogen substituted imidazoles of common structure 55 were transformed to the triaryl aldehyde substituted imidazoles of common structure 56 by using n-BuLi and N,N- dimethylformamide and the aldehyde group was oxidized using CrCh in H2SO4 (Jones reagent). It was also possible to use other oxidation reagents, like oxone ( Org . Lett. 2003, 5, 1031-1034) or potassium permanganate (Org. Lett. 2010, 12, 3618-3621) or pyridinium chlorochromate

( Synthesis , 2005, 2487-2490) yielded the corresponding triaryl carboxylic acid substituted imidazoles of common structure 57.

General scheme 2b:

Using the same conditions as described above benzimidamides 62 were cyclized with bromobenzyloxy arylalkylketones of common structure 54 to imidazoles of common structure 64. The methyl ester of imidazoles 64 were then subsequently hydrolyzed with lithium hydroxide yielded into the carboxylic acid of imidazoles of common structure 57.

General scheme 3:

Alternatively 55 was directly converted into 57, by using a lithium base to form the in situ organo-lithium-species of 55, which was treated with continuous C0₂-gas stream at low temperature to yielded 57 (Tozawa H.; Kitamura K.; Hamura T. Chem. Lett. 2017, 46, 5, 703 - 706).

General scheme 4:

57 (I)

The final compounds of general structural formula (I) were obtained by hydrogenation using palladium on charcoal (10%-w/w) of the benzyl protected imidazoles of common structure 57. To deprotect compounds of the general formula 57 to get the final compound of the general structure (I) it was also possible to use BCl3/BBr₃ in CH2CI2 (Protective Groups in Organic Synthesis, third edition 1999, p. 254 and 267).

General scheme 5:

Alternatively, benzyloxy arylalkylketones of common structure 69 can be synthesized by starting from commercially available 2-hydroxybenzaldehydes of common structure 66.

2-Hydroxybenzaldehydes 66 were reacted in the presence of benzyl bromide, potassium iodide and potassium carbonate resulting in 2-benzyloxybenzaldehydes 67. Substituent R³ was introduced via Grignard- reaction (Jiang D., Peng J., Chen, Y. Org. Lett. 2008, 10, 9, 1695 - 1698) affording the alcohols 68 which were then subsequently oxidized to benzyloxy arylalkylketones of common structure 69 under Jones conditions (Kalendra, D. M., Sickles, B. R. J. Org. Chem. 2003, 68, 4, 1594 - 1596).

General scheme 6:

Alternatively substituted benzyloxy arylalkylketones 69 can also be obtained via the addition of Weinreb-amide 72 to the in situ generated organo-lithium-species of 2- benzyloxybromides 73 by using a lithium base under standard conditions. The Weinreb- amides 72 were obtained from the appropriate carboxylic acids 70 using carbonyldiimidazole as the coupling reagent (Coe J. W., Bianco K. E.; Boscoe B. P., Brooks P.

R.; Cox E. D., Vetelino M. G. J. Org. Chem. 2003, 68, 26, 9964 - 9970). The 2-benzyloxybromo- benzenes 73 were synthesized from the commercially available corresponding 2-hydroxybromo- benzenes by using benzyl bromide, potassium iodide and potassium carbonate under standard conditions.

General procedure 7:

2-Benzyloxy benzophenones of common structures 69 were converted to the

bromobenzyloxy arylalkylketones 54 by using phenyl trimethylammonium tribromide

(WO2007/44796, 2007) as a mild alternative to other bromination conditions (Watanuki S.

Sakamoto S., Harada H., Kikuchi K., Kuramochi T., Kawaguchi K.-l., Okazaki T., Tsukamoto, S.- I. Heterocycles 2004, 62, 127 - 130). Novel intermediate compounds deriving from any of the herein described preparation procedures shall also be covered from the present invention.

EXAMPLES

The invention is illustrated in more detail by the following examples.

I. Preparation of Example Compounds

Abbrevations

BuLi n-Butyllithium

EtOAc Ethylacetate

CH2CI2 Dichloromethane

Et₂0 Diethylether

MeOH Methanol

EtOH Ethanol

brine Aqueous saturated sodium chloride solution

Chloroform-d Deuterated chloroform

DMSO-cfe Deuterated dimethylsulfoxid

s Singlet

br s Bright Singlet

d Doublet

dd Double Doublets

dt Doublet of Triplets

td Triplet of Doublets

hept. Heptett

m Multi plet

q Quartet

d Chemical shift

ppm Parts per million

M Molarity

mm Millimolar

umol Mikromolar

9 Gram

mg Milligram

I Liter

mL Milliliter

h Hours

min Minute

%-w/w Percentage by mass

TLC Thin layer chromatography

UHPLC Ultra high pressure liquid chromatography

MS Mass spectroscopy

ESI Electronic spray ionization m/z mass to charge ratio

H⁺ Proton

MHz Mega Hertz

s.m. starting material

Jones Reagent CrCh in H2SO4

Cr0₃ Chromium trioxide

H2SO4 Sulfuric acid

Bn Benzyl

MS Mass spectra

ESI Electrospray ionisation

SNAP Biotage-column-brandname for flash column chromatography

R_f Retention Factor

TLC Thin Layer Chromatography

Chemical nomenclature

The chemical names of the intermediates and the final Exampoe Compounds were generated by using Chem Draw Professional 17.0.

All R_f values were determined using the following TLC plates: Merck, TLC Silcagel 60 F254 .

Intermediates

A. 2-(benzyloxy)-N-(4-bromophenyl)benzimidamide

Sodium bis(trimethylsilyl)amide solution (140 mL, 0.14 mol, 1 M in THF) was added to a solution of 4-bromoaniline (20.64 g, 0.12 mol) in 600 ml THF at 0°C. After 15 min stirring, 2- (benzyloxy)benzonitrile (29.29 g, 0.14 mol) was added and the reaction mixture was allowed to warm up to 20°C and was stirred for 12 h. Saturated aqueous N H4CI (200 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 100 ml). The combined organic phases were dried over Na₂S0₄, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (34.8 g, 0.091 mol, 76%).

MS (ESI+): m/z 381 [M]⁺.

B. 2,4-bis(2-(benzyloxy)phenyl)-1 -(4-bromophenyl)-1 H-imidazole

2-(Benzyloxy)-N-(4-bromophenyl)benzimidamide (19.3 g, 0.051 mol), 1-(2-(benzyloxy)phenyl)-2- bromoethan-1-one (17 g, 0.056 mol) and sodiumbicarbonate (8.5 g, 0.101 mol) in 800 mL isopropanol were heated at 80°C for 12 h. The resulting mixture was filtered at 80°C, evaporated and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (18.9 g, 0.032 mol, 63%).

¹ H NMR (400 MHz, MeOD): d 8.1 (m, 1 H), 7.65 (s, 1 H), 7.57 (s, 1 H), 7.48 (m, 2H), 7.35 (m, 4H), 7.25 (m, 6H), 7.10 (m, 3H), 6.95 (m, 3H), 6.75 (m, 2H), 5.2 (s, 2H), 4.7 (s, 2H).

MS (ESI+): m/z 588 [M+H]⁺.

C. 4-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1 -yl)benzaldehyde

To a solution of 2,4-bis(2-(benzyloxy)phenyl)-1-(4-bromophenyl)-1 H-imidazole (10 g, 11.02 mmol) in 200 mL THF at -75°C r?-butyllithium (11.7 ml, 18.72 mmol, 1.6 M in hexane) was added. After 60 min stirring at -75°C, dimethylformamide DMF (7 ml, 85.1 1 mmol, 5 eq) was added and the reaction mixture was stirred 1 h at -75°C. Then the reaction mixture was warmed up to 20°C. Saturated aqueous NH₄CI solution (100 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 80 ml). The combined organic phases were dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (4.7 g, 8.68 mmol, 51%).

¹ H NMR (400 MHz, DMSO): d 9.9 (s, 1 H), 8.2 (m, 1 H), 7.87 (s, 1 H), 7.80 (m, 2H), 7.60 (m, 1 H), 7.57 (m, 2H), 7.40 (m, 5H), 7.23 (m, 5H), 7.15 (m, 2H), 7.1 (m, 1 H), 7.05 (m, 1 H), 6.97 (m, 1 H),

6.90 (m, 1 H), 5.3 (s, 2H), 4.7 (s, 2H).

MS (ESI+): m/z 536 [M]⁺.

D. 4-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1 -yl)benzoic acid

To a solution of 4-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)benzaldehyde (1.5 g, 2.8 mmol) in 50 ml acetone Jones reagent (1.8 ml, 2 M CrC>3 in aqueous H₂SO₄) was added and the resulting mixture was stirred for 45 min at 20°C. After the acetone was evaporated, ethylacetate was added (100 ml) and the mixture was washed with saturated aqueous NaHCCh solution (2x 120 ml), dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (1.3 g, 2.35 mmol, 84%).

¹ H NMR (400 MHz, DMSO): d 12.9 (s, 1 H), 8.2 (m, 1 H), 7.9 (s, 1 H), 7.65 (m, 1 H), 7.55 (m, 2H), 7.45 (m, 1 H), 7.35 (m, 1 H), 7.25 (m, 2H), 7.15 (m, 10H), 7.05 (m, 2H), 6.9 (m, 2H), 5.3 (s, 2H), 4.8 (s, 2H).

MS (ESI+): m/z 553 [M+H]⁺.

E. 2-(benzyloxy)-N-(4-bromo-3-methoxyphenyl)benzimidamide

Sodium bis(trimethylsilyl)amide solution (149 ml, 0.149 mol, 1M in THF) was added to a solution of 4-bromo-3-methoxyaniline (20 g, 0.099 mol) in 600 ml THF at 0°C. After 15 min stirring 2- (benzyloxy)benzonitrile (26 g, 0.124 mol) was added and the resulting solution was stirred overnight at 20°C. Saturated aqueous NH4CI solution (200 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 100 ml). The combined organic phases were dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (31.4 g, 0.076 mol, 77%).

MS (ESI+): m/z 411 [M]⁺. F. 2,4-bis(2-(benzyloxy)phenyl)-1 -(4-bromo-3-methoxyphenyl)-1 H-imidazole

2-(benzyloxy)-N-(4-bromo-3-methoxyphenyl)benzimidamide (9.5 g, 0.023 mol) and 1-(2- (benzyloxy)phenyl)-2-bromoethan-1-one (7.75 g, 0.025 mol) and sodiumbicarbonate (3.86 g, 0.046 mol) in 800 ml isopropanol were heated overnight at 80°C. The resulting mixture was filtered at 60°C, evaporated and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (8.7 g, 0.014 mol, 61%).

¹ H NMR (400 MHz, DMSO): d 8.2 (m, 1 H), 7.8 (s, 1 H), 7.58 (m, 3H), 7.48 (m, 1 H), 7.35 (m, 4H), 7.2 (m, 5H), 7.05 (m, 2H), 6.95 (m, 3H), 6.63 (m, 1 H), 6.5 (m, 1 H), 5.3 (s, 2H), 4.8 (s, 2H).

G. 4-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)-2-methoxybenzaldehyde

To a solution of 2,4-bis(2-(benzyloxy)phenyl)-1-(4-bromo-3-methoxyphenyl)-1 H-imidazole (10 g, 16.2 mmol) in 200 ml THF at -75°C n-BuLi (11.5 ml, 17.8 mmol, 1.6 M in hexane) was added.

After 60 min stirring at -75°C, dimethylformamide DMF (7 ml, 85.1 1 mmol, 5.5 eq) was added and the reaction mixture was stirred 1 h at -75°C. Then the reaction mixture was warmed up to 20°C. Saturated aqueous NH₄CI solution(100 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 80 ml). The combined organic phases were dried over Na₂S0₄, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (4.9 g, 8.6 mmol, 53%).

MS (ESI+): m/z 566 [M]⁺. H. 4-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)-2-methoxybenzoic acid

To a solution of 4-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)-2-methoxybenzaldehyde (6 g, 10.6 mmol) in 200 ml acetone, Jones reagent (6.6 ml, 2 M CrCh in aqueous H₂SO₄) was added and the resulting mixture was stirred for 45 min at 20°C. After the acetone was evaporated, ethylacetate was added (100 ml) and the mixture was washed with saturated aqueous NaHCC>3 (2x 120 ml), dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (5 g, 8.6 mmol, 81%). MS (ESI+): m/z 583 [M+H]⁺.

I. 2-(benzyloxy)-N-(3-bromo-5-methoxyphenyl)benzimidamide

Sodium bis(trimethylsilyl)amide solution (75 ml, 0.074 mol, 1M in THF) was added to a solution of 3-bromo-5-methoxyaniline (10 g, 0.05 mol) in 300 ml THF at 0°C. After 15 min stirring 2-

(benzyloxy)benzonitrile (13 g, 0.062 mol) was added and the resulting was stirred for 12 h at 20°C. Saturated aqueous NH4CI solution (200 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 100 ml). The combined organic phases were dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (14.9 g, 0.036 mol, 73%).

MS (ESI+): m/z 411 [M]⁺.

J. 2,4-bis(2-(benzyloxy)phenyl)-1 -(3-bromo-5-methoxyphenyl)-1 H-imidazole

2-(benzyloxy)-N-(3-bromo-5-methoxyphenyl)benzimidamide (10 g, 0.024 mol) and 1-(2- (benzyloxy)phenyl)-2-bromoethan-1-one (8.4 g, 0.027 mol) and sodiumbicarbonate (4.1 g, 0.049 mol) in 400 ml isopropanol were heated for 12 h at 80°C. The resulting mixture was filtered at 60°C, evaporated and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (9.9 g, 0.016 mol, 66%).

MS (ESI+): m/z 618 [M+H]⁺.

K. 3-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)-5-methoxybenzaldehyde

To a solution of 2,4-bis(2-(benzyloxy)phenyl)-1-(3-bromo-5-methoxyphenyl)-1 H-imidazole (5 g,

8.1 mmol) in 100 ml THF at -75°C n-BuLi (5.5 ml, 16 mmol, 1.6 M in hexane) was added. After 60 min stirring at -75°C, dimethylformamide DMF (6 ml, 85 mmol, 5.5 eq) was added and the reaction mixture was stirred 1 h at -75°C. Then the reaction mixture was warmed up to 20°C. Saturated aqueous NH₄CI solution (100 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 80 ml). The combined organic phases were dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (2.3 g, 4.1 mmol, 51 %).

MS (ESI+): m/z 566 [M]⁺.

L 3-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1 -yl)-5-methoxybenzoic acid

To a solution of 3-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1 -yl)-5-methoxybenzaldehyde (0.6 g, 1.1 mmol) in 50 ml acetone, Jones reagent (0.6 ml, 2 M CrC>3 in aqueous H2SO4) was added and the resulting mixture was stirred for 45 min at 20°C. After the acetone was evaporated, ethylacetate was added (100 ml) and the mixture was washed with saturated aqueous NaHCCh (2x 120 ml), dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (0.55 g, 9.4 mmol, 89%).

MS (ESI+): m/z 583 [M+H]⁺. M. 4-(4-(2-(benzyloxy)-4-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1 H-imidazol-1- yl)benzaldehyde

To a solution of 4-(2-(benzyloxy)-4-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1-(4-bromophenyl)- 1 H-imidazole (5 g, 8.1 mmol) in 100 ml_ THF at -75°C n-butyllithium (5.5 ml, 8.9 mmol, 1.6 M in hexane) was added. After 60 min stirring at -75°C, dimethylformamide DMF (3.2 ml, 40.5 mmol, 5.5 eq) was added and the reaction mixture was stirred 1 h at -75°C. Then the reaction mixture was warmed up to 20°C. Saturated aqueous NH CI solution (100 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 80 ml). The combined organic phases were dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (2.3 g, 4.05 mmol, 50%).

MS (ESI+): m/z 566 [M]⁺.

N. 4-(4-(2-(benzyloxy)-4-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)benzoic acid

To a solution of 4-(4-(2-(benzyloxy)-4-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1 H-imidazol-1- yl)benzaldehyde (4 g, 7.06 mmol) in 150 ml acetone Jones reagent (4.4 ml, 2 M CrC»3 in aqueous H2SO4) was added and the resulting mixture was stirred for 45 min at 20°C. After the acetone was evaporated, ethylacetate was added (100 ml) and the mixture was washed with saturated aqueous NaHCC solution (2x 120 ml), dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (3.2 g, 5.5 mmol, 78%).

¹ H NMR (400 MHz, DMSO): 5 13.1 (s, 1 H), 8.1 (m, 1 H), 7.8 (m, 2H), 7.7 (s, 1 H), 7.6 (m, 3H), 7.4 (m, 4H), 7.2 (m, 3H), 7.1 (m, 3H), 6.9 (m, 3H), 6.7 (m, 1 H), 6.6 (m, 1 H), 5.3 (s, 2H), 4.7 (s, 2H), 3.8 (s, 3H). O. 4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1-(4-bromophenyl) -1H-imidazole

2-(Benzyloxy)-N-(4-bromophenyl)benzimidamide (10 g, 0.026 mol), 1-(2-(benzyloxy)-5- methoxyphenyl)-2-bromoethan-1-one (9.7 g, 0.029 mol) and sodiumbicarbonate (4.1 g, 0.052 mol) in 600 ml_ isopropanol were heated for 12 h at 80°C. The resulting mixture was filtered at 60°C, evaporated and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (10.7 g, 0.017 mol, 66%).

MS (ESI+): m/z 618 [M+H]⁺.

P. 4-(4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)

-1H-imidazol-1-yl)benzaldehyde

To a solution of 4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1-(4-bromophenyl)- 1 H-imidazole (5 g, 8.1 mmol) in 100 ml_ THF at -75°C n-butyllithium (5.5 ml, 18.72 mmol, 1.6 M in hexane) was added. After 60 min stirring at -75°C, dimethylformamide DMF (3.2 ml, 40.5 mmol, 5.5 eq) was added and the reaction mixture was stirred 1 h at -75°C. Then the reaction mixture was warmed up to 20°C. Saturated aqueous NH₄CI solution (100 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 80 ml). The combined organic phases were dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (2.4 g, 4.21 mmol, 52%).

MS (ESI+): m/z 566 [M]⁺. Q. 4-(4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1H-imidazol-1- yl)benzoic acid

To a solution of 4-(4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1 H-imidazol-1- yl)benzaldehyde (4 g, 7.06 mmol) in 150 ml acetone, Jones reagent (4.4 ml, 2 M CrCb in aqueous H2SO4) was added and the resulting mixture was stirred for 45 min at 20°C. After the acetone was evaporated, ethylacetate was added (100 ml) and the mixture was washed with saturated aqueous NaHCCh solution (2x 120 ml), dried over Na2SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (3.3 g, 5.6 mmol, 79%).

