TW202102478A - Novel iron chelators - Google Patents

Abstract

The invention relates to novel compounds of the general formula (I)

Description

Novel iron chelate

Invention field

The present invention relates to novel compounds of general formula (I), pharmaceutical compositions containing them, and their use as medicines, especially for use as iron chelate, and more particularly for prevention and/or treatment related to or caused by Diseases caused by the following: excessive or increased iron levels in mammals, increased iron absorption or iron overload, such as especially thalassemia, hemochromatosis and ineffective erythropoiesis, or related to blood transfusion or Diseases caused by blood transfusions.

Background of the invention Biophysiology background

Iron is an indispensable trace element in almost all living organisms, especially related to growth and blood formation. In this regard, the balance of iron metabolism is mainly regulated by the hemoglobin of aging red blood cells and the iron recovery level absorbed by the duodenum of dietary iron. The released iron is absorbed through the intestinal tract, especially through a specific transfer system (DMT-1, ferroportin), and transferred to the blood circulation, thereby transporting it to the appropriate tissues and organs (transferrin (transferrin)). ), transferrin receptor).

In the human body, elemental iron is very important, especially for oxygen transport, oxygen absorption, cell functions, such as mitochondrial electron transport, cognitive functions, etc., and ultimately for overall energy metabolism.

On average, the human body contains 4 to 5 g of iron, which is present in enzymes, in hemoglobin and myoglobin, and stored or preserved in the form of ferritin and hemosiderin. About half of this iron, about 2 g, is present as heme iron, which is bound in the hemoglobin of red blood cells. Since these red blood cells have only a limited life span (75-150 days), they must continue to form new red blood cells, while old red blood cells are degraded (more than 2 million red blood cells are formed per second). This high regenerative ability is achieved by macrophages engulfing senescent red blood cells, lysing them, and recovering iron to maintain iron metabolism. In this way, most of the iron required for red blood cell production is provided, about 25 mg per day.

The daily iron requirement for adults is 0.5 to 1.5 mg per day, and infants and women during pregnancy require 2 to 5 mg iron per day. For example, the daily iron loss due to skin and epithelial cell peeling is very low. Increased iron loss, for example, occurs during menstrual bleeding in women. In healthy adults, the normal loss of about 1 mg of iron per day is usually replaced by daily food intake, thus rebalancing the daily iron requirement to a moderate level.

The level of iron is adjusted by absorption. The absorption rate of iron in food is between 6 and 12%, and it can be as high as 25% in the case of iron deficiency. The absorption rate is regulated by the organism and depends on the iron demand and the amount of iron reserves. In this process, the human body uses divalent and trivalent iron ions. Normally, the iron (III) compound is dissolved in the stomach at a sufficiently acidic pH and can then be absorbed. The absorption of iron is carried out in the upper small intestine by mucosal cells. In this process, trivalent non-heme iron is first reduced to Fe(II) in the intestinal cell membrane for absorption by, for example, iron reductase (membrane-bound duodenal cytochrome b), so that it can be subsequently used by the transport protein DMT1 (two Valence metal transporter 1) transports it into intestinal cells. On the contrary, heme iron enters the intestinal cells through the cell membrane without any change. In intestinal cells, iron is either stored in ferritin in the form of iron storage, or released into the blood by the transport protein transferrin.

Hepcidin and transporterin both play a central role in the regulation of iron transport and absorption. The ferric iron transported into the blood by transferrin is converted into ferric iron by oxidase (ceruloplasmin, hephaestin), and then the ferric iron is transferred by iron The protein is transported to the relevant location in the organism (see, for example, "Balancing acts: molecular control of mammalian iron metabolism". MW Hentze, Cell 117, 2004, 285-297).

Mammals cannot actively excrete iron. Iron metabolism is essentially controlled by the release of hepcidin from macrophages, hepatocytes and intestinal cells through iron. Hepcidin is a peptide hormone produced in the liver. The main 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 it has been found in amines Two forms of shortened base end, hepcidin-22 and hepcidin-20. Hepcidin works by absorbing iron through the intestine and through the placenta, and by releasing iron from the reticuloendothelial system. In the body, hepcidin is synthesized from the liver known as pro-hepcidin, and pro-hepcidin is encoded by a gene known as the HAMP gene. The formation of hepcidin is directly regulated by the iron level of the organism, that is, if enough iron and oxygen are supplied to the organism, more hepcidin will be formed, and if the iron and oxygen levels are low or the red blood cells are produced In the case of increasing, less hepcidin is formed. In small intestinal mucosal cells and in macrophages, hepcidin binds to the transport protein transferrin, which usually transports the iron recovered by macrophages from the inside of the cell to the blood.

The transport protein transferrin is a transmembrane protein composed of 571 amino acids and is expressed in the liver, spleen, kidney, heart, intestine and placenta. In particular, transferrin is located in the basolateral membrane of intestinal epithelial cells. Transferrin exports Fe ²⁺ to the blood. Hepcidin binds to transferrin and triggers the internalization and degradation of transferrin, while inhibiting iron transport to the blood. If transferferrin is inactivated by, for example, hepcidin, so that it cannot export iron stored in mucosal cells, the stored iron will be lost through feces as the cells fall off naturally. Therefore, when transferrin is inactivated or inhibited, for example, by hepcidin, the absorption of iron in the intestine is reduced. In addition, transferrin is clearly located in the mononuclear phagocyte system to which macrophages belong. When iron metabolism is impaired by chronic inflammation, hepcidin plays an important role here. In the case of inflammation, the increase in interleukin-6, in particular, triggers an increase in the level of hepcidin. As a result, hepcidin binds to the transferrin of macrophages, thereby blocking the release of stored iron, and ultimately leading to inflammatory anemia (ACD or AI). On the other hand, if the serum iron level is lowered, the production of hepcidin in the hepatocytes of the liver is reduced, so that less hepcidin is released, and accordingly, less transferrin is inactivated, and a large amount of stored Iron is transported into the serum. The hepcidin-transferrin system directly regulates iron metabolism. In principle, the hepcidin-transferrin regulatory mechanism is based on the following two opposite principles:

On the one hand, the increase in hepcidin causes the inactivation of transferrin, which blocks the release of stored iron from the cells into the serum, thus lowering the serum iron level. Under pathological conditions, a decrease in serum iron level will lead to a decrease in hemoglobin level and a decrease in erythrocyte production, thus leading to iron deficiency anemia.

On the other hand, the reduction of hepcidin leads to an increase in active transferrin, which then allows to enhance the release of stored iron and enhance, for example, food intake, thus increasing the serum iron level. Under pathological conditions, elevated iron levels lead to excessive iron in the organs. Iron excess conditions and diseases

The iron excess state and disease are characterized by excessive iron levels in the organs. Among them, the problem is caused by non-transferrin-bound iron (NTBI) due to excessive serum iron levels. NTBI is rapidly absorbed non-specifically by organs, resulting in iron accumulation in tissues and organs. Excess iron causes many diseases and adverse medical conditions, including heart, kidney, liver, and endocrine damage. In addition, iron accumulation in the brain has been observed in patients suffering from neurodegenerative diseases such as, for example, Alzheimer's disease and Parkinson's disease. As a particularly harmful aspect of excess free iron, the formation of undesired free radicals must be mentioned. In particular, iron (II) ions catalyze the formation of reactive oxygen species (ROS) (especially through the Fenton reaction). These ROS cause damage to DNA, lipids, proteins, and carbohydrates, and have profound effects on cells, tissues, and organs. The formation of ROS is well known and described in the literature as causing so-called oxidative stress.

Iron excess may occur, for example, due to genetic defects, such as in the iron excess disease hemochromatosis. Hemochromatosis is an iron excess disease caused by a mutation in a gene that controls the synthesis of hepcidin or a mutation in the hepcidin gene itself, or a mutation in transferrin leads to severe iron excess, which causes the heart, kidney, liver, and Endocrine damage.

In the known iron excess disease, thalassemia b, mutations in the beta globulin gene cause reduced hemoglobin production and ineffective red blood cell production. Due to the damage and death of developing red blood cells in the bone marrow, the appropriate number of red blood cells cannot be produced. . This causes an increase in the rate of erythrocyte production and a decrease in the level of hepcidin, so that more iron is available to increase erythropoiesis activity. This improper reaction leads to excess iron. The red blood cells in thalassemia have a shortened half-life due to the toxicity of the unbalanced ratio of ava- and beta-hemoglobin subunits.

In addition, known diseases related to iron excess are diseases related to ineffective erythropoiesis, such as myelodysplastic syndrome (also known as MDS or myelodysplastic), polycythemia vera and the like.

In addition, mutations in genes involved in the induction of systemic iron reserves, such as hepcidin (Hamp1), hemochromatosis protein (HFE), hemojuvelin (HJV), and transferrin receptor 2 (TFR2) caused mice and Men with excessive iron. Accordingly, there can be mentioned diseases related to HFE and gene mutations, diseases related to chronic hemolysis, sickle cell disease, hematocrit, glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency), hematopoietic Erythrpoietic porphyria and Friedrich's Ataxia. In addition, the subgroups of iron excess include blood transfusion iron excess, iron poisoning, pulmonary hemosiderosis, osteopenia, insulin resistance, African iron excess, Hallerwarden-Spar Hallervordan Spatz disease (Hallervordan Spatz disease), ferritinemia, ceruloplasma protein deficiency, neonatal hemochromatosis and red blood cell diseases, including thalassemia b, thalassemia A, severe and moderate thalassemia, sickle Cell disease and myelodysplastic syndrome.

Other diseases and/or disorders and/or conditions related to elevated iron levels include, but are not limited to, diseases with elevated iron levels, including ataxia, Friedrich's ataxia, and age-related macular degeneration , Age-related cataracts, age-related retinal diseases and neurodegenerative diseases, where such neurodegenerative diseases include Alzheimer’s disease, Parkinson’s disease, pantothenate kinase-related neurodegeneration, restless legs syndrome and Huntington’s disease.

Blood transfusion may also lead to iron excess. For example, in some of the diseases mentioned in this case that are treated with blood transfusion, such as transfusion-dependent thalassemia and myelodysplastic syndrome (MDS, myelodysplastic syndrome). Prior art iron overdose therapy

The modern way to treat iron excess is based on the above-mentioned hepcidin-transferrin regulation mechanism, and provide hepcidin agonists or hepcidin mimics, transferrin inhibitors or inhibit the biochemical regulation pathways in iron metabolism Or a compound that controls the effect. This treatment method is based on direct action through the main regulator hepcidin, by providing a substitute or supply of hepcidin or by inhibiting transferferrin to block the excessive absorption of iron and directly participate in the disturbed iron metabolism pathway.

For example, known mimics of hepcidins include the so-called minihepcidins described in WO 2013/086143. Mini-hepcidin is a small synthetic peptide analogue of the N-terminus of hepcidin. The N-terminus of hepcidin is essential for the interaction between hepcidin and transferrin. The first 9 amino acids based on hepcidin (DTHFPICIF) are sufficient in terms of in vitro activity (as measured by transferrin-GFP degradation) and mini-hepcidin was developed. Mini-hepcidin has a modified hepcidin-9 amino acid sequence, which exhibits enhanced resistance to proteolysis and enhanced biophysical interaction with transferrin. Mini-hepcidin is described as being useful in the treatment of iron excess in humans caused by hepcidin deficiency.

WO 2015/069660 describes a method for increasing the expression of hepcidin by administering modified iron-binding/releasing transferrin to reduce non-transferrin-bound iron (NTBI) for the treatment of iron excess conditions.

Many of the compounds that act as hepcidin agonists or hepcidin mimetics are relatively high molecular weight compounds, especially those compounds that are mainly obtainable through genetic engineering. Various other methods based on biomolecular interactions and biomolecules have been described. The disadvantage is that the preparation of such biomolecular compounds is complicated and highly sensitive. It is reported that at least one therapeutic Fpn antibody is effective in humans: "LY2928057 binds to transferrin and blocks the interaction with hepcidin, excreting iron, resulting in serum iron and transferrin saturation in monkeys and humans ( TSat) level is elevated and hepcidin is increased. In CKD patients, LY2928057 leads to a slower decrease in hemoglobin and a decrease in ferritin (compared to placebo)". See Sheetz 2019 BrJClinPharmacol.

Low-molecular-weight compounds that occupy a position in iron metabolism and have inhibitory or promoting effects are known from the following, for example, WO2008/151288, WO2008/118790, WO2008/115999 and WO2008/109840, regarding the use of divalent metal transporter-1 (DMT1) Inhibitor compound; WO2008/123093, an agent for the prevention or treatment of iron excess disease, containing 22 beta-methoxy olean-12-en-3-beta, 24 (4 beta) -Diols; EP1074254 and EP1072265, on the use of catechin- and flavonoid-structured plant polyphenols to treat iron excess.

WO2017/068089 (and its corresponding US2018/0319783) and WO2017/068090 and WO2018/192973 describe novel low-molecular-weight compounds that act as inhibitors of transferrin in the treatment of iron excess conditions and iron excess diseases, and further propose To the possible combination therapy with conventional iron chelate drugs such as Deferasirox (Deferasirox).

One of the currently accepted methods for direct treatment of iron excess is based on the concept of reducing serum iron content by increasing the amount of iron removed from the body. Among otherwise healthy people, the oldest known and still conventional treatment includes regularly scheduled phlebotomy (bleeding). At the first diagnosis, a very frequent phlebotomy is usually arranged, such as once a week until the iron level reaches the normal range, and then depending on the patient’s iron load, a phlebotomy is scheduled once a month or every three months. Surgery.

For patients who cannot tolerate routine blood draws, chelates are often used to remove excess iron in the serum.

The well-known and established drugs used in iron chelation therapy include, for example, deferoxamine (also known as desferrioxamine B), N'-{5-[acetyl (hydroxy) amine Yl]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide Or Deferal®), which is a bacterial ferrophile. Iron removal as a chelate can bind iron in the blood and enhance iron removal through urine and feces. The typical treatment for chronic iron overdose is daily subcutaneous injections for 8-12 hours. The parenteral injection composition of deferoxamine-B salt is described in, for example, WO 1998/25887.

Two other established iron chelating drugs approved for patients who receive regular blood transfusions to treat thalassemia and develop iron excesses are deferiprone and deferiprone. Deferarox (Exjade®, 4-(3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzoic acid), which is described in, for example, WO 1997/ 49395 or Heinz et al. " 4-[3,5-Bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoid Acid: A novel Efficient and Selective Iron(III) Complexing Agent " ; Angewandte Chemie, Int. Edt., Vol. 38, No. 17, pages 2568 – 2570, 1999 scientific paper, and deferiprone (Ferriprox®, 3-hydroxy-1,2-lutidine-4(1H )-Ketone) also acts as iron chelate, so it is suitable as a medicine 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 information on The general technical background information of 2-hydroxyphenyl substituted imidazole has no further relationship with the specific technical field of this application.

Other compounds that act as iron chelates for the treatment of iron excess have been described, for example in WO2013/142258, regarding encapsulated granules of diethylenetriaminepentaacetate (DTPA) and zinc salt; in WO2003/ 041709, regarding 4-hydroxy-2-alkylquinoline, for example 4-hydroxy-2-nonylquinoline as iron chelate; in WO1998/09626, regarding composition based on dithiocarbamate Chelate for the treatment of iron excess state; in WO2015/077655, about the role of desferrithiocin derivatives as iron chelate for the treatment of iron excess disease; or in WO2005/051411, about grass-based Flavin and its derivatives are novel antibiotics or antifungal agents, which are described as acting as iron chelates and used to treat iron excess diseases.

Chelation therapy to treat excess iron or excess iron is well established and provides a simple and direct possibility to quickly remove the excess iron in chelated form from the body, so when an excess iron occurs, such as during blood transfusions, Quickly balance excess iron. However, the established drugs known for iron chelation therapy exhibit several disadvantages. In addition to iron energy (deferoxamine B), the oral administration activity is low and insufficient, and requires parenteral administration, such as subcutaneous infusion. However, this requires the use of medical equipment, such as infusion syringes and equipment, infusion devices, and electric drives. In addition, infusions or injections always carry the risk that the puncture may be contaminated with infected or inflammatory microorganisms. Parenteral administration is more costly, and requires medical treatment and treatment at a hospital or doctor's office, which further increases the cost of treatment and may have a negative impact on patient compliance. Conversely, the oral route of administration is cheaper and beneficial in terms of patient compliance, and therefore is preferable.

Other well-established oral iron chelates, such as deferriox (Exjade®) and deferiprox® (Ferriprox®) exhibit undesirable toxicity potential and undesirable adverse effects. The European Medicines Agency (EMA) has issued a warning that when the maximum recommended dose is increased from 30 mg/kg to 40 mg/kg per day, the toxicity of deferasirox appears to increase. The FDA reported the results of a 4-week oral toxicity study in rats. Deferarox (Exjade ^® ) has significant toxicological effects and observed mortality (see, for example, Tamal K. Chakraborti, NDA No. 21 – 882, pages 420 to 424) . The prescribing information for deferasirox includes warnings about kidney, liver failure, and/or gastrointestinal bleeding. Exjade may cause kidney damage including kidney failure, liver damage including failure, and gastrointestinal bleeding. In some reported cases, these reactions were fatal. These reactions are more commonly observed in patients with advanced age, high-risk myelodysplastic syndrome (MDS), underlying renal or liver function impairment, or low platelet count (<50 x 10 ^{9 /L).} Exjade therapy requires close patient monitoring, including laboratory tests of kidney and liver function.

purpose

The object of the present invention is to provide novel iron chelating compounds. In particular, the novel iron chelate should be a therapeutically effective and safe compound that can be used as a medicine, especially for the treatment of excessive or increased iron levels, increased iron absorption or excess iron in mammals. Diseases or conditions related to or caused by them. The novel iron chelate should be particularly effective in the treatment of iron excess diseases, such as thalassemia and hemochromatosis, or suitable for reducing iron excess related to blood transfusion or caused by blood transfusion. Another object of the present invention is to provide novel iron chelating compounds with high iron binding affinity. In addition, the novel iron chelating compound should exhibit sufficient complex stability to safely remove the bound iron from the body. Another object of the present invention is that the novel iron chelating compound should exhibit high selectivity to iron. It is particularly desirable to provide novel iron chelating compounds that achieve the best balance between iron binding capacity or complex stability, iron release from the complex, and/or selectivity. High selectivity and an optimal balance of iron binding and release are particularly important to avoid uncontrolled absorption of all iron from the body, tissues and cells. Another object of the present invention is to provide novel therapeutically effective and safe iron chelating compounds, which have low or reduced adverse effects and good compatibility compared with known chelates. Another object of the present invention is to provide novel therapeutically effective and safe iron chelating compounds, which have low or reduced toxicity compared to known chelates, which are particularly important for long-term administration. In particular, excessive iron usually requires continuous treatment throughout the entire life cycle, so medicines with long-term compatibility and safety are required. Another object of the present invention is to provide novel therapeutically effective and safe iron chelating compounds, which have good or improved solubility compared to known chelates. Another object of the present invention is to provide novel therapeutically effective and safe iron chelating compounds for oral administration. In another purpose, compared to biomolecular compounds, the novel compounds should have a defined structure (stoichiometry), and should be prepared by simple synthetic methods.

This goal is achieved by the development of a chemical formula defined in this case, for example, especially a novel compound according to formula (I), which has been found to act as an improved iron chelate and is therefore suitable for prevention and/or treatment and lactation The iron level in animals is too high or increased, the increase in iron absorption or iron excess is related to or caused by diseases, or the reduction of iron excess caused by blood transfusion.

The inventor surprisingly found that the novel compound with the general structural formula (I) defined in this case, as an iron chelate, has low toxicity, high affinity and selectivity, sufficient stability and good solubility, and is particularly suitable for use as an iron chelate. A therapeutically effective and safe iron chelate as a medicine, especially for the prevention and/or treatment of excessive or increased iron levels, increased iron absorption or iron excess in mammals, such as especially thalassemia, Diseases or conditions related to or caused by hemochromatosis, or reduction of iron excess caused by blood transfusion. The reduced toxicity of the novel compounds is particularly advantageous for long-term administration in the treatment of iron excess. The novel compound is further proved to be a suitable iron chelate for oral administration. Due to the lower cost and pharmacological work, as well as increased patient compliance and safety, oral administration is a better route of administration.

其中 –COR¹ 基團代表–(C=O)-R¹ 基團，其中 R¹ 選自於由下列構成之群組： -           -OH， -           C₁ -C₄ -烷氧基， -           具有1至3個鹵素原子的C₁ -C₄ -鹵烷基， -           具有1至3個鹵素原子的C₁ -C₄ -鹵烷氧基， -           去質子基團–O^⊖ 或其鹽形式； R² 代表獨立地選自於由下列構成之群組的一或更多個取代基： -           氫， -           鹵素， -           -OH， -           可帶有1、2或3個取代基的直鏈或支鏈C₁ -C₆ -烷基， -           可帶有1、2或3個取代基的C₃ -C₆ -環烷基，及 -           可帶有1、2或3個取代基的C₁ -C₆ -烷氧基， 其中烷基、環烷基和烷氧基的該等取代基可相同或不同且可獨立地選自於由鹵素、C₁ -C₃ -烷基、C₁ -C₃ -烷氧基構成之群組，其中該烷基-和烷氧基-取代基各自可帶有1、2或3個獨立地選自鹵素、C₁ -C₃ -烷基和C₁ -C₃ -烷氧基的另外取代基； R³ 選自於由下列構成之群組： -           氫， -           可帶有1、2或3個取代基的直鏈或支鏈C1-C4-烷基，及 -           可帶有1、2或3個取代基的C₃ -C₆ -環烷基， 其中烷基和環烷基的該等取代基可相同或不同且可獨立地選自於由鹵素、C₁ -C₃ -烷基和C₁ -C₃ -烷氧基構成之群組，其中該烷基-和烷氧基-取代基各自可帶有1、2或3個獨立地選自鹵素、C₁ -C₃ -烷基和C₁ -C₃ -烷氧基的另外取代基； R⁴ 和R⁵ 各自代表獨立地選自於由下列構成之群組的一或更多個取代基： -           氫， -           鹵素， -           -OH， -           可帶有1、2或3個取代基的直鏈或支鏈C₁ -C₆ -烷基， -           可帶有1、2或3個取代基的C₃ -C₆ -環烷基，及 -           可帶有1、2或3個取代基的C₁ -C₆ -烷氧基， 其中烷基、環烷基和烷氧基的該等取代基可相同或不同且可獨立地選自於由鹵素、氰基、C₁ -C₃ -烷基和C₁ -C₃ -烷氧基構成之群組，其中該烷基-和烷氧基-取代基各自可帶有1、2或3個獨立地選自C₁ -C₃ -烷基和C₁ -C₃ -烷氧基的另外取代基； R⁶ 和R^{6 ’} 各自代表獨立地選自於由下列構成之群組的一或更多個取代基： -           氫， -           負電荷^⊖ 或其鹽形式； 及其藥學上可接受的鹽。 定義Accordingly, in the first aspect, the present invention relates to a novel compound of general formula (I)

The -COR ¹ group represents the -(C=O)-R ¹ group, where R ^{1 is} selected from the group consisting of:--OH,-C ₁ -C ₄ -alkoxy,-has 1 C ₁ -C ₄ ^-haloalkyl with up to 3 halogen atoms,-C ₁ -C ₄ -haloalkoxy with 1 to 3 halogen atoms,-deprotonated group -O ⊖ or its salt form; R ² represents one or more substituents independently selected from the group consisting of:-hydrogen,-halogen,--OH,-linear or branched chain which may have 1, 2 or 3 substituents C ₁ -C ₆ -alkyl,-C _{3 -C 6} -cycloalkyl which may have 1, 2 or 3 substituents, and-C ₁ -C which may have 1, 2 or 3 substituents ₆ -Alkoxy, wherein the substituents of alkyl, cycloalkyl and alkoxy may be the same or different and may be independently selected from halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -A group consisting of alkoxy, wherein the alkyl- and alkoxy-substituents may each carry 1, 2 or 3 independently selected from halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -Additional substituents of alkoxy; R ^{3 is} selected from the group consisting of:-hydrogen,-linear or branched C1-C4-alkyl which may have 1, 2 or 3 substituents, _{And-C 3} -C ₆ -cycloalkyl which may have 1, 2 or 3 substituents, wherein the substituents of alkyl and cycloalkyl may be the same or different and may be independently selected from halogen, The _{group consisting of C 1} -C ₃ -alkyl and C ₁ -C ₃ -alkoxy, wherein the alkyl- and alkoxy-substituents may each carry 1, 2 or 3 independently selected from halogens , C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy; R ⁴ and R ⁵ each represent one or more substituents independently selected from the group consisting of :-Hydrogen,-halogen,--OH,-linear or branched C ₁ -C ₆ -alkyl which may have 1, 2 or 3 substituents,-may have 1, 2 or 3 substituents C ₃ -C _{6 -cycloalkyl, and-C 1} -C ₆ -alkoxy which may have 1, 2 or 3 substituents, wherein alkyl, cycloalkyl and alkoxy are substituted The groups can be the same or different and can be independently selected from halogen, cyano, C _The group consisting of 1 -C ₃ -alkyl and C ₁ -C ₃ -alkoxy, wherein the alkyl- and alkoxy-substituents may each carry 1, 2 or 3 independently selected from C ₁ Additional substituents of -C ₃ -alkyl and C ₁ -C ₃ ^{-alkoxy; R 6} and R ^{6 ′} each represent one or more substituents independently selected from the group consisting of:- Hydrogen, ^{-negative charge⊖} or its salt form; and its pharmaceutically acceptable salt. definition

The term "substituted" means the selection of one or more hydrogen atoms on a designated atom or group to be replaced with the designated group, provided that the designated atom's normal valence in the present situation is not exceeded. Combinations of substituents and/or variables are allowed.

