Modified ferroportin inhibitors

Abstract

This invention relates to a novel compound having general formula (I), characterized in that at least one of groups A and B contains at least three rings; a pharmaceutical composition comprising the compound and its use as a pharmaceutical agent, particularly as an inhibitor of ferroportin, especially for the prevention and / or treatment of diseases caused by increased iron levels or increased iron absorption and / or iron excess due to a lack of hepcidin or abnormal iron metabolism.

Description

Technical Field

[0001] Invention Field

[0002] This invention relates to a novel compound having general formula (I). And its pharmaceutically acceptable salts. The compounds of general formula (I) of the present invention act as ferroportin inhibitors and are therefore particularly suitable as preventive and / or therapeutic agents for diseases caused by increased iron levels or increased iron absorption due to hepcidin deficiency or abnormal iron metabolism. The compounds of general formula (I) of the present invention are also particularly suitable for the prevention and / or treatment of iron excess, including thalassemia, sickle cell anemia and hemochromatosis, and for the prevention and / or treatment of diseases associated with or caused by increased iron levels, increased iron absorption or iron excess. Prior Technology

[0003] [Background of the Invention and Prior Art]

[0004] Iron is an essential micronutrient for almost all organisms, especially related to growth and blood formation. In this context, the balance of iron metabolism is primarily regulated by the level of iron recovery from heme in aging red blood cells and the absorption of dietary iron in the duodenum. Released iron is absorbed through the intestines, particularly via a specific transport system (DMT-1, membrane iron transporter) into the bloodstream, where it is delivered to appropriate tissues and organs (transferrin, transferrin receptor).

[0005] Mammals cannot actively excrete iron. Iron metabolism is primarily controlled by hepcidin (a peptide hormone produced in the liver), which releases iron through macrophages, hepatocytes, and intestinal cells. Hepcidin acts on the absorption of iron through the intestines and placenta and on the release of iron from the reticuloendothelial system. In vivo, hepcidin is synthesized in the liver from a gene called hepcidinogen, which is encoded by a gene called the HAMP gene. The formation of hepcidin is directly related to the organism's iron levels; that is, if the organism is provided with sufficient iron and oxygen, more hepcidin will be formed, and if the iron and oxygen levels are low, or if erythrocyte production is increased, less hepcidin will be formed. In the small intestinal mucosal cells and macrophages, hepcidin binds to the transport protein membrane iron transporter (which normally transports phagocytosed circulating iron from inside the cell into the bloodstream).

[0006] Membrane siderotransporters are transmembrane proteins composed of 571 amino acids, formed in the liver, spleen, kidneys, heart, intestines, and placenta. In particular, membrane siderotransporters are confined to the basolateral membrane of intestinal epithelial cells. Membrane siderotransporters bound in this manner thus function to transport iron into the bloodstream. In this case, membrane siderotransporters are most likely to transport iron in the form of Fe²⁺. If hepcidin binds to membrane siderotransporters, the membrane siderotransporters are transported into the cell interior, where they are broken down, thereby almost completely blocking the release of phagocytosed circulating iron from the cell. If membrane siderotransporters are inactivated by, for example, hepcidin, they cannot transport iron stored in mucosal cells, and the stored iron is lost through feces with the natural shedding of cells. Therefore, when membrane siderotransporters are inactivated or inhibited by, for example, hepcidin, iron absorption in the intestine is reduced. Furthermore, membrane siderotransporters are distinctly confined to the reticuloendothelial system (RES), to which macrophages also belong. On the other hand, if serum iron levels decrease, the production of hepcidin in hepatocytes of the liver decreases, resulting in the release of less hepcidin. Consequently, fewer membrane iron transport proteins lose their activity, allowing more stored iron to be transported into the serum.

[0007] Therefore, the hepcidin-membrane iron transporter system directly regulates iron metabolism, and thus, disruption of the hepcidin regulatory mechanism has a direct impact on iron metabolism in organisms. In principle, the hepcidin-membrane iron transporter regulatory mechanism operates through the following two opposing principles: On the one hand, increased hepcidin leads to the inactivation of membrane iron transport proteins, thus hindering the release of stored iron from cells into the serum, thereby lowering serum iron levels. Under pathological conditions, decreased serum iron levels result in decreased heme levels and reduced erythrocyte production, leading to iron deficiency anemia.