¹ H NMR (400 MHz, DMSO): 5 13.1 (s, 1 H), 7.9 (s, 1 H), 7.8 (m, 2H), 7.7 (m, 1 H), 7.5 (m, 3H), 7.4 (m, 4H), 7.2 (m, 3H), 7.1 (m, 4H), 6.9 (m, 3H), 6.8 (m, 1 H), 5.2 (s, 2H), 4.7 (s, 2H), 3.7 (s, 3H). R. 2-(benzyloxy)-N-(3-bromo-4-methoxyphenyl)benzimidamide

Sodium bis(trimethylsilyl)amide solution (150 ml, 0.15 mol, 1M in THF) was added to a solution of 3-bromo-4-methoxyaniline (20 g, 0.1 mol) in 600 ml THF at 0°C. After 15 min stirring 2- (benzyloxy)benzonitrile (26 g, 0.124 mol) was added and the reaction mixture was allowed to warm up to 20°C and was stirred for 12 h. Saturated aqueous N H4CI (200 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 100 ml). The combined organic phases were dried over Na2SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (30.2 g, 0.073 mol, 74%).

MS (ESI+): m/z 381 [M]⁺.

S. 2,4-bis(2-(benzyloxy)phenyl)-1-(3-bromo-4-methoxyphenyl)-1H-imidazole

2-(benzyloxy)-N-(3-bromo-4-methoxyphenyl)benzimidamide (10 g, 0.024 mol) and 1-(2- (benzyloxy)phenyl)-2-bromoethan-1-one (8.4 g, 0.027 mol) and sodiumbicarbonate (4.1 g, 0.049 mol) in 800 ml isopropanol were heated for 12 h at 80°C. The resulting mixture was filtered at 60°C, evaporated and the crude product was purified by flash column chromatography (using a

100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (9.2 g, 0.015 mol, 61 %).

MS (ESI+): m/z 618 [M+H]⁺. T. 5-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1 -yl)-2-methoxybenzaldehyde

To a solution of 2,4-bis(2-(benzyloxy)phenyl)-1-(3-bromo-4-methoxyphenyl)-1 H-imidazole (5 g,

8.1 mmol) in 200 ml THF at -75°C n-BuLi (5.5 ml, 16 mmol, 1.6 M in hexane) was added. After 60 min stirring at -75°C, dimethylformamide DMF (6 ml, 85 mmol, 5.5 eq) was added and the reaction mixture was stirred 1 h at -75°C. Then the reaction mixture was warmed up to 20°C.

Saturated aqueous NFUCI solution (100 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 80 ml). The combined organic phases were dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (2.4 g, 4.2 mmol, 52%).

¹ H NMR (400 MHz, DMSO): d 9.9 (s, 1 H), 8.2 (m, 1 H), 7.87 (s, 1 H), 7.80 (m, 2H), 7.60 (m, 1 H), 7.57 (m, 2H), 7.40 (m, 5H), 7.23 (m, 5H), 7.15 (m, 2H), 7.1 (m, 1 H), 7.05 (m, 1 H), 6.97 (m, 1 H), 6.90 (m, 1 H), 5.3 (s, 2H), 4.7 (s, 2H).

MS (ESI+): m/z 536 [M]⁺.

U. 5-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1 -yl)-2-methoxybenzoic acid

To a solution of 5-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)-2-methoxybenzaldehyde (4 g, 7.06 mmol) in 100 ml acetone, Jones reagent (4.4 ml, 2 M CrCh in aqueous H2SO4) was added and the resulting mixture was stirred for 45 min at 20°C. After the acetone was evaporated, ethylacetate was added (100 ml) and the mixture was washed with saturated aqueous NaHCCh solution (2x 120 ml), dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (3.3 g, 5.6 mmol, 79%).

MS (ESI+): m/z 583 [M+H]⁺.

V. 4-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1 -yl)-2-fluorobenzaldehyde

To a solution of 2,4-bis(2-(benzyloxy)phenyl)-1-(4-bromo-3-fluorophenyl)-1 H-imidazole (7.2 g, 11.9 mmol) in 200 ml THF at -75°C n-BuLi (8.2 ml, 13.1 mmol, 1.6 M in hexane) was added. After

60 min stirring at -75°C, dimethylformamide DMF (5.1 ml, 65.5 mmol, 5.5 eq) was added and the reaction mixture was stirred 1 h at -75°C. Then the reaction mixture was warmed up to 20°C. Saturated aqueous NFUCI solution (100 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 80 ml). The combined organic phases were dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g

SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (3.5 g, 6.3 mmol, 53%).

MS (ESI+): m/z 554 [M]⁺.

W. 4-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1 -yl)-2-fluorobenzoic acid

To a solution of 4-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)-2-fluorobenzaldehyde (3 g,

5.41 mmol) in 100 ml acetone, Jones reagent (3.4 ml, 2 M CrCb in aqueous H₂SO₄) was added and the resulting mixture was stirred for 45 min at 20°C. After the acetone was evaporated, ethylacetate was added (100 ml) and the mixture was washed with saturated aqueous NaHCCb solution (2x 120 ml), dried over Na₂SC>₄, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (2.6 g, 4.5 mmol, 83%).

MS (ESI+): m/z 571 [M+H]⁺.

X. 2,4-bis(2-(benzyloxy)-5-methoxyphenyl)-1-(4-bromophenyl)-1 H-imidazole

2-(benzyloxy)-N-(4-bromophenyl)-5-methoxybenzimidamide (5 g, 12.12 mmol) and 1-(2- (benzyloxy)-5-methoxyphenyl)-2-bromoethan-1-one (4.5 g, 13.4 mmol) and sodiumbicarbonate (2.1 g, 24.4 mmol) in 200 ml isopropanol were heated for 12 h at 80°C. The resulting mixture was filtered at 60°C, evaporated and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (4.9 g, 7.5 mmol, 62%).

1 H NMR (400 MHz, DMSO): d 7.8 (s, 1 H), 7.7 (d, 1 H), 7.5 (m, 4H), 7.3 (m, 3H), 7.2 (m, 3H), 7.1 (m, 2H), 6.9 (m, 5H), 6.8 (m, 1 H), 6.7 (m, 1 H), 5.2 (s, 2H), 4.7 (s, 2H), 3.8 (s, 6H).

Y. 4-(2,4-bis(2-(benzyloxy)-5-methoxyphenyl)-1H-imidazol-1-yl)benzaldehyde

To a solution of 2,4-bis(2-(benzyloxy)-5-methoxyphenyl)-1-(4-bromophenyl)-1 H-imidazole (5 g,

7.7 mmol) in 100 ml THF at -75°C n-BuLi (5.3 ml, 18.72 mmol, 1.6 M in hexane) was added. After 60 min stirring at -75°C, dimethylformamide DMF (3.3 ml, 42.4 mmol, 5 eq) was added and the reaction mixture was stirred 1 h at -75°C. Then the reaction mixture was warmed up to 20°C. Saturated aqueous NH4CI solution (100 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 80 ml). The combined organic phases were dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (2.3 g, 3.8 mmol, 49 %).

¹ H NMR (400 MHz, DMSO): 0 10.0 (s, 1 H), 7.9 (s, 1 H), 7.8 (d, 2H), 7.7 (d, 1 H), 7.5 (m, 2H), 7.3 (m, 3H), 7.2 (m, 6H), 7.1 (d, 1 H), 7.0 (m, 1 H), 6.9 (m, 3H), 6.8 (m, 1 H), 5.2 (s, 2H), 4.6 (s, 2H),

3.7 (s, 6H).

Z. 4-(2,4-bis(2-(benzyloxy)-5-methoxyphenyl)-1H-imidazol-1-yl)benzoic acid

To a solution of 4-(2,4-bis(2-(benzyloxy)-5-methoxyphenyl)-1 H-imidazol-1-yl)benzaldehyde (4 g,

6.7 mmol) in 150 ml acetone, Jones reagent (4.2 ml, 2 M CrCb in aqueous H2SO4) was added and the resulting mixture was stirred for 45 min at 20°C. After the acetone was evaporated, ethylacetate was added (100 ml) and the mixture was washed with saturated aqueous NaHCC>3 solution (2x 120 ml), dried over Na2SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (1.3 g, 5.43 mmol, 81%).

MS (ESI+): m/z 613 [M+H]⁺.

AA. 2-(benzyloxy)-N-(5-bromo-2-methoxyphenyl)benzimidamide

Sodium bis(trimethylsilyl)amide solution (150 ml, 0.149 mol, 1M in THF) was added to a solution of 5-bromo-2-methoxyaniline (20 g, 0.099 mol) in 600 ml THF at 0°C. After 15 min stirring 2- benzyloxybenzonitrile (26 g, 0.124 mol) was added and the reaction mixture was allowed to warm up to 20°C and was stirred for 12 h. Saturated aqueous N H4CI (200 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 100 ml). The combined organic phases were dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (28.9 g, 0.070 mol, 71%).

MS (ESI+): m/z 411 [M]⁺.

AB. 2,4-bis(2-(benzyloxy)phenyl)-1-(5-bromo-2-methoxyphenyl)-1H-imidazole

2-(benzyloxy)-N-(5-bromo-2-methoxyphenyl)benzimidamide (8 g, 19.5 mmol) and 1-(2- (benzyloxy)phenyl)-2-bromoethan-1-one (6.5 g, 21.4 mmol) and sodiumbicarbonate (3.3 g, 39 mmol) in 200 ml isopropanol were heated for 12 h at 80°C. The resulting mixture was filtered at 60°C, evaporated and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (7.8 g, 12.6 mmol, 63%).

MS (ESI+): m/z 618 [M+H]⁺.

AC. 3-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1 -yl)-4-methoxybenzaldehyde

To a solution of 2,4-bis(2-(benzyloxy)phenyl)-1-(5-bromo-2-methoxyphenyl)-1 H-imidazole (5.5 g, 8.90 mmol) in 200 ml THF at -75°C n-BuLi (5.9 ml, 9.80 mmol, 1.6 M in hexane) was added. After 60 min stirring at -75°C, dimethylformamide DMF (3.8 ml, 49 mmol, 5 eq) was added and the reaction mixture was stirred 1 h at -75°C. Then the reaction mixture was warmed up to 20°C. Saturated aqueous NH₄CI solution (100 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 80 ml). The combined organic phases were dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (2.7 g, 4.72 mmol, 53%).

MS (ESI+): m/z 567 [M+H]⁺.

AD. 3-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1 -yl)-4-methoxybenzoic acid

To a solution of 3-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)-4-methoxybenzaldehyde (10 g, 17.65 mmol) in 150 ml acetone, Jones reagent (11 ml, 2 M CrCh in aqueous H₂SO₄) was added and the resulting mixture was stirred for 45 min at 20°C. After the acetone was evaporated, ethylacetate was added (100 ml) and the mixture was washed with saturated aqueous NaHCCb solution (2x 120 ml), dried over Na2SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (6.27 g, 0.011 mol, 61%).

MS (ESI+): m/z 583 [M+H]⁺.

AE. 2-(benzyloxy)-N-(3-bromo-4-methoxyphenyl)benzimidamide

Sodium bis(trimethylsilyl)amide solution (140 ml, 0.14 mol, 1M in THF) was added to a solution of 3-bromo-4-methoxyaniline (24.25 g, 0.12 mol) in 600 ml THF at 0°C. After 15 min stirring 2-

(benzyloxy)benzonitrile (29.30 g, 0.14 mol) was added and the reaction mixture was allowed to warm up to 20°C and was stirred for 12 h. Saturated aqueous NH₄CI (200 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 100 ml). The combined organic phases were dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (35 g, 0.085 mol, 71%).

MS (ESI+): m/z 411 [M]⁺.

AF. 4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1-(3-bromo-4- methoxyphenyl)-1 H-imidazole

2-(benzyloxy)-N-(3-bromo-4-methoxyphenyl)benzimidamide (13 g, 31.6 mmol) and 1-(2- (benzyloxy)-5-methoxyphenyl)-2-bromoethan-1-one (11.6 g, 37.9 mmol) and sodiumbicarbonate (5.3 g, 63.2 mmol) in 200 ml isopropanol were heated for 12 h at 80°C. The resulting mixture was filtered at 60°C, evaporated and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (12.5 g, 0.019 mol, 62%).

MS (ESI+): m/z 648 [M+H]⁺.

AG. 5-(4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1H-imidazol-1-yl)-2- methoxybenzaldehyde

To a solution of 4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1-(3-bromo-4- methoxyphenyl)-1 H-imidazole (6.8 g, 10.5 mmol) in 200 ml THF at -75°C n-BuLi (7.2 ml, 11.6 mmol, 1.6 M in hexane) was added. After 60 min stirring at -75°C, dimethylformamide DMF (4.5 ml, 57.8 mmol, 5 eq) was added and the reaction mixture was stirred 1 h at -75°C. Then the reaction mixture was warmed up to 20°C. Saturated aqueous NH CI solution (100 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 80 ml). The combined organic phases were dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (3.26 g, 5.46 mmol, 52%).

MS (ESI+): m/z 597 [M+H]⁺.

AH. 5-(4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1H-imidazol-1-yl)-2- methoxybenzoic acid

To a solution of 5-(4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)- 2-methoxybenzaldehyde (5.5 g, 9.22 mmol) in 100 ml acetone, Jones reagent (5.8 ml, 2 M CrCb in aqueous H₂SO₄) was added and the resulting mixture was stirred for 45 min at 20°C. After the acetone was evaporated, ethylacetate was added (100 ml) and the mixture was washed with saturated aqueous NaHCC>₃ solution (2x 120 ml), dried over Na₂S0₄, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (4.74 g, 7.74 mmol, 84%).

MS (ESI+): m/z 613 [M+H]⁺.

Al. 1 -(2-(benzyloxy)phenyl)propan-1 -one

1 -(2- Hydroxyphenyl) propan- 1 -one (200 g, 1.33 mol), Potassium carbonate (239 g, 1.73 mol) and Potassium iodide (44.2 g, 266 mmol) were suspended in acetone (1.78 I). Then, benzyl bromide (159 ml_, 1.46 mol) was dropped to the suspension via addition funnel, rinsing with additional acetone (20 ml_). The reaction mixture was heated to reflux for 16 h. The suspension was allowed to cool down to 40-50 °C, before it was filtered. The filtrate was concentrated under reduced pressure and the crude material was recrystallized from Eί_å0 to afford the titled compound (321 g, 1.33 mmol, 100%) as an off-white solid. ¹ H NMR (400 MHz, Chloroform-d) d 7.69 (dd, 1 H), 7.53 - 7.30 (m, 6H), 7.03-7.00 (m, 2H), 5.16 (s, 2H), 2.99 (q, 2H), 1.12 (t, 3H) ppm. UHPLC/MS (ESI): [m/z\. 241 [M+H]⁺.

AJ. 1 -(2-(benzyloxy)phenyl)-2-bromopropan-1 -one

1-(2-(benzyloxy)phenyl)propan-1-one ( 80.0 g, 333 mmol) was dissolved in dry tetrahydrofuran (420 ml.) and then, treated with Phenyltrimethylammonium tribromide (131 g, 350 mmol) in three portions. The resulting suspension was stirred at 20-25 °C. After TLC indicated full consumption of the s. m., the suspension was filtered and the filtrate was treated with aqueous saturated sodium bicarbonate solution. Phases were separated and the aqueous phase was re-extracted with ethyl acetate (2x). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography to obtain the titled compound (98.7 g, 309 mmol, 93%) as a yellowish solid. ¹ H NMR (400 MHz, DMSO-cfe) d 7.60 (dd, 1 H), 7.57-7.55 (m, 1 H), 7.54 - 7.47 (m, 2H), 7.45 - 7.36 (m, 2H), 7.39 - 7.30 (m, 1 H), 7.26 (d, 1 H), 7.08-7.04 (m, 1 H), 5.57 (q, 1 H), 5.25 (s, 2H), 1.66 (d, 3H). UHPLC/MS (ESI): [m/z]: 320 [M+H]⁺.

A.K. 2-(benzyloxy)-5-methoxybenzaldehyde

2-Hydroxy- 5-methoxybenzaldehyde (19.9 g, 131 mmol), Potassium carbonate (23.5 g, 170 mmol) and Potassium iodide (28.2 g, 170 mmol) were suspended in acetone (260 ml_). Then, Benzyl bromide (17.1 ml_, 144 mmol) was dropped to the suspension via addition funnel, rinsing with additional acetone (10 ml_). The reaction mixture was heated to reflux for 16 h. The suspension was allowed to cool down to 40-50 °C, before it was filtered. The filtrate was concentrated under reduced pressure and the crude material was puridied by flash column chromatography to afford the titled compound ( 30.1 g, 124 mmol, 95%) as an off-white solid. ¹ H NMR (400 MHz, Chloroform-d) d 10.5 (s, 1 H), 7.46 - 7.32 (m, 6H), 7.11 (dd, 1 H), 7.00 (d, 1 H), 5.15 (s, 2H), 3.80 (s, 3H) ppm. UHPLC/MS (ESI): [m/z] 243 [M+H]⁺.

AL 1 -(2-(benzyloxy)-5-methoxyphenyl)propan-1 -ol

In a two-necked flask 2-(benzyloxy)-5-methoxybenzaldehyde (15.0 g, 61.9 mmol) was dissolved in dry THF (250 ml_). The solution was cooled to 0 °C, before, Ethyl magnesium bromide solution (3M in Et₂0, 26.8 ml_, 80.5 mmol) was added dropwise over 20 min via addition funnel. The reaction mixture was stirred at 0 °C. After TLC indicated full consumption of the s.m., the reaction mixture was quenched by addition of aqueous saturated ammonium chloride solution. The phases were separated and the aqueous phase was re-extracted with ethyl acetate (3x).

The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material ( 15.4 g, 56.5 mmol, 91 %) was used in the next step without further purification. ¹H NMR (400 MHz, Chloroform-d) d 7.44 - 7.30 (m, 6H), 6.94 (d, 1 H), 6.87 (d, 1 H), 6.74 (dd, 1 H), 5.06 (s, 2H), 4.85 (t, 1 H), 3.78 (s, 3H), 1.88 - 1.76 (m, 2H), 0.96 (t, 3H) ppm. UHPLC/MS (ESI): [m/z]: 256 [M-H20]⁺. AM. 1-(2-(benzyloxy)-5-methoxyphenyl)propan-1 -one

Under an inert atmosphere oxalyl chloride (5.97 mL, 70.5 mmol) was dissolved in

dichloromethane (140 mL) and cooled to -78 °C. Dimethyl sulfoxide (10.0 mL, 141 mmol) was added dropwise. Afterwards, the reaction mixture was allowed to stir for 30 min, before 1-(2- (benzyloxy)-5-methoxyphenyl)propan-1-ol ( 15.4 g, 56.4 mmol), dissolved in dichloromethane (56 mL), was added slowly via syringe. The reaction mixture was stirred 1 h and then, trimethylamine (95 mL) was added. Afterwards, it was allowed to warm-up to 20-25 °C for 16 h. After the addition of water, phases were separated and the aqueous phase was re-extracted with ethyl acetate (3x). The combined organic phase was washed with aqueous 1 N hydrochloric acid and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (Heptane/EtOAc) to afford the titled compound (14.5 g, 53.6 mmol, 95%) as an yellowish oil. ¹H NMR (400 MHz, Chloroform-d) d 7.44 - 7.31 (m, 5H), 7.25 (d, 1 H), 6.98 - 6.92 (m, 2H), 5.1 1 (s, 2H), 3.79 (s, 3H), 3.00 (q, 2H), 1.12 (t, 3H) ppm. UHPLC/MS (ESI): [m/z]: 271 [M+H]⁺.