The term "optionally substituted" means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, by replacing a hydrogen atom with any non-hydrogen substituent on an available carbon or nitrogen atom, an optionally substituted group may be substituted with as many optional substituents as it can accommodate. Generally, unless otherwise indicated, the number of optional substituents can be 1, 2, 3, 4, or 5, especially 1, 2, or 3 when present.

As used in this case, the term "one or more", for example, in the definition of the substituents of the compound of general formula (I) of the present invention, means "1, 2, 3, 4 or 5, especially 1, 2, 3 or 4, more particularly 1, 2 or 3, even more particularly 1 or 2".

In addition, if it is used in this case, the position where individual substituents are connected to the rest of the molecule can be indicated by the pound sign (#) or dashed line in the substituent in the drawn structure.

When used in this specification, the term "including" or "including" includes "consisting of".

If in this manual, any item is called "as mentioned in this case", it means that it can be mentioned anywhere in this manual.

The term "mammal" includes humans and animals, preferably humans. In addition, the terms mentioned in this specification or the scope of the patent application have the following meanings:

The term "halogen" or "halogen atom" refers to fluorine, chlorine, bromine or iodine atoms, especially fluorine, chlorine or bromine atoms, more preferably fluorine or chlorine, most preferably fluorine.

The term "alkyl" generally includes linear or branched saturated monovalent hydrocarbon groups, preferably containing 1 to 6, particularly preferably 1 to 4, and even more preferably 1, 2 or 3 carbon atoms. In particular, the term "C ₁ -C ₆ -alkyl" refers to a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. In particular, the term "C ₁ -C ₄ -alkyl" refers to a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, or 4 carbon atoms. In particular, the group has 1, 2 or 3 carbon atoms ("C ₁ -C ₃ -alkyl"). Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, isobutyl or tertiary butyl, n-pentyl, isopentyl, secondary pentyl, tertiary pentyl Base, 2-methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethyl Butyl, 3-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1-ethyl-1-methyl Propyl, or its isomers. Preferred are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl and tertiary butyl. More preferred are C ₁ -C ₃ alkyl groups, especially methyl, ethyl and isopropyl. More preferred are C ₁ and C ₂ alkyl groups, such as methyl and ethyl. The best is methyl.

The term "cycloalkyl" generally refers to a saturated monovalent monocyclic hydrocarbon ring containing 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. In particular, the term "C ₃ -C ₆ -cycloalkyl" means a saturated monovalent monocyclic hydrocarbon ring containing 3, 4, 5 or 6 carbon atoms. The C ₃ -C ₆ -cycloalkyl group is, for example, a monocyclic hydrocarbon ring, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and cyclopropyl is particularly preferred.

The term "alkoxy" generally refers to linear or branched saturated monovalent alkyl-O- groups, where the term "alkyl" has the meaning defined above. In particular, the term "C ₁ ‑C ₆ ‑alkoxy" or "C ₁ ‑C ₄ ‑alkoxy" or "C ₁ ‑C ₃ ‑alkoxy" refers to the formula (C ₁ ‑C ₆ ‑ Alkyl)‑O-, (C ₁ ‑C ₄ ‑alkyl)‑O- or (C ₁ ‑C ₃ ‑alkyl)‑O-, where in each case “C ₁ ‑C ₆ ‑alkyl ", "C ₁ ‑C ₄ ‑Alkyl" and "C ₁ ‑C ₃ ‑Alkyl" have the meanings defined above. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, secondary butoxy, isobutoxy or tertiary butoxy, or isomers thereof. Preferred are methoxy and ethoxy, most preferred is methoxy.

The alkyl group, cycloalkyl group and/or alkoxy group defined in this case may have one or more substituents, especially 1, 2 or 3 substituents.

The preferred substituents of the alkyl group, cycloalkyl group and/or alkoxy group defined in this case can be independently selected from the group containing halogen, cyano group, alkyl group or alkoxy group, each as defined in this case. Particularly preferred substituents of alkyl, cycloalkyl and/or alkoxy as defined in this case are selected from halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy. Wherein, the alkyl- and alkoxy-substituents themselves may also carry 1, 2 or 3 independently selected from halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy. Substituents.

In particular, the alkyl group substituted by one or more halogen atoms as defined in the present case can also be represented by the term "haloalkyl", for example, especially "C ₁ -C ₆ -haloalkyl" or "C ₁ -C ₄ ‑Haloalkyl” means a linear or branched saturated monovalent hydrocarbon group, where the terms “alkyl”, “C ₁ ‑C ₆ ‑alkyl” or “C ₁ ‑C ₄ ‑alkyl” are as defined above, One or more of the hydrogen atoms are replaced by halogen atoms the same or differently. In particular, the halogen atom is a chlorine and/or fluorine atom, preferably a fluorine atom. More specifically, all the halogen atoms are fluorine atoms (for example, "C ₁ -C ₄ -fluoroalkyl"). Examples of C ₁ ‑C ₄ ‑haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, trifluoromethyl, Bromomethyl, 1-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, difluoroethyl, such as 1,2- Difluoroethyl, 1,2-dichloroethyl, 1,2-dibromoethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2-dibromoethyl, 2,2,2-Trifluoroethyl, heptafluoroethyl, 1-fluoropropyl, 1-chloropropyl, 1-bromopropyl, 2-fluoropropyl, 2-chloropropyl, 2-bromopropyl Group, 3-fluoropropyl, 3-chloropropyl, 3-bromopropyl, 1,2-difluoropropyl, 1,2-dichloropropyl, 1,2-dibromopropyl, 2,3 -Difluoropropyl, 2,3-dichloropropyl, 2,3-dibromopropyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, 2-fluorobutyl, 2-chlorobutyl, 2-bromobutyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl, 4,4,4-trifluorobutyl, 2,2 ,3,3,4,4,4-Heptafluorobutyl, perfluorobutyl, etc. Trifluoromethyl is particularly preferred.

In particular, the alkyl group substituted by one or more halogen atoms as defined in this case can also be represented by the term "haloalkoxy", for example, especially "C ₁ -C ₆ -haloalkoxy" or "C _1- C ₄ ‑haloalkoxy", which means a linear or branched saturated monovalent hydrocarbon group, in which the term "alkoxy", "C ₁ ‑C ₆ ‑alkoxy" or "C ₁ ‑C ₄ ‑alkane "Oxy" is the same as defined above, wherein one or more of the hydrogen atoms are replaced by halogen atoms identically or differently. In particular, the halogen atom is a chlorine and/or fluorine atom, preferably a fluorine atom. More specifically, all the halogen atoms are fluorine atoms (for example, "C ₁ -C ₄ -fluoroalkoxy"). Examples of C ₁ ‑C ₄ ‑haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2‑trifluoroethoxy or pentafluoroethoxy, trifluoro Methoxy is particularly preferred.

The term "C ₁ -C ₄ "when used herein, for example, in "C ₁ ‑C ₄ ‑alkyl", "C ₁ ‑C ₄ ‑haloalkyl", "C ₁ ‑C ₄ ‑alkoxy" Or in the _{context of the definition of "C 1} ‑C ₄ ‑haloalkoxy", it means an alkyl or alkoxy group with a limited number of carbon atoms from 1 to 4, that is, 1, 2, 3, or 4 carbon atoms .

In addition, as used in this case, the term “C ₃ -C ₆ ”when used herein, for example, in the _{context of the definition of “C 3} ‑C ₆ ‑cycloalkyl”, means a limited number of carbons from 3 to 6 Atom, that is, a cycloalkyl group of 3, 4, 5, or 6 carbon atoms.

When a range of values is given, the range covers every value and sub-range within the range. For example: "C ₁ -C ₆ "covers C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₁ -C ₆ , C ₁ -C ₅ , C ₁ -C ₄ , C ₁ -C ₃ , C ₁ -C ₂ , C ₂ -C ₆ , C ₂ -C ₅ , C ₂ -C ₄ , C ₂ -C ₃ , C ₃ -C ₆ , C ₃ -C ₅ and C ₃ -C ₄ ; "C ₁ -C ₄ "covers C ₁ , C ₂ , C ₃ , C ₄ , C ₁ -C ₄ , C ₁ -C ₃ , C ₁ -C ₂ , C ₂ -C ₄ , C ₂ -C ₃ and C ₃ -C ₄ ; "C ₁ -C ₃ "covers C ₁ , C ₂ , C ₃ , C ₁ -C ₃ , C ₁ -C ₂ and C ₂ -C ₃ ; "C ₃ -C ₆ " Covers C ₃ , C ₄ , C ₅ , C ₆ , C ₃ -C ₆ , C ₃ -C ₅ , C ₃ -C ₄ , C ₄ -C ₆ , C ₄ -C ₅ and C ₅ -C ₆ .

According to the present invention, the group -COR represents the carbonyl group -(C=O)-R. Among them, preferably, the group R represents an -OH group to form a carboxylic acid group -(=O)-OH. Such carbonyl or carboxylic acid groups can also exist in the deprotonated ^form- (C=O)-O ⊖ or any salt form thereof.

其中 基團–COOR^1# 代表基團–(C=O)-O-R^1# ，其中 R^1# 選自於由下列構成之群組： -           氫， -           直鏈或支鏈C₁ -C₄ -烷基， -           具有1至3個鹵素原子的C₁ -C₄ -鹵烷基，及 -           負電荷^⊖ 或其鹽形式； R² 代表獨立地選自於由下列構成之群組的一或更多個取代基： -           氫， -           鹵素， -           -OH， -           可帶有1、2或3個取代基的直鏈或支鏈C₁ -C₆ -烷基， -           可帶有1、2或3個取代基的C₃ -C₆ -環烷基，及 -           可帶有1、2或3個取代基的C₁ -C₆ -烷氧基， 其中烷基、環烷基和烷氧基的該等取代基可相同或不同並可獨立地選自於由鹵素、C₁ -C₃ -烷基和C₁ -C₃ -烷氧基構成之群組，其中該烷基-和烷氧基-取代基各自可帶有1、2或3個獨立地選自鹵素、C₁ -C₃ -烷基和C₁ -C₃ -烷氧基的另外取代基； R³ 選自於由下列構成之群組： -           氫， -           可帶有1、2或3個取代基的直鏈或支鏈C₁ -C₄ -烷基，及 -           可帶有1、2或3個取代基的C₃ -C₆ -環烷基， 其中烷基、環烷基和烷氧基的該等取代基可相同或不同並可獨立地選自於由鹵素、C₁ -C₃ -烷基和C₁ -C₃ -烷氧基構成之群組，其中該烷基-和烷氧基-取代基之各者可帶有1、2或3個獨立地選自鹵素、C₁ -C₃ -烷基和C₁ -C₃ -烷氧基的另外取代基； R⁴ 和R⁵ 各自代表獨立地選自於由下列構成之群組的一或更多個取代基： -           氫， -           鹵素， -           -OH， -           可帶有1、2或3個取代基的直鏈或支鏈C₁ -C₆ -烷基， -           可帶有1、2或3個取代基的C₃ -C₆ -環烷基，及 -           可帶有1、2或3個取代基的C₁ -C₆ -烷氧基， 其中烷基、環烷基和烷氧基的該等取代基可相同或不同並可獨立地選自於由鹵素、C₁ -C₃ -烷基和C₁ -C₃ -烷氧基構成之群組，其中該烷基-和烷氧基-取代基之各者可帶有1、2或3個獨立地選自C₁ -C₃ -烷基和C₁ -C₃ -烷氧基的另外取代基； 及其藥學上可接受的鹽。In the second aspect, the present invention relates to a novel compound of general formula (II)

The group –COOR ^1# represents the group –(C=O)-OR ^1# , where R ^{1# is} selected from the group consisting of:-hydrogen,-linear or branched C ₁ -C _4- Alkyl,-C _{1 -C 4} ^-haloalkyl having 1 to 3 halogen atoms, and-negatively charged⊖ or its salt form; R ² represents one or more independently selected from the group consisting of Multiple substituents:-hydrogen,-halogen,-OH,-linear or branched C ₁ -C ₆ -alkyl which may carry 1, 2 or 3 substituents,-may carry 1, 2 or C ₃ -C ₆ -cycloalkyl with 3 substituents, and-C ₁ -C ₆ -alkoxy with 1, 2 or 3 substituents, of which alkyl, cycloalkyl and alkoxy The substituents may be the same or different and may be independently selected from the group consisting of halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy, wherein the alkyl- and alkoxy The radical-substituents may each carry 1, 2 or 3 additional substituents independently selected from halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy; R ^{3 is} selected from Composition group:-hydrogen,-linear or branched C ₁ -C ₄ -alkyl which may have 1, 2 or 3 substituents, and-C which may have 1, 2 or 3 substituents _3- C ₆ -Cycloalkyl, wherein the substituents of alkyl, cycloalkyl and alkoxy may be the same or different and may be independently selected from halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -Alkoxy group, wherein each of the alkyl- and alkoxy-substituents may carry 1, 2 or 3 independently selected from halogen, C ₁ -C ₃ -alkyl And another substituent of _{C 1} -C ₃ ^{-alkoxy; R 4} and R ⁵ each represent one or more substituents independently selected from the group consisting of:-hydrogen,-halogen,-- OH,-linear or branched C ₁ -C ₆ -alkyl which may have 1, 2 or 3 substituents,-C ₃ -C _{6 -cycloalkane which may have 1, 2 or 3 substituents Group, and-C 1} -C ₆ -alkoxy which may have 1, 2 or 3 substituents, wherein the substituents of alkyl, cycloalkyl and alkoxy may be the same or different and may be independently Selected from the group consisting of halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy , Wherein each of the alkyl- and alkoxy-substituents may carry 1, 2 or 3 additional substitutions _{independently selected from C 1} -C ₃ -alkyl and C ₁ -C _{3 -alkoxy} Base; and pharmaceutically acceptable salts thereof.

In the third aspect, the present invention relates to a novel compound having the above general formula (I) or (II), wherein R ² represents one or more substituents independently selected from the group consisting of:- Hydrogen,-halogen,--OH,-linear or branched C ₁ -C ₆ -alkyl which may have 1, 2 or 3 substituents,-C which may have 1, 2 or 3 substituents _3- C _{6 -cycloalkyl, and-C 1} -C ₆ -alkoxy which may have 1, 2 or 3 substituents, wherein the substituents of alkyl, cycloalkyl and alkoxy may be The same or different and can be independently selected from the group consisting of halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy, wherein the alkyl- and alkoxy-substituents may each be With 1, 2 or 3 _{additional substituents independently selected from halogen and C 1} -C ₃ -alkoxy; R ^{3 is} selected from the group consisting of:-hydrogen,-may carry 1, 2 or 3 substituents, straight-chain or branched C1-C4- alkyl, and - which may have 1, 2 or 3 substituents C ₃ -C ₆ - cycloalkyl, wherein alkyl, cycloalkyl and The substituent of the alkoxy group is selected from C ₁ -C ₃ -alkyl; R ⁴ and R ⁵ each represent one or more substituents independently selected from the group consisting of:-hydrogen,-halogen, --OH,-linear or branched C ₁ -C ₆ -alkyl which may have 1, 2 or 3 substituents,-C ₃ -C ₆ -which may have 1, 2 or 3 substituents _{Cycloalkyl, and C 1} -C ₆ -alkoxy which may have 1, 2 or 3 substituents, wherein the substituents of alkyl, cycloalkyl and alkoxy may be the same or different and may Independently selected from the group consisting of halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy, wherein the alkyl- and alkoxy-substituents may each carry 1, 2 Or 3 additional substituents independently selected from C ₁ -C ₃ -alkoxy; and pharmaceutically acceptable salts thereof.

In the fourth aspect, the present invention relates to a novel compound having the above general formula (I) or (II), wherein R ² represents one or more substituents independently selected from the group consisting of:- hydrogen, - halogen, - it may carry 1, 2 or 3 substituents, straight-chain or branched C ₁ -C ₄ - alkyl, and - C may carry 1, 2 or 3 substituents ₁ -C ₄ -Alkoxy, wherein the substituents of alkyl and alkoxy may be the same or different and may be independently selected from halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy Constitute the group, wherein the alkyl- and alkoxy-substituents may each carry 1, 2 or 3 _{additional substituents independently selected from halogen and C 1} -C ₃ -alkoxy; R ^{3 is} selected From the group consisting of:-hydrogen,-linear or branched C ₁ -C ₄ -alkyl which may have 1, 2 or 3 substituents, and-may have 1, 2 or 3 The C ₃ -C ₆ -cycloalkyl group of the substituent, wherein the substituents of the alkyl group and the cycloalkyl group are selected from the group consisting of C ₁ -C ₃ -alkyl; R ⁴ and R ⁵ each represent independently selected from the group consisting of One or more substituents of the group:-hydrogen, -OH,-linear or branched C ₁ -C ₃ -alkyl, and-C ₁ -C ₄ -alkoxy; and pharmaceutically acceptable Accepted salt.

In another aspect of the present invention, the substituents of the above general formula (I) or (II) independently have the following preferred meanings: 1) Respectively, R ¹ is -OH and R ^1# is hydrogen. 2) R ^{2 is} selected from the group consisting of:-hydrogen,-halogen, for example preferably fluorine,-C ₁ -C ₃ -alkyl, which may be substituted by 1, 2 or 3 halogen atoms, for example Preferably it is trifluoromethyl,-C ₁ -C ₃ -alkoxy, for example, is preferably methoxy,-C ₁ -C ₃ -alkoxy, which may be substituted by 1 or 2 alkoxy groups, For example, an ethoxy group substituted with a methoxy group or an ethoxy group substituted with a methoxy group is preferred. 3) R ^{3 is} selected from the group consisting of:-hydrogen,-C ₁ -C ₄ -alkyl, for example preferably methyl, ethyl or isobutyl,-C ₁ -C ₃ -alkyl , Which may be substituted by an alkoxy group, for example preferably a methyl group substituted by a methoxy group, -C ₃ -C ₆ -cycloalkyl group, for example a cyclopropyl group. 4) R ^{4 is} selected from the group consisting of:-hydrogen,-halogen, for example, preferably fluorine,-C ₁ -C ₃ -alkoxy, for example, preferably methoxy. 5) R ^{5 is} selected from the group consisting of:-hydrogen,-halogen, for example, preferably fluorine,-C ₁ -C ₃ -alkoxy, for example, preferably methoxy. 6) R ⁶ and R ^6'are each hydrogen.

The present invention also covers combinations of specific examples according to the above-mentioned various aspects.

In terms of suitability for use as an iron chelate, it is particularly important that the compound of the present invention forms a sufficiently stable and highly selective complex with iron. Therefore, in a further aspect, the potential of this novel compound as an effective and safe iron chelate can be deduced from its affinity for chelating iron and forming iron complexes. The affinity for binding iron can also be called complex activity, which in principle corresponds to its dissociation or equilibrium constant.

However, not only the high affinity, but also the stability of the complex compound is also very important. It is very important that enough iron is combined with enough complex stability to safely remove the chelated iron from the body, and the affinity should not be so high that all organisms can be extracted from tissues and cells. Physiological iron.

In addition, it is desirable to mainly combine iron instead of other metals, for example, ^{high selectivity such as Cu 2+} , Zn ²⁺ , Ni ²⁺ , Mg ²⁺ or Ca ^2+.

The affinity or complex activity of the compound of the present invention for iron and the selectivity for various metals can be defined by the so-called pM/pFe value, where "M" indicates "metal" (pM), such as iron (pFe) ). The pM/pFe value can be determined according to the potentiometric titration method described in detail in methods A) and B) in the following examples, of which method A) is preferred. Among them, the potentiometric titration is carried out in a water/DMSO solution mixture to determine the equilibrium constant for the formation of complexes.

Accordingly, in another aspect, the present invention relates to a novel compound of general formula (I), (II) or (III) as defined anywhere in this case, which is also characterized by the complex activity represented by the pFe value Or the selectivity is at least (≥)19, preferably at least (≥)20. In addition, the pFe value is preferably not more than 27. The pFe value of the novel compound of the present invention is preferably in the range of 19-27, more preferably in the range of 20-27, even more preferably in the range of 20-25. As described above, the pFe value characterizes the affinity of the chelate (ligand) to iron, and reflects the binding activity, and thus reflects the strength or stability of the iron complex and its selectivity to iron.

If the pFe value is less than 19, the affinity to bind iron stably and selectively is insufficient. Although it may form a complex with iron, the stability of the complex may be impaired before the complexed iron is removed from the body. The complex may dissociate anywhere it passes through the body and release the complex again. He's the iron. In addition, compounds with a pFe value lower than 19 may not be sufficient to selectively chelate iron, but instead chelate other metals with better pM values as described below.

If the pFe value is higher than 27, the affinity may be too high, and uncontrolled iron binding may occur, resulting in uncontrolled and undesired extraction of iron from tissues and cells, instead of only chelating iron excessively. Too much iron.

The pFe value defined in this case can be determined by the potentiometric titration method described in detail in methods A) and B) in the following examples, of which method A) is preferred.

In another aspect, the present invention relates to a novel compound having general formula (I), (II) or (III) as defined anywhere in this case, which is also characterized by the fact that the metal Cu ²⁺ , Zn ²⁺ , Ni ²⁺ The selectivity of one or more of, Mg ²⁺ or Ca ²⁺ is represented by the following pM value: metal element pM value Cu ²⁺ ＜ 15 Zn ²⁺ ＜ 8 Ni ²⁺ ＜ 8 Mg ²⁺ ＜ 8 Ca ²⁺ ＜ 8

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

Among them, the pM value characterizes the selectivity of the compound of the present invention to bind to individual metals Cu ²⁺ , Zn ²⁺ , Ni ²⁺ , Mg ²⁺ or Ca ^2+.

If the pM value of an individual metal exceeds the defined upper limit, the affinity for the individual metal becomes too high and the affinity for the target metal iron (Fe ³⁺ ) may decrease. Therefore, the pM value of the metallic element Cu ²⁺ , Zn ²⁺ , Ni ²⁺ , Mg ²⁺ or Ca ²⁺ should generally be lower than the pFe value.

A particularly preferred example relates to novel compounds with general formula (I), (II) or (III) as defined anywhere in this case, which is also characterized by the selectivity to Zn, which is defined by pM value (pZn value) < 8 said.

In another specific example, the novel compound is characterized by selectivity to Zn, which is represented by a pM value (pZn value)<8 and is represented by at least one of the above-mentioned additional pM values.

The pM value defined in this case can be determined by the potentiometric titration method that is the same as the pFe value as detailed in the following examples (Method A) and B).

As mentioned above, the pM/pFe value characterizes the affinity of the compound of the present invention to individual metal elements, and thus reflects the binding activity to individual metal elements. The pM/pFe value represents a logarithmic value.

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

It is particularly preferred that the novel compound is characterized by one or more of the aforementioned characteristics: pFe value, pM value of one or more of the metals shown, and/or solubility.

2

3

4

5

6

7

8

9

10

11

12

13

14

15  

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

或其藥學上可接受的鹽。Particularly preferably, the compound according to the present invention is selected from the compounds shown in Table 1 below: Exp. number structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

twenty one

twenty two

twenty three

twenty four

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

Or a pharmaceutically acceptable salt thereof.

及其藥學上可接受的鹽。In a particularly preferred aspect, the present invention relates to a novel compound having the above general formula (I) or (II), which is represented by the formula (III) according to Example 40:

And pharmaceutically acceptable salts thereof.

The pharmaceutically acceptable salt of the compound according to the present invention includes, for example, a salt with a suitable pharmaceutically acceptable base, for example, a salt with an alkali metal or alkaline earth metal hydroxide, such as NaOH, KOH, Ca( OH) ₂ , Mg(OH) ₂ .

The novel compound of the present invention may exist in an amorphous, crystalline or partially crystalline form, or it may also exist in a hydrate. Medical use

It has been surprisingly found that the novel compound according to formula (I) as defined above and its other specific examples function as iron chelate, which has improved therapeutic efficacy and improved pharmaceutical administration characteristics, making it particularly suitable for use as pharmaceuticals, for example, It is used as an iron chelate in the living body.

As mentioned above, as an important feature that determines the applicability of the therapeutic iron chelate toxicity, in addition to its efficacy in reducing iron excess in tissues (such as the liver), affinity, selectivity, and complex compounds can also be mentioned. Stability and solubility.