[0008] On the other hand, a decrease in hepcidin leads to an increase in active membrane iron transport proteins, thereby allowing the release of stored iron and increasing iron uptake from sources such as food, thus increasing serum iron levels. In pathological conditions, elevated iron levels can lead to iron overload.

[0009] The hallmark of iron excess and related diseases is an excessively high iron level. In particular, an excessively high serum iron level leads to problems with non-transferrin-bound iron (NTBI). NTBI is rapidly and non-specifically absorbed by organs, resulting in iron accumulation in tissues and organs. Iron excess can cause a number of diseases and undesirable conditions, including damage to the heart, liver, and endocrine system. Furthermore, iron accumulation in the brain has been observed in patients with neurodegenerative diseases such as Alzheimer's and Parkinson's. A particularly harmful aspect of excess free iron must be mentioned is the formation of unwanted free radicals. In particular, iron(II) ions catalyze the formation of reactive oxygen species (ROS) (especially through the Fenton reaction). These ROS damage DNA, lipids, proteins, and carbohydrates, with profound effects on cells, tissues, and organs, and are well-known and described in the literature, leading to so-called oxidative stress.

[0010] In addition to conventional methods of treating iron excess by removing iron from the body, such as chelating agents like deferoxamine (also known as deferoxamine B,N'-{5-[acetylated(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyl)pentyl]-N-hydroxybutyridine or Desferal®), deferasirox (Exjade®, 4-(3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzoic acid) and deferiprone (Ferriprox®, 3-hydroxy-1,2-dimethylpyridin-4(1H)-one), compounds have been described as hepcidin agonists or compounds that inhibit or support biochemical regulatory pathways in iron metabolism, such as hepcidin mimic peptides. This treatment method is based on directly intervening in the disrupted iron metabolism pathway by providing hepcidin mimics or hepcidin agonists, which act directly through the main regulator hepcidin, thus functioning as a hepcidin substitute or supplier. The method is based on the principle of treating iron excess (i.e., hyperferrocyanosis) by inhibiting membrane iron transport proteins through a hepcidin-deactivation mechanism.

[0011] Membrane transfer protein inhibitors and their preparation methods have been described in WO2017 / 068089, WO2017 / 068090, and international application WO2021 / 191202. Furthermore, international application WO2018 / 192973 describes the preparation and crystallization of various specific salts of selected membrane transfer protein inhibitors as described in WO2017 / 068089 and WO2017 / 068090.

[0012] WO2011 / 029832 relates to thiazoles that act as hepcidin antagonists and The compound is an azole compound, and its indications are for the treatment of iron deficiency diseases. Summary of the Invention

[0013] [Purpose of this invention]

[0014] The object of this invention is to provide a novel, therapeutically effective compound for the prevention and treatment of iron metabolism abnormalities associated with increased iron levels, particularly iron overload. In another object, the novel compound should exhibit few side effects and very low toxicity, along with good bioavailability and compatibility. Furthermore, compared to known iron chelating compounds, such a novel compound should be suitable for preventing increased iron levels and related diseases, rather than removing excess iron from the body after iron overload has already occurred. In yet another object, compared to known biomolecular compounds such as antibodies, the novel compound should have a defined structure (stoichiometry) and should be prepared by simple synthetic methods, exhibiting lower sensitivity and improved durability.

[0015] This objective is achieved by developing novel compounds based on chemical formulas as defined herein, such as, in particular, formula (I), which have been found to act as inhibitors of membrane iron transport proteins and are therefore suitable for inhibiting iron transport. Thus, they can effectively prevent and treat iron metabolism abnormalities associated with increased iron levels, such as, in particular, iron excess, as well as prevent and treat diseases caused by hepcidin deficiency, diseases associated with or caused by increased iron levels or iron excess, and diseases associated with ineffective erythropoiesis. Implementation

[0016] [Detailed Description of the Invention]