AN. 1 -(2-(benzyloxy)-5-methoxyphenyl)-2-bromopropan-1 -one

1-(2-(benzyloxy)-5-methoxyphenyl)propan-1-one (14.5, 53.6 mmol) was dissolved in dry tetrahydrofurane (60 ml.) and then, treated with Phenyltrimethylammonium tribromide (24.4 g, 65 mmol) in three portions. The resulting suspension was stirred at 20-25 °C. After TLC indicated full consumption of s.m., the suspension was filtered and treated with aqueous saturated sodium bicarbonate solution. Phases were separated and the aqueous phase was re-extracted with ethyl acetate (2x). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (Heptane/EtOAc) to obtain the titled compound (8.36 g, 23.4 mmol,

44%) as a yellowish solid. ¹ H NMR (400 MHz, Chloroform-d) d 7.47 - 7.33 (m, 5H), 7.26 (d, 1 H), 7.02 (dd, 1 H), 6.96 (d, 1 H), 5.54 (q, 1 H), 5.17 - 5.08 (m, 2H), 3.80 (s, 3H), 1.76 (d, 3H) ppm. UHPLC/MS (ESI): [m/z]: 350 [M+H]⁺.

AO. 1-(2-(benzyloxy)phenyl)butan-1-ol

In a two-necked flask 2-Benzyloxybenzaldehyde (10.6 g, 49.9 mmol) was dissolved in dry diethylether (200 mL). The solution was cooled to 0 °C, before, Propyl magnesium chloride solution (2M in Et₂0, 50 mL, 100 mmol) was added dropwise over 20 min via addition funnel. The reaction mixture was stirred at 0 °C. After TLC indicated full consumption of the starting material, the reaction mixture was quenched by addition of aqueous saturated ammonium chloride solution. Phases were separated and the aqueous phase was re-extracted with diethyl ether (2x). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material ( 12.3 g, 48.1 mmol, 96%) was used in the next step without further purification. ¹H NMR (400 MHz Chloroform-d) d 7.44-7.33 (m, 6H), 7.23 (td, 1 H), 7.00-6.94 (m, 2H), 5.12 8s, 2H), 4.97 (dd, 1 H), 2.38 (br s, 1 H), 1.87-1.73 (m, 2H), 1.55-1.31 (m, 2H), 0.93 (t, 3H) ppm. UHPLC/MS (ESI): [m/z]: 239 [M-H₂0]⁺.

AP. 1-(2-(benzyloxy)phenyl)butan-1-one

1-(2-(benzyloxy)phenyl)butan-1-ol ( 12.3 g, 48.1 mmol) was dissolved in acetone (320 mL) and cooled to 0 °C. Then, Jones Reagent (2M, 26.5 mL, 52.9 mmol) was added. The reaction mixture was allowed to warm-up to 20-25 °C. Stirring was continued for 1 h. The reaction mixture was concentrated under reduced pressure to 1/10 of its volume, then, diluted with water (300 mL) and thereafter, extracted with diethyl ether (5x). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography to obtain the titled compound (9.15 g, 36.0 mmol, 75%) as an yellowish oil which crystallized on standing. ¹ H NMR (400 MHz Chloroform-d) d 7.67 (dd, 1 H), 7.45-7.33 (m, 6H), 7.03-6.99 (m, 2H), 5.15 (s, 2H), 2.94 (t, 2H), 1.66 (h, 2H), 0.85 (t,

3H) ppm. UHPLC/MS (ESI): [m/z]\ 255 [M+H⁺]⁺.

AQ. 1 -(2-(benzyloxy)phenyl)-2-bromobutan-1-one

1-(2-(benzyloxy)phenyl)butan-1-one (9.15 g, 36.0 mmol) was dissolved in dry tetrahydrofuran (70.0 mL) and then, treated with Phenyltrimethylammonium tribromide (14.9 g, 39.6 mmol) in three portions. The resulting suspension was stirred at 20-25 °C. After TLC indicated full consumption of s.m., the suspension was filtered and treated with aqueous saturated sodium bicarbonate solution. Phases were separated and the aqueous phase was re-extracted with ethyl acetate (2x). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (Heptane/EtOAc) to obtain the titled compound as a yellowish solid (9.36 g, 28.1 mmol, 78%). ¹ H NMR (400 MHz, Chloroform-d) d 7.72 (d, 1 H), 7.51 - 7.33 (m, 6H), 7.08 - 6.99 (m, 2H), 5.33 (dd, 1 H), 5.21 - 5.07 (m, 2H), 2.18 - 2.03 (m, 1 H), 2.00-1.89 (m, 1 H), 0.88 (t, 3H) ppm. UHPLC/MS (ESI): [m/z]\ 333 [M+H]⁺.

AR. 1 -(2-(benzyloxy)phenyl)-4-methylpentan-1 -ol

In a two-necked flask 2-Benzyloxybenzaldehyde (16.3 g, 76.9 mmol) was dissolved in dry diethyl ether (150 mL). The solution was cooled to 0 °C, before, Isopentyl magnesium bromide solution (2M in Et₂0, 50 mL, 100 mmol) was added dropwise over 20 min via addition funnel. The reaction mixture was stirred at 0 °C. After TLC indicated full consumption of the starting material, the reaction mixture was quenched by addition of aqueous saturated ammonium chloride solution. The phases were separated and the aqueous phase was re-extracted with diethyl ether (2x). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material ( 21.2 g, 74.5 mmol, 97%) was used in the next step without further purification. ¹H NMR (400 MHz, Chloroform-d) d 7.46 - 7.27 (m, 6H), 7.25-7.21 (m, 1 H), 7.02 - 6.92 (m, 2H), 5.11 (s, 2H), 4.91 (t, 1 H), 1.86-1.75 (m, 2H), 1.61-1.51 (m, 1 H), 1.46 - 1.30 (m, 1 H), 1.26 - 1.12 (m, 1 H) 0.87 (d, 3H), 0.86 (d, 3H) ppm. UHPLC/MS (ESI): [m/z] 267 [M-H₂0]⁺.

AS. 1 -(2-(benzyloxy)phenyl)-4-methylpentan-1 -one

1-(2-(benzyloxy)phenyl)-4-methylpentan-1-ol ( 21.2 g, 74.4 mmol) was dissolved in acetone (500 ml_) and cooled to 0 °C. Then, Jones Reagent (2M, 40.9 ml_, 81.8 mmol) was added. The reaction mixture was allowed to warm-up to 20-25 °C. Stirring was continued for 1 h. The reaction mixture was concentrated under reduced pressure to 1/10 of its volume, then, diluted with water (300 ml.) and thereafter, extracted with diethyl ether (5x). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography to obtain the titled compound (11.2 g, 39.7 mmol, 53%) as an colorless oil. ¹ H NMR (400 MHz, Chloroform-d) d 7.68-7.65 (m, 1 H), 7.48 - 7.30 (m, 6H), 7.03-6.99 (m, 2H), 5.15 (s, 2H), 3.02 - 2.82 (m, 2H), 1.58-1.41 (m, 3H), 0.80 (d, 6H). ppm. UHPLC/MS (ESI): [ m/z ]: 283 [M+H⁺]⁺-

AT. 1 -(2-(benzyloxy)phenyl)-2-bromo-4-methylpentan-1 -one

1-(2-(benzyloxy)phenyl)-4-methylpentan-1-one ( 1 1.2 g, 39.5 mmol) was dissolved in dry tetrahydrofuran (150 mL) and then, treated with Phenyltrimethylammonium tribromide (16.3 g, 43.4 mmol) in three portions. The resulting suspension was stirred at 20-25 °C. After TLC indicated full consumption of the s.m., the suspension was filtered and treated with aqueous saturated sodium bicarbonate solution. Phases were separated and the aqueous phase was re extracted with ethyl acetate (2x). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography to obtain the titled compound (7.63 g, 21.1 mmol, 53%) as a yellowish solid. ¹ H NMR (400 MHz, Chloroform-d) d 7.74 (dd, 1 H), 7.51 - 7.31 (m, 6H), 7.10 - 7.00 (m, 2H), 5.46 (dd, 1 H), 5.20 - 5.07 (m, 2H), 1.97-1.90 (m, 1 H), 1.87-1.80 (m, 1 H), 1.78 - 1.68 (m, 1 H), 0.83 (d, 3H), 0.63 (d, J = 6.4 Hz, 3H) ppm. UHPLC/MS (ESI): [m/z]\ 362 [M+H]⁺.

AU. 2-cyclopropyl-N-methoxy-N-methylacetamide

Cyclopropylacetic acid (10.1 g, 99.9 mmol) was dissolved in dichloromethane (333 mL) and treated with carbonyldiimidazole (17.8 g, 110 mmol). After stirring for 4h N,O- Dimethylhydroxylamine hydrochloride (1 10 mL) was added. The reaction mixture was stirred at 20 -25 °C for 16 h. Then, aqueous 1 M hydrochloric acid was added to quench the reaction. Phases were separated and the aqueous phase was extracted with dichloromethane (3x). The combined organic phase was with aqueous 1 M hydrochloric acid, aqoues 50%-w/w sodium carbonate solution and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material (14.7 g, quant.) was used without further purification in the next step. Ή NMR (400 MHz, Chloroform-d) d 3.66 (s, 3H), 3.19 (s, 3H), 2.34 (d, 2H), 1.17 - 0.99 (m, 1 H), 0.64 - 0.41 (m, 2H), 0.18-0.14 (m, 2H) ppm. UHPLC/MS (ESI): [m/z]: 144 [M+H]T

AV. 1-(benzyloxy)-2-bromobenzene

2-Bromophenol (30.0 g,173 mmol), potassium carbonate (31.2 g, 225 mmol) and potassium iodide (5.76 g, 34.7 mmol) were suspended in acetone (350 ml_). The mixture was treated with benzyl bromide (22.7 ml_, 191 mmol) and then, heated to reflux for 16 h. The suspension was allowed to cool down to 40-50 °C, before it was filtered. The filtrate was concentrated under reduced pressure and the crude material was purified by flash column chromatography

(Heptane/EtOAc) obtaining the titled compound (35.0 g, 133 mmol, 77%) as an off-white solid. UHPLC/MS (ESI): [m/z]: 263 [M+H]⁺.

AW. 1 -(2-(benzyloxy)phenyl)-2-cyclopropylethan-1 -one

1-(Benzyloxy)-2-bromobenzene (17.0 g, 64.5 mmol) was dissolved in dry tetrahydrofuran (100 mL). The solution was cooled to -78 °C and then, treated dropwise with n-BuLi (2.5 M in hexane, 28.3 mL, 70.8 mmol) over 10 min. After 1 h stirring at -78 °C, 2-cyclopropyl-N-methoxy-N- methylacetamide (XX, 9.24 g, 64.5 mmol), dissolved in dry tetrahydrofuran (150 mL), was dropped to the reaction mixture via addition funnel over 15 min. After stirring at -78 °C for 1 h, the reaction mixture was allowed to warm-up to 20-25°C, before it was quenched by addition of aqueous 1 M hydrochloric acid. Phases were separated and the aqueous phase was extracted with diethyl ether (3x). The combined organic phase was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography to afford the titled compound XX (10.5 g, 39.5 mmol, 61 %) as an oil which crystallized on standing . ¹ H NMR (400 MHz, Chloroform-d) d 7.70 (dd, 1 H), 7.46 - 7.30 (m, 7H), 7.04-6.99 (m, 2H), 5.15 (s, 2H), 2.88 (d, 2H), 1.17 - 1.00 (m, 1 H), 0.57 - 0.32 (m, 2H), 0.05-0.02 (m, 2H) ppm. UHPLC/MS (ESI): [m/z]: 267 [M+H]⁺.

AX. 1 -(2-(benzyloxy)phenyl)-2-bromo-2-cyclopropylethan-1 -one

1-(2-(benzyloxy)phenyl)-2-cyclopropylethan-1-one (10.5 g, 39.5 mmol) was dissolved in dry THF (50.0 ml.) and then, treated with Phenyltrimethylammonium tribromide (14.9 g, 39.5 mmol) in three portions. The resulting suspension was stirred at 20-25 °C. After TLC indicated full consumption of s.m., the suspension was filtered and treated with aqueous saturated sodium bicarbonate solution. The phases were separated and the aqueous phase was re-extracted with ethyl acetate (2x). The combined organic phase was washed with brine, dried over Na₂SC>4, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (Heptane/EtOAc) to obtain the titled compound (11.9 g, 39.0 mmol,

99%) as a greyish to greenish oil which crystallized on standing. ¹H NMR (400 MHz, Chloroform- d) d 7.75 (dd, 1 H), 7.52 - 7.33 (m, 6H), 7.16 - 6.84 (m, 2H), 5.22 - 5.02 (m, 2H), 4.81 (d, 1 H), 1.71-1.62 (m, 1 H), 0.81 - 0.61 (m, 2H), 0.24 - 0.06 (m, 2H) ppm. UHPLC/MS (ESI): [m/z]\ 306 [M+H]⁺.

AY. 2-(benzyloxy)benzimidamide

2-(Benzyloxy)benzonitrile (5.11 g, 24.4 mmol) was added in small portions to 0-5°C -cooled solution of lithium bis(trimethylsilyl)amide (1M in Et₂0, 50 mL, 50 mmol) in dry diethyl ether (50 ml_). Afterwards, the reaction mixture was allowed to warm up to 20-25 °C and was stirred for 16 h. The reaction mixture was quenched by addition of aqueous 3M hydrochloric acid and was diluted with diethyl ether and water. Phases were separated and the organic phase was reextracted twice with aqueous 1M hydrochloric. The combined aqueous phase was basified carefully with solid sodium hydroxide to pH > 12 and then extracted with dichloromethane (5x). The combined organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. 2-(benzyloxy)benzimidamide (1.16 g, 5.13 mmol, 21%) was obtained as a brownish solid and was used without further purification in the next step. ¹ H NMR (400 MHz, DMSO-cfe) d 7.54 - 7.42 (m, 3H), 7.43 - 7.25 (m, 4H), 7.14 (d, 1 H), 7.00 - 6.92 (m, 1 H), 5.15 (s, 2H) ppm. UHPLC/MS (ESI): [m/z]\ 227 [M+H]⁺.

AZ. Methyl 4-((amino(2-(benzyloxy)phenyl)methylene)amino)-2-methoxybenzoate

In a flask 2-(benzyloxy)benzimidamide ( 1.19 g, 5.16 mmol), (3-methoxy-4- (methoxycarbonyl)phenyl)-boronic acid (1.33 g, 6.31 mmol), copper(ll) acetate monohydrate (210 mg, 1.05 mmol) and cesium pivalate (491 mg, 2.10 mmol) were suspended in dimethyl formamide (21 mL). The flask was sealed with a rubber stopper kept open with a needle to the ambient atmosphere. The reaction mixture was heated to 50 °C until complete consumption of the starting material was indicated by TLC. The reaction mixture was cooled down to 20-25 °C, quenched by addition of aqueous 2M ammonium hydroxide solution and extracted with ethyl acetate (5x). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (C^Ch/MeOH) to obtain the titled compound (1.49 g, 3.82 mmol, 73%) as a light brown foam. UHPLC/MS (ESI): [m/z\. 391 [M+H]⁺.

BA. Methyl 5-((amino(2-(benzyloxy)phenyl)methylene)amino)-2-methoxybenzoate

In a flask 2-(benzyloxy)benzimidamide ( 1.33 g, 5.88 mmol), (4-methoxy-3- (methoxycarbonyl)phenyl)-boronic acid (1.48 g, 7.05 mmol), copper(ll) acetate monohydrate (235 mg, 1.18 mmol) and cesium pivalate (552 mg, 2.36 mmol) were suspended in dimethyl formamide (24 mL). The flask was sealed with a rubber stopper and kept open with a needle to the ambient atmosphere. The reaction mixture was heated to 50 °C until complete consumption of the s.m. was indicated by TLC. The reaction mixture was cooled down to 20-25 °C, quenched by addition of aqueous 2M ammonium hydroxide solution and extracted with ethyl acetate (5x). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH₂Cl2/MeOH) to obtain the titled compound(1.17 g, 3.01 mmol, 51 %) as a light brown foam. UHPLC/MS (ESI): [m/z\. 391 [M+H]⁺.

BB. 4-(2,4-bis(2-(benzyloxy)phenyl)-5-methyl-1 H-imidazol-1 -yl)-2-methoxybenzoic acid

Methyl 4-((amino(2-(benzyloxy)phenyl)methylene)amino)-2-methoxybenzoate ( 3.48 g, 8.91 mmol), 1-(2-(benzyloxy)phenyl)-2-bromopropan-1-one ( 3.13 g, 9.80 mmol) and sodium bicarbonate (1.50 g, 17.8 mmol) were suspended in /so-propanol (40.0 ml.) and then heated to reflux for 16 h. The reaction mixture was allowed to cool down to 50 °C, before it was filtered and concentrated under reduced pressure.

The crude material was dissolved in a tetrahydrofuran/water-mixture (2:1 , 45 mL) and treated with lithium hydroxide (656 mg, 27.4 mmol) in one portion. The reaction mixture was stirred 16 h at 20-25 °C. After acidification to pH = 2-3 using aqueous 3M hydrochloric acid, the reaction mixture was extracted with ethyl acetate (5x). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified (ChhCh/MeOH) by flash column chromatography to afford 4-(2,4-bis(2- (benzyloxy)phenyl)-5-methyl-1 H-imidazol-1-yl)-2-methoxybenzoic acid ( 2.17 g, 3.64 mmol, 41 %).

¹H NMR (400 MHz, DMSO-de) d 12.8 (s, 1 H), 7.57 (d, 1 H), 7.54 (d, 1 H), 7.47-7.45 (m, 3H), 7.37 - 7.27 (m, 5H), 7.26-7.22 (m, 3H), 7.19 (dd, 1 H), 7.1 1 -7.03 (m, 3H), 7.00 (td, 1 H), 6.89 (d, 1 H), 6.71 (d, 1 H), 6.64 (dd, 1 H), 5.16 (s, 2H), 4.85 (s, 2H), 3.43 (s, 3H), 1 .98 (s, 3H) ppm. UHPLC/MS (ESI): [m/z]: 597 [M+H]⁺.