The applicability and excellence of the novel compounds according to the present invention are shown in more detail in the following examples.

Due to the special applicability of the compound defined in this case as a therapeutically effective and safe iron chelate, the compound of the present invention is particularly suitable for preventing and/or treating conditions or diseases related to, accompanied by or caused by the following : Increased iron level, increased iron absorption, excessive iron or ineffective erythrocyte production in mammals.

The novel compounds of the present invention are more particularly suitable for use as iron chelates in vivo in the following conditions: increased iron levels in mammals, increased iron absorption, and iron excess caused by blood transfusion, especially in this case In the blood transfusion given under the condition or disease (such as thalassemia, myelodysplastic syndrome (MDS, myelodysplastic)).

It is related to, related to, caused by, or caused by, or caused by, increased or excessive iron level, increased iron absorption, or excessive iron (such as excessive iron in serum or tissue), or ineffective erythrocyte production. Disorders especially include thalassemia, including thalassemia A, thalassemia b, and thalassemia D.

It is related to, related to, caused by, or caused by, or caused by, increased or excessive iron level, increased iron absorption, or excessive iron (such as excessive iron in serum or tissue), or ineffective erythrocyte production. Conditions further include hemoglobinopathy, such as hemoglobin E disease (HbE), hemoglobin H disease (HbH), hemochromatosis, hemolytic anemia, such as sickle cell anemia (sickle cell disease) and congenital erythropoiesis Congenital dyserythropoietic anemia.

Diseases or disorders related to increased or excessive iron levels, increased iron absorption, excess iron (such as excessive iron in tissue), related to, caused by, or caused by, further include neurodegenerative diseases, For example, Alzheimer's disease and Parkinson's disease, where the compound is considered effective by limiting the deposition or increase of iron in tissues or cells.

The novel compound of the present invention is more suitable for the prevention and/or treatment of the formation of free radicals, reactive oxygen species (ROS) and oxidative stress caused by excessive iron or iron content, and the prevention and/or treatment of excessive iron or iron The heart, kidney, liver, and endocrine damage caused by excess iron, as well as the prevention and/or treatment of inflammation triggered by or excessive iron.

Diseases related to ineffective erythropoiesis include, among others, thalassemia, myelodysplastic syndrome (MDS, myelodysplastic syndrome) and polycythemia vera, and congenital dysplasia anemia.

Additional diseases, disorders, and/or conditions that can be treated with the novel compounds of the present invention include iron excess or iron excess, which is caused by genes involved in sensing systemic iron reserves, such as hepcidin (Hamp1), hemochromatosis protein (HFE), Caused by mutations in hemojuvelin (HJV) and transferrin receptor 2 (TFR2), such as diseases related to mutations in HFE and HJV genes, mutations in transferrin, chronic hemolysis-related diseases, sickle cell disease Subgroups of, hematocrit, glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency), hematopoietic porphyrosis, Friedrich's ataxia, and iron excess, such as iron excess from blood transfusion , Iron poisoning, pulmonary hemosiderinosis, osteopenia, insulin resistance, African iron excess, Hallerwarden-Spartz disease, methemorinemia, ceruloplasma protein deficiency, neonatal Hemochromatosis and red blood cell diseases including thalassemia, including thalassemia A, thalassemia b and thalassemia D, thalassemia moderate, sickle cell disease and myelodysplastic syndromes.

Additional diseases and/or disorders and/or conditions related to elevated iron levels that can be treated by the novel compounds of the present invention include, but are not limited to, diseases with elevated iron levels, including ataxia, Friedrich's ataxia Disorders, age-related macular degeneration, age-related cataracts, age-related retinal diseases, and neurodegenerative diseases such as pantothenate kinase-related neurodegenerative, restless legs syndrome, and Huntington’s disease. Dosage form

In view of this, another object of the present invention relates to a medicine containing one or more of the novel compounds as defined above, for example especially for the prevention and/or prevention of any indication, disorder, state, disease or disease as defined above Or therapeutic drugs.

Another aspect of the present invention relates to pharmaceutical compositions and drugs, which comprise one or more of the novel compounds according to the present invention as defined above and optionally one or more pharmacologically acceptable carriers and/or Auxiliary substances and/or solvents.

Another aspect of the present invention relates to pharmaceutical compositions and drugs, which comprise one or more of the novel compounds according to the present invention as defined above and optionally one or more additional pharmaceutically effective compounds or co-drugs.

The pharmaceutical composition contains, for example, up to 99% by weight, or up to 90% by weight, or up to 80% by weight, or up to 70% by weight, of the compound of the present invention, and the rest are separately provided by pharmacologically acceptable carriers and/or adjuvants and /Or solvent and/or optionally another pharmaceutically active compound.

Pharmaceutically acceptable carriers, auxiliary substances or solvents are common pharmaceutical carriers, auxiliary substances or solvents, including various organic or inorganic carriers and/or auxiliary materials, because they are commonly used for pharmaceutical purposes, especially for Solid drug formulations. Examples include excipients such as sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate; binding agents such as cellulose, methyl cellulose, hydroxypropyl cellulose, Polypropylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, starch; disintegrating agents, such as starch, hydrolyzed starch, carboxymethyl cellulose, calcium salt of carboxymethyl cellulose, hydroxypropyl starch, ethylene dichloride Sodium alkoxide starch, sodium bicarbonate, calcium phosphate, calcium citrate; lubricant, such as magnesium stearate, talc, sodium lauryl sulfate; flavorant, such as citric acid, menthol, glycine, orange powder ; Preservatives, such as sodium benzoate, sodium bisulfite, parabens (such as methyl paraben, ethyl paraben, propyl paraben, butyl paraben); Stabilizing agents, such as citric acid, sodium citrate, acetic acid and polycarboxylic acids in the titriplex series, such as, for example, diethylenetriaminepentaacetic acid (DTPA); suspending agents, such as methylcellulose, polyvinylpyrrolidone, Aluminum stearate; dispersant; diluent, such as water, organic solvent; wax, fat and oil, such as beeswax, cocoa butter; polyethylene glycol; white petrolatum, etc.

Liquid pharmaceutical formulations such as solutions, suspensions and gels usually contain liquid carriers such as water and/or pharmaceutically acceptable organic solvents. Furthermore, such liquid formulations may also contain, for example, the above-defined pH adjusters, emulsifiers or dispersants, buffers, preservatives, wetting agents, gelatinizers (such as methyl cellulose), dyes and/or Flavouring agent. The compositions can 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 glucose, maltose, boric acid, sodium tartrate, propylene glycol and other inorganic or organic soluble substances. The viscosity of the liquid composition can be adjusted by a pharmaceutically acceptable thickener, such as methyl cellulose. Other suitable thickeners include, for example, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, and the like. The preferred concentration of thickener will depend on the agent selected.

A pharmaceutically acceptable preservative can be used to increase the shelf life of the liquid composition. Although various preservatives can also be used, including, for example, paraben, thimerosal, chlorobutanol, and benzalkonium chloride, benzyl alcohol may be suitable.

The above pharmaceutical composition is in principle suitable for use in, for example, intravenous, intraperitoneal, intramuscular, intravaginal, intrabuccal, transdermal, subcutaneous, mucosal and skin, oral, rectal, transdermal, topical, intradermal, and gastric Or intracutaneous administration, and can be provided in the following forms: for example, pill, lozenge, enteric-coated lozenge, film lozenge, layered lozenge, for oral, subcutaneous or skin administration (especially as a patch) Sustained release formulations, reservoir formulations, dragees, suppositories, gels, ointments, syrups, granules, suppositories, emulsions, dispersions, microcapsules, micro formulations, nano formulations, liposome formulations, capsules , Enteric-coated capsules, powders, inhalation powders, microcrystalline formulations, inhalation sprays, spreading powders (epipastics), drops, nasal drops, nasal sprays, aerosols, ampoules, solutions, liquids, suspensions, infusions Or injection and so on.

However, oral administration and oral administration forms based thereon, such as pills, lozenges, enteric-coated lozenges, film lozenges, layered lozenges, sustained-release formulations for oral administration, dragees, syrups, granules, microcapsules, Capsules, enteric-coated capsules, powders, drops, ampoules, solutions, liquids and suspensions are preferred.

Another object of the present invention relates to medicines or combined preparations, which contain one or more of the novel compounds as defined above and at least one additional pharmaceutically active compound or co-drug, for example especially for the prevention and treatment of iron excess and related Symptom compound.

Preferably, at least one additional pharmacologically active compound or co-drug is a compound for the prevention and treatment of any state, disorder or disease as defined above, especially for the prevention and treatment of thalassemia, hemochromatosis, neurodegenerative diseases ( Such as Alzheimer’s disease or Parkinson’s disease) and related symptoms of pharmaceutically active compounds.

More preferably, at least one additional pharmaceutically active compound or co-drug is also an iron chelating compound, a hepcidin agonist or a hepcidin mimic, a synthetic hepcidin or a modified analog thereof, including a mini hepcidin Or transferrin inhibitor or a combination thereof.

Suitable iron chelating co-drugs can be selected from the group consisting of removing iron (DFO; Desferal®; N'-[5-(acetyl-hydroxy-amino)pentyl]-N-[5-[3-(5-amine Pentyl-hydroxy-aminomethanyl) propylamino]pentyl)-N-hydroxy-butanediamide), deferasirox (Exjade®; 4-(3,5-bis(2- Hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzoic acid), deferiprone (DFP; Ferriprox®) and/or deferritrin. For example, an oral iron chelate of deferoxone and deferiprone is preferred as a co-drug.

或其任何藥學上可接受的鹽，例如特別是如WO2018/192973所述的鹽，特別包括具有下式的3HCl鹽

具有下式的1:1硫酸鹽

及其同質多形體。Suitable transferrin inhibitors can be selected from the compounds described in WO2017/068089, WO2017/068090 and WO2018/192973. In a preferred aspect of the invention, at least one additional pharmaceutically active compound or co-drug is a transferrin inhibitor according to the formula

Or any pharmaceutically acceptable salt thereof, for example, in particular, the salt as described in WO2018/192973, in particular including the 3HCl salt having the following formula

1:1 sulfate with the formula

And its homogeneous polymorphs.

At least one additional pharmaceutically active compound or co-drug for reducing iron excess or for treating iron excess may be selected from Tmprss6, apolipoprotein, curcumin, SSP-004184 targeting ASO and siRNA.

At least one additional pharmaceutically active compound or co-drug may be selected from antioxidants, such as n-acetylcysteine; antidiabetic drugs, such as GLP-1 receptor agonists; antibiotics, such as vancomycin (Van) or Tobramycin; a drug used to treat malaria; an anticancer agent; an antifungal drug; a drug used to treat neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, including dopamine agonists, For example, Levodopa; antiviral drugs, such as interferon-α or ribavirin; immunosuppressive agents, such as cyclosporin A or cyclosporin A derivatives; iron supplements; vitamin supplements Erythrocyte production stimulants, including antagonists of TGF beta superfamily members (such as Luspatercept), antibodies that generate activin receptor ligand traps, antibody fragments, non-antibody scaffold drugs or cells; EPO and ESA, HDAC inhibitors; anti-p-selectin Abs, HA (associated with SCD), drugs that target HbS aggregation; anti-inflammatory biological agents; antithrombolytic agents; statins; vasopressors; and Compounds that affect muscle contractility.

或其任何藥學上可接受的鹽，以及根據下式的運鐵素抑制劑

或其任何藥學上可接受的鹽，例如特別是3HCl鹽或1:1硫酸鹽。A very preferred combination of the novel iron chelate according to the present invention and another pharmaceutically active compound or co-drug is related to the combination of a compound according to formula (III)

Or any pharmaceutically acceptable salt thereof, and a transferrin inhibitor according to the following formula

Or any pharmaceutically acceptable salt thereof, such as particularly 3HCl salt or 1:1 sulfate salt.

Another object of the present invention relates to the use of the novel compound as defined above by itself for combination therapy (fixed dose or free dose combination for continuous use) with one or two other active ingredients (drug, co-drug). Such combination therapy comprises co-administration of the novel compound of the present invention and at least one additional pharmaceutically active compound (co-drug).

Combination therapy that presents a fixed-dose combination therapy includes co-administration of the compound of the present invention in a fixed-dose formulation and at least one additional pharmaceutically active compound. Combination therapy that presents free-dose combination therapy includes the co-administration of a compound of the present invention and at least one additional pharmaceutically active compound of several individual compounds presenting free-dose, by simultaneous administration of the individual compounds or by sequential use These individual compounds are distributed over a period of time. The at least one additional pharmaceutically active compound (co-drug) is preferably selected from the drugs defined above, preferably drugs used to reduce iron excess, such as the above-defined transferrin inhibitor or the above-defined iron chelate Compounds, or antioxidants, antidiabetics, antibiotics, drugs for the treatment of malaria, anticancer agents, antifungals, drugs for the treatment of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s Viral drugs, immunosuppressants, iron supplements, vitamin supplements, erythropoiesis stimulators, anti-inflammatory biological agents, antithrombolytic agents, statins, vasopressors, and compounds that affect muscle contractility, etc. As defined above.

Another object of the present invention relates to the use of the above-mentioned combination for the prevention and/or treatment of conditions or diseases caused by iron excess or iron quality conditions, such as especially thalassemia and hemochromatosis, and other conditions described in the application.

Another object of the present invention relates to the use of the compound defined in this case or the above-mentioned combination therapy in this case in combination with blood transfusion.

The compounds, drugs and or combined preparations according to the present invention can be administered orally, parenterally and intravenously, preferably orally. Refer to the above description for the appropriate dosage form.

In a preferred embodiment of the present invention, the compounds are administered in the form of tablets or capsules, as defined above. These can be expressed, for example, in an acid-resistant form or a pH-dependent coating.

The compound of the present invention as an active substance can be administered in a unit dose of, for example, 0.001 mg/kg to 500 mg/kg body weight, for example, 1 to 4 times a day. However, the dosage can be increased or decreased according to age, weight, patient condition, severity of disease, or type of administration.

Accordingly, another object of the present invention relates to the use of the above-defined compound, drug, composition and combined preparation for the preparation of a drug, especially for the prevention and treatment of any indication, state, disease or disease as defined above , Especially for oral administration.

Another object of the present invention relates to a method for prevention and treatment as defined above, for example, particularly for prevention and/or treatment related to increased or excessive iron levels, and in particular excess iron, caused by increased iron levels. Condition, disease or disease caused by excessive or excessive iron content or increased or excessively excessive iron content, related to the increase in iron level or iron storage caused by the increase in iron level For diseases and diseases related to ineffective erythropoiesis, the method includes administering the compound, drug, composition or combination preparation as defined above to a patient (human or animal) in need thereof.

Among them, diseases related to, related to, or caused by or caused by an increase in iron level or excessive iron are those defined as above.

Another object of the present invention relates to the use of the compound as defined above for the preparation of a medicament, especially for the prevention and treatment of any indication, condition, disorder or disease as defined above. Preparation method and synthetic route

The compounds according to the present invention with general structural formulas (I), (II) and (III) can basically be obtained by the method described below and shown in the following general scheme (general scheme). Accordingly, another object of the present invention is a method for preparing the compounds of general formula (I), (II) and (III) described in this case.

通用方案 1 ：

The compound according to the present invention with the general structural formula (I) is obtained by the synthesis method described below in the following general scheme and general scheme. Among them, the substituent may have the meaning described anywhere in this case:

General plan 1 :

The synthesis starts from a substituted aniline with common structure 51 available on the market, using sodium bis(trimethylsilyl)amide as a base, and under alkaline conditions, the substituted aniline is converted into a substituted aniline with a substituted nitrile 52. Benzamidine with common structure 53. It is also possible to use other bases, such as sodium hydride (Advanced Synthesis and Catalysis, 2016, vol. 358, 17, p. 2759 – 2766). Afterwards, the addition of benzamidine 53 together with the bromobenzyloxyaryl alkyl ketone with the common structure 54 produces a triaryl haloimidazole with the common structure 55 (US5616601). General scheme 1a :

The preparation of amidines with common structure 62 , which has introduced carboxylic acid functional groups, is synthesized from benzonitrile with common structure 59. Treat 59 with benzyl(trimethylsilyl)amide to obtain amidine 60 (Baumann M., Baxendale IR, Bioorg. and Med. Chem . 2017 , 25, 23 , 6218-6223). Then, under open flask conditions, copper(II) acetate monohydrate was used as a catalyst, and oxidatively coupled with boric acid of common structure 61 to obtain substituted benzamidine 62 (Li J.; Benard S., Neuville L.; Zhu J. Org. Lett . 2012 , 14, 23 , 5980 – 5983). General plan 2 :

Using n -BuLi and N, N - dimethyl Amides having the common structural halogenated triaryl imidazole 55 into a common structure with the Third substituted aryl aldehyde 56 using imidazo disposed of H ₂ SO CrO _{4 3} ( Jones reagent oxidizes aldehyde groups. It is also possible to use other oxidants, such as oxone ( Org. Lett. 2003 , 5 , 1031-1034) or potassium permanganate ( Org. Lett. 2010 , 12 , 3618-3621) or pyridinium Chlorochromate ( Synthesis , 2005 , 2487-2490) generates corresponding triarylcarboxylic acid substituted imidazoles with common structure 57. General scheme 2b :

Using the same conditions as above, benzamidine 62 was cyclized to imidazole 64 with a common structure with bromobenzyloxyaralkanone having a common structure 54 . Then, the methyl ester of imidazole 64 is hydrolyzed with lithium hydroxide to generate imidazole carboxylic acid with common structure 57. General plan 3 :

Alternatively, 55 is directly converted into 57 , the in-situ organolithium species of 55 is formed by using lithium base, and the in-situ organolithium species is _{treated with continuous CO 2} gas flow at low temperature to generate 57 (Tozawa H.; Kitamura K.; Hamura T. Chem. Lett 2017 , 46, 5 , 703 – 706). General scheme 4 :

Palladium on carbon (10%-w/w) was used to hydrogenate the benzyl-protected imidazole with common structure 57 to obtain the final compound with general structural formula (I). To the compound of the general formula 57 to deprotection to obtain the final compound having the general structure (I) of the, also possible to use place of CH ₂ Cl BCl _{2 3 / BBr 3 (Protective Groups in} Organic Synthesis, third edition 1999, p. 254 and 267). General plan 5 :

Alternatively, the benzyloxyaralkanone with the common structure 69 can be synthesized by starting with the commercially available 2-hydroxybenzaldehyde with the common structure 66.

2-Hydroxybenzaldehyde 66 is reacted in the presence of benzyl bromide, potassium iodide and potassium carbonate to obtain 2-benzyloxybenzaldehyde 67 . The substituent R ³ (Jiang D., Peng J., Chen, Y. Org. Lett. 2008 , 10, 9 , 1695 – 1698) was introduced through Grignard- reaction to obtain alcohol 68 , and then under Jones conditions It is oxidized to a benzyloxyaralkanone with a common structure of 69 (Kalendra, DM, Sickles, BR J. Org. Chem. 2003 , 68, 4 , 1594 – 1596). General plan 6 :

Alternatively, benzyloxy arylalkyl ketone 69 can also be permeable Zagreb temperature --72 added to a base generated in situ using a lithium 2-benzyloxy-bromide under standard conditions Amides (Weinreb -amide) 73 Of organolithium species to obtain.

Temperature Zagreb - Amides 72 using carbonyldiimidazole as a coupling agent to obtain (Coe JW from the appropriate carboxylic acid 70, Bianco KE; Boscoe BP, Brooks PR; Cox ED, Vetelino MG J. Org Chem 2003, 68.. , 26 , 9964 – 9970). 2-Benzyloxybromo-benzene 73 is synthesized from the commercially available corresponding 2-hydroxybromo-benzene under standard conditions by using benzyl bromide, potassium iodide, and potassium carbonate. General process 7 :

The 2-benzyloxybenzophenone with the common structure 69 is converted to bromobenzyl by using phenyltrimethylammonium tribromide (WO2007/44796, 2007 ) as a mild substitute for other bromination conditions Oxyaryl alkyl ketone 54 (Watanuki S. Sakamoto S., Harada H., Kikuchi K., Kuramochi T., Kawaguchi K.-I., Okazaki T., Tsukamoto, S.-I. Heterocycles 2004 , 62 , 127 – 130).

Novel intermediate compounds derived from any of the preparation methods described in this case should also be included in the present invention. Example

The present invention is illustrated in more detail by the following examples. I. Preparation of Example Compounds abbreviation BuLi N-butyl lithium EtOAc Ethyl acetate CH ₂ Cl ₂ Dichloromethane Et ₂ O Ether MeOH Methanol EtOH Ethanol Salt water Saturated sodium chloride aqueous solution Chloroform- d Deuterated chloroform DMSO- d ₆ Deuterated dimethyl sulfide s Singlet br s Open-line singlet d Duality dd Dual duality dt Double state of triplet td Triplet hept. Sevent State m Polymorphism q Quartet δ chemical shift ppm millionth M Molar concentration mm Millimoles umol Micromolar g Gram mg Milligrams l Rise mL Milliliters H hour min minute %-w/w Mass percentage TLC Thin layer chromatography UHPLC UHP Liquid Chromatography MS Mass spectrometry ESI Electronic spray ionization m/z Mass-to-charge ratio H ⁺ Proton MHz Megahertz sm Starting material Jones Reagent Place CrO ₃ in H ₂ SO ₄ CrO ₃ Chromium trioxide H ₂ SO ₄ sulfuric acid Bn Benzyl MS Mass spectrometry ESI Electrospray ionisation SNAP Biotage-Column-Brand Name for Fast Column Chromatography R _f Retention factor TLC Thin layer chromatography Chemical naming

The chemical names of the intermediate and final example compounds were generated using Chem Draw Professional 17.0. .

All R _f values were determined using the following TLC plate: Merck, TLC Silcagel 60 F ₂₅₄ . Intermediate A. 2- (benzyloxy) -N- (4- bromophenyl) benzoyl amine

Add a solution of sodium bis(trimethylsilyl)amide (140 mL, 0.14 mol, 1M in THF) to a solution of 4-bromoaniline (20.64 g, 0.12 mol) in 600 ml THF at 0°C. After stirring for 15 min, 2-(benzyloxy)benzonitrile (29.29 g, 0.14 mol) was added, and the reaction mixture was heated to 20° C. and stirred for 12 h. Saturated _{aqueous NH 4} Cl solution (200 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column, with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain 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 )-1H- imidazole

Make 2-(benzyloxy)-N-(4-bromophenyl) benzamidine (19.3 g, 0.051 mol) and 1-(2-(benzyloxy)benzene in 800 mL isopropanol Base)-2-bromoethan-1-one (17 g, 0.056 mol) and sodium bicarbonate (8.5 g, 0.101 mol) were heated at 80°C for 12 h. The resulting mixture was filtered at 80°C, drained, and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain The title compound (18.9 g, 0.032 mol, 63%) as a beige solid.

¹ H NMR (400 MHz, MeOD): δ 8.1 (m, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 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 )-1H- imidazol- 1 -yl ) benzaldehyde

2,4-Bis(2-(benzyloxy)phenyl)-1-(4-bromophenyl)-1H-imidazole (10 g, 11.02 mmol) in 200 mL THF at -75°C Add n-butyl lithium (11.7 ml, 18.72 mmol, 1.6 M in hexane) to the solution. After stirring at -75°C for 60 min, dimethylformamide DMF (7 ml, 85.11 mmol, 5 eq) was added, and the reaction mixture was stirred at -75°C for 1 h. The reaction mixture was then warmed to 20°C. Saturated _{aqueous NH 4} Cl (100 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 80 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column, with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain the title compound as a light brown solid (4.7 g, 8.68 mmol, 51%).

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

MS (ESI+): m/z 536 [M] ⁺ . D. 4-(2,4- bis (2-( benzyloxy ) phenyl )-1H- imidazol- 1 -yl ) benzoic acid

4-(2,4-bis(2-(benzyloxy)phenyl)-1H-imidazol-1-yl)benzaldehyde (1.5 g, 2.8 mmol) in 50 ml acetone was added to Jones reagent ( 1.8 ml, 2 M CrO ₃ , placed in H ₂ SO ₄ aqueous solution), and the resulting mixture was stirred at 20°C for 45 min. After the acetone was drained, ethyl acetate (100 ml) was added, and the mixture was _{washed with a saturated aqueous NaHCO 3} solution (2×120 ml), dried with Na ₂ SO ₄ , filtered, and drained. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 25% methanol in dichloromethane) to obtain the title compound as a white solid (1.3 g, 2.35 mmol , 84%).