[0017] The inventors have surprisingly discovered that specific compounds having the structure of general formula (I) as defined herein act as inhibitors of membrane iron transport proteins, thus effectively inhibiting iron transport, and are therefore particularly suitable as pharmaceutical agents, especially for the treatment and / or prevention of diseases caused by hepcidin deficiency, diseases associated with ineffective erythropoiesis, or iron metabolism abnormalities leading to increased iron levels, such as, in particular, iron excess states, such as, in particular, thalassemia and hemochromatosis. In particular, this new compound has proven suitable for the treatment of thalassemia and hemochromatosis. This new compound is also suitable for the treatment of diseases caused by pathologically low hepcidin levels and is suitable for inhibiting iron transport. In particular, the new compounds described herein exhibit good metabolic stability and good bioavailability, making them particularly suitable as pharmaceutical compounds.

[0018] Accordingly, the present invention relates to a novel compound having general formula (I), in l is an integer of 1 or 2; m and n are independent integers of 1, 2, or 3; X1 is N, S, or O; X 2 is N, S, O, or CR 4; X 3 is C or N; However, the condition is that one of X1 and X2 is N. And if X3 is N, then X2 is CR4; and where... R 4 represents - H, - Halogen, - Straight-chain or branched C1-C3-alkyl, or - Straight-chain or branched C1-C3-haloalkyl, A represents one of the following groups: (a-1), (a-2), (a-3), (a-4), and (a-5). (a-1) (a-2) (a-3) (a-4) (a-5) * indicates the binding position; R1 and R2 represent independently - H, - Halogen, - Straight-chain or branched C1-C3-alkyl, - Straight-chain or branched C1-C3-haloalkyl, or - Straight-chain or branched C1-C3-alkoxy groups; In equations (a-2), (a-3), and (a-4), one of C1, C2, and C3 exists; and in equation (a-5), both C4 and C5 exist; and C1, C2, C3, C4, and C5 independently represent - Fused 6-membered aryl ring, - Dysmerized 5- or 6-membered heteroaryl rings, - Fused 5- or 6-membered cycloalkyl rings, or - Fused 5- or 6-membered heterocyclic rings; and Groups (a-2), (a-3), (a-4), and (a-5) have 0, 1, 2, or 3 substituents, which are independently selected from... - Halogen, - Straight-chain or branched C1-C3-alkyl, - Straight-chain or branched C1-C3-haloalkyl, or - Straight-chain or branched C1-C3-alkoxy groups; B represents one of the following groups: (b-1), (b-2), and (b-3). (b-1) (b-2) (b-3) * indicates the binding position; R 3 represents - H, - Unsubstituted or substituted 6-membered aryl groups, - Unsubstituted or substituted 5 or 6-membered heteroaryl groups, - Unsubstituted or substituted bicyclic heteroaryl groups, - 5 or 6-membered cycloalkyl, - 5 or 6-membered heterocyclic groups, - 5 or 6-membered heterocyclic alkyl groups, - 6-membered aryl, - Unsubstituted or substituted 6-membered aryynyl group, - Unsubstituted or substituted 5 or 6-membered heteroaryynyl groups, or - Phenyl, which forms a fused bicyclic ring with a 5- or 6-membered cycloalkyl or heterocyclic group; Z 1 represents N or C, However, the condition is that there is no more than one Z1 representing N; In equations (b-2) and (b-3), there exists one of D1, D2, and D3 that represents - Fused 6-membered aryl ring, - Dysmerized 5- or 6-membered heteroaryl rings, - Fused 5- or 6-membered cycloalkyl rings, - Fused 5- or 6-membered heterocyclic rings; and Groups (b-2) and (b-3) have 0, 1, 2, or 3 substituents, which are independently selected from... - Halogen, - Straight-chain or branched C1-C3-alkyl, - Straight-chain or branched C1-C3-haloalkyl, - Straight-chain or branched C1-C3-alkoxy groups; Z2 and Z3 represent N or C, However, the condition is that Z2 can represent N when D2 exists, and Z3 can represent N when D3 exists; The compound (I) therein is characterized in that at least one of groups A and B contains at least three rings; And its pharmaceutically acceptable salts. [definition]

[0019] The term "substituted" means that one or more hydrogen atoms on a specified atom or group are replaced by a selection of the indicated group, provided that the replacement does not exceed the constant valence of the specified atom under existing conditions. Combinations of substituents and / or variants are permitted.