BC. 5-(2,4-bis(2-(benzyloxy)phenyl)-5-methyl-1 H-imidazol-1 -yl)-2-methoxybenzoic acid

Methyl 5-((amino(2-(benzyloxy)phenyl)methylene)amino)-2-methoxybenzoate ( 1.17 g, 3.00 mmol), 1-(2-(benzyloxy)phenyl)-2-bromopropan-1-one ( 1.05 g, 3.30 mmol) and sodium bicarbonate (500 mg, 6.00 mmol) were suspended in /so-propanol (20.0 ml.) and then heated to reflux for 16 h. The reaction mixture was allowed to cool down to 50 °C, before it was filtered and concentrated under reduced pressure.

The crude material was dissolved in a tetrahydrofuran/water-mixture (2: 1 , 18 ml.) and treated with lithium hydroxide (276 mg, 1 1.5 mmol) in one portion. The reaction mixture was stirred for 16 h at 20-25 °C. After acidification to pH = 2-3 using aqueous 3M hydrochloric, the reaction mixture was extracted with ethyl acetate (5x). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH₂Cl2/MeOH) to afford 5-(2,4-bis(2- (benzyloxy)phenyl)-5-methyl-1 H-imidazol-1-yl)-2-methoxybenzoic acid (720 mg, 1.21 mmol,

40%). Ή NMR (400 MHz, DMSO-cfe) d 13.01 (s, 1 H), 7.62 (s, 1 H), 7.55 - 7.46 (m, 4H), 7.46 - 7.40 (m, 3H), 7.37 - 7.26 (m, 7H), 7.25-7.05 (m, 6H), 5.20 (s, 2H), 5.04 (s, 2H), 3.83 (s, 3H), 1.99 (s, 3H) ppm. UHPLC/MS (ESI): [m/z]\ 597 [M+H]⁺.

BD. 4-(4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-5-methyl-1 H- imidazol-1-yl)-2-methoxybenzoic acid

Methyl 4-((amino(2-(benzyloxy)phenyl)methylene)amino)-2-methoxybenzoate ( 1.90 g, 4.87 mmol), 1-(2-(benzyloxy)-5-methoxyphenyl)-2-bromopropan-1-one ( 1.87 g, 5.35 mmol) and sodium bicarbonate (820 mg, 9.74 mmol) were suspended in /so-propanol (20.0 mL) and then, heated to reflux for 16 h. The reaction mixture was allowed to cool down to 50 °C, before it was filtered and concentrated under reduced pressure. The crude material was dissolved in a tetrahydrofuran/water-mixture (2:1 , 60 ml.) and treated with lithium hydroxide (412 mg, 17.2 mmol) in one portion. The reaction mixture was stirred 16 h at 20-25 °C. After acidification to pH = 2-3 using aqueous 3M hydrochloric acid, the reaction mixture was extracted with ethyl acetate (5x). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH₂Cl2/MeOH) to afford 4-(4-(2- (benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-5-methyl-1 H-imidazol-1-yl)-2- methoxybenzoic acid ( 1.34 g, 2.14 mmol, 44%). UHPLC/MS (ESI): [m/z]\ 627 [M+H]⁺.

BE. 4-(2,4-bis(2-(benzyloxy)phenyl)-5-cyclopropyl-1 H-imidazol-1-yl)-2-methoxybenzoic acid

Methyl 4-((amino(2-(benzyloxy)phenyl)methylene)amino)-2-methoxybenzoate ( 1.50 g, 3.84 mmol), 1-(2-(benzyloxy)phenyl)-2-bromo-2-cyclopropylethan-1-one (1.46 g, 4.23 mmol) and sodium bicarbonate (645 mg, 7.68 mmol) were suspended in /so-propanol (15.0 mL) and then, heated to reflux for 16 h. The reaction mixture was allowed to cool down to 50 °C, before it was filtered and concentrated under reduced pressure.

The crude material was dissolved in a tetrahydrofuran/water-mixture (2:1 , 50 mL) and treated with lithium hydroxide (367 mg, 15.4 mmol) in one portion. The reaction mixture was stirred for 16 h at 20-25 °C. After acidification to pH = 2-3 using aqueous 3M hydrochloric acid, the reaction mixture was extracted with ethyl acetate (5x). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (C^Ch/MeOH) to afford 4-(2,4-bis(2- (benzyloxy)phenyl)-5-cyclopropyl-1 H-imidazol-1-yl)-2-methoxybenzoic acid (850 mg, 1.36 mmol, 36%). UHPLC/MS (ESI): [m/z]: 623 [M+H]⁺.

BF. 5-(2,4-bis(2-(benzyloxy)phenyl)-5-cyclopropyl-1 H-imidazol-1-yl)-2-methoxybenzoic acid

Methyl 5-((amino(2-(benzyloxy)phenyl)methylene)amino)-2-methoxybenzoate (2.57 g, 6.58 mmol), 1-(2-(benzyloxy)phenyl)-2-bromo-2-cyclopropylethan-1-one ( 2.50 g, 7.24 mmol) and sodium bicarbonate (1.11 g, 13.2 mmol) were suspended in /so-propanol (27.0 mL) and then, heated to reflux for 16 h. The reaction mixture was allowed to cool down to 50 °C, before it was filtered and concentrated under reduced pressure.

The crude material was dissolved in a tetrahydrofuran/water-mixture (2:1 , 51 ml.) and treated with lithium hydroxide (1.00 g, 23.8 mmol) in one portion. The reaction mixture was stirred for 16 h at 20-25 °C. After acidification to pH = 2-3 using aqueous 3M hydrochloric acid, the reaction mixture was extracted with ethyl acetate (5x). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH₂Cl2/MeOH) to afford 5-(2,4-bis(2- (benzyloxy)phenyl)-5-cyclopropyl-1 H-imidazol-1-yl)-2-methoxybenzoic acid (1.61 g, 2.59 mmol, 39%). UHPLC/MS (ESI): [m/z\. 623 [M+H]⁺.

BG. 4-(2,4-bis(2-(benzyloxy)phenyl)-5-ethyl-1 H-imidazol-1 -yl)-2-methoxybenzoic acid

Methyl 4-((amino(2-(benzyloxy)phenyl)methylene)amino)-2-methoxybenzoate ( 1.50 g, 3.84 mmol), 1-(2-(benzyloxy)phenyl)-2-bromobutan-1-one ( 1.41 g, 4.23 mmol) and sodium bicarbonate (645 mg, 7.68 mmol) were suspended in /so-propanol (15.0 ml.) and then, heated to reflux for 16 h. The reaction mixture was allowed to cool down to 50 °C, before it was filtered and concentrated under reduced pressure.

The crude material was dissolved in a tetrahydrofuran/water-mixture (2:1 , 30 ml.) and treated with lithium hydroxide (321 mg, 13.4 mmol) in one portion. The reaction mixture was stirred for 16 h at 20-25 °C. After acidification to pH = 2-3 using aqueous 3M hydrochloric, the reaction mixture was extracted with ethyl acetate (5x). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH₂Cl2/MeOH) to afford 4-(2,4-bis(2- (benzyloxy)phenyl)-5-ethyl-1 H-imidazol-1-yl)-2-methoxybenzoic acid (700 mg, 1.15 mmol, 30%). UHPLC/MS (ESI): [m/z]\ 61 1 [M+H]⁺.

BH. 4-(2,4-bis(2-(benzyloxy)phenyl)-5-isobutyl-1 H-imidazol-1-yl)-2-methoxybenzoic acid

Methyl 4-((amino(2-(benzyloxy)phenyl)methylene)amino)-2-methoxybenzoate ( 2.49 g, 6.39 mmol), 1-(2-(benzyloxy)phenyl)-2-bromo-4-methylpentan-1-one ( 2.54 g, 7.09 mmol) and sodium bicarbonate (1.07g, 12.8 mmol) were suspended in /so-propanol (30.0 mL) and then, heated to reflux for 16 h. The reaction mixture was allowed to cool down to 50 °C, before it was filtered and concentrated under reduced pressure.

The crude material was dissolved in a tetrahydrofuran/water-mixture (2:1 , 18 ml.) and treated with lithium hydroxide (956 mg, 39.9 mmol) in one portion. The reaction mixture was stirred 6 h at 20-25 °C. After acidification to pH = 2-3 using aqueous 3M hydrochloric acid, the reaction mixture was extracted with ethyl acetate (5x). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH₂Cl2/MeOH) to afford 4-(2,4-bis(2- (benzyloxy)phenyl)-5-ethyl-1 H-imidazol-1-yl)-2-methoxybenzoic acid (XX, 890 mg, 1.39 mmol, 20%). UHPLC/MS (ESI): [m/z\. 639 [M+H]⁺.

Bl. 5-(2,4-bis(2-(benzyloxy)phenyl)-5-isobutyl-1 H-imidazol-1-yl)-2-methoxybenzoic acid

Methyl 5-((amino(2-(benzyloxy)phenyl)methylene)amino)-2-methoxybenzoate ( 2.49 g, 6.39 mmol), 1-(2-(benzyloxy)phenyl)-2-bromo-4-methylpentan-1-one (2.54 g, 7.09 mmol) and sodium bicarbonate (1.07g, 12.8 mmol) were suspended in /so-propanol (30.0 mL) and then heated to reflux for 16 h. The reaction mixture was allowed to cool down to 50 °C, before it was filtered and concentrated under reduced pressure.

The crude material was dissolved in a tetrahydrofuran/water-mixture (2:1 , 18 mL) and treated with lithium hydroxide (956 mg, 39.9 mmol) in one portion. The reaction mixture was stirred for 16 h at 20-25 °C. After acidification to pH = 2-3 using aqueous 3M hydrochloric acid, the reaction mixture was extracted with ethyl acetate (5x). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (C^Ch/MeOH) to afford 4-(2,4-bis(2- (benzyloxy)phenyl)-5-ethyl-1 H-imidazol-1-yl)-2-methoxybenzoic acid (990 mg, 1.55 mmol, 24%). UHPLC/MS (ESI): [m/z]: 639 [M+H]⁺.

BJ. 4-(2-(benzyloxy)-4-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1 -(4-bromophenyl)-1 H- imidazole

2-(Benzyloxy)-N-(4-bromophenyl)benzimidamide (24.8 g, 0.065 mol), 1-(2-(benzyloxy)-4- methoxyphenyl)-2-bromoethan-1-one (24.1 g, 0.072 mol) and sodiumbicarbonate (10.9 g, 0.130 mol) in 800 ml_ isopropanol were heated at 80°C for 12 h. The resulting mixture was filtered at 80°C, evaporated and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (24.5 g, 0.040 mol, 61 %).

R_f (petrolether: ethylacetate 5:1). 0.54

BK. 2-(benzyloxy)-N-(4-bromo-3-fluorophenyl)benzimidamide

Sodium bis(trimethylsilyl)amide solution (79 ml_, 0.079 mol, 1 M in THF) was added to a solution of 4-bromo-3-fluoroaniline (10.07 g, 0.053 mol) in 400 ml THF at 0°C. After 15 min stirring, 2- (benzyloxy)benzonitrile (13.81 g, 0.066 mol) was added and the reaction mixture was allowed to warm up to 20°C and was stirred for 12 h. Saturated aqueous NH₄CI (200 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 100 ml). The combined organic phases were dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (15 g, 0.038 mol, 71%).

R_f (petrolether: ethylacetate 1 :1): 0.77

BL 2,4-bis(2-(benzyloxy)phenyl)-1-(4-bromo-3-fluorophenyl)-1 H-imidazole

2-(Benzyloxy)-N-(4-bromo-3-fluorophenyl)benzimidamide (9.98 g, 0.025 mol), 1-(2- (benzyloxy)phenyl)-2-bromoethan-1-one (8.54 g, 0.028 mol) and sodiumbicarbonate (4.2 g,

0.050 mol) in 400 mL isopropanol were heated at 80°C for 12 h. The resulting mixture was filtered at 80°C, evaporated and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (8.9 g, 0.015 mol, 59%).

R_f (petrolether: ethylacetate 5:1): 0.24

BM. 2-(benzyloxy)-N-(4-bromo-3-(trifluoromethyl)phenyl)benzimidamide

Sodium bis(trimethylsilyl)amide solution (63 mL, 0.063 mol, 1 M in THF) was added to a solution of 4-bromo-3-(trifluoromethyl)aniline (10.08 g, 0.042 mol) in 400 ml THF at 0°C. After 15 min stirring, 2-(benzyloxy)benzonitrile (10.88 g, 0.052 mol) was added and the reaction mixture was allowed to warm up to 20°C and was stirred for 12 h. Saturated aqueous NH₄CI (200 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 100 ml). The combined organic phases were dried over Na₂S0₄, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (13.6 g,

0.030 mol, 72%).

R_f (petrolether: ethylacetate 5:1): 0.11

BN. 2,4-bis(2-(benzyloxy)phenyl)-1-(4-bromo-3-(trifluoromethyl)phenyl)-1 H-imidazole

2-(Benzyloxy)-N-(4-bromo-3-(trifluoromethyl)phenyl)benzimidamide (9 g, 0.020 mol), 1-(2- (benzyloxy)phenyl)-2-bromoethan-1-one (6.7 g, 0.022 mol) and sodiumbicarbonate (3.7 g, 0.040 mol) in 200 ml_ isopropanol were heated at 80°C for 12 h. The resulting mixture was filtered at 80°C, evaporated and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (7.9 g, 0.012 mol, 60%).

R_f (petrolether: ethylacetate 1 :1): 0.29

BO. 4-(2,4-bis(2-(benzyloxy)phenyl)-1H-imidazol-1 -yl)-2-(trifluoromethyl)benzaldehyde

To a solution of 2,4-bis(2-(benzyloxy)phenyl)-1-(4-bromo-3-(trifluoromethyl)phenyl)-1 H-imidazole (8.5 g, 13.0 mmol) in 200 mL THF at -75°C n-butyllithium (8.9 ml, 14.30 mmol, 1.6 M in hexane) was added. After 60 min stirring at -75°C, dimethylformamide DMF (5.6 ml, 71.5 mmol, 5.5 eq) was added and the reaction mixture was stirred 1 h at -75°C. Then the reaction mixture was warmed up to 20°C. Saturated aqueous NH₄CI solution (100 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 80 ml). The combined organic phases were dried over Na₂S0₄, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (3.9 g, 6.4 mmol, 49%).

R_f (petrolether: ethylacetate 1 :1): 0.70

BP. 4-(2,4-bis(2-(benzyloxy)phenyl)-1H-imidazol-1 -yl)-2-(trifluoromethyl)benzoic acid

To a solution of 4-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)-2- (trifluoromethyl)benzaldehyde (4 g, 6.62 mmol) in 100 ml acetone Jones reagent (4.2 ml, 2 M CrCh in aqueous H2SO4) was added and the resulting mixture was stirred for 45 min at 20°C. After the acetone was evaporated, ethylacetate was added (100 ml) and the mixture was washed with saturated aqueous NaHCC>3 solution (2x 120 ml), dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (3.33 g, 5.35 mmol, 81 %).

R_f (petrolether: ethylacetate 1 :1): 0.32

BQ. 2-(benzyloxy)-N-(4-bromophenyl)-5-methoxybenzimidamide

Sodium bis(trimethylsilyl)amide solution (45 ml_, 0.045 mol, 1 M in THF) was added to a solution of 4-bromoaniline (7.5 g, 0.044 mol) in 300 ml THF at 0°C. After 15 min stirring, 2-(benzyloxy)-5- methoxybenzonitrile (7 g, 0.029 mol) was added and the reaction mixture was allowed to warm up to 20°C and was stirred for 12 h. Saturated aqueous NH CI (200 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 100 ml). The combined organic phases were dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (12.7 g, 0.031 mol, 71%).

R_f (petrolether: ethylacetate 1 :1): 0.22

BR. 2-(benzyloxy)-N-(3-bromo-5-(trifluoromethyl)phenyl)benzimidamide

Sodium bis(trimethylsilyl)amide solution (63 ml_, 0.063 mol, 1 M in THF) was added to a solution of 3-bromo-5-(trifluoromethyl)aniline (10 g, 0.042 mol) in 400 ml THF at 0°C. After 15 min stirring, 2-(benzyloxy)benzonitrile (11 g, 0.053 mol) was added and the reaction mixture was allowed to warm up to 20°C and was stirred for 12 h. Saturated aqueous NH₄CI (200 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 100 ml). The combined organic phases were dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (13.9 g, 0.031 mol, 74%).

R_f (petrolether: ethylacetate 1 :1): 0.16

BS. 2,4-bis(2-(benzyloxy)phenyl)-1-(3-bromo-5-(trifluoromethyl)phenyl)-1 H-imidazole

2-(Benzyloxy)-N-(3-bromo-5-(trifluoromethyl)phenyl)benzimidamide (6 g, 0.013 mol), 1-(2- (benzyloxy)phenyl)-2-bromoethan-1-one (4.4 g, 0.015 mol) and sodiumbicarbonate (2.3 g, 0.027 mol) in 150 ml_ isopropanol were heated at 80°C for 12 h. The resulting mixture was filtered at 80°C, evaporated and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (5.7 g, 8.7 mmol, 65%).

R_f (petrolether: ethylacetate 1 :1): 0.6

BT. 3-(2,4-bis(2-(benzyloxy)phenyl)-1H-imidazol-1 -yl)-5-(trifluoromethyl)benzaldehyde

To a solution of 2,4-bis(2-(benzyloxy)phenyl)-1-(3-bromo-5-(trifluoromethyl)phenyl)-1 H-imidazole (2.2 g, 3.4 mmol) in 120 ml. THF at -75°C n-butyllithium (2.3 ml, 3.7 mmol, 1.6 M in hexane) was added. After 60 min stirring at -75°C, dimethylformamide DMF (1.5 ml, 18.6 mmol, 5.5 eq) was added and the reaction mixture was stirred 1 h at -75°C. Then the reaction mixture was warmed up to 20°C. Saturated aqueous N UCI solution (100 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 80 ml). The combined organic phases were dried over Na SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (1.08 g, 1.8 mmol, 53%).

R_f (petrolether: ethylacetate 1 :1): 0.62

BV. 3-(2,4-bis(2-(benzyloxy)phenyl)-1H-imidazol-1 -yl)-5-(trifluoromethyl)benzoic acid

To a solution of 3-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)-5-

(trifluoromethyl)benzaldehyde (0.8 g, 1.32 mmol) in 50 ml acetone Jones reagent (0.9 ml, 2 M CrCh in aqueous H₂SO₄) was added and the resulting mixture was stirred for 45 min at 20°C. After the acetone was evaporated, ethylacetate was added (100 ml) and the mixture was washed with saturated aqueous NaHCCh solution (2x 120 ml), dried over Na2SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (0.71 g, 1.14 mmol, 86%).

R_f (petrolether: ethylacetate 1 :1): 0.16

BW. 2-(benzyloxy)-N-(3-bromo-4-fluorophenyl)benzimidamide

Sodium bis(trimethylsilyl)amide solution (79 ml_, 0.079 mol, 1 M in THF) was added to a solution of 3-bromo-4-fluoroaniline (10.07 g, 0.053 mol) in 400 ml THF at 0°C. After 15 min stirring, 2- (benzyloxy)benzonitrile (13.81 g, 0.066 mol) was added and the reaction mixture was allowed to warm up to 20°C and was stirred for 12 h. Saturated aqueous NH₄CI (200 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 100 ml). The combined organic phases were dried over Na2SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (21.2 g, 0.053 mol, 78%).