¹ H NMR (400 MHz, DMSO): δ 12.9 (s, 1H), 8.2 (m, 1H), 7.9 (s, 1H), 7.65 (m, 1H), 7.55 (m, 2H), 7.45 (m, 1H), 7.35 (m, 1H), 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) benzoyl amine

Add bis(trimethylsilyl) amide sodium solution (149 ml, 0.149 mol, 1M in THF) to 4-bromo-3-methoxyaniline (20 g, 0.099 mol) at 0°C and place at 600 ml THF solution. After stirring for 15 min, 2-(benzyloxy)benzonitrile (26 g, 0.124 mol) was added, and the resulting solution was stirred at 20°C overnight. Saturated _{aqueous NH 4} Cl solution (200 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column, with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain 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 )- 1H- imidazole

Make 2-(benzyloxy)-N-(4-bromo-3-methoxyphenyl)benzamidine (9.5 g, 0.023 mol), 1-(2-( Benzyloxy)phenyl)-2-bromoethan-1-one (7.75 g, 0.025 mol) and sodium bicarbonate (3.86 g, 0.046 mol) were heated at 80°C overnight. The resulting mixture was filtered at 60°C, drained, and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain The title compound (8.7 g, 0.014 mol, 61%) as a beige solid.

¹ H NMR (400 MHz, DMSO): δ 8.2 (m, 1H), 7.8 (s, 1H), 7.58 (m, 3H), 7.48 (m, 1H), 7.35 (m, 4H), 7.2 (m, 5H), 7.05 (m, 2H), 6.95 (m, 3H), 6.63 (m, 1H), 6.5 (m, 1H), 5.3 (s, 2H), 4.8 (s, 2H). G. 4-( 2,4- Bis (2-( benzyloxy ) phenyl )-1H- imidazol- 1 -yl )-2 -methoxybenzaldehyde

2,4-Bis(2-(benzyloxy)phenyl)-1-(4-bromo-3-methoxyphenyl)-1H-imidazole (10 g, 16.2 mmol) in 200 mL THF Add n- BuLi (11.5 ml, 17.8 mmol, 1.6 M in hexane) to the solution at -75°C. After stirring at -75°C for 60 min, dimethylformamide DMF (7 ml, 85.11 mmol, 5.5 eq) was added, and the reaction mixture was stirred at -75°C for 1 h. The reaction mixture was then warmed to 20°C. Saturated _{aqueous NH 4} Cl (100 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 80 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain 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 )-1H- imidazol- 1 -yl )-2- methoxy Benzoic acid

4-(2,4-bis(2-(benzyloxy)phenyl)-1H-imidazol-1-yl)-2-methoxybenzaldehyde (6 g, 10.6 mmol) in 200 ml acetone Jones reagent (6.6 ml, 2 M CrO ₃ , placed in H ₂ SO ₄ aqueous solution) was added to the solution, and the resulting mixture was stirred at 20° C. for 45 min. After the acetone was drained, ethyl acetate (100 ml) was added, and the mixture was _{washed with a saturated aqueous NaHCO 3} solution (2×120 ml), dried with Na ₂ SO ₄ , filtered, and drained. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 25% methanol in dichloromethane) to obtain 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) benzoyl amine

Add bis(trimethylsilyl) amide sodium solution (75 ml, 0.074 mol, 1M, placed in THF) to 3-bromo-5-methoxyaniline (10 g, 0.05 mol) at 0°C and place at 300 ml THF solution. After stirring for 15 min, 2-(benzyloxy)benzonitrile (13 g, 0.062 mol) was added, and the resultant was stirred at 20°C for 12 h. Saturated _{aqueous NH 4} Cl solution (200 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column, with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain 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 )- 1H- imidazole

Make 2-(benzyloxy)-N-(3-bromo-5-methoxyphenyl)benzamidine (10 g, 0.024 mol), 1-(2-( Benzyloxy)phenyl)-2-bromoethan-1-one (8.4 g, 0.027 mol) and sodium bicarbonate (4.1 g, 0.049 mol) were heated at 80°C for 12 h. The resulting mixture was filtered at 60°C, drained, and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain The title compound (9.9 g, 0.016 mol, 66%) as a beige solid.

MS (ESI+): m/z 618 [M+H] ⁺ . K. 3-(2,4- bis (2-( benzyloxy ) phenyl )-1H- imidazol- 1 -yl )-5- Methoxybenzaldehyde

2,4-Bis(2-(benzyloxy)phenyl)-1-(3-bromo-5-methoxyphenyl)-1H-imidazole (5 g, 8.1 mmol) in 100 mL THF Add n- BuLi (5.5 ml, 16 mmol, 1.6 M in hexane) to the solution at -75°C. After stirring at -75°C for 60 min, dimethylformamide DMF (6 ml, 85 mmol, 5.5 eq) was added, and the reaction mixture was stirred at -75°C for 1 h. The reaction mixture was then warmed to 20°C. Saturated _{aqueous NH 4} Cl (100 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 80 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column, with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain 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 )-1H- imidazol- 1 -yl )-5- methoxy Benzoic acid

P-3-(2,4-bis(2-(benzyloxy)phenyl)-1H-imidazol-1-yl)-5-methoxybenzaldehyde (0.6 g, 1.1 mmol) in 50 ml acetone Jones reagent (0.6 ml, 2 M CrO ₃ , placed in H ₂ SO ₄ aqueous solution) was added to the solution, and the resulting mixture was stirred at 20°C for 45 min. After the acetone was drained, ethyl acetate (100 ml) was added, and the mixture was _{washed with a saturated aqueous NaHCO 3} solution (2×120 ml), dried with Na ₂ SO ₄ , filtered, and drained. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 25% methanol in dichloromethane) to obtain 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-( benzyl (Oxy ) phenyl )-1H- imidazol- 1 -yl ) benzaldehyde

4-(2-(benzyloxy)-4-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1-(4-bromophenyl)-1H-imidazole Add n-butyl lithium (5.5 ml, 8.9 mmol, 1.6 M in hexane) to a solution of (5 g, 8.1 mmol) in 100 mL THF at -75°C. After stirring at -75°C for 60 min, dimethylformamide DMF (3.2 ml, 40.5 mmol, 5.5 eq) was added, and the reaction mixture was stirred at -75°C for 1 h. The reaction mixture was then warmed to 20°C. Saturated _{aqueous NH 4} Cl (100 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 80 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column, with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain 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 )-1H- imidazol- 1 -yl ) benzoic acid

4-(4-(2-(benzyloxy)-4-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1H-imidazol-1-yl)benzaldehyde (4 g, 7.06 mmol) in 150 ml of acetone was added to Jones reagent (4.4 ml, 2 M CrO ₃ in H ₂ SO ₄ aqueous solution), and the resulting mixture was stirred at 20° C. for 45 min. After the acetone was drained, ethyl acetate (100 ml) was added, and the mixture was _{washed with a saturated aqueous NaHCO 3} solution (2×120 ml), dried with Na ₂ SO ₄ , filtered, and drained. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 25% methanol in dichloromethane) to obtain the title compound as a white solid (3.2 g, 5.5 mmol , 78%).

¹ H NMR (400 MHz, DMSO): δ 13.1 (s, 1H), 8.1 (m, 1H), 7.8 (m, 2H), 7.7 (s, 1H), 7.6 (m, 3H), 7.4 (m, 4H), 7.2 (m, 3H), 7.1 (m, 3H), 6.9 (m, 3H), 6.7 (m, 1H), 6.6 (m, 1H), 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

Make 2-(benzyloxy)-N-(4-bromophenyl)benzamide (10 g, 0.026 mol), 1-(2-(benzyloxy) in 600 mL isopropanol -5-Methoxyphenyl)-2-bromoethan-1-one (9.7 g, 0.029 mol) and sodium bicarbonate (4.1 g, 0.052 mol) were heated at 80°C for 12 h. The resulting mixture was filtered at 60°C, drained, and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain The title compound (10.7 g, 0.017 mol, 66%) as a beige solid.

MS (ESI+): m/z 618 [M+H] ⁺ . P. 4-(4-(2-( benzyloxy )-5 -methoxyphenyl )-2-(2-( benzyl (Oxy ) phenyl )-1H- imidazol- 1 -yl ) benzaldehyde

4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1-(4-bromophenyl)-1H-imidazole Add n-butyl lithium (5.5 ml, 18.72 mmol, 1.6 M in hexane) to a solution of (5 g, 8.1 mmol) in 100 mL THF at -75°C. After stirring at -75°C for 60 min, dimethylformamide DMF (3.2 ml, 40.5 mmol, 5.5 eq) was added, and the reaction mixture was stirred at -75°C for 1 h. The reaction mixture was then warmed to 20°C. Saturated _{aqueous NH 4} Cl (100 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 80 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column, with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain 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

4-(4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1H-imidazol-1-yl)benzaldehyde (4 g, 7.06 mmol) in 150 ml of acetone was added to Jones reagent (4.4 ml, 2 M CrO ₃ in H ₂ SO ₄ aqueous solution), and the resulting mixture was stirred at 20° C. for 45 min. After the acetone was drained, ethyl acetate (100 ml) was added, and the mixture was _{washed with a saturated aqueous NaHCO 3} solution (2×120 ml), dried with Na ₂ SO ₄ , filtered, and drained. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 25% methanol in dichloromethane) to obtain the title compound as a white solid (3.3 g, 5.6 mmol , 79%).

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

Add bis(trimethylsilyl) amide sodium solution (150 ml, 0.15 mol, 1M, placed in THF) to 3-bromo-4-methoxyaniline (20 g, 0.1 mol) at 0°C and place at 600 ml THF solution. After stirring for 15 min, 2-(benzyloxy)benzonitrile (26 g, 0.124 mol) was added, and the reaction mixture was heated to 20° C. and stirred for 12 h. Saturated _{aqueous NH 4} Cl solution (200 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain 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

Make 2-(benzyloxy)-N-(3-bromo-4-methoxyphenyl)benzamidine (10 g, 0.024 mol), 1-(2-( Benzyloxy)phenyl)-2-bromoethan-1-one (8.4 g, 0.027 mol) and sodium bicarbonate (4.1 g, 0.049 mol) were heated at 80°C for 12 h. The resulting mixture was filtered at 60°C, drained, and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain The title compound (9.2 g, 0.015 mol, 61%) as a beige solid.

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

2,4-Bis(2-(benzyloxy)phenyl)-1-(3-bromo-4-methoxyphenyl)-1H-imidazole (5 g, 8.1 mmol) in 200 mL THF Add n- BuLi (5.5 ml, 16 mmol, 1.6 M in hexane) to the solution at -75°C. After stirring at -75°C for 60 min, dimethylformamide DMF (6 ml, 85 mmol, 5.5 eq) was added, and the reaction mixture was stirred at -75°C for 1 h. The reaction mixture was then warmed to 20°C. Saturated _{aqueous NH 4} Cl (100 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 80 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column, with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain the title compound as a light brown solid (2.4 g, 4.2 mmol, 52%).

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

MS (ESI+): m/z 536 [M] ⁺ . U. 5-(2,4- bis (2-( benzyloxy ) phenyl )-1H- imidazol- 1 -yl )-2- methoxy Benzoic acid

5-(2,4-bis(2-(benzyloxy)phenyl)-1H-imidazol-1-yl)-2-methoxybenzaldehyde (4 g, 7.06 mmol) in 100 ml acetone Jones reagent (4.4 ml, 2 M CrO ₃ , placed in H ₂ SO ₄ aqueous solution) was added to the solution, and the resulting mixture was stirred at 20°C for 45 min. After the acetone was drained, ethyl acetate (100 ml) was added, and the mixture was _{washed with a saturated aqueous NaHCO 3} solution (2×120 ml), dried with Na ₂ SO ₄ , filtered, and drained. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 25% methanol in dichloromethane) to obtain 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 )-1H- imidazol- 1 -yl )-2- Fluorobenzaldehyde

P-2,4-bis(2-(benzyloxy)phenyl)-1-(4-bromo-3-fluorophenyl)-1H-imidazole (7.2 g, 11.9 mmol) in 200 mL THF in- Add n- BuLi (8.2 ml, 13.1 mmol, 1.6 M in hexane) to the 75°C solution. After stirring at -75°C for 60 min, dimethylformamide DMF (5.1 ml, 65.5 mmol, 5.5 eq) was added, and the reaction mixture was stirred at -75°C for 1 h. The reaction mixture was then warmed to 20°C. Saturated _{aqueous NH 4} Cl (100 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 80 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain the title compound as a light brown solid (3.5 g, 6.3 mmol, 53%).

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

MS (ESI+): m/z 554 [M] ⁺ . W. 4-(2,4- bis (2-( benzyloxy ) phenyl )-1H- imidazol- 1 -yl )-2- fluorobenzene Formic acid

A solution of 4-(2,4-bis(2-(benzyloxy)phenyl)-1H-imidazol-1-yl)-2-fluorobenzaldehyde (3 g, 5.41 mmol) in 100 ml acetone Jones reagent (3.4 ml, 2 M CrO ₃ , placed in H ₂ SO ₄ aqueous solution) was added, and the resulting mixture was stirred at 20° C. for 45 min. After the acetone was drained, ethyl acetate (100 ml) was added, and the mixture was _{washed with a saturated aqueous NaHCO 3} solution (2×120 ml), dried with Na ₂ SO ₄ , filtered, and drained. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 25% methanol in dichloromethane) to obtain 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 )-1H- imidazole

Make 2-(benzyloxy)-N-(4-bromophenyl)-5-methoxybenzamidine (5 g, 12.12 mmol), 1-(2-( Benzyloxy)-5-methoxyphenyl)-2-bromoethane-1-one (4.5 g, 13.4 mmol) and sodium bicarbonate (2.1 g, 24.4 mmol) were heated at 80°C for 12 h. The resulting mixture was filtered at 60°C, drained, and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain The title compound (4.9 g, 7.5 mmol, 62%) as a beige solid.

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

2,4-Bis(2-(benzyloxy)-5-methoxyphenyl)-1-(4-bromophenyl)-1H-imidazole (5 g, 7.7 mmol) in 100 mL THF Add n- BuLi (5.3 ml, 18.72 mmol, 1.6 M in hexane) to the solution at -75°C. After stirring at -75°C for 60 min, dimethylformamide DMF (3.3 ml, 42.4 mmol, 5 eq) was added, and the reaction mixture was stirred at -75°C for 1 h. The reaction mixture was then warmed to 20°C. Saturated _{aqueous NH 4} Cl (100 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 80 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column, with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain the title compound as a light brown solid (2.3 g, 3.8 mmol, 49 %).

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

4-(2,4-bis(2-(benzyloxy)-5-methoxyphenyl)-1H-imidazol-1-yl)benzaldehyde (4 g, 6.7 mmol) in 150 ml acetone Jones reagent (4.2 ml, 2 M CrO ₃ , placed in H ₂ SO ₄ aqueous solution) was added to the solution, and the resulting mixture was stirred at 20°C for 45 min. After the acetone was drained, ethyl acetate (100 ml) was added, and the mixture was _{washed with a saturated aqueous NaHCO 3} solution (2×120 ml), dried with Na ₂ SO ₄ , filtered, and drained. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 25% methanol in dichloromethane) to obtain 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) benzoyl amine.

Add bis(trimethylsilyl) amide sodium solution (150 ml, 0.149 mol, 1M in THF) to 5-bromo-2-methoxyaniline (20 g, 0.099 mol) at 0°C and place at 600 ml THF solution. After stirring for 15 min, 2-benzyloxybenzonitrile (26 g, 0.124 mol) was added, and the reaction mixture was heated to 20°C and stirred for 12 h. Saturated _{aqueous NH 4} Cl solution (200 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column, with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain 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

Make 2-(benzyloxy)-N-(5-bromo-2-methoxyphenyl)benzamidine (8 g, 19.5 mmol), 1-(2-( Benzyloxy)phenyl)-2-bromoethan-1-one (6.5 g, 21.4 mmol) and sodium bicarbonate (3.3 g, 39 mmol) were heated at 80°C for 12 h. The resulting mixture was filtered at 60°C, drained, and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain The title compound (7.8 g, 12.6 mmol, 63%) as a beige solid.

MS (ESI+): m/z 618 [M+H] ⁺ . AC. 3-(2,4- bis (2-( benzyloxy ) phenyl )-1H- imidazol- 1 -yl )-4- Methoxybenzaldehyde

2,4-Bis(2-(benzyloxy)phenyl)-1-(5-bromo-2-methoxyphenyl)-1H-imidazole (5.5 g, 8.90 mmol) in 200 mL THF Add n- BuLi (5.9 ml, 9.80 mmol, 1.6 M in hexane) to the solution at -75°C. After stirring at -75°C for 60 min, dimethylformamide DMF (3.8 ml, 49 mmol, 5 eq) was added, and the reaction mixture was stirred at -75°C for 1 h. The reaction mixture was then warmed to 20°C. Saturated _{aqueous NH 4} Cl (100 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 80 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column, with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain 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 )-1H- imidazol- 1 -yl )-4- Methoxybenzoic acid

P-3-(2,4-bis(2-(benzyloxy)phenyl)-1H-imidazol-1-yl)-4-methoxybenzaldehyde (10 g, 17.65 mmol) in 150 ml acetone Jones reagent (11 ml, 2 M CrO ₃ , placed in H ₂ SO ₄ aqueous solution) was added to the solution, and the resulting mixture was stirred at 20°C for 45 min. After the acetone was drained, ethyl acetate (100 ml) was added, and the mixture was _{washed with a saturated aqueous NaHCO 3} solution (2×120 ml), dried with Na ₂ SO ₄ , filtered, and drained. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 25% methanol in dichloromethane) to obtain 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) benzoyl amine

Add bis(trimethylsilyl) amide sodium solution (140 ml, 0.14 mol, 1M, in THF) to 3-bromo-4-methoxyaniline (24.25 g, 0.12 mol) at 0°C and place at 600 ml THF solution. After stirring for 15 min, 2-(benzyloxy)benzonitrile (29.30 g, 0.14 mol) was added, and the reaction mixture was heated to 20° C. and stirred for 12 h. Saturated _{aqueous NH 4} Cl solution (200 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain 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 )-1H- imidazole

Make 2-(benzyloxy)-N-(3-bromo-4-methoxyphenyl)benzamidine (13 g, 31.6 mmol), 1-(2-( Benzyloxy)-5-methoxyphenyl)-2-bromoethane-1-one (11.6 g, 37.9 mmol) and sodium bicarbonate (5.3 g, 63.2 mmol) were heated at 80°C for 12 h. The resulting mixture was filtered at 60°C, drained, and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain The title compound (12.5 g, 0.019 mol, 62%) as a beige solid.

MS (ESI+): m/z 648 [M+H] ⁺ . AG. 5-(4-(2-( benzyloxy )-5 -methoxyphenyl )-2-(2-( benzyl (Oxy ) phenyl )-1H- imidazol- 1 -yl )-2 -methoxybenzaldehyde

4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1-(3-bromo-4-methoxybenzene N- BuLi (7.2 ml, 11.6 mmol, 1.6 M in hexane) was added to a solution of 200 mL of THF at -75°C in 200 mL of THF (6.8 g, 10.5 mmol). After stirring at -75°C for 60 min, dimethylformamide DMF (4.5 ml, 57.8 mmol, 5 eq) was added, and the reaction mixture was stirred at -75°C for 1 h. The reaction mixture was then warmed to 20°C. Saturated _{aqueous NH 4} Cl (100 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 80 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column, with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain 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-( benzyl (Oxy ) phenyl )-1H- imidazol- 1 -yl )-2- methoxybenzoic acid

P-5-(4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1H-imidazol-1-yl)-2 -Methoxybenzaldehyde (5.5 g, 9.22 mmol) in 100 ml of acetone was added to Jones reagent (5.8 ml, 2 M CrO ₃ in H ₂ SO ₄ aqueous solution), and the resulting mixture was stirred at 20°C for 45 min. After the acetone was drained, ethyl acetate (100 ml) was added, and the mixture was _{washed with a saturated aqueous NaHCO 3} solution (2×120 ml), dried with Na ₂ SO ₄ , filtered, and drained. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 25% methanol in dichloromethane) to obtain the title compound as a white solid (4.74 g, 7.74 mmol , 84%).

MS (ESI+): m/z 613 [M+H] ⁺ . AI. 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 l). Then, benzyl bromide (159 mL, 1.46 mol) was dropped into the suspension through the addition funnel and rinsed with additional acetone (20 mL). The reaction mixture was heated to reflux for 16 h. The suspension was cooled to 40-50°C and then filtered. The filtrate was concentrated under reduced pressure, and the crude material _{was recrystallized from Et 2} O to obtain the title compound (321 g, 1.33 mmol, 100%) as an off-white solid. ¹ H NMR (400 MHz, chloroform- d ) δ 7.69 (dd, 1H), 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- bromo Propan- 1 -one

Dissolve 1-(2-(benzyloxy)phenyl)propan-1-one (80.0 g, 333 mmol) in anhydrous tetrahydrofuran (420 mL), and then divide into three portions of phenyltrimethylammonium tribromide ( 131 g, 350 mmol) treatment. The resulting suspension was stirred at 20-25°C. After TLC indicated that sm was completely consumed, the suspension was filtered and the filtrate was treated with a saturated aqueous sodium bicarbonate solution. The multiple phases were separated and the aqueous phase was extracted again 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 title compound (98.7 g, 309 mmol, 93%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.60 (dd, 1H), 7.57-7.55 (m, 1H), 7.54 – 7.47 (m, 2H), 7.45 – 7.36 (m, 2H), 7.39 – 7.30 (m, 1H), 7.26 (d, 1H), 7.08-7.04 (m, 1H), 5.57 (q, 1H), 5.25 (s, 2H), 1.66 (d, 3H). UHPLC/MS (ESI): [ m/z ]: 320 [M+H] ⁺ . AK 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 into the suspension through the addition funnel and rinsed with additional acetone (10 mL). The reaction mixture was heated to reflux for 16 h. The suspension was cooled to 40-50°C and then filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by flash column chromatography to obtain the title compound (30.1 g, 124 mmol, 95%) as an off-white solid. ¹ H NMR (400 MHz, chloroform- d ) δ 10.5 (s, 1H), 7.46 – 7.32 (m, 6H), 7.11 (dd, 1H), 7.00 (d, 1H), 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-neck 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, and then ethylmagnesium bromide solution (3M, placed in Et ₂ O, 26.8 mL, 80.5 mmol) was added dropwise through the addition funnel over 20 min. The resulting suspension was stirred at 0°C. After TLC indicated that sm was completely consumed, the reaction mixture was quenched by adding saturated aqueous ammonium chloride solution. The multiple phases were separated and the aqueous phase was extracted again 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. ¹ H NMR (400 MHz, chloroform- d ) δ 7.44 – 7.30 (m, 6H), 6.94 (d, 1H), 6.87 (d, 1H), 6.74 (dd, 1H), 5.06 (s, 2H), 4.85 (t, 1H), 3.78 (s, 3H), 1.88 – 1.76 (m, 2H), 0.96 (t, 3H) ppm. UHPLC/MS (ESI): [ m/z ]: 256 [M-H2O] ⁺ . AM. 1-(2-( Benzyloxy )-5 -methoxyphenyl ) propan- 1 -one

Under an inert atmosphere, dissolve oxalic chloride (5.97 mL, 70.5 mmol) in dichloromethane (140 mL) and cool to -78 °C. Add dimethyl sulfoxide (10.0 mL, 141 mmol) dropwise. After that, the reaction mixture was stirred for 30 min, and then 1-(2-(benzyloxy)-5-methoxyphenyl)propan-1-ol ( 15.4 g, 56.4 mmol). The reaction mixture was stirred for 1 h, then trimethylamine (95 mL) was added. After that, it was heated to 20-25 °C for 16 h. After adding water, the multiple phases were separated and the aqueous phase was extracted again with ethyl acetate (3x). The combined organic phase was washed with 1N aqueous 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 obtain the title compound (14.5 g, 53.6 mmol, 95%) as a pale yellow oil. ¹ H NMR (400 MHz, chloroform- d ) δ 7.44 – 7.31 (m, 5H), 7.25 (d, 1H), 6.98 – 6.92 (m, 2H), 5.11 (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- bromoprop- 1 -one

Dissolve 1-(2-(benzyloxy)-5-methoxyphenyl)-1-propanone (14.5, 53.6 mmol) in anhydrous tetrahydrofuran (60 mL), and then divide into three phenyl groups. Treat with trimethylammonium bromide (24.4 g, 65 mmol). The resulting suspension was stirred at 20-25°C. After TLC indicated that sm was completely consumed, the suspension was filtered and treated with a saturated aqueous sodium bicarbonate solution. The multiple phases were separated and the aqueous phase was extracted again 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 title compound (8.36 g, 23.4 mmol, 44%) as a pale yellow solid. ¹ H NMR (400 MHz, chloroform- d ) δ 7.47 – 7.33 (m, 5H), 7.26 (d, 1H), 7.02 (dd, 1H), 6.96 (d, 1H), 5.54 (q, 1H), 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-neck flask, dissolve 2-benzyloxybenzaldehyde (10.6 g, 49.9 mmol) in anhydrous ether (200 mL). The solution was cooled to 0 °C, and then propylmagnesium chloride solution (2M, placed in Et ₂ O, 50 mL, 100 mmol) was added dropwise through the addition funnel over 20 min. The resulting suspension was stirred at 0°C. After TLC indicated that the starting material was completely consumed, the reaction mixture was quenched by adding saturated aqueous ammonium chloride solution. The multiple phases were separated and the aqueous phase was extracted again with 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. ¹ H NMR (400 MHz chloroform- d ) δ 7.44-7.33 (m, 6H), 7.23 (td, 1H), 7.00-6.94 (m, 2H), 5.12 8s, 2H), 4.97 (dd, 1H), 2.38 (br s, 1H), 1.87-1.73 (m, 2H), 1.55-1.31 (m, 2H), 0.93 (t, 3H) ppm. UHPLC/MS (ESI): [ m/z ]: 239 [MH ₂ O] ⁺ . AP. 1-(2-( Benzyloxy ) phenyl ) butan- 1 -one