[0020] The terms "optionally substituted" or "optionally substituented" mean that the number of substituents may be equal to or not equal to 0. Unless otherwise stated, an optionally substituted group can be formed by replacing any available carbon or nitrogen atom with as many optional substituents as possible that a hydrogen atom can accommodate, using non-hydrogen substituents. Typically, the number of optional substituents may be 1, 2, 3, 4, or 5, especially 1, 2, or 3.

[0021] In the definition of substituents in the compound of general formula (I) of this invention, if the term "one or more" is used, it means "1, 2, 3, 4 or 5, especially 1, 2, 3 or 4, more particularly 1, 2 or 3, or even more particularly 1 or 2".

[0022] The terms “comprising” or “containing” when used in the scope of an invention application or specification include “consisting of”.

[0023] If any term is referred to as “as it is mentioned herein” or “as it is defined herein (anywhere)” in this specification, it means that it may be referred to anywhere in this specification or may have the meaning as defined anywhere in this specification. The terms used in the scope of the patent application and the specification have the following meanings:

[0024] "Halogen" or "halogen atom" refers to a fluorine, chlorine, bromine, or iodine atom, especially a fluorine, chlorine, or bromine atom, with chlorine or fluorine being a preferred choice, bromine or fluorine being an even better choice, and fluorine being the most desirable.

[0025] The term "C1-C3 alkyl" refers to a straight or branched, saturated, monovalent hydroxyl group having 1, 2, or 3 carbon atoms, such as methyl, ethyl, n-propyl, or isopropyl.

[0026] The C1-C3-alkyl group may optionally be substituted with one or two substituents, preferably one substituent. This optional substituent is preferably selected from the group consisting of: halogens (forming halogen-substituted C1-C3-alkyl groups as defined below, also referred to herein as “C1-C3-haloalkyl”), aryl, heteroaryl, cycloalkyl, or heterocyclic rings. Examples include C3-C6 cycloalkyl groups containing preferably 3, 4, 5, or 6 carbon atoms, preferably such as cyclopropyl and cyclohexyl (also referred to herein as “C1-C3-cycloalkyl”), C5-C6 member heterocyclic rings, preferably such as... linyl and piperin The compounds are alkyl (also referred to herein as "heterocyclic alkyl"), aryl rings, preferably phenyl (also referred to herein as "aryl"), or C5-C6 heteroaryl rings (also referred to herein as "heteroaryl").

[0027] The term "C1-C3-haloalkyl" refers to a straight-chain or branched, saturated, monovalent C1-C3-alkyl group having the meaning defined above, wherein one or more hydrogen atoms are substituted by the same or different halogen atoms. Specifically, the halogen atom is a chlorine or fluorine atom. More specifically, the halogen atom is a fluorine atom, and even more specifically, all halogen atoms are fluorine atoms ("C1-C3-fluoroalkyl"). The C1-C3-haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, or 1,3-difluoropropyl-2-yl, wherein trifluoromethyl is particularly preferred.

[0028] The term “C1-C3-alkoxy” means a straight or branched, saturated, monovalent group of the formula (C1-C3-alkyl)-O- (wherein the definition of the term “C1-C3-alkyl” is as above), such as methoxy, ethoxy, n-propoxy, or isopropoxy, with methoxy being particularly preferred.

[0029] The term "amine carbonyl" refers to the group -[NR y-(C=O)-], or, in the case where the terminal amine carbonyl is substituent, it can be represented by the group NR yR z(C=O)-, wherein R y and R z preferably and independently represent H or C 1-C 3-alkyl, preferably such as methyl, including amine carbonyl, monoalkyl-amine carbonyl and dialkyl-amine carbonyl.

[0030] Generally, the term "aryl" includes aromatic hydrocarbon residues containing 6 to 14 carbon atoms (excluding carbon atoms of possible substituents), which can be monocyclic or bicyclic, including, for example, phenyl, naphthyl, phenanthryl, and anthracene. Preferably, a 6-membered aryl group, such as phenyl.