R_f (petrolether: ethylacetate 5:1): 0.11

BX. 2,4-bis(2-(benzyloxy)phenyl)-1-(3-bromo-4-fluorophenyl)-1 H-imidazole

2-(Benzyloxy)-N-(3-bromo-4-fluorophenyl)benzimidamide (9.98 g, 0.025 mol), 1-(2- (benzyloxy)phenyl)-2-bromoethan-1-one (8.39 g, 0.028 mol) and sodiumbicarbonate (4.2 g, 0.050 mol) in 400 ml. isopropanol were heated at 80°C for 12 h. The resulting mixture was filtered at 80°C, evaporated and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (10.9 g, 0.018 mol, 72%).

R_f (petrolether: ethylacetate 5:1): 0.3

BY. 5-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1 -yl)-2-fluorobenzaldehyde

To a solution of 2,4-bis(2-(benzyloxy)phenyl)-1-(3-bromo-4-fluorophenyl)-1 H-imidazole (10 g,

16.6 mmol) in 150 mL THF at -75°C n-butyllithium (11.4 ml, 18.2 mmol, 1.6 M in hexane) was added. After 60 min stirring at -75°C, dimethylformamide DMF (7.1 ml, 91.2 mmol, 5.5 eq) was added and the reaction mixture was stirred 1 h at -75°C. Then the reaction mixture was warmed up to 20°C. Saturated aqueous NhUCI solution (100 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 80 ml). The combined organic phases were dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (5.2 g, 9.25 mmol, 56%).

R_f (petrolether: ethylacetate 1 :1): 0.44

BZ. 5-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1 -yl)-2-fluorobenzoic acid

To a solution of 5-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1 -yl)-2-fluorobenzaldehyde (5.77 g, 10.40 mmol) in 100 ml acetone Jones reagent (6.5 ml, 2 M CrCh in aqueous H₂SO₄) was added and the resulting mixture was stirred for 45 min at 20°C. After the acetone was evaporated, ethylacetate was added (100 ml) and the mixture was washed with saturated aqueous NaHCCh solution (2x 120 ml), dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (4.8 g, 8.43 mmol, 81%).

R_f (petrolether: ethylacetate 1 :1): 0.16

CA. 4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1-(4-bromo-3- (trifluoromethyl)phenyl)-1 H-imidazole

2-(Benzyloxy)-N-(4-bromo-3-(trifluoromethyl)phenyl)benzimidamide (9 g, 0.020 mol), 1-(2- (benzyloxy)-5-methoxyphenyl)-2-bromoethan-1-one (7.37 g, 0.022 mol) and sodiumbicarbonate (3.7 g, 0.040 mol) in 400 mL isopropanol were heated at 80°C for 12 h. The resulting mixture was filtered at 80°C, evaporated and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (10.72 g, 0.016 mol, 78%).

R_f (petrolether: ethylacetate 5:1): 0.38 CB. 4-(4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1H-imidazol-1-yl)-2-

(trifluoromethyl)benzaldehyde

To a solution of 4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1-(4-bromo-3- (trifluoromethyl)phenyl)-1 H-imidazole (8.1 g, 11.83 mmol) in 150 mL THF at -75°C n-butyllithium (8.1 ml, 13.01 mmol, 1.6 M in hexane) was added. After 60 min stirring at -75°C,

dimethylformamide DMF (5.1 ml, 65.1 mmol, 5.5 eq) was added and the reaction mixture was stirred 1 h at -75°C. Then the reaction mixture was warmed up to 20°C. Saturated aqueous NH4CI solution (100 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 80 ml). The combined organic phases were dried over Na₂S04, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (4.43 g, 6.97 mmol, 59%).

R_f (petrolether: ethylacetate 1 :1): 0.48

CC. 4-(4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1H-imidazol-1-yl)-2-

(trifluoromethyl)benzoic acid

To a solution of 4-(4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)- 2-(trifluoromethyl)benzaldehyde (2 g, 3.15 mmol) in 100 ml acetone Jones reagent (2 ml, 2 M CrCh in aqueous H₂SO₄) was added and the resulting mixture was stirred for 45 min at 20°C. After the acetone was evaporated, ethylacetate was added (100 ml) and the mixture was washed with saturated aqueous NaHCCh solution (2x 120 ml), dried over Na2SC>4, filtered and

evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (2.1 g, 3.15 mmol, 86%).

R_f (petrolether: ethylacetate 1 :1): 0.14

CE. 2-(benzyloxy)-N-(3-bromo-4-(2-(2-methoxyethoxy)ethoxy)phenyl)benzimidamide

Sodium bis(trimethylsilyl)amide solution (26 ml_, 0.026 mol, 1 M in THF) was added to a solution of 3-bromo-4-(2-(2-methoxyethoxy)ethoxy)aniline (5 g, 0.017 mol) in 120 ml THF at 0°C. After 15 min stirring, 2-(benzyloxy)benzonitrile (5.4 g, 0.026 mol) was added and the reaction mixture was allowed to warm up to 20°C and was stirred for 12 h. Saturated aqueous NH4CI (200 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 100 ml). The combined organic phases were dried over Na2SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (6.97 g,

0.014 mol, 81 %).

R_f (petrolether: ethylacetate 5:1): 0.13

CF. 2,4-bis(2-(benzyloxy)phenyl)-1-(3-bromo-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-1 H- imidazole

2-(Benzyloxy)-N-(3-bromo-4-(2-(2-methoxyethoxy)ethoxy)phenyl)benzimidamide (8.1 g, 0.016 mol), 1-(2-(benzyloxy)phenyl)-2-bromoethan-1-one (8.39 g, 0.028 mol) and sodiumbicarbonate (5.5 g, 0.018 mol) in 150 ml. isopropanol were heated at 80°C for 12 h. The resulting mixture was filtered at 80°C, evaporated and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (9.4 g, 0.0133 mol, 82%).

R_f (petrolether: ethylacetate 5:1): 0.39 CG. 5-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1 -yl)-2-(2-(2- methoxyethoxy)ethoxy)benzaldehyde

To a solution of 2,4-bis(2-(benzyloxy)phenyl)-1-(3-bromo-4-(2-(2-methoxyethoxy)ethoxy)phenyl)- 1 H-imidazole (4.8 g, 6.8 mmol) in 100 ml_ THF at -75°C n-butyllithium (4.7 ml, 7.5 mmol, 1.6 M in hexane) was added. After 60 min stirring at -75°C, dimethylformamide DMF (3 ml, 37.4 mmol, 5.5 eq) was added and the reaction mixture was stirred 1 h at -75°C. Then the reaction mixture was warmed up to 20°C. Saturated aqueous N UCI solution (100 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 80 ml). The combined organic phases were dried over Na2SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (2.9 g, 4.42 mmol, 65%).

R_f (petrolether: ethylacetate 1 :1): 0.4

CH. 5-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1 -yl)-2-(2-(2-methoxyethoxy)ethoxy) benzoic acid

To a solution of 5-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1 -yl)-2-(2-(2-methoxyethoxy)ethoxy) benzaldehyde (2.8 g, 4.28 mmol) in 100 ml acetone Jones reagent (2.7 ml, 2 M CrCb in aqueous H₂SO₄) was added and the resulting mixture was stirred for 45 min at 20°C. After the acetone was evaporated, ethylacetate was added (100 ml) and the mixture was washed with saturated aqueous NaHCCh solution (2x 120 ml), dried over Na2SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (2.64 g, 3.93 mmol, 92%).

R_f (petrolether: ethylacetate 1 :1): 0.22

Cl. 2-(benzyloxy)-N-(3-bromo-4-(2-methoxyethoxy)phenyl)benzimidamide

Sodium bis(trimethylsilyl)amide solution (31 ml_, 0.031 mol, 1 M in THF) was added to a solution of 3-bromo-4-(2-methoxyethoxy)aniline (5 g, 0.020 mol) in 150 ml THF at 0°C. After 15 min stirring, 2-(benzyloxy)benzonitrile (6.4 g, 0.030 mol) was added and the reaction mixture was allowed to warm up to 20°C and was stirred for 12 h. Saturated aqueous NH₄CI (200 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 100 ml). The combined organic phases were dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (8.3 g, 0.018 mol, 89%).

R_f (petrolether: ethylacetate 5:1): 0.15

CJ. 2,4-bis(2-(benzyloxy)phenyl)-1-(3-bromo-4-(2-methoxyethoxy)phenyl)-1H-imidazole

2-(Benzyloxy)-N-(3-bromo-4-(2-methoxyethoxy)phenyl)benzimidamide (4.9 g, 0.011 mol), 1-(2- (benzyloxy)phenyl)-2-bromoethan-1-one (3.6 g, 0.012 mol) and sodiumbicarbonate (1.8 g, 0.022 mol) in 150 ml_ isopropanol were heated at 80°C for 12 h. The resulting mixture was filtered at 80°C, evaporated and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (6.3 g, 9.5 mmol, 88%).

R_f (petrolether: ethylacetate 5:1): 0.45

CK. 5-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1 -yl)-2-(2-methoxyethoxy)benzaldehyde

To a solution of 2,4-bis(2-(benzyloxy)phenyl)-1-(3-bromo-4-(2-methoxyethoxy)phenyl)-1 H- imidazole (3.7 g, 5.6 mmol) in 100 ml. THF at -75°C n-butyllithium (3.8 ml, 6.1 mmol, 1.6 M in hexane) was added. After 60 min stirring at -75°C, dimethylformamide DMF (2.4 ml, 30.8 mmol, 5.5 eq) was added and the reaction mixture was stirred 1 h at -75°C. Then the reaction mixture was warmed up to 20°C. Saturated aqueous NFUCI solution (100 ml) was added and the resulting mixture was extracted with ethylacetate (3 x 80 ml). The combined organic phases were dried over Na₂SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 100% ethylacetate in petrolether) to afford the title compound as a light brown solid (2.42 g, 3.97 mmol, 71 %).

R_f (petrolether: ethylacetate 1 :1): 0.27

CL 5-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1 -yl)-2-(2-methoxyethoxy)benzoic acid

To a solution of 5-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)-2-(2- methoxyethoxy)benzaldehyde (2.1 g, 3.44 mmol) in 100 ml acetone Jones reagent (2.2 ml, 2 M CrCh in aqueous H₂SO₄) was added and the resulting mixture was stirred for 45 min at 20°C. After the acetone was evaporated, ethylacetate was added (100 ml) and the mixture was washed with saturated aqueous NaHCC>3 solution (2x 120 ml), dried over Na2SC>4, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (2.03 g, 3.23 mmol, 94%).

R_f (petrolether: ethylacetate 1 :1): 0.18

Final Example Compounds

1. Example Compound No. 01 :

4-(2,4-bis(2-hydroxyphenyl)-1 H-imidazol-1-yl)benzoic acid

4-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)benzoic acid (1.30 g, 2.35 mmol) was dissolved in methanol (900 ml) under nitrogen. Then Palladium (100 mg, 10 wt. % on carbon) was added and H₂-gas was passed through the resulted mixture for 3 h under stirring at 20°C. Then the reaction was stirred for 12 h at 20°C. The mixture was flushed with nitrogen, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (0.68 g, 1.83 mmol, 78%).

¹ H NMR (400 MHz, DMSO): d 13.0 (s, 1 H), 11.3 (s, 1 H), 10.4 (s, 1 H), 8.1 (s, 1 H), 8.0 (m, 2H), 7.85 (m, 1 H), 7.5 (m, 2H), 7.3 (m, 2H), 7.1 (m, 1 H), 6.85 (m, 4H).

MS (ESI+): m/z 373 [M+H]⁺.

2. Example Compound No. 03:

4-(2,4-bis(2-hydroxyphenyl)-1 H-imidazol-1-yl)-2-methoxybenzoic acid

4-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)-2-methoxybenzoic acid (1 g, 1.71 mmol) was dissolved in methanol (900 ml) under nitrogen. Then Palladium (100 mg, 10 wt. % on carbon) was added and H₂-gas was passed through the resulted mixture for 3 h under stirring at 20°C. Then the reaction was stirred for 12 h at 20°C. The mixture was flushed with nitrogen, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (0.5 g, 1.24 mmol, 72%).

¹ H NMR (400 MHz, DMSO): d 12.7 (s, 1 H), 11.3 (s, 1 H), 10.6 (s, 1 H), 8.11 (s, 1 H), 7.82 (m, 1 H), 7.67 (m, 1 H), 7.3 (m, 2H), 7.1 (m, 2H), 7.0 (m, 1 H), 6.85 (m, 4H), 3.7 (s, 3H).

3. Example Compound No. 09:

3-(2,4-bis(2-hydroxyphenyl)-1 H-imidazol-1-yl)-5-methoxybenzoic acid

3-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)-5-methoxybenzoic acid (0.5 g, 0.86 mmol) was dissolved in methanol (900 ml) under nitrogen. Then Palladium (100 mg, 10 wt. % on carbon) was added and H₂-gas passed through the mixture for 3 h under stirring at 20°C. Then the reaction was stirred for 12 h at 20°C. The mixture was flushed with nitrogen, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (0.27 g, 0.66 mmol, 77%).

¹ H NMR (400 MHz, DMSO): d 12.9 (s, 1 H), 11.4 (s, 1 H), 10.6 (s, 1 H), 8.1 (s, 1 H), 7.83 (m, 1 H), 7.46 (m, 2H), 7.24 (m, 2H), 7.19 (m, 1 H), 7.1 (m, 1 H), 6.85 (m, 4H), 3.7 (s, 3H).

4. Example Compound No. 05:

4-(4-(2-hydroxy-4-methoxyphenyl)-2-(2-hydroxyphenyl)-1 H-imidazol-1-yl)benzoic acid

4-(4-(2-(benzyloxy)-4-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)benzoic acid (0.8 g, 1.37 mmol) was dissolved in methanol (900 ml) under nitrogen. Then Palladium (80 mg, 10 wt. % on carbon) was added and H₂-gas passed through the mixture for 3 h under stirring at 20°C. Then the reaction was stirred for 12 h at 20°C. The mixture was flushed with nitrogen, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (0.43 g, 1.06 mmol, 77%).

¹ H NMR (400 MHz, DMSO): d 13.1 (s, 1 H), 11.4 (s, 1 H), 10.5 (s, 1 H), 8.0 (m, 3H), 7.7 (m, 1 H), 7.4 (m, 2H), 7.2 (m, 2H), 6.8 (m, 2H), 6.5 (m, 2H), 3.7 (s, 3H).

5. Example Compound No. 06:

4-(4-(2-hydroxy-5-methoxyphenyl)-2-(2-hydroxyphenyl)-1 H-imidazol-1-yl)benzoic acid

4-(4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)benzoic acid (1.4 g, 2.35 mmol) was dissolved in methanol (900 ml) under nitrogen. Then Palladium (140 mg, 10 wt. % on carbon) was added and H2-gas passed through the mixture for 3 h under stirring at 20°C. Then the reaction was stirred for 12 h at 20°C. The mixture was flushed with nitrogen, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (0.73 g, 1.83 mmol, 76%).

¹ H NMR (400 MHz, DMSO): d 13.1 (s, 1 H), 11.8 (s, 1 H), 10.3 (s, 1 H), 8.1 (s, 1 H), 7.9 (m, 2H), 7.4 (m, 3H), 7.2 (m, 2H), 6.8 (m, 2H), 6.7 (m, 1 H), 3.7 (s, 3H). 6. Example Compound No. 07:

5-(2,4-bis(2-hydroxyphenyl)-1 H-imidazol-1-yl)-2-methoxybenzoic acid

In a round bottomed flask, 5-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)-2-methoxybenzoic acid (1 g, 1.72 mmol) was dissolved in methanol (900 ml) under nitrogen. Then Palladium (200 mg, 10 wt. % on carbon) was added and H₂-gas passed through the mixture for 3 h under stirring at 20°C. Then the reaction was stirred for 12 h at 20°C. The mixture was flushed with nitrogen, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (0.53 g, 1.3 mmol, 76%).

¹ H NMR (400 MHz, DMSO): d 13.1 (s, 1 H), 11.2 (s, 1 H), 10.6 (s, 1 H), 7.9 (s, 1 H), 7.8 (m, 1 H), 7.6 (m, 1 H), 7.5 (m, 1 H), 7.2 (m, 4H), 6.9 (m, 3H), 6.7 (m, 1 H), 3.8 (s, 3H).

7. Example Compound No. 12:

4-(2,4-bis(2-hydroxyphenyl)-1 H-imidazol-1-yl)-2-fluorobenzoic acid

In a round bottomed flask, 4-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)-2-fluorobenzoic acid (1 g, 1.75 mmol) was dissolved in methanol (900 ml) under nitrogen. Then Palladium (200 mg, 10 wt. % on carbon) was added and H2-gas passed through the mixture for 3 h under stirring at 20°C. Then the reaction was stirred for 12 h at 20°C. The mixture was flushed with nitrogen, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (0.51 g, 1.3 mmol, 74%).

¹ H NMR (400 MHz, DMSO): d 13.4 (s, 1 H), 11.2 (s, 1 H), 10.2 (s, 1 H), 8.1 (s, 1 H), 7.9 (m, 2H), 7.3 (m, 4H), 7.1 (m, 1 H), 6.9 (m, 4H). 8. Example Compound No. 14:

4-(2,4-bis(2-hydroxyphenyl)-1 H-imidazol-1-yl)-2-(trifluoromethyl)benzoic acid

In a round bottomed flask, 4-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)-2- (trifluoromethyl)benzoic acid (1 g, 1.61 mmol) was dissolved in methanol (900 ml) under nitrogen. Then Palladium (200 mg, 10 wt. % on carbon) was added and H₂-gas passed through the mixture for 3 h under stirring at 20°C. Then the reaction was stirred for 12 h at 20°C. The mixture was flushed with nitrogen, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (0.55 g, 1.24 mmol, 77%).

¹ H NMR (400 MHz, DMSO): d 13.7 (s, 1 H), 11.3 (s, 1 H), 10.1 (s, 1 H), 8.2 (s, 1 H), 7.9 (m, 2H), 7.8 (m, 1 H), 7.7 (m, 1 H), 7.4 (m, 1 H), 7.3 (m, 1 H), 7.1 (m, 1 H), 6.9 (m, 3H), 6.8 (m, 1 H).

9. Example Compound No. 18:

4-(2,4-bis(2-hydroxy-5-methoxyphenyl)-1 H-imidazol-1 -yl)benzoic acid

In a round bottomed flask, 4-(2,4-bis(2-(benzyloxy)-5-methoxyphenyl)-1 H-imidazol-1-yl)benzoic acid (2 g, 3.26 mmol) was dissolved in methanol (900 ml) under nitrogen. Then Palladium (200 mg, 10 wt. % on carbon) was added and H₂-gas passed through the mixture for 3 h under stirring at 20°C. Then the reaction was stirred for 12 h at 20°C. The mixture was flushed with nitrogen, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (1.03 g, 2.38 mmol, 73%).