Dissolve 1-(2-(benzyloxy)phenyl)butan-1-ol (12.3 g, 48.1 mmol) in acetone (320 mL) and cool to 0 °C. Then, it was added Jones reagent (2M, 26.5 mL, 52.9 mmol ). The reaction mixture was warmed to 20-25 °C. Continue to stir for 1 h. The reaction mixture was concentrated under reduced pressure to 1/10 of its volume, then diluted with water (300 mL), and then extracted with 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 title compound (9.15 g, 36.0 mmol, 75%) as a pale yellow oil, which crystallized on standing. ¹ H NMR (400 MHz chloroform- d ) δ 7.67 (dd, 1H), 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- bromobut- 1 -one

Dissolve 1-(2-(benzyloxy)phenyl)butan-1-one (9.15 g, 36.0 mmol) in anhydrous tetrahydrofuran (70.0 mL), and then divide into three portions of phenyltrimethylammonium tribromide ( 14.9 g, 39.6 mmol) treatment. The resulting suspension was stirred at 20-25°C. After TLC indicated that sm was completely consumed, the suspension was filtered and treated with a saturated aqueous sodium bicarbonate solution. The multiple phases were separated and the aqueous phase was extracted again 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 title compound (9.36 g, 28.1 mmol, 78%) as a pale yellow solid. ¹ H NMR (400 MHz, chloroform- d ) δ 7.72 (d, 1H), 7.51 – 7.33 (m, 6H), 7.08 – 6.99 (m, 2H), 5.33 (dd, 1H), 5.21 – 5.07 (m, 2H), 2.18 – 2.03 (m, 1H), 2.00-1.89 (m, 1H), 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-neck flask, dissolve 2-benzyloxybenzaldehyde (16.3 g, 76.9 mmol) in anhydrous ether (150 mL). The solution was cooled to 0 °C, and then the isoamyl magnesium bromide solution (2M, placed in Et ₂ O, 50 mL, 100 mmol) was added dropwise through the addition funnel over 20 min. The resulting suspension was stirred at 0°C. After TLC indicated that the starting material was completely consumed, the reaction mixture was quenched by adding saturated aqueous ammonium chloride solution. The multiple phases were separated and the aqueous phase was extracted again with 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. ¹ H NMR (400 MHz, chloroform- d ) δ 7.46 – 7.27 (m, 6H), 7.25-7.21 (m, 1H), 7.02 – 6.92 (m, 2H), 5.11 (s, 2H), 4.91 (t, 1H), 1.86-1.75 (m, 2H), 1.61-1.51 (m, 1H), 1.46 – 1.30 (m, 1H), 1.26 – 1.12 (m, 1H) 0.87 (d, 3H), 0.86 (d, 3H) ) ppm.UHPLC/MS (ESI): [ m/z ]: 267 [MH ₂ O] ⁺ . AS. 1-(2-( benzyloxy ) phenyl )-4 -methylpentan- 1 -one

Dissolve 1-(2-(benzyloxy)phenyl)-4-methylpentan-1-ol (21.2 g, 74.4 mmol) in acetone (500 mL) and cool to 0 °C. Then, it was added Jones reagent (2M, 40.9 mL, 81.8 mmol ). The reaction mixture was warmed to 20-25 °C. Continue to stir for 1 h. The reaction mixture was concentrated under reduced pressure to 1/10 of its volume, then diluted with water (300 mL), and then extracted with 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 title compound (11.2 g, 39.7 mmol, 53%) as a colorless oil. ¹ H NMR (400 MHz, chloroform- d ) δ 7.68-7.65 (m, 1H), 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

Dissolve 1-(2-(benzyloxy)phenyl)-4-methylpentan-1-one (11.2 g, 39.5 mmol) in anhydrous tetrahydrofuran (150 mL), and then divide into three phenyl groups. Treat with trimethylammonium bromide (16.3 g, 43.4 mmol). The resulting suspension was stirred at 20-25°C. After TLC indicated that sm was completely consumed, the suspension was filtered and treated with a saturated aqueous sodium bicarbonate solution. The multiple phases were separated and the aqueous phase was extracted again 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 title compound (7.63 g, 21.1 mmol, 53%) as a pale yellow solid. ¹ H NMR (400 MHz, chloroform- d ) δ 7.74 (dd, 1H), 7.51 – 7.31 (m, 6H), 7.10 – 7.00 (m, 2H), 5.46 (dd, 1H), 5.20 – 5.07 (m, 2H), 1.97-1.90 (m, 1H), 1.87-1.80 (m, 1H), 1.78 – 1.68 (m, 1H), 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

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

Suspended 2-bromophenol (30.0 g, 173 mmol), potassium carbonate (31.2 g, 225 mmol) and potassium iodide (5.76 g, 34.7 mmol) 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 cooled to 40-50°C and then filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by flash column chromatography (heptane/EtOAc) to obtain the title 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

Dissolve 1-(benzyloxy)-2-bromobenzene (17.0 g, 64.5 mmol) in dry tetrahydrofuran (100 mL). The solution was cooled to -78 °C, and then treated with n- BuLi (2.5 M in hexane, 28.3 mL, 70.8 mmol) dropwise for more than 10 min. After stirring for 1 h at -78 °C, dissolve 2-cyclopropyl-N-methoxy-N-methylacetamide ( XX , 9.24) in anhydrous tetrahydrofuran (150 mL) through the addition funnel for more than 15 minutes. g, 64.5 mmol) dropped into the reaction mixture. After stirring at -78 °C for 1 h, the reaction mixture was warmed to 20-25 °C, and then quenched by adding 1M aqueous hydrochloric acid. The multiple phases were separated and the aqueous phase was extracted with ether (3x). Dried combined organic phases were washed with brine, Na ₂ SO _4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography to obtain the title compound XX (10.5 g, 39.5 mmol, 61%) as an oil, which crystallized on standing. ¹ H NMR (400 MHz, chloroform- d ) δ 7.70 (dd, 1H), 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, 1H), 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

Dissolve 1-(2-(benzyloxy)phenyl)-2-cyclopropylethan-1-one (10.5 g, 39.5 mmol) in dry THF (50.0 mL), and then divide the phenyl group into three parts. Treat with trimethylammonium tribromide (14.9 g, 39.5 mmol). The resulting suspension was stirred at 20-25°C. After TLC indicated that sm was completely consumed, the suspension was filtered and treated with a saturated aqueous sodium bicarbonate solution. The multiple phases were separated and the aqueous phase was extracted again with ethyl acetate (2x). Dried combined organic phases were washed with brine, Na ₂ SO _4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (heptane/EtOAc) to obtain the title compound (11.9 g, 39.0 mmol, 99%) as a gray to green oil, which crystallized on standing. ¹ H NMR (400 MHz, chloroform- d ) δ 7.75 (dd, 1H), 7.52 – 7.33 (m, 6H), 7.16 – 6.84 (m, 2H), 5.22 – 5.02 (m, 2H), 4.81 (d, 1H), 1.71-1.62 (m, 1H), 0.81 – 0.61 (m, 2H), 0.24 – 0.06 (m, 2H) ppm. UHPLC/MS (ESI): [ m/z ]: 306 [M+H] ⁺ . AY. 2-( Benzyloxy ) benzamidine

Add 2-(benzyloxy)benzonitrile (5.11 g, 24.4 mmol) in small portions to lithium bis(trimethylsilyl)amide (1M, place in Et ₂ O, 50 mL, 50 mmol) Cool the solution at 0-5°C in anhydrous ether (50 mL). After that, the reaction mixture was warmed to 20-25 °C and stirred for 16 h. The reaction mixture was quenched with the addition of 3M aqueous hydrochloric acid, and diluted with ether and water. The multiple phases were separated, and the organic phase was extracted two more times with 1M aqueous hydrochloric acid. The combined aqueous phase was carefully basified 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)benzamidine (1.16 g, 5.13 mmol, 21%) was obtained as a brown solid, which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.54 – 7.42 (m, 3H), 7.43 – 7.25 (m, 4H), 7.14 (d, 1H), 7.00 – 6.92 (m, 1H), 5.15 (s , 2H) ppm. UHPLC/MS (ESI): [ m/z ]: 227 [M+H] ⁺ . AZ. 4-(( Amino (2-( benzyloxy ) phenyl ) methylene ) Amino )-2 -methoxybenzoic acid methyl ester

In a flask, mix 2-(benzyloxy)benzamidine (1.19 g, 5.16 mmol), (3-methoxy-4-(methoxycarbonyl)phenyl)-boronic acid (1.33 g, 6.31 mmol) ), copper(II) acetate monohydrate (210 mg, 1.05 mmol) and cesium pivalate (491 mg, 2.10 mmol) were suspended in dimethylformamide (21 mL). Seal the flask with a rubber stopper and keep it in contact with the surrounding atmosphere with a needle. The reaction mixture was heated to 50 °C until TLC indicated complete consumption of starting material. The reaction mixture was cooled to 20-25 °C, quenched by addition of 2M aqueous ammonium hydroxide, 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 (CH ₂ Cl ₂ /MeOH) to obtain the title compound (1.49 g, 3.82 mmol, 73%) as a light brown foam. UHPLC/MS (ESI): [ m/z ]: 391 [M+H] ⁺ . BA. 5-(( Amino (2-( benzyloxy ) phenyl ) methylene ) amino )-2 - methoxybenzoate

In a flask, mix 2-(benzyloxy)benzamidine (1.33 g, 5.88 mmol), (4-methoxy-3-(methoxycarbonyl)phenyl)-boronic acid (1.48 g, 7.05 mmol) ), copper(II) acetate monohydrate (235 mg, 1.18 mmol) and cesium pivalate (552 mg, 2.36 mmol) were suspended in dimethylformamide (24 mL). Seal the flask with a rubber stopper and keep it in contact with the surrounding atmosphere with a needle. The reaction mixture was heated to 50 °C until TLC indicated complete consumption of sm. The reaction mixture was cooled to 20-25 °C, quenched by addition of 2M aqueous ammonium hydroxide, 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 (CH ₂ Cl ₂ /MeOH) to obtain the title 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- 1H - imidazol-1-yl) -2-methoxy-benzoic acid

The 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 isopropanol (40.0 mL) and heated to reflux , Up to 16 hours. The reaction mixture was cooled to 50 °C, then it was filtered and concentrated under reduced pressure.

The crude material was dissolved in a tetrahydrofuran/water mixture (2:1, 45 mL) and treated once with lithium hydroxide (656 mg, 27.4 mmol). The reaction mixture was stirred at 20-25 °C for 16 h. After acidification with 3M aqueous hydrochloric acid to pH=2-3, 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 (CH ₂ Cl ₂ /MeOH) to obtain 4-(2,4-bis(2-(benzyloxy)phenyl)-5-methyl-1H-imidazole -1-yl)-2-methoxybenzoic acid (2.17 g, 3.64 mmol, 41%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.8 (s, 1H), 7.57 (d, 1H), 7.54 (d, 1H), 7.47-7.45 (m, 3H), 7.37-7.27 (m, 5H ), 7.26-7.22 (m, 3H), 7.19 (dd, 1H), 7.11-7.03 (m, 3H), 7.00 (td, 1H), 6.89 (d, 1H), 6.71(d, 1H), 6.64 ( dd, 1H), 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 -1H- imidazol- 1 -yl )-2- methoxybenzoic acid

The 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 isopropanol (20.0 mL) and heated to reflux , Up to 16 hours. The reaction mixture was cooled to 50 °C, then 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, 11.5 mmol) once. The reaction mixture was stirred at 20-25 °C for 16 h. . After acidification with 3M aqueous hydrochloric acid to pH=2-3, 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 (CH ₂ Cl ₂ /MeOH) to obtain 5-(2,4-bis(2-(benzyloxy)phenyl)-5-methyl-1H-imidazole -1-yl)-2-methoxybenzoic acid (720 mg, 1.21 mmol, 40%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.01 (s, 1H), 7.62 (s, 1H), 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 -1H- imidazol- 1 -yl )-2- methoxybenzoic acid

The 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) suspended in isopropanol (20.0 mL) Medium, then heated to reflux for 16 hours. The reaction mixture was cooled to 50 °C, then 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) once. The reaction mixture was stirred at 20-25 °C for 16 h. . After acidification with 3M aqueous hydrochloric acid to pH=2-3, 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 (CH ₂ Cl ₂ /MeOH) to obtain 4-(4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2- Benzyloxy)phenyl)-5-methyl-1H-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 - 1H- imidazol- 1 -yl )-2- methoxybenzoic acid

The 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) suspended in isopropanol (15.0 mL) Medium, then heated to reflux for 16 hours. The reaction mixture was cooled to 50 °C, then 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) once. The reaction mixture was stirred at 20-25 °C for 16 h. . After acidification with 3M aqueous hydrochloric acid to pH=2-3, 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 (CH ₂ Cl ₂ /MeOH) to obtain 4-(2,4-bis(2-(benzyloxy)phenyl)-5-cyclopropyl-1H- 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 - 1H- imidazol- 1 -yl )-2- methoxybenzoic acid

The 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) suspended in isopropanol (27.0 mL) Medium, then heated to reflux for 16 hours. The reaction mixture was cooled to 50 °C, then it was filtered and concentrated under reduced pressure.

The crude material was dissolved in a tetrahydrofuran/water mixture (2:1, 51 mL) and treated once with lithium hydroxide (1.00 g, 23.8 mmol). The reaction mixture was stirred at 20-25 °C for 16 h. . After acidification with 3M aqueous hydrochloric acid to pH=2-3, 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 (CH ₂ Cl ₂ /MeOH) to obtain 5-(2,4-bis(2-(benzyloxy)phenyl)-5-cyclopropyl-1H- 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- 1H - imidazol-1-yl) -2-methoxy-benzoic acid

The 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 isopropanol (15.0 mL) and heated to reflux , Up to 16 hours. The reaction mixture was cooled to 50 °C, then it was filtered and concentrated under reduced pressure.

The crude material was dissolved in a tetrahydrofuran/water mixture (2:1, 30 mL) and treated once with lithium hydroxide (321 mg, 13.4 mmol). The reaction mixture was stirred at 20-25 °C for 16 h. . After acidification with 3M aqueous hydrochloric acid to pH=2-3, 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 (CH ₂ Cl ₂ /MeOH) to obtain 4-(2,4-bis(2-(benzyloxy)phenyl)-5-ethyl-1H-imidazole -1-yl)-2-methoxybenzoic acid (700 mg, 1.15 mmol, 30%). .. UHPLC / MS (ESI) : [m / z]: 611 [M + H] + BH 4- (2,4- bis (2- (benzyloxy) phenyl) -5-isobutyl - 1H- imidazol- 1 -yl )-2- methoxybenzoic acid

The 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) suspended in isopropanol (30.0 mL) , And then heated to reflux for 16 hours. The reaction mixture was cooled to 50 °C, then 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) once. The reaction mixture was stirred at 20-25 °C for 6 h. . After acidification with 3M aqueous hydrochloric acid to pH=2-3, 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 (CH ₂ Cl ₂ /MeOH) to obtain 4-(2,4-bis(2-(benzyloxy)phenyl)-5-ethyl-1H-imidazole -1-yl)-2-methoxybenzoic acid ( XX , 890 mg, 1.39 mmol, 20%). .. UHPLC / MS (ESI) : [m / z]: 639 [M + H] + BI 5- (2,4- bis (2- (benzyloxy) phenyl) -5-isobutyl - 1H- imidazol- 1 -yl )-2- methoxybenzoic acid

The 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) suspended in isopropanol (30.0 mL) , And then heated to reflux for 16 hours. The reaction mixture was cooled to 50 °C, then 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) once. The reaction mixture was stirred at 20-25 °C for 16 h. . After acidification with 3M aqueous hydrochloric acid to pH=2-3, 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 (CH ₂ Cl ₂ /MeOH) to obtain 4-(2,4-bis(2-(benzyloxy)phenyl)-5-ethyl-1H-imidazole -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 )-1H- imidazole

Make 2-(benzyloxy)-N-(4-bromophenyl)benzamidine (24.8 g, 0.065 mol), 1-(2-(benzyloxy)- 4-Methoxyphenyl)-2-bromoethan-1-one (24.1 g, 0.072 mol) and sodium bicarbonate (10.9 g, 0.130 mol) were heated at 80°C for 12 h. The resulting mixture was filtered at 80°C, drained, and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain The title compound (24.5 g, 0.040 mol, 61%) as a beige solid. R _f (petroleum ether: ethyl acetate 5:1). 0.54 BK. 2-( benzyloxy )-N-(4- bromo- 3- fluorophenyl ) benzamidine

Add the sodium bis(trimethylsilyl)amide solution (79 mL, 0.079 mol, 1M in THF) to 4-bromo-3-fluoroaniline (10.07 g, 0.053 mol) in 400 ml THF at 0°C The solution. After stirring for 15 min, 2-(benzyloxy)benzonitrile (13.81 g, 0.066 mol) was added, and the reaction mixture was heated to 20° C. and stirred for 12 h. Saturated _{aqueous NH 4} Cl solution (200 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain the title compound as a light brown solid (15 g, 0.038 mol, 71%). R _f (petroleum ether: ethyl acetate 1:1): 0.77 BL. 2,4- bis (2-( benzyloxy ) phenyl )-1-(4- bromo- 3- fluorophenyl )-1H - imidazole

Make 2-(benzyloxy)-N-(4-bromo-3-fluorophenyl)benzamidine (9.98 g, 0.025 mol), 1-(2-(benzyl) in 400 mL of isopropanol (Oxy)phenyl)-2-bromoethan-1-one (8.54 g, 0.028 mol) and sodium bicarbonate (4.2 g, 0.050 mol) were heated at 80°C for 12 h. The resulting mixture was filtered at 80°C, drained, and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain The title compound (8.9 g, 0.015 mol, 59%) as a beige solid. R _f (petroleum ether: ethyl acetate 5:1): 0.24 BM. 2-( benzyloxy )-N-(4- bromo- 3-( trifluoromethyl ) phenyl ) benzamidine

Add bis(trimethylsilyl) amide sodium solution (63 mL, 0.063 mol, 1M in THF) to 4-bromo-3-(trifluoromethyl)aniline (10.08 g, 0.042 mol) in 400 ml A solution of THF at 0°C. After stirring for 15 min, 2-(benzyloxy)benzonitrile (10.88 g, 0.052 mol) was added, and the reaction mixture was heated to 20° C. and stirred for 12 h. Saturated _{aqueous NH 4} Cl solution (200 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column, with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain the title compound as a light brown solid (13.6 g, 0.030 mol, 72%). R _f (petroleum ether: ethyl acetate 5:1): 0.11 BN. 2,4- bis (2-( benzyloxy ) phenyl )-1-(4- bromo- 3-( trifluoromethyl ) Phenyl )-1H- imidazole

Make 2-(benzyloxy)-N-(4-bromo-3-(trifluoromethyl)phenyl)benzamidine (9 g, 0.020 mol), 1-( 2-(Benzyloxy)phenyl)-2-bromoethan-1-one (6.7 g, 0.022 mol) and sodium bicarbonate (3.7 g, 0.040 mol) were heated at 80°C for 12 h. The resulting mixture was filtered at 80°C, drained, and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain The title compound (7.9 g, 0.012 mol, 60%) as a beige solid. R _f (petroleum ether: ethyl acetate 1:1): 0.29 BO. 4-(2,4- bis (2-( benzyloxy ) phenyl )-1H- imidazol- 1 -yl )-2-( Trifluoromethyl ) benzaldehyde

P-2,4-bis(2-(benzyloxy)phenyl)-1-(4-bromo-3-(trifluoromethyl)phenyl)-1H-imidazole (8.5 g, 13.0 mmol) in Add n-butyl lithium (8.9 ml, 14.30 mmol, 1.6 M in hexane) to a solution of 200 mL THF at -75°C. After stirring at -75°C for 60 min, dimethylformamide DMF (5.6 ml, 71.5 mmol, 5.5 eq) was added, and the reaction mixture was stirred at -75°C for 1 h. The reaction mixture was then warmed to 20°C. Saturated _{aqueous NH 4} Cl (100 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 80 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain the title compound as a light brown solid (3.9 g, 6.4 mmol, 49%). R _f (petroleum ether: ethyl acetate 1:1): 0.70 BP. 4-(2,4- bis (2-( benzyloxy ) phenyl )-1H- imidazol- 1 -yl )-2-( Trifluoromethyl ) benzoic acid

4-(2,4-bis(2-(benzyloxy)phenyl)-1H-imidazol-1-yl)-2-(trifluoromethyl)benzaldehyde (4 g, 6.62 mmol) A solution of 100 ml of acetone was added to Jones reagent (4.2 ml, 2 M CrO ₃ , placed in H ₂ SO ₄ aqueous solution), and the resulting mixture was stirred at 20° C. for 45 min. After the acetone was drained, ethyl acetate (100 ml) was added, and the mixture was _{washed with a saturated aqueous NaHCO 3} solution (2×120 ml), dried with Na ₂ SO ₄ , filtered, and drained. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 25% methanol in dichloromethane) to obtain the title compound as a white solid (3.33 g, 5.35 mmol , 81%). R _f (petroleum ether: ethyl acetate 1:1): 0.32 BQ. 2-( benzyloxy )-N-(4- bromophenyl )-5- methoxybenzamidine

Add bis(trimethylsilyl) amide sodium solution (45 mL, 0.045 mol, 1M in THF) to 4-bromoaniline (7.5 g, 0.044 mol) in 300 ml THF at 0°C. After stirring for 15 min, 2-(benzyloxy)-5-methoxybenzonitrile (7 g, 0.029 mol) was added, and the reaction mixture was heated to 20° C. and stirred for 12 h. Saturated _{aqueous NH 4} Cl solution (200 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain the title compound as a light brown solid (12.7 g, 0.031 mol, 71%). R _f (petroleum ether: ethyl acetate 1:1): 0.22 BR. 2-( benzyloxy )-N-(3- bromo -5-( trifluoromethyl ) phenyl ) benzamidine

Add bis(trimethylsilyl) amide sodium solution (63 mL, 0.063 mol, 1M in THF) to 3-bromo-5-(trifluoromethyl)aniline (10 g, 0.042 mol) in 400 ml A solution of THF at 0°C. After stirring for 15 min, 2-(benzyloxy)benzonitrile (11 g, 0.053 mol) was added, and the reaction mixture was heated to 20° C. and stirred for 12 h. Saturated _{aqueous NH 4} Cl solution (200 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain the title compound as a light brown solid (13.9 g, 0.031 mol, 74%). R _f (petroleum ether: ethyl acetate 1:1): 0.16 BS. 2,4- bis (2-( benzyloxy ) phenyl )-1-(3- bromo -5-( trifluoromethyl ) Phenyl )-1H- imidazole

Make 2-(benzyloxy)-N-(3-bromo-5-(trifluoromethyl)phenyl)benzamidine (6 g, 0.013 mol), 1-( 2-(Benzyloxy)phenyl)-2-bromoethan-1-one (4.4 g, 0.015 mol) and sodium bicarbonate (2.3 g, 0.027 mol) were heated at 80°C for 12 h. The resulting mixture was filtered at 80°C, drained, and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain The title compound (5.7 g, 8.7 mmol, 65%) as a beige solid. R _f (petroleum ether: ethyl acetate 1:1): 0.6 BT. 3-(2,4- bis (2-( benzyloxy ) phenyl )-1H- imidazol- 1 -yl )-5-( Trifluoromethyl ) benzaldehyde

P-2,4-bis(2-(benzyloxy)phenyl)-1-(3-bromo-5-(trifluoromethyl)phenyl)-1H-imidazole (2.2 g, 3.4 mmol) in Add n-butyl lithium (2.3 ml, 3.7 mmol, 1.6 M in hexane) to a solution of 120 mL THF at -75°C. After stirring at -75°C for 60 min, dimethylformamide DMF (1.5 ml, 18.6 mmol, 5.5 eq) was added, and the reaction mixture was stirred at -75°C for 1 h. The reaction mixture was then warmed to 20°C. Saturated _{aqueous NH 4} Cl (100 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 80 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column, with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain the title compound as a light brown solid (1.08 g, 1.8 mmol, 53%). R _f (petroleum ether: ethyl acetate 1:1): 0.62 BV. 3-(2,4- bis (2-( benzyloxy ) phenyl )-1H- imidazol- 1 -yl )-5-( Trifluoromethyl ) benzoic acid

P-3-(2,4-bis(2-(benzyloxy)phenyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)benzaldehyde (0.8 g, 1.32 mmol) A solution of 50 ml of acetone was added to Jones reagent (0.9 ml, 2 M CrO ₃ in H ₂ SO ₄ aqueous solution), and the resulting mixture was stirred at 20° C. for 45 min. After the acetone was drained, ethyl acetate (100 ml) was added, and the mixture was _{washed with a saturated aqueous NaHCO 3} solution (2×120 ml), dried with Na ₂ SO ₄ , filtered, and drained. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 25% methanol in dichloromethane) to obtain the title compound as a white solid (0.71 g, 1.14 mmol , 86%). R _f (petroleum ether: ethyl acetate 1:1): 0.16 BW. 2-( benzyloxy )-N-(3- bromo- 4- fluorophenyl ) benzamidine

Add bis(trimethylsilyl) amide sodium solution (79 mL, 0.079 mol, 1M in THF) to 3-bromo-4-fluoroaniline (10.07 g, 0.053 mol) in 400 ml THF at 0°C The solution. After stirring for 15 min, 2-(benzyloxy)benzonitrile (13.81 g, 0.066 mol) was added, and the reaction mixture was heated to 20° C. and stirred for 12 h. Saturated _{aqueous NH 4} Cl solution (200 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column, with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain the title compound as a light brown solid (21.2 g, 0.053 mol, 78%). R _f (petroleum ether: ethyl acetate 5:1): 0.11 BX. 2,4- bis (2-( benzyloxy ) phenyl )-1-(3- bromo- 4- fluorophenyl )-1H - imidazole

Make 2-(benzyloxy)-N-(3-bromo-4-fluorophenyl)benzamidine (9.98 g, 0.025 mol), 1-(2-(benzyl) in 400 mL of isopropanol (Oxy)phenyl)-2-bromoethan-1-one (8.39 g, 0.028 mol) and sodium bicarbonate (4.2 g, 0.050 mol) were heated at 80°C for 12 h. The resulting mixture was filtered at 80°C, drained, and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain The title compound (10.9 g, 0.018 mol, 72%) as a beige solid. R _f (petroleum ether: ethyl acetate 5:1): 0.3 BY. 5-(2,4- bis (2-( benzyloxy ) phenyl )-1H- imidazol- 1 -yl )-2- fluoro Benzaldehyde

P-2,4-bis(2-(benzyloxy)phenyl)-1-(3-bromo-4-fluorophenyl)-1H-imidazole (10 g, 16.6 mmol) in 150 mL THF in- Add n-butyl lithium (11.4 ml, 18.2 mmol, 1.6 M in hexane) to the 75°C solution. After stirring at -75°C for 60 min, dimethylformamide DMF (7.1 ml, 91.2 mmol, 5.5 eq) was added, and the reaction mixture was stirred at -75°C for 1 h. The reaction mixture was then warmed to 20°C. Saturated _{aqueous NH 4} Cl (100 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 80 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain the title compound as a light brown solid (5.2 g, 9.25 mmol, 56%). R _f (petroleum ether: ethyl acetate 1:1): 0.44 BZ. 5-(2,4- bis (2-( benzyloxy ) phenyl )-1H- imidazol- 1 -yl )-2- fluoro benzoic acid

A solution of 5-(2,4-bis(2-(benzyloxy)phenyl)-1H-imidazol-1-yl)-2-fluorobenzaldehyde (5.77 g, 10.40 mmol) in 100 ml acetone Jones reagent (6.5 ml, 2 M CrO ₃ , placed in H ₂ SO ₄ aqueous solution) was added, and the resulting mixture was stirred at 20° C. for 45 min. After the acetone was drained, ethyl acetate (100 ml) was added, and the mixture was _{washed with a saturated aqueous NaHCO 3} solution (2×120 ml), dried with Na ₂ SO ₄ , filtered, and drained. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 25% methanol in dichloromethane) to obtain the title compound as a white solid (4.8 g, 8.43 mmol , 81%). R _f (petroleum ether: ethyl acetate 1:1): 0.16 CA. 4-(2-( benzyloxy )-5 -methoxyphenyl )-2-(2-( benzyloxy ) benzene Yl )-1-(4- bromo- 3-( trifluoromethyl ) phenyl )-1H- imidazole

Make 2-(benzyloxy)-N-(4-bromo-3-(trifluoromethyl)phenyl)benzamidine (9 g, 0.020 mol), 1-( 2-(Benzyloxy)-5-methoxyphenyl)-2-bromoethane-1-one (7.37 g, 0.022 mol) and sodium bicarbonate (3.7 g, 0.040 mol) heated at 80°C for 12 h. The resulting mixture was filtered at 80°C, drained, and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain The title compound (10.72 g, 0.016 mol, 78%) as a beige solid. R _f (petroleum ether: ethyl acetate 5:1): 0.38 CB. 4-(4-(2-( benzyloxy )-5 -methoxyphenyl )-2-(2-( benzyloxy) (Yl ) phenyl )-1H- imidazol- 1 -yl )-2-( trifluoromethyl ) benzaldehyde

4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1-(4-bromo-3-(trifluoromethane) (Yl)phenyl)-1H-imidazole (8.1 g, 11.83 mmol) in 150 mL of THF at -75°C was added n-butyllithium (8.1 ml, 13.01 mmol, 1.6 M in hexane). After stirring at -75°C for 60 min, dimethylformamide DMF (5.1 ml, 65.1 mmol, 5.5 eq) was added, and the reaction mixture was stirred at -75°C for 1 h. The reaction mixture was then warmed to 20°C. Saturated _{aqueous NH 4} Cl (100 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 80 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column, with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain the title compound as a light brown solid (4.43 g, 6.97 mmol, 59%). R _f (petroleum ether: ethyl acetate 1:1): 0.48 CC. 4-(4-(2-( benzyloxy )-5 -methoxyphenyl )-2-(2-( benzyloxy) (Yl ) phenyl )-1H- imidazol- 1 -yl )-2-( trifluoromethyl ) benzoic acid

4-(4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-(benzyloxy)phenyl)-1H-imidazol-1-yl)-2 -(Trifluoromethyl)benzaldehyde (2 g, 3.15 mmol) in 100 ml of acetone was added to Jones reagent (2 ml, 2 M CrO ₃ in H ₂ SO ₄ aqueous solution), and the resulting mixture was heated at 20 Stir at ℃ for 45 min. After the acetone was drained, ethyl acetate (100 ml) was added, and the mixture was _{washed with a saturated aqueous NaHCO 3} solution (2×120 ml), dried with Na ₂ SO ₄ , filtered, and drained. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 25% methanol in dichloromethane) to obtain the title compound as a white solid (2.1 g, 3.15 mmol , 86%). R _f (petroleum ether: ethyl acetate 1:1): 0.14 CE. 2-( benzyloxy )-N-(3- bromo- 4-(2-(2 -methoxyethoxy ) ethoxy (Yl ) phenyl ) benzamidine

Add bis(trimethylsilyl) amide sodium solution (26 mL, 0.026 mol, 1M in THF) to 3-bromo-4-(2-(2-methoxyethoxy)ethoxy)aniline (5 g, 0.017 mol) in a solution of 120 ml THF at 0°C. After stirring for 15 min, 2-(benzyloxy)benzonitrile (5.4 g, 0.026 mol) was added, and the reaction mixture was heated to 20° C. and stirred for 12 h. Saturated _{aqueous NH 4} Cl solution (200 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain the title compound as a light brown solid (6.97 g, 0.014 mol, 81%). R _f (petroleum ether: ethyl acetate 5:1): 0.13 CF. 2,4- bis (2-( benzyloxy ) phenyl )-1-(3- bromo- 4-(2-(2- (Methoxyethoxy ) ethoxy ) phenyl )-1H- imidazole

Make 2-(benzyloxy)-N-(3-bromo-4-(2-(2-methoxyethoxy)ethoxy)phenyl)benzamidine in 150 mL isopropanol (8.1 g, 0.016 mol), 1-(2-(benzyloxy)phenyl)-2-bromoethane-1-one (8.39 g, 0.028 mol) and sodium bicarbonate (5.5 g, 0.018 mol) in Heat at 80°C for 12 h. The resulting mixture was filtered at 80°C, drained, and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain The title compound (9.4 g, 0.0133 mol, 82%) as a beige solid. R _f (petroleum ether: ethyl acetate 5:1): 0.39 CG. 5-(2,4- bis (2-( benzyloxy ) phenyl )-1H- imidazol- 1 -yl )-2-( 2-(2 -Methoxyethoxy ) ethoxy ) benzaldehyde

2,4-Bis(2-(benzyloxy)phenyl)-1-(3-bromo-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-1H -Imidazole (4.8 g, 6.8 mmol) in 100 mL THF at -75°C was added with n-butyl lithium (4.7 ml, 7.5 mmol, 1.6 M in hexane). After stirring at -75°C for 60 min, dimethylformamide DMF (3 ml, 37.4 mmol, 5.5 eq) was added, and the reaction mixture was stirred at -75°C for 1 h. The reaction mixture was then warmed to 20°C. Saturated _{aqueous NH 4} Cl (100 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 80 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column, with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain the title compound as a light brown solid (2.9 g, 4.42 mmol, 65%). R _f (petroleum ether: ethyl acetate 1:1): 0.4 CH. 5-(2,4- bis (2-( benzyloxy ) phenyl )-1H- imidazol- 1 -yl )-2-( 2-(2 -Methoxyethoxy ) ethoxy ) benzoic acid

P-5-(2,4-bis(2-(benzyloxy)phenyl)-1H-imidazol-1-yl)-2-(2-(2-methoxyethoxy)ethoxy) A solution of benzaldehyde (2.8 g, 4.28 mmol) in 100 ml of acetone was added to Jones reagent (2.7 ml, 2 M CrO ₃ in H ₂ SO ₄ aqueous solution), and the resulting mixture was stirred at 20° C. for 45 min. After the acetone was drained, ethyl acetate (100 ml) was added, and the mixture was _{washed with a saturated aqueous NaHCO 3} solution (2×120 ml), dried with Na ₂ SO ₄ , filtered, and drained. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 25% methanol in dichloromethane) to obtain the title compound as a white solid (2.64 g, 3.93 mmol , 92%). R _f (petroleum ether: ethyl acetate 1:1): 0.22 CI. 2-( benzyloxy )-N-(3- bromo- 4-(2 -methoxyethoxy ) phenyl ) benzyl Amidine

Add sodium bis(trimethylsilyl)amide solution (31 mL, 0.031 mol, 1M in THF) to 3-bromo-4-(2-methoxyethoxy)aniline (5 g, 0.020 mol) Place a solution of 150 ml THF at 0°C. After stirring for 15 min, 2-(benzyloxy)benzonitrile (6.4 g, 0.030 mol) was added, and the reaction mixture was heated to 20° C. and stirred for 12 h. Saturated _{aqueous NH 4} Cl solution (200 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain the title compound as a light brown solid (8.3 g, 0.018 mol, 89%). R _f (petroleum ether: ethyl acetate 5:1): 0.15 CJ. 2,4- bis (2-( benzyloxy ) phenyl )-1-(3- bromo- 4-(2 -methoxy) (Ethoxy ) phenyl )-1H- imidazole

Make 2-(benzyloxy)-N-(3-bromo-4-(2-methoxyethoxy)phenyl) benzamidine (4.9 g, 0.011 mol) placed in 150 mL of isopropanol , 1-(2-(benzyloxy)phenyl)-2-bromoethane-1-one (3.6 g, 0.012 mol) and sodium bicarbonate (1.8 g, 0.022 mol) were heated at 80°C for 12 h. The resulting mixture was filtered at 80°C, drained, and the crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain The title compound (6.3 g, 9.5 mmol, 88%) as a beige solid. R _f (petroleum ether: ethyl acetate 5:1): 0.45 CK. 5-(2,4- bis (2-( benzyloxy ) phenyl )-1H- imidazol- 1 -yl )-2-( 2 -methoxyethoxy ) benzaldehyde

2,4-Bis(2-(benzyloxy)phenyl)-1-(3-bromo-4-(2-methoxyethoxy)phenyl)-1H-imidazole (3.7 g, 5.6 Add n-butyl lithium (3.8 ml, 6.1 mmol, 1.6 M in hexane) to a solution in 100 mL THF at -75°C. After stirring at -75°C for 60 min, dimethylformamide DMF (2.4 ml, 30.8 mmol, 5.5 eq) was added, and the reaction mixture was stirred at -75°C for 1 h. The reaction mixture was then warmed to 20°C. Saturated _{aqueous NH 4} Cl (100 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 80 ml). The combined organic phases were dried over Na ₂ SO _4, filtered and sucked dry. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column, with a gradient of 0 to 100% ethyl acetate in petroleum ether) to obtain the title compound as a light brown solid (2.42 g, 3.97 mmol, 71%). R _f (petroleum ether: ethyl acetate 1:1): 0.27 CL. 5-(2,4- bis (2-( benzyloxy ) phenyl )-1H- imidazol- 1 -yl )-2-( 2 -methoxyethoxy ) benzoic acid

P-5-(2,4-Bis(2-(benzyloxy)phenyl)-1H-imidazol-1-yl)-2-(2-methoxyethoxy)benzaldehyde (2.1 g, 3.44 Add Jones reagent (2.2 ml, 2 M CrO ₃ in H ₂ SO ₄ aqueous solution) in 100 ml acetone solution, and stir the resulting mixture at 20° C. for 45 min. After the acetone was drained, ethyl acetate (100 ml) was added, and the mixture was _{washed with a saturated aqueous NaHCO 3} solution (2×120 ml), dried with Na ₂ SO ₄ , filtered, and drained. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 25% methanol in dichloromethane) to obtain the title compound as a white solid (2.03 g, 3.23 mmol , 94%). R _f (petroleum ether: ethyl acetate 1:1): 0.18 Final Example Compound 1. Example Compound No. 01 : 4-(2,4- bis (2- hydroxyphenyl )-1H- imidazole- 1- Base ) benzoic acid

4-(2,4-bis(2-(benzyloxy)phenyl)-1H-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 H ₂ gas was passed through the resulting mixture with stirring at 20° C. for 3 hours. The reaction was then allowed to stir at 20°C for 12 h. The mixture was flushed with nitrogen, filtered and drained. The crude product was purified by flash column chromatography (using a 100 g SNAP Ultra column with a gradient of 0 to 25% methanol in dichloromethane) to obtain the title compound as a white solid (0.68 g, 1.83 mmol , 78%).

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

MS (ESI+): m/z 373 [M+H] ⁺ . 2. Example compound No. 03 : 4-(2,4- bis (2- hydroxyphenyl )-1H- imidazol- 1 -yl )- 2 -methoxybenzoic acid

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

¹ H NMR (400 MHz, DMSO): δ 12.7 (s, 1H), 11.3 (s, 1H), 10.6 (s, 1H), 8.11 (s, 1H), 7.82 (m, 1H), 7.67 (m, 1H), 7.3 (m, 2H), 7.1 (m, 2H), 7.0 (m, 1H), 6.85 (m, 4H), 3.7 (s, 3H). 3. Example compound number. 09 : 3-( 2,4- Bis (2- hydroxyphenyl )-1H- imidazol- 1 -yl )-5- methoxybenzoic acid

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

¹ H NMR (400 MHz, DMSO): δ 12.9 (s, 1H), 11.4 (s, 1H), 10.6 (s, 1H), 8.1 (s, 1H), 7.83 (m, 1H), 7.46 (m, 2H), 7.24 (m, 2H), 7.19 (m, 1H), 7.1 (m, 1H), 6.85 (m, 4H), 3.7 (s, 3H). 4. Example compound No. 05 : 4-( 4-(2- hydroxy- 4 -methoxyphenyl )-2-(2- hydroxyphenyl )-1H- imidazol- 1 -yl ) benzoic acid

Under nitrogen, 4-(4-(2-(benzyloxy)-4-methoxyphenyl-2-(2-(benzyloxy)phenyl)-1H-imidazol-1-yl) Benzoic acid (0.8 g, 1.37 mmol) was dissolved in methanol (900 ml). Then palladium (80 mg, 10 wt.% on carbon) was added and H ₂ gas was passed through the mixture with stirring at 20° C. for 3 hours. Then the reaction was allowed to proceed. Stir at 20°C for 12 h. The mixture was flushed with nitrogen, filtered, and drained. The crude product was subjected to flash column chromatography (using 100 g SNAP Ultra column with a gradient of 0 to 25% methanol in dichloromethane). Extraction) and purification to obtain the title compound (0.43 g, 1.06 mmol, 77%) as a white solid.

¹ H NMR (400 MHz, DMSO): δ 13.1 (s, 1H), 11.4 (s, 1H), 10.5 (s, 1H), 8.0 (m, 3H), 7.7 (m, 1H), 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 embodiment: 4- (4- (2-hydroxy - 5 -methoxyphenyl )-2-(2- hydroxyphenyl )-1H- imidazol- 1 -yl ) benzoic acid

Under nitrogen, 4-(4-(2-(benzyloxy)-5-methoxyphenyl-2-(2-(benzyloxy)phenyl)-1H-imidazol-1-yl) Benzoic acid (1.4 g, 2.35 mmol) was dissolved in methanol (900 ml). Then palladium (140 mg, 10 wt.% on carbon) was added and H ₂ gas was passed through the mixture with stirring at 20° C. for 3 hours. Then the reaction was allowed to proceed. Stir for 12 h at 20°C. The mixture was flushed with nitrogen, filtered, and drained. The crude product was subjected to flash column chromatography (using 100 g SNAP Ultra column with a gradient of 0-25% methanol in dichloromethane Extraction) and purification to obtain the title compound (0.73 g, 1.83 mmol, 76%) as a white solid.

¹ H NMR (400 MHz, DMSO): δ 13.1 (s, 1H), 11.8 (s, 1H), 10.3 (s, 1H), 8.1 (s, 1H), 7.9 (m, 2H), 7.4 (m, 3H), 7.2 (m, 2H), 6.8 (m, 2H), 6.7 (m, 1H), 3.7 (s, 3H). 6. Example compound number. 07 : 5-(2,4- bis (2 - hydroxyphenyl) lH-imidazol-1-yl) -2-methoxy-benzoic acid

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

¹ H NMR (400 MHz, DMSO): δ 13.1 (s, 1H), 11.2 (s, 1H), 10.6 (s, 1H), 7.9 (s, 1H), 7.8 (m, 1H), 7.6 (m, 1H), 7.5 (m, 1H), 7.2 (m, 4H), 6.9 (m, 3H), 6.7 (m, 1H), 3.8 (s, 3H). 7. Example compound number. 12 : 4-( 2,4- Bis (2- hydroxyphenyl )-1H- imidazol- 1 -yl )-2- fluorobenzoic acid

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

¹ H NMR (400 MHz, DMSO): δ 13.4 (s, 1H), 11.2 (s, 1H), 10.2 (s, 1H), 8.1 (s, 1H), 7.9 (m, 2H), 7.3 (m, 4H), 7.1 (m, 1H), 6.9 (m, 4H). 8. Example compound number. 14 : 4-(2,4- bis (2- hydroxyphenyl )-1H- imidazol- 1 -yl ) -2-( Trifluoromethyl ) benzoic acid

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

¹ H NMR (400 MHz, DMSO): δ 13.7 (s, 1H), 11.3 (s, 1H), 10.1 (s, 1H), 8.2 (s, 1H), 7.9 (m, 2H), 7.8 (m, 1H), 7.7 (m, 1H), 7.4 (m, 1H), 7.3 (m, 1H), 7.1 (m, 1H), 6.9 (m, 3H), 6.8 (m, 1H). 9. Example compounds No. 18 : 4-(2,4- bis (2- hydroxy -5 -methoxyphenyl )-1H- imidazol- 1 -yl ) benzoic acid

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

¹ H NMR (400 MHz, DMSO): δ 13.1 (s, 1H), 10.7 (s, 1H), 10.5 (s, 1H), 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 )-1H- imidazol- 1 -yl ) -4 -Methoxybenzoic acid

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

¹ H NMR (400 MHz, DMSO): δ 13.1 (s, 1H), 11.8 (s, 1H), 11.0 (s, 1H), 8.1 (m, 1H), 7.9 (m, 1H), 7.8 (m, 2H), 7.3 (m, 1H), 7.2 (m, 2H), 6.9 (m, 4H), 6.7 (m, 1H), 3.7 (s, 3H).

MS (ESI+): m/z 403 [M+H] ⁺ . 11. Example compound No. 32 : 5-(4-(2- hydroxy -5 -methoxyphenyl )-2-(2- hydroxy (Phenyl )-1H- imidazol- 1 -yl )-2- methoxybenzoic acid

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

¹ H NMR (400 MHz, DMSO): δ 13.1 (s, 1H), 10.8 (s, 1H), 10.4 (s, 1H), 8.0 (s, 1H), 7.7 (m, 1H), 7.5 (m, 1H), 7.4 (m, 1H), 7.2 (m, 3H), 6.8 (m, 4H), 3.8 (s, 3H), 3.7 (s, 3H). 12. Example compound number. 15 : 3-( 2,4- Bis (2- hydroxyphenyl )-1H- imidazol- 1 -yl )-5-( trifluoromethyl ) benzoic acid

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

¹ H NMR (400 MHz, DMSO): δ 13.6 (s, 1H), 11.4 (s, 1H), 10.1 (s, 1H), 8.3 (s, 1H), 8.2 (m, 2H), 7.9 (s, 1H), 7.8 (m, 1H), 7.4 (m, 1H), 7.3 (m, 1H), 7.1 (m, 1H), 6.9 (m, 3H), 6.3 (m, 1H). 13. Example compounds No. 16 : 5-(2,4- bis (2- hydroxyphenyl )-1H- imidazol- 1 -yl )-2- fluorobenzoic acid

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

¹ H NMR (400 MHz, DMSO): δ 13.2 (s, 1H), 11.1 (s, 1H), 10.2 (s, 1H), 8.2 (s, 1H), 8.0 (m, 2H), 7.7 (m, 1H), 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 )-1H- imidazol- 1 -yl )-2-( trifluoromethyl ) benzoic acid

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

¹ H NMR (400 MHz, DMSO): δ 13.8 (s, 1H), 10.9 (s, 1H), 10.1 (s, 1H), 8.3 (s, 1H), 7.9 (m, 1H), 7.8 (s, 1H), 7.7 (m, 1H), 7.4 (m, 2H), 7.3 (m, 1H), 6.9 (m, 1H), 6.8 (m, 3H), 3.7 (s, 3H). 15. Example compounds No. 43 : 5-(2,4- bis (2- hydroxyphenyl )-1H- imidazol- 1 -yl )-2-(2-(2 -methoxyethoxy ) ethoxy ) benzoic acid

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

¹ H NMR (400 MHz, DMSO): δ 12.8 (s, 1H), 11.3 (s, 1H), 10.9 (s, 1H), 8.0 (s, 1H), 7.8 (m, 1H), 7.7 (m, 1H), 7.5 (m, 1H), 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 )-1H- imidazol- 1 -yl )-2-(2 -methoxy Ethoxy ) benzoic acid

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

¹ H NMR (400 MHz, DMSO): δ 12.6 (s, 1H), 11.5 (s, 1H), 11.1 (s, 1H), 8.0 (s, 1H), 7.7 (m, 1H), 7.6 (m, 1H), 7.4 (m, 1H), 7.2 (m, 2H), 7.1 (m, 2H), 6.9 (m, 3H), 6.8 (m, 1H), 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 -1H- imidazol- 1 -yl )-2- Methoxybenzoic acid

Add 5-(2,4-bis(2-(benzyloxy)phenyl)-5-methyl-1H-imidazol-1-yl)-2-methoxybenzoic acid (2.76 g, 4.62 mmol) Dissolve in ethanol (20 mL) and degas the resulting solution for 15 min using a stream of nitrogen. Add palladium on charcoal (10%-w/w, 280 mg) to the solution, and switch the nitrogen stream to a hydrogen stream. After TLC indicated that sm was completely consumed, the reaction mixture was extracted with ethanol and filtered through a short pad of celite. The filtrate was concentrated under reduced pressure, and the resulting crude material was purified by flash column chromatography (heptane/THF) to obtain the title compound (1.43 mg, 3.43 mmol, 74%) as an off-white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.4 (br s, 2H), 7.71 (d, 1H), 7.48 (dd, 1H), 7.22 – 7.12 (m, 3H), 7.01-6.97 (m, 2H), 6.94 – 6.88 (m, 2H), 6.87 – 6.80 (m, 1H), 6.69 (m, 1H), 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 -1H- imidazol- 1 -yl )-2- methoxybenzoic acid