¹ H NMR (400 MHz, DMSO): d 13.1 (s, 1 H), 10.7 (s, 1 H), 10.5 (s, 1 H), 8.0 (m, 3H), 7.4 (m, 3H), 6.7 (m, 5H), 3.7 (s, 3H), 3.5 (s, 3H).

10. Example Compound No. 08:

3-(2,4-bis(2-hydroxyphenyl)-1 H-imidazol-1-yl)-4-methoxybenzoic acid

In a round bottomed flask, 3-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)-4-methoxybenzoic acid (1.0 g, 1.63 mmol) was dissolved in methanol (900 ml) under nitrogen. Then Palladium (200 mg, 10 wt. % on carbon) was added and H₂-gas passed through the mixture for 3 h under stirring at 20°C. Then the reaction was stirred for 12 h at 20°C. The mixture was flushed with nitrogen, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (0.5 g, 1.15 mmol, 70%).

¹ H NMR (400 MHz, DMSO): d 13.1 (s, 1 H), 11.8 (s, 1 H), 1 1.0 (s, 1 H), 8.1 (m, 1 H), 7.9 (m, 1 H), 7.8 (m, 2H), 7.3 (m, 1 H), 7.2 (m, 2H), 6.9 (m, 4H), 6.7 (m, 1 H), 3.7 (s, 3H).

MS (ESI+): m/z 403 [M+H]⁺.

11. Example Compound No. 32:

5-(4-(2-hydroxy-5-methoxyphenyl)-2-(2-hydroxyphenyl)-1 H-imidazol-1-yl)-2- methoxybenzoic acid

In a round bottomed flask, 5-(4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1 H- imidazol-1-yl)-2-methoxybenzoic acid (2.5 g, 4.08 mmol) was dissolved in methanol (1900 ml) under nitrogen. Then Palladium (500 mg, 10 wt. % on carbon) was added and H₂-gas passed through the mixture for 3 h under stirring at 20°C. Then the reaction was stirred for 12 h at 20°C. The mixture was flushed with nitrogen, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (1.43 g, 1.83 mmol, 81%).

¹ H NMR (400 MHz, DMSO): d 13.1 (s, 1 H), 10.8 (s, 1 H), 10.4 (s, 1 H), 8.0 (s, 1 H), 7.7 (m, 1 H), 7.5 (m, 1 H), 7.4 (m, 1 H), 7.2 (m, 3H), 6.8 (m, 4H), 3.8 (s, 3H), 3.7 (s, 3H).

12. Example Compound No. 15:

3-(2,4-bis(2-hydroxyphenyl)-1 H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid

In a round bottomed flask, 3-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)-5- (trifluoromethyl)benzoic acid (0.75 g, 1.21 mmol) was dissolved in methanol (900 ml) under nitrogen. Then Palladium (100 mg, 10 wt. % on carbon) was added and H₂-gas passed through the mixture for 3 h under stirring at 20°C. Then the reaction was stirred for 12 h at 20°C. The mixture was flushed with nitrogen, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (0.37 g, 0.85 mmol, 70%).

1 H NMR (400 MHz, DMSO): d 13.6 (s, 1 H), 11.4 (s, 1 H), 10.1 (s, 1 H), 8.3 (s, 1 H), 8.2 (m, 2H), 7.9 (s, 1 H), 7.8 (m, 1 H), 7.4 (m, 1 H), 7.3 (m, 1 H), 7.1 (m, 1 H), 6.9 (m, 3H), 6.3 (m, 1 H).

13. Example Compound No. 16:

5-(2,4-bis(2-hydroxyphenyl)-1 H-imidazol-1-yl)-2-fluorobenzoic acid

In a round bottomed flask, 5-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)-2-fluorobenzoic acid (1.00 g, 1.75 mmol) was dissolved in methanol (900 ml) under nitrogen. Then Palladium (100 mg, 10 wt. % on carbon) was added and H₂-gas passed through the mixture for 3 h under stirring at 20°C. Then the reaction was stirred for 12 h at 20°C. The mixture was flushed with nitrogen, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (0.52 g, 1.33 mmol, 76%).

¹ H NMR (400 MHz, DMSO): d 13.2 (s, 1 H), 11.1 (s, 1 H), 10.2 (s, 1 H), 8.2 (s, 1 H), 8.0 (m, 2H), 7.7 (m, 1 H), 7.9 (m, 2H), 7.3 (m, 2H), 6.9 (m, 4H).

14. Example Compound No. 41 :

4-(4-(2-hydroxy-5-methoxyphenyl)-2-(2-hydroxyphenyl)-1 H-imidazol-1-yl)-2- (trifluoromethyl)benzoic acid

In a round bottomed flask, 4-(4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1 H- imidazol-1-yl)-2-(trifluoromethyl)benzoic acid (0.5 g, 0.77 mmol) was dissolved in methanol (900 ml) under nitrogen. Then Palladium (100 mg, 10 wt. % on carbon) was added and H₂-gas passed through the mixture for 3 h under stirring at 20°C. Then the reaction was stirred for 12 h at 20°C. The mixture was flushed with nitrogen, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (0.25 g, 0.52 mmol, 68%).

¹ H NMR (400 MHz, DMSO): d 13.8 (s, 1 H), 10.9 (s, 1 H), 10.1 (s, 1 H), 8.3 (s, 1 H), 7.9 (m, 1 H), 7.8 (s, 1 H), 7.7 (m, 1 H), 7.4 (m, 2H), 7.3 (m, 1 H), 6.9 (m, 1 H), 6.8 (m, 3H), 3.7 (s, 3H).

15. Example Compound No. 43:

5-(2,4-bis(2-hydroxyphenyl)-1 H-imidazol-1-yl)-2-(2-(2-methoxyethoxy)ethoxy)benzoic acid

In a round bottomed flask, 5-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)-2-(2-(2- methoxyethoxy)ethoxy)benzoic acid (2.58 g, 3.85 mmol) was dissolved in methanol (900 ml) under nitrogen. Then Palladium (250 mg, 10 wt. % on carbon) was added and H₂-gas passed through the mixture for 3 h under stirring at 20°C. Then the reaction was stirred for 12 h at 20°C. The mixture was flushed with nitrogen, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (1.4 g, 2.85 mmol, 74%).

¹ H NMR (400 MHz, DMSO): d 12.8 (s, 1 H), 11.3 (s, 1 H), 10.9 (s, 1 H), 8.0 (s, 1 H), 7.8 (m, 1 H), 7.7 (m, 1 H), 7.5 (m, 1 H), 7.2 (m, 4H), 6.8 (m, 4H), 4.2 (m, 2H), 3.8 (m, 2H), 3.6 (m, 2H), 3.4 (m, 2H), 3.2 (s, 3H).

16. Example Compound No. 44:

5-(2,4-bis(2-hydroxyphenyl)-1 H-imidazol-1-yl)-2-(2-methoxyethoxy)benzoic acid

In a round bottomed flask, 5-(2,4-bis(2-(benzyloxy)phenyl)-1 H-imidazol-1-yl)-2-(2- methoxyethoxy)benzoic acid (1.06 g, 1.69 mmol) was dissolved in methanol (900 ml) under nitrogen. Then Palladium (100 mg, 10 wt. % on carbon) was added and hh-gas passed through the mixture for 3 h under stirring at 20°C. Then the reaction was stirred for 12 h at 20°C. The mixture was flushed with nitrogen, filtered and evaporated. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column eluted with a gradient of 0 to 25% methanol in dichloromethane) to afford the title compound as a white solid (0.68 g, 1.83 mmol, 71%).

¹ H NMR (400 MHz, DMSO): d 12.6 (s, 1 H), 11.5 (s, 1 H), 1 1.1 (s, 1 H), 8.0 (s, 1 H), 7.7 (m, 1 H), 7.6 (m, 1 H), 7.4 (m, 1 H), 7.2 (m, 2H), 7.1 (m, 2H), 6.9 (m, 3H), 6.8 (m, 1 H), 4.2 (m, 2H), 3.7 (m, 2H), 3.4 (s, 3H).

17. Example Compound No. 40:

4-(2,4-bis(2-hydroxyphenyl)-5-methyl-1 H-imidazol-1-yl)-2-methoxybenzoic acid

5-(2,4-bis(2-(benzyloxy)phenyl)-5-methyl-1 H-imidazol-1-yl)-2-methoxybenzoic acid (2.76 g, 4.62 mmol) was dissolved in ethanol (20 mL) and the resulting solution was degassed for 15 min using a nitrogen-stream. To the solution was added palladium on charcoal (10%-w/w, 280 mg) and the nitrogen-stream was switched to a hydrogen-stream. After TLC indicated full consumption of the s.m. the reaction mixture was filtered through a short pad of Celite eluting with ethanol. The filtrate was concentrated under reduced pressure and the resulting crude material was purified by flash column chromatography (Heptane/THF) to afford the titled compound ( 1.43 mg, 3.43 mmol, 74%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-cfe) d ¹ H NMR (400 MHz, DMSO-cfe) d 11.4 (br s, 2H), 7.71 (d, 1 H), 7.48 (dd, 1 H), 7.22 - 7.12 (m, 3H), 7.01-6.97 (m, 2H), 6.94 - 6.88 (m, 2H), 6.87 - 6.80 (m, 1 H), 6.69 (m, 1 H), 3.73 (s, 3H), 2.21 (s, 3H) ppm. UHPLC/MS (ESI): [m/z]\ 417 [M+H]⁺.

18. Example Compound No. 45:

5-(2,4-bis(2-hydroxyphenyl)-5-methyl-1 H-imidazol-1-yl)-2-methoxybenzoic acid

5-(2,4-bis(2-(benzyloxy)phenyl)-5-methyl-1 H-imidazol-1-yl)-2-methoxybenzoic acid (720 mg, 1.21 mmol) was dissolved in ethanol (24 mL) and the resulting solution was degassed for 15 min using a nitrogen-stream. To the solution was added Palladium on charcoal (10%-w/w, 72 mg) and the nitrogen-stream was switched to a hydrogen-stream. After TLC indicated full consumption of the s.m. the reaction mixture was filtered through a short pad of Celite eluting with ethanol. The filtrate was reduced under reduced pressure and the resulting crude material was purified by flash column chromatography (CH₂Cl2/MeOH) to afford the titled compound (350 mg, 840 umol, 69%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-cfe) d 12.8 (br s, 1 H), 10.9 (br s, 1-2H), 7.71 (d, 1 H), 7.61 (dd, 1 H), 7.43 (dd, 1 H), 7.32 - 7.20 (m, 4H), 7.04 (d, 1 H), 6.95 (t, 1 H), 6.90 (d, 1 H), 6.80 (t, 1 H), 3.85 (s, 3H), 2.11 (s, 3H) ppm. UHPLC/MS (ESI): [m/z]\ 417 [M+H]⁺.

19. Example Compound No. 56:

4-(4-(2-hydroxy-5-methoxyphenyl)-2-(2-hydroxyphenyl)-5-methyl-1 H-imidazol-1-yl)-2- methoxybenzoic acid

4-(4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-5-methyl-1 H-imidazol-1-yl)-2- methoxybenzoic acid ( 1.34 g, 2.14 mmol) was dissolved in ethanol (50 mL) and the resulting solution was degassed for 15 min using a nitrogen-stream. To the solution was added palladium on charcoal (10%-w/w, 134 mg) and the nitrogen-stream was switched to a hydrogen-stream. After TLC indicated full consumption of the s.m., the reaction mixture was filtered through a short pad of Celite eluting with ethanol. The filtrate was concentrated under reduced pressure and the resulting crude material was purified by flash column chromatography (C^Ch/MeOH) to afford the titled compound (500 mg, 1.12 mmol, 52%) as an off-white solid. ¹ H NMR (400 MHz, DMSO- cfe) d 7.73 (d, 1 H), 7.24 - 7.13 (m, 2H), 7.04 - 6.96 (m, 3H), 6.89 - 6.81 (m, 2H), 6.79 (dd, 1 H), 6.73-6.69 (m, 1 H), 3.74 (s, 3H), 3.74 (s, 3H), 2.23 (s, 3H) ppm. UHPLC/MS (ESI): [m/z]\ 447 [M+H]⁺.

20. Example Compound No. 57:

4-(5-cyclopropyl-2,4-bis(2-hydroxyphenyl)-1H-imidazol-1-yl)-2-methoxybenzoic acid

4-(2,4-bis(2-(benzyloxy)phenyl)-5-cyclopropyl-1 H-imidazol-1-yl)-2-methoxybenzoic acid ( 850 mg, 1.36 mmol) was dissolved in methanol (50 mL) and the resulting solution was degassed for 15 min using a nitrogen-stream. To the solution was added palladium on charcoal (10%-w/w, 85 mg) and the nitrogen-stream was switched to a hydrogen-stream. After TLC indicated full

consumption of the s.m., the reaction mixture was filtered through a short pad of Celite eluting with methanol. The filtrate was concentrated under reduced pressure and the resulting crude material was purified by flash column chromatography (CH₂Cl2/MeOH) to afford the titled compound (270 mg, 610 umol, 45%) as an off-white solid. ¹H NMR (400 MHz, DMSO-cfe) d 7.78 (dd, 1 H), 7.67 (d, 1 H), 7.24 - 7.07 (m, 4H), 7.00 (dd, 1 H), 6.95 - 6.84 (m, 2H), 6.83 - 6.71 (m, 2H), 3.68 (s, 3H), 2.08-2.01 (m, 1 H), 0.78 - 0.65 (m, 2H), 0.26 - -0.07 (m, 2H) ppm. UHPLC/MS (ESI): [m/z\. 443 [M+H]⁺.

21. Example Compound No. 78:

5-(5-cyclopropyl-2,4-bis(2-hydroxyphenyl)-1H-imidazol-1-yl)-2-methoxybenzoic acid

5-(2,4-bis(2-(benzyloxy)phenyl)-5-cyclopropyl-1 H-imidazol-1-yl)-2-methoxybenzoic acid ( 1.61 g, 2.59 mmol) was dissolved in methanol (26 mL) and the resulting solution was degassed for 15 min using a nitrogen-stream. To the solution was added palladium on charcoal (10%-w/w, 161 mg) and the nitrogen-stream was switched to a hydrogen-stream. After TLC indicated full consumption of the s.m., the reaction mixture was filtered through a short pad of Celite eluting with methanol. The filtrate was concentrated under reduced pressure and the resulting crude material was purified by flash column chromatography (C^Ch/MeOH) to afford the titled compound (940 mg, 2.12 mmol, 82%) as an off-white solid. ¹H NMR (400 MHz, DMSO-cfe) d 7.76 - 7.71 (m, 1 H), 7.66 - 7.53 (m, 2H), 7.29 - 7.12 (m, 4H), 7.00 - 6.88 (m, 2H), 6.85 (d, 1 H), 6.78 (t, 1 H), 3.84 (s, 3H), 1.86-1.79 (m, 1 H), 0.66-0.62 (m, 2H), 0.26 - 0.16 (m, 2H) ppm. UHPLC/MS (ESI): [m/z]\ 443 [M+H]⁺.

22. Example Compound No. 62:

4-(5-ethyl-2,4-bis(2-hydroxyphenyl)-1 H-imidazol-1-yl)-2-methoxybenzoic acid

4-(2,4-bis(2-(benzyloxy)phenyl)-5-ethyl-1 H-imidazol-1-yl)-2-methoxybenzoic acid ( 700 mg, 1.15 mmol) was dissolved in methanol (50 ml.) and the resulting solution was degassed for 15 min using a nitrogen-stream. To the solution was added palladium on charcoal (10%-w/w, 85 mg) and the nitrogen-stream was switched to a hydrogen-stream. After TLC indicated full consumption of the s.m. the reaction mixture was filtered through a short pad of Celite eluting with methanol. The filtrate was concentrated under reduced pressure and the resulting crude material was purified by flash column chromatography (CH₂Cl2/MeOH) to afford the titled compound (273 mg, 634 umol, 55%) as an off-white solid. ¹H NMR (400 MHz, DMSO-cfe) 5 7.73 (d, 1 H), 7.47 (dd, 1 H), 7.25 (d, 1 H), 7.20-7.14 (m, 2H), 7.04 (dd, 1 H), 6.99 (dd, 1 H), 6.92 (d, 2H), 6.84 (dd, 1 H), 6.71-6.67 (m,

1 H), 3.76 (s, 3H), 2.68 (q, 2H), 0.96 (t, 3H) ppm. UHPLC/MS (ESI): [m/z]\ 431 [M+H]⁺.

23. Example Compound No. 76:

4-(2,4-bis(2-hydroxyphenyl)-5-isobutyl-1 H-imidazol-1-yl)-2-methoxybenzoic acid

4-(2,4-bis(2-(benzyloxy)phenyl)-5-isobutyl-1 H-imidazol-1-yl)-2-methoxybenzoic acid (890 mg,

1.39 mmol) was dissolved in methanol (80 mL) and the resulting solution was degassed for 15 min using a nitrogen-stream. To the solution was added palladium on charcoal (10%-w/w, 90 mg) and the nitrogen-stream was switched to a hydrogen-stream. After TLC indicated full consumption of the s.m. the reaction mixture was filtered through a short pad of Celite eluting with methanol. The filtrate was concentrated under reduced pressure and the resulting crude material was purified by flash column chromatography (CH₂Cl2/MeOH) to afford the titled compound (400 mg, 872 umol, 63%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-cfe) d 7.75 (d, 1 H), 7.48 (dd, 1 H), 7.23 (d, 1 H), 7.19-7.13 (m, 2H), 7.00 (dd, 1 H), 6.93 - 6.86 (m, 3H), 6.84 (dd, 1 H), 6.65 (td, 1 H), 3.75 (s, 3H), 2.60 (d, 2H), 1.50 (hept, 1 H), 0.62 (d, 6H) ppm. UHPLC/MS (ESI): [m/z\. 459 [M+H]⁺.

24. Example Compound No. 77:

5-(2,4-bis(2-hydroxyphenyl)-5-isobutyl-1 H-imidazol-1-yl)-2-methoxybenzoic acid

5-(2,4-bis(2-(benzyloxy)phenyl)-5-isobutyl-1 H-imidazol-1-yl)-2-methoxybenzoic acid (990 mg,

1.55 mmol) was dissolved in methanol (120 mL) and the resulting solution was degassed for 15 min using a nitrogen-stream. To the solution was added palladium on charcoal (10%-w/w, 100 mg) and the nitrogen-stream was switched to a hydrogen-stream. After TLC indicated full consumption of the s.m. the reaction mixture was filtered through a short pad of Celite eluting with methanol. The filtrate was concentrated under reduced pressure and the resulting crude material was purified by flash column chromatography (Ch^Ch/MeOH) to afford the titled compound (530 mg, 1.16 mmol, 75%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-cfe) d 7.63 (d, 1 H), 7.54 (dd, 1 H), 7.47 (dd, 1 H), 7.26 (d,1 H), 7.18-7.12 (m,2H), 6.94 - 6.86 (m, 3H), 6.83

(dd, 1 H), 6.64 (t, 1 H), 3.88 (s, 3H), 2.52 (d, 2H), 1.50 (hept, 1 H), 0.61 (d, 6H) ppm. UHPLC/MS (ESI): [m/z\. 459 [M+H]⁺.