Add 5-(2,4-bis(2-(benzyloxy)phenyl)-5-methyl-1H-imidazol-1-yl)-2-methoxybenzoic acid (720 mg, 1.21 mmol) Dissolve in ethanol (24 mL) and degas the resulting solution for 15 min using a stream of nitrogen. Add palladium on charcoal (10%-w/w, 72 mg) to the solution, and switch the nitrogen stream to a hydrogen stream. After TLC indicated that sm was completely consumed, the reaction mixture was extracted with ethanol and filtered through a short pad of celite. The filtrate was concentrated under reduced pressure, and the resulting crude material was purified by flash column chromatography (CH ₂ Cl ₂ /MeOH) to obtain the title compound (350 mg, 840 umol, 69%) as an off-white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.8 (br s, 1H), 10.9 (br s, 1-2H), 7.71 (d, 1H), 7.61 (dd, 1H), 7.43 (dd, 1H) ), 7.32 – 7.20 (m, 4H), 7.04 (d, 1H), 6.95 (t, 1H), 6.90 (d, 1H), 6.80 (t, 1H), 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 -methoxybenzene) Yl )-2-(2 -hydroxyphenyl )-5- methyl -1H- imidazol- 1 -yl )-2- methoxybenzoic acid

The 4-(4-(2-(benzyloxy)-5-methoxyphenyl)-2-(2-benzyloxy)phenyl)-5-methyl-1H-imidazole-1- Di)-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. Add palladium on charcoal (10%-w/w, 134 mg) to the solution, and switch the nitrogen stream to a hydrogen stream. After TLC indicated that sm was completely consumed, the reaction mixture was extracted with ethanol and filtered through a short pad of celite. The filtrate was concentrated under reduced pressure, and the resulting crude material was purified by flash column chromatography (CH ₂ Cl ₂ /MeOH) to obtain the title compound (500 mg, 1.12 mmol, 52%) as an off-white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.73 (d, 1H), 7.24 – 7.13 (m, 2H), 7.04 – 6.96 (m, 3H), 6.89 – 6.81 (m, 2H), 6.79 (dd , 1H), 6.73-6.69 (m, 1H), 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- methoxy Benzoic acid

Add 4-(2,4-bis(2-(benzyloxy)phenyl)-5-cyclopropyl-1H-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 stream of nitrogen. Add palladium on charcoal (10%-w/w, 85 mg) to the solution, and switch the nitrogen stream to a hydrogen stream. After TLC indicated that sm was completely consumed, the reaction mixture was extracted with methanol and filtered through a short pad of celite. The filtrate was concentrated under reduced pressure, and the resulting crude material was purified by flash column chromatography (CH ₂ Cl ₂ /MeOH) to obtain the title compound (270 mg, 610 umol, 45%) as an off-white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.78 (dd, 1H), 7.67 (d, 1H), 7.24 – 7.07 (m, 4H), 7.00 (dd, 1H), 6.95 – 6.84 (m, 2H ), 6.83 – 6.71 (m, 2H), 3.68 (s, 3H), 2.08-2.01 (m, 1H), 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-methoxy-benzoic acid

Add 5-(2,4-bis(2-(benzyloxy)phenyl)-5-cyclopropyl-1H-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 stream of nitrogen. Add palladium on charcoal (10%-w/w, 161 mg) to the solution, and switch the nitrogen flow to a hydrogen flow. After TLC indicated that sm was completely consumed, the reaction mixture was extracted with methanol and filtered through a short pad of celite. The filtrate was concentrated under reduced pressure, and the resulting crude material was purified by flash column chromatography (CH ₂ Cl ₂ /MeOH) to obtain the title compound (940 mg, 2.12 mmol, 82%) as an off-white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.76 – 7.71 (m, 1H), 7.66 – 7.53 (m, 2H), 7.29 – 7.12 (m, 4H), 7.00 – 6.88 (m, 2H), 6.85 (d, 1H), 6.78 (t, 1H), 3.84 (s, 3H), 1.86-1.79 (m, 1H), 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 )-1H - imidazol-1-yl) -2-methoxy-benzoic acid

Add 4-(2,4-bis(2-(benzyloxy)phenyl)-5-ethyl-1H-imidazol-1-yl)-2-methoxybenzoic acid (700 mg, 1.15 mmol) Dissolve in methanol (50 mL) and degas the resulting solution for 15 min using a stream of nitrogen. Add palladium on charcoal (10%-w/w, 85 mg) to the solution, and switch the nitrogen stream to a hydrogen stream. After TLC indicated that sm was completely consumed, the reaction mixture was extracted with methanol and filtered through a short pad of celite. The filtrate was concentrated under reduced pressure, and the resulting crude material was purified by flash column chromatography (CH ₂ Cl ₂ /MeOH) to obtain the title compound (273 mg, 634 umol, 55%) as an off-white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.73 (d, 1H), 7.47 (dd, 1H), 7.25 (d, 1H), 7.20-7.14 (m, 2H), 7.04 (dd, 1H), 6.99 (dd, 1H), 6.92 (d, 2H), 6.84 (dd, 1H), 6.71-6.67 (m, 1H), 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- 1H- imidazol- 1 -yl )-2- methoxybenzoic acid

Add 4-(2,4-bis(2-(benzyloxy)phenyl)-5-isobutyl-1H-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 stream of nitrogen. Add palladium on charcoal (10%-w/w, 90 mg) to the solution, and switch the nitrogen flow to hydrogen flow. After TLC indicated that sm was completely consumed, the reaction mixture was extracted with methanol and filtered through a short pad of celite. The filtrate was concentrated under reduced pressure, and the resulting crude material was purified by flash column chromatography (CH ₂ Cl ₂ /MeOH) to obtain the title compound (400 mg, 872 umol, 63%) as an off-white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.75 (d, 1H), 7.48 (dd, 1H), 7.23 (d, 1H), 7.19-7.13 (m, 2H), 7.00 (dd, 1H), 6.93 – 6.86 (m, 3H), 6.84 (dd, 1H), 6.65 (td, 1H), 3.75 (s, 3H), 2.60 (d, 2H), 1.50 (hept, 1H), 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- 1H- imidazol- 1 -yl )-2- methoxybenzoic acid

Add 5-(2,4-bis(2-(benzyloxy)phenyl)-5-isobutyl-1H-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 stream of nitrogen. Add palladium on charcoal (10%-w/w, 100 mg) to the solution, and switch the nitrogen stream to a hydrogen stream. After TLC indicated that sm was completely consumed, the reaction mixture was extracted with methanol and filtered through a short pad of celite. The filtrate was concentrated under reduced pressure, and the resulting crude material was purified by flash column chromatography (CH ₂ Cl ₂ /MeOH) to obtain the title compound (530 mg, 1.16 mmol, 75%) as an off-white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.63 (d, 1H), 7.54 (dd, 1H), 7.47 (dd, 1H), 7.26 (d,1H), 7.18-7.12 (m,2H), 6.94 – 6.86 (m, 3H), 6.83 (dd, 1H), 6.64 (t, 1H), 3.88 (s, 3H), 2.52 (d, 2H), 1.50 (hept, 1H), 0.61 (d, 6H) ppm. UHPLC/MS (ESI): [ m/z ]: 459 [M+H] ⁺ . II. Physical and chemical test II-I. pM / pFe value - potentiometer titration test

比較配位體：        地拉羅司(Exjade®)pM 值係用於測定相較於金屬元素Cu²⁺ 、Zn²⁺ 、Ni²⁺ 、Mg²⁺ 、Ca²⁺ 作為水溶性NO₃ 鹽的選擇性。所有使用的溶液皆為置於HNO₃ 的2%標準溶液(金屬元素的水溶性鹽) 滴定儀器The determination of complex activity, stability and selectivity can be determined by potentiometric titration and evaluation of the dissociation constant formed by the complex. Method A) - measured value of the test compound pM ligand: Example Compound No. embodiments .40

Comparing ligands: Exjade® pM value is used to determine the water-soluble NO ₃ salt ^{compared to the metal elements Cu 2+} , Zn ²⁺ , Ni ²⁺ , Mg ²⁺ , and Ca ²⁺ Selective. All the solutions used are 2% standard solutions (water-soluble salts of metal elements) _{placed in HNO 3 Titration instrument}

Potentiometric titration is performed with the help of Titrando 904 (dosimeter and pH/mV meter) with the exchange unit 806 of Metrohm AG. The exchange device is equipped with a burette tip with an anti-diffusion plug that can be immersed in the measuring solution. The titration experiment is controlled by the Tiamo program. pH electrode

The pH measurement is carried out with the following single-pole measurement battery electrodes: -SCHOTT® instrument N62 obtained from SI Analytics GmbH, with 3 mol/L KCl as a bridge electrolyte, platinum membrane, Silamid® reference and Metrohm brand joint dual junction electrode Potentiometric titration in water/DMSO solution mixture

0.10 -3.84 0.043 67.472 18.112 309.406 705.575 30.48 0.12 -3.78 0.036 67.532 18.105 356.022 661.531 34.99 0.14 -3.67 0.019 67.642 18.088 398.939 620.939 39.12 0.16 -3.51 -0.010 67.802 18.059 438.541 583.367 42.91 0.18 -3.32 -0.052 67.992 18.017 475.193 548.508 46.42 0.20 -3.10 -0.104 68.212 17.965 509.110 515.992 49.66 表2：用於製備1.0升溶劑的部分過量莫耳體積、部分莫耳體積和DMSO必需體積(在298 K下以mL為單位)。Due to the low solubility in pure water, it is necessary to measure the equilibrium constant of the ligand in the water/DMSO medium. The titration experiment in the water/DMSO solution mixture is carried out at a certain molar fraction. By measuring the equilibrium constant of different molar fractions and extrapolating the value, the constant of pure water can be estimated. For the preparation of all these solutions, it is important to consider the volume shrinkage during the mixing of DMSO and pure water, because it is not an ideal solution. The volume of DMSO required to prepare 1.0 liter of solution is summarized in Table 2 ^[1] .

0.10 -3.84 0.043 67.472 18.112 309.406 705.575 30.48 0.12 -3.78 0.036 67.532 18.105 356.022 661.531 34.99 0.14 -3.67 0.019 67.642 18.088 398.939 620.939 39.12 0.16 -3.51 -0.010 67.802 18.059 438.541 583.367 42.91 0.18 -3.32 -0.052 67.992 18.017 475.193 548.508 46.42 0.20 -3.10 -0.104 68.212 17.965 509.110 515.992 49.66 Table 2: Part of the excess molar volume, part of the molar volume and necessary volume of DMSO (in mL at 298 K) used to prepare 1.0 liter of solvent.

All solutions were prepared with deionized water and DMSO (for analysis, ACS, Reag. Ph. Eur., AppliChem). In addition, in order to ensure a constant ionic strength, all solutions are prepared with a concentration of 0.1 mol/L KCl and KCl as a supporting electrolyte (for analysis, EMSURE, ACS, ISO, Reag. Ph. Eur., Merck).

A 50.0 mL sample (Eppendorf Multipette E3x, combitip: 50.0 mL) of the prepared solution was thermostated at 298 K (Huber Ministat CC 3 recirculation cooler) in a double-walled glass container. Sweep the glass container with nitrogen that has passed through the 0.1 mol/L KCl solution.

Use 0.1 mol/L KOH or 0.1 mol/L HCl solution as the titrant together with an appropriate amount of DMSO to provide the desired molar ratio. First, the DMSO solvent (ρ _DMSO = 1.09566 g/cm ³ ) ^{[2] is} weighed into a 1.0-liter flask. Then KOH or HCl (both Titrisol, Merck) is added in the presence of nitrogen. Subsequently, the flask was filled with water to the calibration mark. The warm mixture was left to cool to 293 K in the presence of nitrogen. Optimally, the flask is gradually filled to the calibration mark several times at this temperature. A constant volume should have been reached.

Before and after all measurements, the standard electrode potential E° and the ion product p K _W need to be determined by potentiometric titration with 50.0 mL of 2.0 mmol/L HCl solution and 0.1 mol/L KOH (Titrisol, Merck) as the titrant. The standard electrode potential E° and p K _W are also measured at the same molar fraction of DMSO as the measurement. Both values are calculated using the Elektroden Kalibrierung ^[3] program. The average value of the titrated E° and the average value of p K _W before and after the actual measurement are used to evaluate the equilibrium constant. To prepare a 2.0 mmol/L Hcl solution, weigh DMSO in a 1.0-liter volumetric flask. Then add 2 mL of 1.0 mol/L HCl, and add the amount of solid KCl required to achieve an ionic strength of 0.1 mol/L to the flask. Fill the flask to the calibration mark with water. Allow it to cool to 293 K, causing volume shrinkage. Therefore, it is necessary to gradually fill the solution to the calibration mark with water several times. A constant volume should have been reached.

Prepare the sample solution in a 110 mL volume flask. All components are weighed on a precision balance. First weigh the DMSO into the flask. Furthermore, the ligand is weighed and then KCl (c = 0.1 mol/L) is weighed and added to the solution mixture. If necessary, add the metal ion stock solution (ICP standard solution, 1000 mg/L metal, Carl Roth) to the 110 mL flask. Ligand and KCl can be dissolved well by ultrasonic treatment. The flask was thermostated at 293 K and filled to the calibration mark several times. A constant volume should have been reached.

The pH was adjusted by adding 0.1 mol/L KOH (TitriPUR, Merck) to the flask with Eppendorf Multipette. Continuous spectrophotometric titration

The continuous spectrophotometric titration system and the continuous potentiometric titration are carried out at the same time. When performing the potential titration as described above, the immersion probe (Excalibur Lab, Hellma) was submerged in the sample solution. Use the titration computer to send the trigger signal to the spectrophotometer (TIDAS S 500-MCS UV/NIR 1910, J&M Analytik AG) to record the spectrum before each new titrant is added. Absorption data is recorded in the range of 200 ＜ λ ＜ 1000 nm, but the range of 400 ＜ λ ＜ 900 nm is used for evaluation. Both titration experiments can be used to determine the equilibrium constant. ^{The continuous titrations were studied with a total Fe 3+} 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. The spectrum of ^{a 0.2 mmol/L Fe 3+} solution prepared from an iron stock solution was also collected. The mismatch constant is ^{calculated using the HypSpec 2014 [4,5]} program. Calculation of equilibrium constant

All equilibrium constants are calculated as concentration constants. In addition, the pH is defined as -log [H ⁺ ]. The equilibrium constant is determined by means of a computer program. In order to evaluate potentiometric titration and spectrophotometric titration, Hyperquad 2013 ^[4] and HypSpec 2014 ^[4,5] programs were used respectively.

In order to evaluate the titration experiment with the Hyperquad 2013 program, the ion product p K _W of water with a constant value under the given titration conditions is required. For different mole fraction of water / DMSO solution _{used, p K W (p K W} = -log K W, K W = [H +] × [OH -]) is measured as described in Section 1.1.3 Determined by titrations performed before and after. The values obtained by Elektroden Kalibrierung ^[3] program are: x _DMSO = 0.20 and p K _W 15.57 (average of 53 titrations), x _DMSO = 0.18 and p K _W 15.38 (average of 8 titrations), x _DMSO = 0.16 and p K _W 15.19 (average of 8 titrations) and x _DMSO = 0.14 and p K _W 15.00 (average of 8 titrations). Determine the total concentration of E°, p K _W , ligand and metal ion as a fixed value. In order to determine the p K _A value, the pH value is calculated and the total concentration is determined as a fixed value. In addition, when calculating the complex formation constant, the previously measured p K _A value is also defined as a fixed value.

The equilibrium constant investigated by the spectrophotometric titration experiment was ^{calculated using the HypSpec 2014 [4,5]} program. To determine the complex formation constant, collect ^{the spectra of the Fe 3+} stock solution as described above, and define it as a known spectra and colored species in the program. Define all metal-containing species as colored species. In contrast, ligands and their protonated products are considered colorless species.

The Hyss 2009 ^[6] program is used to calculate the species distribution of all titration experiments.

A similar measurement was performed with water-soluble salts of metal elements to determine the pM value. Result: pM (Method A) Example Compound No. 40 element pM value Cu ²⁺ 14.3 Zn ²⁺ 7.1 Ni ²⁺ 6.7 Mg ²⁺ 6 Ca ²⁺ 6 Table 3: The pM/pFe value of Example Compound No. 40

All measurements are performed at X _DMSO = 0.20.

Using the same method A), the pFe value can be determined similarly, and the results are as follows: The pFe value used to determine the affinity and stability of the complex : iron(III) chloride element pFe value Fe ³⁺ 20.5 Example compounds 1 to 80 in Table 1 above In the range of 19 to 27 Method B) - measured value pFe

In addition, in a method similar to that described in Method A), the pFe values of several example compounds listed below were measured, but using different sample volumes for titration, as follows: Potentiometric Titration of Water/DMSO Solution Mixture

The 50.0 mL/20 ml sample (Eppendorf Multipette E3x, combitip: 50.0 mL/25 ml) of the prepared solution was kept at a constant temperature at 298 K (Huber Ministat CC 3 recirculation cooler) in a double-walled glass container. Sweep the glass container with nitrogen that has passed through the 0.1 mol/L KCl solution.

Prepare the sample solution in a 110 mL/50 ml volume flask. All components are weighed on a precision balance. First weigh the DMSO into the flask. Furthermore, the ligand is weighed and then KCl (c = 0.1 mol/L) is weighed and added to the solution mixture. If necessary, add the metal ion stock solution (ICP standard solution, 1000 mg/L metal, Carl Roth) to the 110 mL/50 ml flask. Ligand and KCl can be dissolved well by ultrasonic treatment. The flask was thermostated at 293 K and filled to the calibration mark several times. A constant volume should have been reached. Calculation of equilibrium constant

All equilibrium constants are calculated as concentration constants. In addition, the pH is defined as -log [H ⁺ ]. The equilibrium constant is determined by means of a computer program. In order to evaluate potentiometric titration and spectrophotometric titration, Hyperquad 2013 ^[4] and HypSpec 2014 ^[4,5] programs were used respectively.

In order to evaluate the titration experiment with the Hyperquad 2013 program, the ion product p K _W of water with a constant value under the given titration conditions is required. For different mole fraction of water / DMSO solution _{used, p K W (p K W} = -log K W, K W = [H +] × [OH -]) is measured as described in Section 1.1.3 Determined by titrations performed before and after. The values obtained with Elektroden Kalibrierung ^[3] program are: x _DMSO = 0.20 and p K _W 15.57 (average of 53 titrations), x _DMSO = 0.18 and p K _W 15.38 (average of 22 titrations), x _DMSO = 0.16 and p K _W 15.19 (average of 8 titrations), x _DMSO = 0.14 and p K _W 15.00 (average of 8 titrations), x _DMSO = 0.12 and p K _W 14.82 (average of 9 titrations) ), x _DMSO = 0.10 and p K _W 14.65 (average of 9 titrations). Determine the total concentration of E°, p K _W , ligand and metal ion as a fixed value. In order to determine the p K _A value, the pH value is calculated and the total concentration is determined as a fixed value. In addition, when calculating the complex formation constant, the previously measured p K _A value is also defined as a fixed value.

The equilibrium constant investigated by the spectrophotometric titration experiment was ^{calculated using the HypSpec 2014 [4,5]} program. To determine the complex formation constant, collect ^{the spectra of the Fe 3+} stock solution as described above, and define it as a known spectra and colored species in the program. Define all metal-containing species as colored species. In contrast, ligands and their protonated products are considered colorless species.

The Hyss 2009 ^[6] program is used to calculate the species distribution of all titration experiments. Result: pFe (Method B) Exp. pFe value 03 22.5 05 23.3 06 22.0 07 22.8 08 22.5 09 22.4 12 20.0 14 20.6 15 21.8 16 22.1 32 22.3 40 21.6 43 20.9 44 23.3 45 21.7 56 20.0 57 21.4 76 20.3 77 20.5 78 21.4 literature:

[1] JTW Lai, FW Lau, D. Robb, P. Westh, G. Nielsen, C. Trandum, A. Hvidt, Y. Koga; J.Solut.Chem. 1995, 24, 89-102.

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

[3] M. Basters; Elektrodenkalibrierung (unveröffentlicht) , Universität 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.

比較配位體： 地拉羅司(Exjade®)

[6] L. Alderighi, P. Gans, A. Ienco, D. Peters, A. Sabatini, A. Vacca; Coord. Chem. Rev. 1999, 184, 311-318. II-II. Water-soluble materials and methods Test compound and formulation ligand: Ligand according to the present invention: Example Compound No. 40

Comparison ligands: Delarox (Exjade®)

The test compound was received in DMSO at a concentration of 20 mM.

As mentioned above, the reference control group was also deployed in DMSO. Working solution

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 control group experiment process

The test compound (10 µL; 20 mM) was added to sterile water (190 µL) in triplicate and shaken at 300 rpm at room temperature. After 90 min, the test compound was filtered by centrifugation (5 min. at 3000 rpm) to obtain an aqueous filtrate. Dispense acetonitrile (20 µL) into a clean 96-well UV/VIS analysis plate, add the aqueous filtrate (80 µL) and analyze the plate. Add the aqueous filtrate (10 µL) to working solution C (90 µL), and then shake the plate for 10 min to prepare a second diluted analysis plate (10 times). The diluted filtrate (80 µL) was then added to acetonitrile (20 µL) and the plate was analyzed. As described below, quantify the results obtained from the standard calibration curve prepared for each test sample.

The following processes have been completed on the Perkin Elmer Janus robot platform: The test compound (15 µL; 20 mM) was added to working solution A (285 µL) to give a stock solution concentration of 1000 µM. Add 150 µL to working solution B (150 µL) to serially dilute the stock solution until it reaches a final concentration of 0.98 µM, and then analyze the calibration range.

The samples were analyzed using the Molecular Devices SPECTRAmax plus microdisk reader at the following wavelengths: 280, 300, 320, 340, 360, 800 nm. result: Test compound Solubility [mg/ml] Example Compound No. 40 0.28 Comparison ligand Exjade® 0.02 III. Pharmacological Test III-I. Example Compound No. 40 Efficacy in Hemochromatosis Mouse Model

Mutations in genes involved in sensing systemic iron reserves, such as hemochromatosis protein (HFE), cause iron excess in mice and men. HFE mutations are the most common cause of hereditary hemochromatosis (HH) in white adults. Most HH patients are homozygous for the missense mutation of the HFE gene, which results in the substitution of the cysteine corresponding to the 282nd amino acid in the HFE protein to tyrosine and is called the C282Y mutation. Mice homozygous for the C282Y mutation (HFE C282Y mice) develop liver iron excess, which makes it a suitable animal model for studying human HH (Levy JE et all, Blood, 1999).

Female and male homozygous HFE C282Y mice (Jackson Laboratories, 129-Hfetm1.1Nca/J, stock number: 005063) aged 9 to 10 weeks of age were given 5, 10, and 30 mg/kg Example compound numbers or carrier (30% Kolliphor/water) is administered orally once a day for 3 weeks, except on weekends. The mice were fed a standard diet (SD, Provimi Kliba, Cat. 3437, Fe about 250 ppm) for 6 hours (3h to 9h after administration). For the remaining 18 hours, provide a low-iron diet (LID, Provimi Kliba, Cat. 2039, Fe = 10.7 ppm). After exposure to SD, Example Compound No. 40 or vehicle administration was repeated for 19 days. At the weekend, the administration was discontinued, and the mice could use LID at will. One hour after the last dose, the mice were euthanized and the liver was collected. The liver iron content was analyzed by inductively coupled plasma emission spectroscopy (ICP-OES). Example Compound No. .40 significantly reduced the liver iron concentration of HFE C282Y mice in a dose-dependent manner (Bonferroni's multiple comparison test one-way ANOVA) (Table 4).

These data confirmed the efficacy of Example Compound No. .40 in reducing liver iron excess in HFE C282Y mice, and provided a proof of concept in a disease model of hereditary hemochromatosis. Liver iron concentration Average [g/mg] SD[g/mg] [ % reduction of carrier ] Carrier 1241.0 973.6 - 5 mg/kg Example Compound No. 40 739.6 218.7 40.4 10 mg/kg Example Compound No. 40 575.5 253.8 53.6 30 mg/kg Example Compound No. 40 474.2 169.9 61.8 Table 4 Efficacy of Example Compound No. 40 in the HFE C282Y mouse model of hemochromatosis. No. 40 or vehicle-treated HFE C282Y mouse group of the total Fe concentration in the liver and the standard deviation (SD) and compared with the vehicle-treated HFE C282Y mice % Reduction. III-II. Example Compound No. 40 Efficacy in Moderate β- Thalassemia Mouse Model

Beta-thalassemia is an inherited anemia caused by mutations in the beta-globin gene of hemoglobin, which results in abnormal red blood cells with a reduced life cycle. Current treatment options for iron excess in beta-thalassemia include blood transfusions that cause iron excess and require iron chelation. Patients with non-transfusion-dependent thalassemia may also develop iron excess due to ineffective red blood cell production and increased iron absorption (Taher A, et al, Lancet 2018). A non-transfusion-dependent β-thalassemia mouse model was used to investigate the effect of Example Compound No. 40 in reducing iron content in organs. (Hbb th3/+, Jackson Laboratories, B6; 129P-Hbb-b1tm1Unc Hbb-b2tm1Unc/J, Stock Number: 002683). Due to the lack of hepcidin level due to the high iron content in the liver, spleen and kidney and the increased expression of transferrin in the duodenum, Hbb th3/+ mice absorbed excess iron (Gardenghi S., Blood, 2007) . Hbb th3/+ mice were administered 10 or 30 mg/kg of Example Compound No. 40 or vehicle (30% Kolliphor/water, 10 mL/kg, Sigma, Cat. C5135) once a day. The mice were fed a standard diet (SD, Provimi Kliba, Cat. 3437, Fe about 250 ppm) for 6 hours (3h to 9h after administration). In the remaining 18h, provide LID (Provimi Kliba, Cat. 2039, Fe = 10.7 ppm). After exposure to SD, Example Compound No. 40 or vehicle administration was repeated for 19 days. At the weekend, the administration was discontinued, and the mice could use LID at will. One hour after the last dose, the mice were euthanized, and the organs were harvested and used for iron content analysis.

The total iron concentration in the liver and kidney of the Hbb th3/+ mice treated with 30 mg/kg Example Compound No. 40 was significantly lower than that in the vehicle-treated mice (Table 5), while the spleen iron was not affected . The total liver iron of the females treated with the vehicle was higher than that of the males, nevertheless, the 30 mg/kg Example Compound No. 40 administration significantly reduced liver iron in both sexes.

One hour after the last administration on day 19, plasma was collected and analyzed for total bilirubin, creatinine, and urea as biomarkers of nephrotoxicity. The compound number of the example was used. 40 treatment versus Hbb th3/+ versus total in mice Bilirubin, creatinine and urea had no effect (Table 5).

At the end of the study, the expression of KIM-1 mRNA in the kidney was evaluated by qPCR. Treatment with Example Compound No. .40 had no effect on the KIM-1 expression in the kidney of Hbb th3/+ mice (Table 5), indicating that the amount of the tested drug did not induce nephrotoxicity in this mouse strain.

Compared to wild-type mice, Hbb th3/+ mice have anemia, and pathologically changed blood parameters indicate ineffective red blood cell production, such as decreased RBC count, decreased hematocrit, increased RDW, increased reticulocyte count, and increased white blood cell count high. Oral administration of Example compound No. 40 in Hbb th3/+ mice did not change RBC parameters for three weeks (not shown). Importantly, compared with the vehicle group, Example Compound No. .40 significantly reduced the counts of blood white blood cells, especially neutrophils (Table 5).

These data confirm that Example Compound No. .40 effectively removes iron from the liver of Hbb th3/+ mice without causing nephrotoxicity. parameter unit Example compound number. 40 10 mg/kg Example compound number. 40 30 mg/kg Decrease in total liver Fe concentration in males/females [µg/g] 22/22% 53/39% Decrease in total kidney Fe concentration in males/females [µg/g] 0/7% 1/16% Increased KIM-1 performance in males/females [Multiple change] 1.16 / 1.00 1.99 / 0.36 Increase in total bilirubin [µmol/L] 26% twenty two % Decrease in white blood cell count [*10E3/µL] 12% twenty three % Decrease in neutrophil count [*10E3/µL] 44% 40% Table 5: Efficacy of Example Compound No. 40 in a mouse model of thalassemia moderate (Hbb th3/+ mice). For all other parameters shown, the data is expressed as a fold change in KIM-1 performance and a% change in carrier. Fold change = 2 ^{((∆Ct(Veh)- ∆Ct ( Example Compound 40))} , where ∆Ct(Veh) is between the reference gene (Gusb) of the vehicle treatment group and the gene of interest (Kim-1) the cycle threshold (Ct) value of the difference, the ACt (Example compound 40) is the difference between the Ct of Gusb and Kim-1 Example compound No. .40 treated groups. IV. toxicity assessment IV-I. large Example Compound No. 40 in Rats for 28- day repeated dose assessment of gastrointestinal, renal and hepatotoxicity

The purpose of this study was to evaluate the potential toxicity of Example Compound No. 40 to the gastrointestinal tract (GIT), kidney and liver after oral administration to rats by gavage for four weeks.

Six-week-old female and male Wistar rats (Charles River Deutschland, Crl: WI (Han)) at 10, 30, and 75 mg/kg body weight ( N = 5 females and 5 males in each group) The example compound No. 40 (batch KUM201) or the carrier (30% Kolliphor / 70% Milli-Q water; N = 3 females and 3 males) was orally administered by gavage once a day. The administration of Example Compound No. 40 was carried out at approximately the same time every day for 28 days, including the day before the scheduled autopsy. Provide free access to granular rodent diet (SM R/MZ, available from SSNIFF® Spezialdiäten GmbH, Soest, Germany) and tap water.

Detailed clinical observations were performed weekly, and at the end of the day of dissection, cage side observations were performed once a day. Starting from day 1, the body weight was measured individually every day, and food consumption was quantified twice a week. On the day of scheduled euthanasia and autopsy, a 0.5 mL volume of blood sample was collected and analyzed for alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT) and alkaline phosphatase (ALP) in plasma. ) As biomarkers of liver toxicity, and creatinine, total bilirubin and urea as biomarkers of nephrotoxicity. The animal is cast to a complete anatomy, including weighing and macro examination of the brain, heart, kidney, liver, lung, and spleen. In addition, GIT brain, heart, kidney, liver, lung, and spleen tissues were submitted to peer-reviewed histopathological examinations.

No animals died during the study. Salvation was observed after administering to several animals at 10, 30 or 75 mg/kg Example Compound No. 40, but it is considered that it is a physiological response to taste rather than a sign of systemic toxicity. In male rats, there was no significant change in body weight (-weight gain), organ weight, or clinical biomarker control group, and it was not found in histopathological examination. It was noted that the female animals administered with 75 mg/kg of Example Compound No. 40 had a slight decrease in body weight and weight gain compared to the control group from day 11 (Figure 1), but there was no corresponding change in food consumption. It was found that the average creatinine level of females in the same group was slightly but statistically increased by 1.18 times compared with the average line of the control group (Dunnett-test was based on a significant combined variance at the 5% level). No gross pathological findings, changes in organ weight or tissue changes related to the administration of Example Compound No. 40 were found. The conclusion that there is no histopathological damage in kidney tissue is that the increase in creatinine in females dosed at 75 mg/kg of Example Compound No. 40 is not related to toxicology.

The results of this study confirmed that by oral administration of Example Compound No. .40 daily for 28 days by gavage, rats of both sexes well tolerated the dose of up to 75 mg/kg. Therefore, both sexes are considered to have a NOAEL of 75 mg/kg per day. mark Control group ( N =3) Example compound number. 40 10 mg/kg daily (N =5) Example compound number. 40 30 mg/kg daily (N =5) Example compound number. 40 75 mg/kg daily (N =5) female male female male female male female male ALAT (U/L) 51.7 (8.4) 94.9 (28.6) 46.3 (9.5) 76.6 (16.3) 58.1 (6.0) 76.8 (15.8) 56.3 (9.3) 73.7 (17.8) ASAT (U/L) 100.9 (11.6) 125.2 (52.0) 116.9 (17.1) 107.6 (16.6) 106.0 (16.9) 117.8 (36.9) 130.1 (57.7) 112.2 (18.5) ALP (U/L) 119 (8) 227 (30) 87 (16) 233 (25) 87 (25) 240 (40) 103 (29) 254 (49) Total bilirubin (umol/L) 2.3 (0.1) 2.7 (0.5) 2.2 (0.3) 2.4 (0.3) 2.3 (0.5) 2.5 (0.3) 2.5 (0.2) 2.2 (0.1) Urea (mmol/L) 6.8 (1.7) 7.8 (0.3) 5.8 (1.0) 9.5 (0.6) 6.8 (1.4) 8.1 (1.4) 7.0 (0.4) 9.7 (1.6) Creatinine (umol/L) 34.3 (2.1) 34.8 (2.9) 36.1 (2.7) 36.6 (2.0) 38.4 (2.6) 35.8 (0.8) 40.3 (1.7) ^* 37.5 (3.3) *Dunnett-test is based on the significant combined variance at the 5% level Table 6. The collation of examination clinical chemistry values on the day of scheduled euthanasia in female rats (control group and groups taking 10, 30 and 75 mg/kg/day of Example Compound No. 40 once a day). Reported is the mean and standard deviation in parentheses

These in vivo experiments show that the compound No. 40 according to the example of the present invention is not toxic to key organs within 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 assessment published ^{for Exjade ®} according to the FDA report of Tamal K. Chakraborti, NDA No. 21 – 882, pages 420 to 424 has been carried out.

The basic test conditions of the study are summarized as follows: Animals: Winster rats (Charles River UK Limited, Crl: WI (Han) were used throughout the study. The animals are approximately 7-8 weeks old, and the weight range of males is 26.7- 239.2 g, the female's weight range was 160.4-168.0 g. Test compound: Example compound No. 40 Method: Example compound No. 40 was given by gavage for 28 consecutive days with daily doses of 75 and 100 mg/kg Rats (5 rats/sex/group) were administered orally to rats (5 rats/sex/group). The control group received the same dose and volume of vehicle (30% Kolliphor / 70% Milli-Q water; 3 rats/sex/group). group).

Observe clinical signs/mortality at least twice a day after administration. Throughout the study, during the pre-administration period, the body weight was recorded at least twice a week, and the body weight was recorded daily from the first day of administration. During the pre-dose period and throughout the study, food consumption was recorded at least twice a day. On the 28th day, all animals were subjected to hematology and serum chemistry analysis during the final dissection. Take the organ weights of the brain, heart, kidneys, liver, lungs, and spleen. Perform microscopic examinations on the gastrointestinal tract, liver and kidneys.

The results achieved compared to the FDA report (Study No. 97400) reported by Tamal et al. cited above for Exjade ^{® are shown in the following table:} Results / parameters Example Compound No. 40 Exjade ^® ( According to Tamal et al ; FDA report ) mortality rate No death 10 deaths/8 deaths occurred at 100mg/kg, which are considered to be related to treatment body weight No reduction/no change 100mg/kg group males reduced by 15%, females reduced by 10% Clinical Chemistry Bilirubin no change Male 100mg/kg plus 300%

Compared to the established chelate drug Exjade ^® (delarosi), the toxicity results clearly show an improvement in toxicity and tolerability.

Therefore, it can be inferred that the iron chelate compound of the present invention is suitable as a novel iron chelate compound with good tolerability and few side effects. In particular, with regard to the lifetime use of chelates in all forms of iron excess, the reduction of toxicity is crucial.

Figure 1 In the 28-day toxicity evaluation of Example Compound No. 40, the female body weight from the day before treatment (Day -1) to the day of scheduled euthanasia (Day 29).

Figure 1 In the 28-day toxicity evaluation of Example Compound No. 40, the female body weight from the day before treatment (Day -1) to the day of scheduled euthanasia (Day 29).

(no)

Claims (17)

A compound according to formula (I)

The -COR ¹ group represents the -(C=O)-R ¹ group, where R ^{1 is} selected from the group consisting of:--OH,-C ₁ -C ₄ -alkoxy,-has 1 C ₁ -C ₄ ^-haloalkyl with up to 3 halogen atoms,-C ₁ -C ₄ -haloalkoxy with 1 to 3 halogen atoms,-deprotonated group -O ⊖ or its salt form; R ² represents one or more substituents independently selected from the group consisting of:-hydrogen,-halogen,--OH,-linear or branched chain which may have 1, 2 or 3 substituents C ₁ -C ₆ -alkyl,-C _{3 -C 6} -cycloalkyl which may have 1, 2 or 3 substituents, and-C ₁ -C which may have 1, 2 or 3 substituents ₆ -Alkoxy, wherein the substituents of alkyl, cycloalkyl and alkoxy may be the same or different and may be independently selected from halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -A group consisting of alkoxy, wherein the alkyl- and alkoxy-substituents may each carry 1, 2 or 3 independently selected from halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -Additional substituents of alkoxy; R ^{3 is} selected from the group consisting of:-hydrogen,-linear or branched C ₁ -C _{4 -alkanes which may carry 1, 2 or 3 substituents Group, and-C 3} -C ₆ -cycloalkyl which may have 1, 2 or 3 substituents, wherein the substituents of the alkyl group and the cycloalkyl group may be the same or different and may be independently selected from The group consisting of halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy, wherein the alkyl- and alkoxy-substituents may each carry 1, 2 or 3 independently selected Additional substituents from halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy; R ⁴ and R ⁵ each represent one or more independently selected from the group consisting of Substituents:-hydrogen,-halogen,--OH,-linear or branched C1-C6-alkyl which may have 1, 2 or 3 substituents,-may have 1, 2 or 3 substituents C3-C6-cycloalkyl, and -C _{1 -C 6} -alkoxy which may have 1, 2 or 3 substituents, wherein the substituents of alkyl, cycloalkyl and alkoxy may be Same or different and can be independently selected from halogen, cyano, C ₁ -C _The group consisting of 3-alkyl and C ₁ -C ₃ -alkoxy, wherein the alkyl- and alkoxy-substituents may each carry 1, 2 or 3 independently selected from C ₁ -C ₃ - alkyl and C ₁ -C ₃ - alkoxy group further substituted; R ⁶ and R ^{6 'each} represent a substituent group independently selected from one or more groups of the following configuration: - hydrogen, - Negative charge ^⊖ or its salt form; and its pharmaceutically acceptable salt. Such as the compound of claim 1, which is represented by formula (II):

The group –COOR ^1# represents the group –(C=O)-OR ^1# , where R ^{1# is} selected from the group consisting of:-hydrogen,-linear or branched C ₁ -C _4- Alkyl,-C _{1 -C 4} ^-haloalkyl having 1 to 3 halogen atoms, and-negatively charged⊖ or its salt form; R ² represents one or more independently selected from the group consisting of Multiple substituents:-hydrogen,-halogen,-OH,-linear or branched C ₁ -C ₆ -alkyl which may carry 1, 2 or 3 substituents,-may carry 1, 2 or C ₃ -C ₆ -cycloalkyl with 3 substituents, and-C ₁ -C ₆ -alkoxy with 1, 2 or 3 substituents, of which alkyl, cycloalkyl and alkoxy The substituents may be the same or different and may be independently selected from the group consisting of halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy, wherein the alkyl- and alkoxy The radical-substituents may each carry 1, 2 or 3 additional substituents independently selected from halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy; R ^{3 is} selected from Composition group:-hydrogen,-linear or branched C ₁ -C ₄ -alkyl which may have 1, 2 or 3 substituents, and-C which may have 1, 2 or 3 substituents ₃ -C ₆ -Cycloalkyl,-wherein the substituents of alkyl, cycloalkyl and alkoxy may be the same or different and may be independently selected from halogen, C ₁ -C ₃ -alkyl and C _The group consisting of 1 -C ₃ -alkoxy, wherein each of the alkyl- and alkoxy-substituents may carry 1, 2 or 3 independently selected from halogens, C ₁ -C ₃ -alkanes group and a C ₁ -C ₃ - alkoxy group further substituted; R ⁴ and R ⁵ each represent independently a substituent selected from the group consisting of one or more of the following configuration: - hydrogen, - halogen, - -OH,-linear or branched C ₁ -C ₆ -alkyl which may have 1, 2 or 3 substituents,-C ₃ -C _{6 -ring which may have 1, 2 or 3 substituents Alkyl, and C 1} -C ₆ -alkoxy which may have 1, 2 or 3 substituents, wherein the substituents of alkyl, cycloalkyl and alkoxy may be the same or different and may be independent Ground is selected from halogen, C ₁ -C ₃ -alkyl and C ₁ -C _The group consisting of 3-alkoxy, wherein each of the alkyl- and alkoxy-substituents may carry 1, 2 or 3 independently selected from C ₁ -C ₃ -alkyl and C _1- Additional substituents of C ₃ -alkoxy; and pharmaceutically acceptable salts thereof. The compound of any one of claim 1 or 2, wherein R ² represents one or more substituents independently selected from the group consisting of:-hydrogen,-halogen,-OH,-may be Straight-chain or branched C ₁ -C ₆ -alkyl with 1, 2 or 3 substituents,-C ₃ -C ₆ -cycloalkyl with 1, 2 or 3 substituents, and-may _{C 1} -C ₆ -Alkoxy with 1, 2 or 3 substituents, wherein the substituents of alkyl, cycloalkyl and alkoxy may be the same or different and may be independently selected from halogens , C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy, wherein the alkyl- and alkoxy-substituents may each carry 1, 2 or 3 independently selected from Halogen and additional substituents of _{C 1} -C ₃ ^{-alkoxy; R 3 is} selected from the group consisting of:-hydrogen,-linear or branched C which may have 1, 2 or 3 substituents _1- C _{4 -alkyl, and-C 3} -C ₆ -cycloalkyl which may have 1, 2 or 3 substituents, wherein the substituents of alkyl, cycloalkyl and alkoxy are selected from C ₁ -C ₃ -alkyl; R ⁴ and R ⁵ each represent one or more substituents independently selected from the group consisting of:-hydrogen,-halogen,--OH,-may carry Straight-chain or branched C ₁ -C ₆ -alkyl with 1, 2 or 3 substituents,-C ₃ -C ₆ -cycloalkyl with 1, 2 or 3 substituents, and-with _{C 1} -C ₆ -Alkoxy with 1, 2 or 3 substituents, wherein the substituents of alkyl, cycloalkyl and alkoxy may be the same or different and may be independently selected from halogen, The _{group consisting of C 1} -C ₃ -alkyl and C ₁ -C ₃ -alkoxy, wherein the alkyl- and alkoxy-substituents may each carry 1, 2 or 3 independently selected from C _{Additional substituents of 1} -C ₃ -alkoxy; and pharmaceutically acceptable salts thereof. The compound according to any one of claims 1 to 3, wherein R ² represents one or more substituents independently selected from the group consisting of:-hydrogen,-halogen,-may carry 1, 2 Or straight or branched C ₁ -C ₄ -alkyl with 3 substituents, and-C ₁ -C ₄ -alkoxy with 1, 2 or 3 substituents, of which alkyl and alkoxy The substituents of the group may be the same or different and may be independently selected from the group consisting of halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy, wherein the alkyl- and alkane The oxy-substituents may each carry 1, 2 or 3 _{additional substituents independently selected from halogen and C 1} -C ₃ -alkoxy; R ^{3 is} selected from the group consisting of:-hydrogen, -Linear or branched C ₁ -C ₄ -alkyl which may have 1, 2 or 3 substituents, and-C ₃ -C _{6 -Cycloalkyl which may have 1, 2 or 3 substituents} , Wherein the substituents of alkyl and cycloalkyl are selected from C ₁ -C ₃ -alkyl; R ⁴ and R ⁵ each represent one or more substituents independently selected from the group consisting of :-Hydrogen,--OH,-linear or branched C ₁ -C ₃ -alkyl, and-C ₁ -C ₄ -alkoxy; and pharmaceutically acceptable salts thereof. The compound according to any one of claims 1 to 4, which is further characterized by a complex activity represented by a pFe value in the range of 19 to 27 measured by potentiometric titration. The compound according to any one of claims 1 to 5, which is further characterized by one or more of the following pM values: Cu ²⁺ pM <15, and/or Zn ²⁺ pM <8, and/or Ni ²⁺ pM <8, and/or Mg ²⁺ pM <8, and/or Ca ²⁺ pM <8, and/or It is preferably at least characterized in that Zn has a pM value (pZn) <8, which is determined by potentiometric titration. Such as the compound of any one of claims 1 to 6, which is represented by the following formula (III)

And pharmaceutically acceptable salts thereof. Such as the compound of any one of claims 1 to 7, which is used as a medicine. The compound according to any one of claims 1 to 7, which is used as an iron chelate in vivo. A compound according to any one of claims 1 to 7, which is used for the prevention and/or treatment of an increase in iron level, an increase in iron absorption, or an excess of iron in a mammal, or an increase in iron level in a mammal, Conditions or diseases caused by increased iron absorption or excess iron, or It is used as an iron chelate in the living body in the condition of increased iron level, increased iron absorption or excess iron in mammals caused by blood transfusion. For the compound provided in claim 10, the condition or disease related to increased iron level, increased iron absorption or excess iron or caused by increased iron level, increased iron absorption or excess iron is selected from thalassemias, including A Thalassemia type, thalassemia b, and thalassemia delta; hemoglobinopathy; hemoglobin E disease; hemoglobin H disease; hemochromatosis; hemolytic anemia, including especially sickle cell anemia or congenital erythropoiesis Congenital dyserythropoietic anemia; and conditions or diseases treated with blood transfusion, such as myelodysplastic syndrome (MDS). Such as the compound provided in claim 10 or 11, which is used for treatment -Diseases related to ineffective erythropoiesis or blood transfusion, such as myelodysplastic syndrome (MDS, myelodysplastic), polycythemia vera (polycythemia vera), and congenital dysmorphic anemia; and/or -Neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, which work by limiting the deposition or increase of iron in tissues or cells; -The formation of free radicals, reactive oxygen species (ROS) and oxidative stress; and/or -Heart, kidney, liver and endocrine damage caused by excessive iron; and/or -Inflammation triggered by too much iron. A compound as defined in any one of claims 1 to 7 or a compound as provided in claims 8 to 12, which is for use in combination therapy, including a) Co-administer the compound as defined in any one of claims 1 to 12 and at least one additional pharmaceutically active compound, wherein aa) The co-administration of the combination therapy can be a fixed drug by co-administering a compound as defined in any one of claims 1 to 12 and at least one additional pharmaceutically active compound presenting a fixed-dose formulation Combined therapy with a large amount; or ab) The co-administration of the combination therapy can be achieved by co-administering several individual compounds presenting a free dose of a compound as defined in any one of claims 1 to 12 and at least one additional pharmaceutically active compound. Dosage combination therapy is performed by administering the individual compounds simultaneously or by using the individual compounds sequentially to distribute over a period of time; or b) Co-administration of the compound as defined in any one of Claims 1 to 12 combined with blood transfusion therapy. A medicine containing one or more of the compounds defined in any one of claims 1 to 7, which may further contain one or more pharmaceutical carriers and/or adjuvants and/or solvents and/ Or at least one additional pharmaceutically active compound. The compound for use in claim 13 or the drug as in claim 14, wherein one or more other pharmaceutically active compounds are selected from active compounds for the prevention and treatment of iron excess, thalassemia or hemochromatosis; for prevention and Active compounds for treating neurodegenerative diseases, such as Alzheimer’s disease or Parkinson’s disease and related symptoms, and iron chelating compounds; preferably selected from the following active compounds for reducing iron excess or iron excess: target To ASO and siRNA Tmprss6, apolipoprotein, synthetic hepcidin and its modified analogues, including mini-hepcidin, hepcidin agonist, transferrin inhibitor, iron chelate, curcumin, SSP-004184, Deferitrin, deferasirox, deferoxamine and/or deferiprone; and/or pharmaceutically active compounds selected from the following: antioxidants, for example Acetylcysteine; antidiabetic drugs, such as GLP-1 receptor agonists; antibiotics, such as vancomycin (Van) or tobramycin; drugs used to treat malaria; anticancer agents ; Antifungal drugs; drugs used to treat neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, including dopamine agonists, such as Levodopa; antiviral drugs, such as interferon-α or Ribavirin; immunosuppressive agents, such as cyclosporin A or cyclosporin A derivatives; iron supplements; vitamin supplements; erythropoiesis stimulators, including antagonists of TGF beta superfamily members ( For example, Luspatercept), antibodies, antibody fragments, non-antibody scaffold drugs or cells that generate activin receptor ligand traps; EPO and ESA, HDAC inhibitors; anti-p-selectin Abs, HA ( Related to SCD), drugs targeting HbS aggregation; anti-inflammatory biological agents; antithrombolytic agents; statins; vasopressors; and compounds that affect muscle contractility; preferably, the at least one additional pharmaceutical activity The compound is selected from iron chelates, which is selected from the group consisting of deferasirox (Exjade®; 4-(3,5-bis(2-hydroxyphenyl)-1H-1,2,4) -Triazol-1-yl)benzoic acid), iron removal energy (DFO; Desferal®; N'-[5-(Acetyl-hydroxy-amino)pentyl]-N-[5-[3-( 5-Aminopentyl-hydroxy-aminomethanyl) propylamino]pentyl)-N-hydroxy-butadiamide), and deferiprone (DFP; Ferriprox®) or selected from transferferrin The group of inhibitors is preferably a transferrin inhibitor according to the following formula

Or any pharmaceutically acceptable salt thereof. Such as the medicine of claim 14 or 15, which contains a compound according to formula (III)

Or any pharmaceutically acceptable salt thereof, and a transferrin inhibitor according to the following formula

Or any pharmaceutically acceptable salt thereof. The compound provided in claims 8 to 13 or the drug as in any one of claims 14 to 16, which is in the form of a formulation for oral administration.

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