II. Physicochemical Assays

ll-l. pM / pFe value - Potentiometric Titration Experiments

The determination of the complex activity and stability as well as the selectivity can be determined by potentiometric titration and evaluation of the dissociation constant of the complex formation.

Method A) - Determination of pM-values

Test Compounds

Ligand: Example Compound No. 40

Comparative Ligand: deferasirox (Exjade®) pM value for determining the selectivity compared to the metal elements Cu²⁺, Zn²⁺, Ni²⁺, Mg²⁺, Ca²⁺ as water soluble NO₃ salts. All used solutions are standard solutions in 2% of HNO₃ (water soluble salts of the metal elements)

Titration Instrumentation

Potentiometric titrations were performed computer assisted with a Titrando 904 (dosimeter and pH/mV meter) with exchange unit 806 from Metrohm AG. The exchange unit was equipped with a burette tip with antidiffusion stopper which can be immerged into the measurement solution.

The titration experiment was controlled by the program Tiamo. pH Electrode

The pH measurements were carried out with the following single-rod measuring cell electrode:

• SCHOTT® Instruments N62 from SI Analytics GmbH, a double junction electrode with 3 mol/L KCI as bridge electrolyte, platinum diaphragm, Silamid® reference and Metrohm connector

Potentiometric titrations in water/DMSO solution mixture

Equilibrium constants of the ligand needed to be measured in a water/DMSO medium because of its low solubility in pure water. Titration experiments in water/DMSO solution mixtures were performed with certain molar fractions. By measuring the equilibrium constants for different molar fractions and extrapolation of the values the constants for pure water have been estimated. It is of importance for the preparation of all these solutions to consider the volume contraction during the mixing of DMSO with pure water since it is not an ideal solution. The DMSO volumes necessary for the preparation of 1.0 litre solution are summarized in Table 2 .

Table 2: Partial excess molar volumes, partial molar volumes and necessary volumes of DMSO for the preparation of 1.0 litre solvent (in mL at 298 K).

All solutions were prepared with deionised water and DMSO (for analysis, ACS, Reag. Ph. Eur., AppliChem). Further, to ensure a constant ionic strength all solutions were prepared with KCI as supporting electrolyte at a concentration 0.1 mol/L KCI (for analysis, EMSURE, ACS, ISO, Reag. Ph. Eur., Merck). A sample of 50.0 ml. (Eppendorf Multipette E3x, combitip: 50.0 ml.) of the prepared solution was thermostated at 298 K (Huber Ministat CC 3 Recirculator Chiller) in a double-walled glass vessel. The glass vessel was flushed with nitrogen gas that has been passed through a 0.1 mol/L KCI solution.

As titrant a solution of 0.1 mol/L KOH or 0.1 mol/L HCI was used with the appropriate amount of DMSO for the desired molar ratio. First the DMSO solvent (PDMSO = 1.09566 g/cm³)^[2] was weighed into a 1.0 litre volumetric flask. Then KOH or HCI (both Titrisol, Merck) was added in the presence of nitrogen. Subsequent, the flask was filled with water to the calibration mark. The warm mixture was left in the presence of nitrogen to cool to 293 K. Optimally the flask was gradually filled to the calibration mark at this temperature several times. A constant volume should have been achieved.

Prior to and after all measurements the standard electrode potential E° and the ionic product pK needed to be determined by a potentiometric titration of 50.0 mL of a 2.0 mmol/L HCI solution with 0.1 mol/L KOH (Titrisol, Merck) as titrant. The determination of the standard electrode potential E° and pK_w was also performed in the same molar fraction of DMSO as the

measurement. Both values were calculated with the program Elektroden Kalibrierung^[3]. The mean values of E° and the mean values of pK_w from the titrations prior to and after the actual measurement were used for the evaluation of the equilibrium constants. To prepare the 2.0 mmol/L HCI solution DMSO was weighed in a 1.0 litre volumetric flask. Then 2 mL 1.0 mol/L HCI was added and the needed amount of solid KCI to achieve an ionic strength of 0.1 mol/L was added to the flask. The flask was filled to the calibration mark with water. It was left to cool to 293 K which causes volume contraction. Therefore, the solution needed to be gradually filled to the calibration mark several times with water. A constant volume should have been achieved.

The sample solution was prepared in a 110 mL volumetric flask. All components were weighed in on a precision balance. First DMSO was weighed into the flask. Further, ligand and then KCI (c = 0.1 mol/L) was weighed in and added to the solution mixture. If needed, the metal ion stock solution (ICP Standard Solution, 1000 mg/L metal, Carl Roth) was added into the 110 mL flask. The ligand and KCI could well be dissolved by ultrasonic treatment. The flask was thermostated at 293 K, filled to the calibration mark several times. A constant volume should have been achieved. pH-adjustments were carried out by adding 0.1 mol/L KOH (TitriPUR, Merck) to the flask with a Eppendorf Multipette.

Continuous spectrophotometric titrations

Continuous spectrophotometric titrations were performed simultaneous with a continuous potentiometric titration. While the potentiometric titration was carried out as previously described the immersion probe (Excalibur Lab, Hellma) was dived into the sample solution. With the titration computer a trigger signal was sent to the spectrophotometer (TIDAS S 500 - MCS UV/NIR 1910, J&M Analytik AG) to record a spectrum just prior to the add-on of each new aliquot of titrant. Absorption data were recorded in the range 200 < l < 1000 nm, however the range 400 < l < 900 nm was used for evaluation. Both titration experiments could be used for the determination of the equilibrium constants. These continuous titrations were studied with a total Fe³⁺ concentration of 0.25 mmol/L / 0.5 mmol/L and a total ligand concentration of 0.50 mmol/L / 1.0 mmol/L, respectively. A spectrum of a 0.2 mmol/L Fe³⁺ solution, prepared with the iron stock solution was also collected. The complexation constant was calculated with the program

HypSpec 2014^[4·⁵¹.

Calculation of equilibrium constants

All equilibrium constants were calculated as concentration constants. Further, the pH was defined as -log[H⁺] The equilibrium constants were determined with the help of computer programs. For the evaluation of potentiometric titrations and spectrophotometric titrations the program Hyperquad 2013^[4] and HypSpec 2014^[4·⁵¹ were employed, respectively.

To evaluate titration experiments with the program Hyperquad 2013 the p w, the ionic product of water, as a constant value for the given titration conditions is required. For the different molar fractions used in water/DMSO solutions the p _w (p _w = -log w, K_w = [H⁺] ^c [OH ]) was determined by the titrations carried out prior to and after the measurements as described in section 1.1.3. The values obtained with the program Elektroden Kalibrierung^[3] were: XDMSO = 0.20 with a pKw 15.57 (mean value of 53 titrations), XDMSO = 0.18 with a p w 15.38 (mean value of 8 titrations), XDMSO = 0.16 with a p _w 15.19 (mean value of 8 titrations) and XDMSO = 0.14 with a pKw 15.00 (mean value of 8 titrations). The E°, p w and the total concentrations of the ligand and metal ion were ascertained as fixed values. For the determination of pK_A values the pH was calculated and the total concentrations were ascertained as fixed values. Furthermore, when refining complex formation constants the pK_A values previously determined are also defined as fixed values.

Equilibrium constants investigated with spectrophotometric titration experiments were calculated with the program HypSpec 2014^[4,S|. For the determination of complex formation constants a spectrum of the Fe³⁺ stock solution was collected as described above and defined in the program as a known spectrum and a coloured species. All metal-containing species were defined as coloured species. In contrast, the ligand and its protonation products were treated as noncoloured species.

Species distributions for all titration experiments were calculated with the program Hyss 2009^[6].

Similar measurements were carried out with the water-soluble salts of the metal elements for determining the pM values.

Results:

pM (Method A)

Table 3: pM/pFe values of Example Compound No. 40 All measurements took place in XDMSO = 0.20. With the same Method A) the pFe-values can be determined similarly with the following results: pFe value for determining the complex affinity and stability: iron(lll) chloride

Method B) Determination of pFe-values

Further, the pFe values were determined for several Example Compounds listed below with a similar method as described for Method A) but using different sample volumes for the titrations as follows: Potentiometric titrations in water/DMSO solution mixture

A sample of 50.0 ml_/20 ml (Eppendorf Multipette E3x, combitip: 50.0 mL/25 ml) of the prepared solution was thermostated at 298 K (Huber Ministat CC 3 Recirculator Chiller) in a double-walled glass vessel. The glass vessel was flushed with nitrogen gas that has been passed through a 0.1 mol/L KCI solution.

The sample solution was prepared in a 110 mL/50 ml volumetric flask. All components were weighed in on a precision balance. First DMSO was weighed into the flask. Further, ligand and then KCI (c = 0.1 mol/L) was weighed in and added to the solution mixture. If needed, the metal ion stock solution (ICP Standard Solution, 1000 mg/L metal, Carl Roth) was added into the 110 ml_/50 ml flask. The ligand and KCI could well be dissolved by ultrasonic treatment. The flask was thermostated at 293 K, filled to the calibration mark several times. A constant volume should have been achieved. Calculation of equilibrium constants

To evaluate titration experiments with the program Hyperquad 2013 the p w, the ionic product of water, as a constant value for the given titration conditions is required. For the different molar fractions used in water/DMSO solutions the pK_w (p _w = -logKw, K_w = [H⁺] ^c [OH ]) was determined by the titrations carried out prior to and after the measurements as described in section 1.1.3. The values obtained with the program Elektroden Kalibrierung^[3] were: XDMSO = 0.20 with a pKw 15.57 (mean value of 53 titrations), XDMSO = 0.18 with a pKw 15.38 (mean value of 22 titrations), XDMSO = 0.16 with a pKw 15.19 (mean value of 8 titrations), XDMSO = 0.14 with a pKw 15.00 (mean value of 8 titrations), XDMSO = 0.12 with a pKw 14.82 (mean value of 9 titrations), XDMSO = 0.10 with a pK_w 14.65 (mean value of 9 titrations). The E°, pKw and the total concentrations of the ligand and metal ion were ascertained as fixed values. For the

determination of pK_A values the pH was calculated and the total concentrations were ascertained as fixed values. Furthermore, when refining complex formation constants the p _A values previously determined are also defined as fixed values.

Equilibrium constants investigated with spectrophotometric titration experiments were calculated with the program HypSpec 2014^{[4 S|}. For the determination of complex formation constants a spectrum of the Fe³⁺ stock solution was collected as described above and defined in the program as a known spectrum and a coloured species. All metal-containing species were defined as coloured species. In contrast, the ligand and its protonation products were treated as noncoloured species.

Results:

pFe (Method B)

Literature:

[1] J. T. W. Lai, F. W. Lau, D. Robb, P. Westh, G. Nielsen, C. Trandum, A. Hvidt, Y. Koga;

J.Solut.Chem. 1995, 24, 89-102.

[2] M. Roses, C. Rafols, E. Bosch; Anal. Chem. 1993, 65, 2294-2299.

[3] M. Basters; Elektrodenkalibrierung (unveroffentlicht), Universitat des Saarlandes, 2012.

[4] P. Gans, A. Sabatini, A. Vacca; Talanta 1996, 43, 1739-1753.

[5] P. Gans, A. Sabatini, A. Vacca; Annali di Chimica 1999, 89, 45-49.

[6] L. Alderighi, P. Gans, A. lenco, D. Peters, A. Sabatini, A. Vacca; Coord. Chem. Rev.

1999, 184, 311-318. ll-ll. Aqueous Solubility

Materials and Methods

Test compounds and Formulation

Ligands:

The test compounds were received in DMSO at a concentration of 20 mM.

Reference controls were also formulated in DMSO as above.

Working solutions

80 % sterile water: 20 % acetonitrile (Working solution A)

75 % sterile water: 20 % acetonitrile: 5% DMSO (Working solution B)

95 % sterile water: 5 % DMSO (Working solution C)

Reference controls

Experimental Procedures

Test compounds (10 pl_; 20 mM) were added to sterile water (190 pl_) in triplicate and shaken at 300 rpm at room temperature. After 90 min. the test compounds were filtered by centrifuge (5 min. at 3000 rpm) to obtain the aqueous filtrate. Acetonitrile (20 pL) was dispensed into clean 96- well UV/VIS analysis plate and aqueous filtrate (80 mI_) added and the plate analysed. A second diluted analysis plate (10 fold) was prepared by adding aqueous filtrate (10 mI_) to working solution C (90 mI_) and the plate shaken for 10 min. The diluted filtrate (80 mI_) was then added to acetonitrile (20 mI_) and the plate analysed. The results obtained were quantified against a standard calibration curve prepared for each test sample as described below.

The following procedure was completed on a Perkin Elmer Janus robotic platform:

Test compound (15 mI_; 20 mM) was added to working solution A (285 mI_) to give a 1000 mM stock concentration. This stock solution was serially diluted by adding 150 pL to working solution B (150 mI_) until a final concentration of 0.98 mM was achieved and the calibration range was subsequently analysed.

Samples were analysed using a Molecular Devices SPECTRAmax plus microplate reader at the following wavelengths: 280, 300, 320, 340, 360, 800 nm.

Results:

III. Pharmacological Assays

lll-l. Efficacy of Example Compound No. 40 in a mouse model of hemochromatosis

Mutations in genes involved in sensing the systemic iron stores, such as the hemochromatosis protein (HFE) cause iron overload in mice and men. HFE mutation is the most frequent cause of hereditary hemochromatosis (HH) in Caucasian adults. Most patients with HH are homozygous for a missense mutation in the HFE gene that results in a cysteine to tyrosine substitution at amino acid 282 in the corresponding HFE protein and is referred to as the C282Y mutation. Mice homozygous for the C282Y mutation (HFE C282Y mice) develop hepatic iron overload, which makes them a suitable animal model for studying HH in humans (Levy JE et all, Blood, 1999). Female and male homozygous HFE C282Y mice (Jackson Laboratories, 129-Hfetm1.1 Nca/J, Stock Number: 005063) at the age of 9 to 10 weeks were dosed orally once daily with Example Compound No. 5, 10, and 30 mg/kg body weight or vehicle (30% Kolliphor / water) for 3 weeks excluding weekends. Mice were fed standard diet (SD, Provimi Kliba, Cat. 3437, Fe approx. 250 ppm) for 6h (from 3h to 9h post-dosing). In the remaining 18h low iron diet (LID, Provimi Kliba, Cat. 2039, Fe = 10.7 ppm) was provided. Dosing of Example Compound No. 40 or vehicle followed by exposure to SD was repeated for 19 days. On weekends, dosing was paused and mice had access to LID ad libitum. One hour after the last dose, mice were euthanized and livers were harvested. Liver iron content was analyzed by inductively coupled plasma-optical emission spectroscopy (ICP-OES). Example Compound No. 40 reduced significantly (one-way ANOVA with Bonferroni's multiple comparison test) liver iron concentration in HFE C282Y mice in a dose- dependent manner(Table 4).

These data demonstrate the efficacy of Example Compound No. 40 to reduce liver iron overload in HFE C282Y mice and provides a proof-of-concept in a disease model of hereditary hemochromatosis.

Table 4 Summary of efficacy of Example Compound No. 40 in the HFE C282Y mouse model of hemochromatosis. Average values and standard deviations (SD) of total Fe concentrations in the livers of groups of HFE C282Y mice treated with the indicated doses of Example Compound No. 40 or vehicle and % reduction compared to vehicle-treated HFE C282Y mice.

Ill-ll. Efficacy of Example Compound No. 40 in a mouse model of b-thalassemia

intermedia

b-Thalassemia is an inherited anemia caused by mutations in the b-globin gene of hemoglobin resulting in abnormal red blood cells with decreased life span. Current treatment options for iron overload in b-thalassemia includes blood transfusion leading to iron overload requiring iron chelation. Patients with transfusion-independent thalassemia may also develop iron overload as a result of increased iron absorption due to ineffective erythropoiesis (Taher A, et al, Lancet 2018). The efficacy of the Example Compound No. 40 in decreasing organ iron content was investigated using a mouse model of transfusion-independent b-thalassemia (Hbb th3/+, Jackson Laboratories, B6; 129P-Hbb-b1tm1 Unc Hbb-b2tm1 Unc/J, Stock Number: 002683). Hbb th3/+ mice absorb excessive amounts of iron as a consequence of inadequately low hepcidin levels relative to the high iron content in liver, spleen and kidney and increased ferroportin expression in duodenum (Gardenghi S., Blood, 2007). Hbb th3/+ mice were dosed once daily with either Example Compound No. 40 at 10 or 30 mg/kg or vehicle (30% Kolliphor / water, 10 mL/kg,

Sigma, Cat. C5135). Mice were fed standard diet (SD, Provimi Kliba, Cat. 3437, Fe approx. 250 ppm) for 6h (from 3h to 9h post-dosing). In the remaining 18h LID (Provimi Kliba, Cat. 2039, Fe = 10.7 ppm) was provided. Dosing of Example Compound No. 40 or vehicle followed by exposure to SD was repeated for 19 days. On weekends, dosing was paused and mice had access to LID ad libitum. One hour after the last dose, mice were euthanized and organs were harvested and used for iron content analysis.

Treatment with Example Compound No. 40 at 30 mg/kg significantly reduced total iron concentration in liver and kidney of Hbb th3/+ mice compared to vehicle-treated mice (Table 5), whereas spleen iron was unaffected. Total liver iron in females treated with vehicle was higher compared to males, nevertheless Example Compound No. 40 dosed at 30 mg/kg significantly reduced liver iron in both genders.

One hour after the last dose on day 19, plasma was collected and analyzed for total bilirubin, creatinine and urea, as biomarkers for nephrotoxicity Treatment with Example Compound No. 40 had no effect on total bilirubin, creatinine, and urea in Hbb th3/+ mice (Table 5).

Expression of KIM-1 mRNA in kidney was assessed by qPCR at the end of the study. Treatment with Example Compound No. 40 had not effect on KIM-1 expression in kidneys of Hbb th3/+ mice (Table 5) suggesting that the doses tested were not inducing nephrotoxicity in this mouse strain. Hbb th3/+ mice are anemic with pathologically altered hematological parameters indicative for ineffective erythropoiesis, such as reduced RBC counts, reduced hematocrit, increased RDW, increased reticulocyte counts and elevated leukocyte counts compared to wildtype mice. Oral administration of Example Compound No. 40 in Hbb th3/+ mice for three weeks did not change RBC parameters (not shown). Importantly, Example Compound No. 40 significantly lowered blood leukocyte counts, particularly neutrophils, compared to the vehicle group (Table 5).

These data demonstrated that Example Compound No. 40 is efficacious in removing iron from livers of Hbb th3/+ mice without inducing nephrotoxicity.

Table 5: Efficacy of Example Compound No. 40 in a mouse model of thalassemia intermedia (Hbb th3/+ mice). Data are expressed fold change for KIM-1 expression and as % change to vehicle for all other parameter shown. Fold change = 2 ^,(''^ct,VehE '^{C1 (Exa,Tlple Compound 40>>}, where ACt(Veh) is the difference between the cycle threshold (Ct) of the reference gene (Gusb) and the gene of interest (Kim-1 ) of the vehicle- treated group and ACt(Example Compound 40) is the difference between Ct of Gusb and Kim-1 of the group treated with Example Compound No. 40.

IV. Toxicity Evaluation

IV-I. 28-Day Repeated Dose Assessment of Gastro-lntestinal, Kidney and Liver Toxicity of Example Compound No. 40 in Rats

The objective of this study was to assess the potential toxicity of Example Compound No. 40 on the gastro-intestinal tract (GIT), kidney and liver after oral administration by gavage to rats over a duration of four weeks.

Female and male Wistar rats (Charles River Deutschland, Crl: WI(Han)) at the age of six weeks were dosed orally by gavage once daily with Example Compound No. 40 (Batch KUM201) at 10, 30 and 75 mg/kg body weight (N = 5 female and 5 male for each group) or with vehicle (30% Kolliphor / 70% Milli-Q water; N = 3 female and 3 male). Administration of Example Compound No. 40 was performed daily for 28 days including the day before scheduled necropsy approximately at the same time per day. Pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiaten GmbH, Soest, Germany) and tap water was provided ad libitum.

A detailed clinical observation was performed weekly ending on the day of necropsy, cage side observations were performed once daily. Starting from day 1 , body weights were measured individually daily and food consumption was quantified twice weekly. On the day of scheduled euthanasia and necropsy, blood samples at a volume of 0.5 mL were collected and plasma was analyzed for alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), and alkaline phosphatase (ALP) as biomarkers for liver toxicity as well as creatinine, total bilirubin, and urea as biomarkers for nephrotoxicity. The animals were subject to a complete necropsy examination, including weighing and macroscopic examination of brain, heart, kidney, liver, lung and spleen. Further, the tissues of GIT brain, heart, kidney, liver, lung and spleen were subject to a peer-reviewed histopathological examination.

None of the animals died during the study. Salvation was observed after dosing for several animals getting 10, 30 or 75 mg/kg Example Compound No. 40 but was considered a physiological response to the taste rather than a sign for systemic toxicity. In male rats, no significant alterations to the control group of body weights (-gains), organ weights or clinical biomarkers occurred, and there were no findings in the histopathological examination. A minor decrease in body weights and body weight gains compared to the control group were noted in females dosed with 75 mg/kg Example Compound No. 40 from day 11 onwards (Figure 1), with no corresponding changes in food consumption. The same group of females examined a slightly but statistically significant increased mean creatinine level of factor 1.18 to the mean of the control group (Dunnett-test based on pooled variance significant at 5% level). No gross pathological findings, changes in organ weights, or tissue alterations related to the administration of Example Compound No. 40 were found. The absence of histopathological lesions in kidney-tissue concludes that increased creatinine in females dosed with 75 mg/kg Example Compound No. 40 was not toxicologically relevant.

The results of this study demonstrated that the daily oral administration of Example Compound No. 40 by gavage for 28 days was well tolerated by rats of both sexes up to a dose of 75 mg/kg. Therefore, the NOAEL was considered to be 75 mg/kg/day for both sexes.

Table 6. Summary of examined clinical chemistry values on the day of scheduled euthanasia of female rats (control and groups getting 10, 30, and 75 mg/kg/day Example Compound No. 40 once daily). Reported is the mean and standard deviation in brackets

These in-vivo experiments show that the Example Compound No. 40 according to the present invention has no toxicity to the critical organs over a period of 4 weeks.

IV-II. Tolerability / Toxicity of Example Compound No. 40

4-Week Oral Toxicity Study in Rats (100mg/kg)

The same toxicity evaluation has been carried out as published for Exjade^® in the FDA report according to Tama! K. Chakraborti, NDA No. 21 - 882, pages 420 to 424.

The essential test conditions of said study are summarized as follows: Animals:

Wistar Rats (Charles River UK Limited, Crl: WI(Han) were used throughout the study. Animals were approximately 7-8 weeks of age and the body weight ranges were 26.7-239.2 g for males and 160.4-168.0 g for females.

Tested Compound:

Example Compound No. 40

Methods:

Example Compound No. 40 was administered orally via gavage to rats (5/sex/group) at daily doses of 75 and 100 mg/kg for 28 consecutive days at a dose volume of 10 ml/kg. The control group received vehicle (30% Kolliphor / 70% Milli-Q water; 3/sex/group) at an equivalent dose volume.

Clinical signs / mortality was observed at least twice daily after dosing. Body weights were recorded at least twice weekly during predose and daily from day 1 of dosing throughout the study. Food consumptions were recorded at least twice daily during predose and throughout the study. Hematology and serum chemistry were performed on all animals at terminal necropsy on day 28. Organ weights were taken for brain, heart, kidneys, liver, lung and spleen. Microscopic examinations were conducted on gastrointestinal tract, liver and kidney.

The achieved results, compared with the results achieved according to the FDA report (Study No. 97400) for Exjade as reported in Tamal et al. cited above, are shown in the following table:

The toxicity results clearly show the improvement in toxicity and tolerability compared to the established chelator drug Exjade^® (deferasirox).

It can therefore be assumed that the iron chelating compounds of the present invention are suitable as new iron chelators with good tolerability and few side effects. In particular, a reduced toxicity is extremely important regarding a lifelong use of a chelator in all forms of iron overload. DESCRIPTION OF THE FIGURES

Fig. 1 Graphical representation of female body weights from one day before treatment (Day -1) to the day of scheduled euthanisation (Day 29) in a 28-days toxicity evaluation of Example Compound No. 40.

Claims

CLAIMS:

1. Compounds according to formula (I)

0)

wherein the group -COR¹ represents a group -(C=0)-R\ wherein

R¹ is selected from the group consisting of

- -OH,

- Ci-C4-alkoxy,

- Ci-C4-halogenoalkyl having 1 to 3 halogen atoms,

- Ci-C4-halogenoalkoxy having 1 to 3 halogen atoms, and

- a deprotonated group -O^Q or a salt form thereof;

- hydrogen,

halogen,

- -OH,

- linear or branched CrC₆-alkyl which may carry 1 , 2 or 3 substituents,

- C3-C6-cycloalkyl which may carry 1 , 2 or 3 substituents, and

- Ci-C₆-alkoxy which may carry 1 , 2 or 3 substituents,

wherein the substituents of alkyl, cycloalkyl and alkoxy may be the same or different and may independently be selected from the group consisting halogen, Ci-C3-alkyl, Ci-C3-alkoxy, wherein the alkyl- and alkoxy-substituent each may carry 1 , 2 or 3 further substituents independently selected from halogen, CrC3-alkyl and CrC3-alkoxy;

R³ is selected from the group consisting of

- hydrogen,

- linear or branched CrC4-alkyl which may carry 1 , 2 or 3 substituents, and

- C3-C6-cycloalkyl which may carry 1 , 2 or 3 substituents,

wherein the substituents of alkyl and cycloalkyl may be the same or different and may independently be selected from the group consisting of halogen, Ci-C3-alkyl and Ci-C3-alkoxy, wherein the alkyl- and alkoxy-substituent each may carry 1 , 2 or 3 further substituents independently selected from halogen, Ci-C3-alkyl and CrC3-alkoxy; R⁴ and R⁵ each represent one or more substituents independently selected from the group consisting of

- hydrogen,

- halogen,

- -OH,

- linear or branched Ci-C₆-alkyl which may carry 1 , 2 or 3 substituents,

- C3-C6-cycloalkyl which may carry 1 , 2 or 3 substituents, and

- Ci-C₆-alkoxy which may carry 1 , 2 or 3 substituents,

wherein the substituents of alkyl, cycloalkyl and alkoxy may be the same or different and may independently be selected from the group consisting of halogen, cyano, CrC3-alkyl and C1-C3- alkoxy, wherein the alkyl- and alkoxy-substituent each may carry 1 , 2 or 3 further substituents independently selected from Ci-C3-alkyl and CrC3-alkoxy;

R⁶ and R⁶ each represent one or more substituents independently selected from the group consisting of

- hydrogen,

- a negative charges, or a salt form thereof; and pharmaceutically acceptable salts thereof.

2. The compounds according to claim 1 , which are represented by the formula (II)

wherein

the group -COOR^1# represents a group -(C=0)-0-R^1#, wherein

R^1# is selected from the group consisting of

hydrogen,

- linear or branched CrC4-alkyl,

- Ci-C4-halogenoalkyl having 1 to 3 halogen atoms, and

- a negative chargee or a salt form thereof;

- hydrogen, - halogen,

- -OH,

- linear or branched Ci-C₆-alkyl which may carry 1 , 2 or 3 substituents,

- C3-C6-cycloalkyl which may carry 1 , 2 or 3 substituents, and

Ci-C₆-alkoxy which may carry 1 , 2 or 3 substituents,

R³ is selected from the group consisting of

hydrogen,

- linear or branched Ci-C4-alkyl which may carry 1 , 2 or 3 substituents, and

C3-C6-cycloalkyl which may carry 1 , 2 or 3 substituents,

- wherein the substituents of alkyl, cycloalkyl and alkoxy may be the same or different and may independently be selected from the group consisting of halogen, CrC3-alkyl and Ci- C3-alkoxy, wherein each of the alkyl- and alkoxy-substituent may carry 1 , 2 or 3 further substituents independently selected from halogen, Ci-C3-alkyl and Ci-C3-alkoxy;

- hydrogen,

halogen,

- -OH,

- linear or branched CrC₆-alkyl which may carry 1 , 2 or 3 substituents,

- C3-C6-cycloalkyl which may carry 1 , 2 or 3 substituents, and

- Ci-C₆-alkoxy which may carry 1 , 2 or 3 substituents,

wherein the substituents of alkyl, cycloalkyl and alkoxy may be the same or different and may independently be selected from the group consisting of halogen, Ci-C3-alkyl and Ci-C3-alkoxy, wherein each of the alkyl- and alkoxy-substituent may carry 1 , 2 or 3 further substituents independently selected from Ci-C3-alkyl and CrC3-alkoxy; and pharmaceutically acceptable salts thereof.

3. The compounds according to any one of the claims 1 or 2, wherein

- hydrogen,

halogen,

- -OH,

- linear or branched CrC₆-alkyl which may carry 1 , 2 or 3 substituents,

- C3-C6-cycloalkyl which may carry 1 , 2 or 3 substituents, and

- Ci-C₆-alkoxy which may carry 1 , 2 or 3 substituents, wherein the substituents of alkyl, cycloalkyl and alkoxy may be the same or different and may independently be selected from the group consisting of halogen, Ci-C3-alkyl and Ci-C3-alkoxy, wherein the alkyl- and the alkoxy-substituent each may carry 1 , 2 or 3 further substituents independently selected from halogen and Ci-C3-alkoxy;

R³ is selected from the group consisting of

- hydrogen,

- linear or branched Ci-C4-alkyl which may carry 1 , 2 or 3 substituents, and

- C3-C6-cycloalkyl which may carry 1 , 2 or 3 substituents,

hydrogen,

- halogen,

- -OH,

- linear or branched Ci-C₆-alkyl which may carry 1 , 2 or 3 substituents,

- C3-C6-cycloalkyl which may carry 1 , 2 or 3 substituents, and

- Ci-C₆-alkoxy which may carry 1 , 2 or 3 substituents,

4. The compounds according to any one of the claims 1 to 3, wherein

R² represents one or more substituents independently selected from the group consisting of hydrogen,

- halogen,

- linear or branched Ci-C4-alkyl which may carry 1 , 2 or 3 substituents, and

- Ci-C4-alkoxy which may carry 1 , 2 or 3 substituents,

wherein the substituents of alkyl and alkoxy may be the same or different and may independently be selected from the group consisting of halogen, Ci-C3-alkyl, and Ci-C3-alkoxy, wherein the alkyl- and the alkoxy-substituent each may carry 1 , 2 or 3 further substituents independently selected from halogen and Ci-C3-alkoxy;

R³ is selected from the group consisting of

- hydrogen,

- linear or branched Ci-C4-alkyl which may carry 1 , 2 or 3 substituents, and

- C3-C6-cycloalkyl which may carry 1 , 2 or 3 substituents,

wherein the substituents of alkyl and cycloalkyl are selected from CrC3-alkyl; R⁴ and R⁵ each represent one or more substituents independently selected from the group consisting of

- hydrogen,

- -OH,

- linear or branched CrC3-alkyl, and

- Ci-C4-alkoxy; and pharmaceutically acceptable salts thereof.

5. The compounds according to any one of the claims 1 to 4, which are further characterized by a complex activity represented by a pFe value in the range of 19 to 27 determined by potentiometric titration.

6. The compounds according to any one of the claims 1 to 5, which are further characterized by one or more of the following pM values

Cu²⁺ pM < 15, and/or

Zn²⁺ pM <8, and/or

Ni²⁺ pM <8, and/or

Mg²⁺ pM <8, and/or

Ca²⁺ pM <8, and/or preferably at least by having a pM value for Zn (pZn) of < 8,

determined by potentiometric titration.

7. A compound according to any one of the claims 1 to 6, which is represented by the formula

(III)

and pharmaceutically acceptable salts thereof.

8. The compounds according to any one of the claims 1 to 7 for the use as a medicament.

9. The compounds according to any one of the claims 1 to 7 for the use as an iron chelator in vivo.

10. The compounds according to any one of the claims 1 to 7 for the use in the prophylaxis and/or treatment of conditions or diseases related to or caused by increased iron levels, increased iron absorption or iron overload in a mammal, or

for the use as an iron chelator in vivo in conditions of increased iron levels, increased iron absorption or iron overload in a mammal caused by blood infusions.

11. The compounds for the use according to claim 10, wherein the conditions or diseases related to or caused by increased iron levels, increased iron absorption or iron overload are selected from thalassemia, including alpha-thalassemia, beta-thalassemia and delta- thalassemia; hemoglobinopathy; hemoglobin E disease; hemoglobin H disease; haemochromatosis; hemolytic anemia, including in particular sickle cell anemia or congenital dyserythropoietic anemia; and conditions or diseases treated with blood transfusions, such as myelodysplastic syndrome (MDS).

12. The compounds for the use according to claim 10 or 11 , for the treatment of

- diseases associated with ineffective erythropoiesis or treated with blood transfusions, such as myelodysplastic syndromes (MDS, myelodysplasia), polycythemia vera and congenital dyserythropoietic anemia; and/or

- neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease by limiting the deposition or increase of iron in tissue or cells;

- formation of radicals, reactive oxygen species (ROS) and oxidative stress; and/or

- cardiac, kidney, liver and endocrine damage caused by iron overload; and/or

inflammation triggered by excess iron.

13. The compounds as defined in any one of the preceding claims 1 to 7 or for the use according to claims 8 to 12 for the use in a combination therapy, comprising

a) co-administration of the compounds as defined in any of the preceding claims with at least one additional pharmaceutically active compound, wherein

a-a) said co-administration of the combination therapy may be carried out in a fixed dose combination therapy by co-administration of the compounds as defined in any of the preceding claims with at least one additional pharmaceutically active compound in a fixed- dose formulation; or

a-b) said co-administration of the combination therapy may be carried out in a free dose combination therapy by co-administration of the compounds as defined in any of the preceding claims and the at least one additional pharmaceutically active compound in free doses of the respective compounds, either by simultaneous administration of the individual compounds or by sequential use of the individual compounds distributed over a time period; or

b) co-administration of the compounds as defined in any of the preceding claims in combination with blood transfusion treatments.

14. A medicament containing one or more of the compounds as defined in any one of the preceding claims 1 to 7, which may further contain one or more pharmaceutical carriers and/or auxiliaries and/or solvents and/or at least one additional pharmaceutically active compound.

15. The compounds for the use according to claim 13 or the medicament according to claim 14, wherein the one or more other pharmaceutically active compounds are selected from active compounds for the prophylaxis and treatment of iron overload, thalassemia, or haemochromatosis, active compounds for the prophylaxis and treatment of neurodegenerative diseases, such as Alzheimer’s disease or Parkinson’s disease, and the associated symptoms, and iron-chelating compounds; preferably active compounds for reducing excess iron or iron overload which are selected from Tmprss6 targeting ASO and siRNA, apotransferrin, synthetic hepcidin and modified analogues thereof, including mini hepcidins, hepcidin agonists, ferroportin inhibitors, iron chelators, curcumin, SSP-004184, Deferitrin, deferasirox, deferoxamine and/or deferiprone; and/or pharmaceutically active compounds which are selected from antioxidants, such as n-acetyl cysteine; anti-diabetics, such as GLP-1 receptor agonists; antibiotics, such as vancomycin (Van) or tobramycin; drugs for the treatment of malaria; anticancer agents; antifungal drugs; drugs for the treatment of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, comprising dopamine agonists such as Levodopa; anti-viral drugs, such as interferon-a or ribavirin; immunosuppressants, such as cyclosporine A or cyclosporine A derivatives; iron supplements; vitamin supplements; red cell production stimulators, including antagonists of TGFbeta superfamily members, such as Luspatercept, antibodies, fragments of antibodies, non-antibody scaffold drugs or cells producing activin receptor ligand traps; EPO and ESA, HDAC inhibitors; anti-p-selectin Abs, HA (relevant for SCD), drugs targeting HbS aggregation; anti-inflammatory biologies; anti-thrombolytics; statins; vasopressors; and inotropic compounds;

preferably the at least one additional pharmaceutically active compound is selected from an iron chelator selected from the group consisting of deferasirox (Exjade®; 4-(3,5-bis(2- hydroxyphenyl)-1 H-1 ,2,4-triazol-1-yl)benzoic acid), deferoxamine (DFO; Desferal®; N'-[5- (Acetyl-hydroxy-amino)pentyl]-N-[5-[3-(5-aminopentyl-hydroxy-carbamoyl)

propanoylamino]pentyl]-N-hydroxy-butane diamide), and deferiprone (DFP; Ferriprox®), or from the group of ferroportin inhibitors, preferably a ferroportin inhibitor according to the formula

or any pharmaceutically acceptable salt thereof.

16. The medicament according to claim 14 or 15, comprising a compound according to the formula (III)

or any pharmaceutically acceptable salts thereof, and

a ferroportin inhibitor according to the formula

or any pharmaceutically acceptable salt thereof.

17. The compounds for the use according to claims 8 to 13 or the medicaments according to any one of claims 14 to 16, which are in the form of a formulation for oral administration.