[0031] Generally, the term "heteroaryl" includes heteroaromatic hydrocarbon residues containing 4 to 9 ring carbon atoms, which additionally contain 1 to 3 identical or different heteroatoms selected from S, O and N in the ring, thus forming 5 to 12 heteroaromatic residues, which can be monocyclic or bicyclic.

[0032] Monocyclic heteroaryl groups preferably include 5- and 6-membered monocyclic heteroaryl groups, such as pyridyl (pyridyl), pyridyl-N-oxide, and pyridyl-N-oxide. pyrimidinyl, pyrimidinyl Thiophene (thiophenyl), furanyl, pyrrolyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, azole or isopropyl Azolyl group, including groups selected from 5-membered heteroaryl groups, such as thiazolyl, such as thiazolyl-2-yl, 2-thiazolyl-2-yl, 2-thiazolyl-4-yl; thiophene (thiophenyl), such as thiophene-3-yl; pyrazolyl, such as 1-pyrazol-4-yl, 3-pyrazol-5-yl; imidazole, such as imidazole-2-yl, 2-imidazole-4-yl, 1-imidazole-4-yl; triazolyl, such as 1-triazol-3-yl, 1-triazol-4-yl, such as 1,2,4-triazol-3-yl or 1,2,3-triazol-4-yl; azole group, such as 2- Azol-4-yl, 2- Azol-5-yl; Diazole groups, such as 1,2,4- Diazol-3-yl, and groups selected from 6-membered heteroaryl groups, such as pyridyl (pyridinyl), such as pyridin-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-pyridin-4-yl, 2-pyridin-6-yl, 3-pyridin-5-yl (pyridin-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-pyridin-4-yl, 2-pyridin-6-yl, 3-pyridin-5-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl. Preferred heteroaryl groups are pyridyl, pyrrole, ... Azolium and tetrazolium groups.

[0033] Bicyclic heteroaryl groups preferably include indole Indole, benzo[b]thiophene, benzo[b]furan, indazolyl, quinolinyl, isoquinolinyl, nitryl, quinazolinyl, quinoline, quinoline Phinyl and benzimidazole groups, such as benzimidazole-2-yl, benzimidazole-4-yl, and benzimidazole-5-yl. The benzimidazole group is particularly preferred.

[0034] Generally, the term "cycloalkyl" includes an aliphatic ring containing 3 to 8, more preferably 5 or 6, cyclic carbon atoms. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, with cyclopentyl and cyclohexyl being preferred.

[0035] Generally, the term "heterocyclic group" includes saturated or unsaturated mono- or bicyclic 4- to 8-member heterocyclic residues containing 1 to 3, preferably 1 to 2, the same or different heteroatoms selected from N, O, and S, including nitro, oxo, pyrrolidyl, pyrazolidyl, imidazodinyl, tetrahydrofuranyl, dioxopentyl, tetrahydrothiophene, oxathionyl, piperidinyl, and piperidinyl. Tetrahydropyranyl, thiocyclohexyl, dithiocyclohexyl, trithiocyclohexyl, tetrahydrothiaranyl linyl, thio phyrin, di Alkyl groups, such as azido-1-yl, azido-2-yl, azido-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophene-2-yl, tetrahydrothiophene-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, etc. linyl-1-yl, linyl-2-yl, linyl-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperidin -1-Base, Piperyl -2-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, etc. Dioxolane-yl and dioxolane-2-yl are particularly preferred. Alkyl, piper base and phyllyl residue.

[0036] The aryl, heteroaryl, cycloalkyl, or heterocyclic group can be bonded by direct bonding, C1-C3-alkyl chain, preferably C1-alkyl chain, or alkynyl chain, such as preferably ethynyl chain (-C≡C-), or the aryl, heteroaryl, cycloalkyl, or heterocyclic group can be condensed with an aromatic ring (preferably a benzene ring) to form a fused ring system as described above.

[0037] The aryl, heteroaryl, cycloalkyl, or heterocyclic group, including fused aryl, heteroaryl, cycloalkyl, and heterocyclic groups, may have one, two, or three identical or different substituents selected from halogens as defined above (preferably F, Br, and Cl), C1-C3-alkyl (preferably methyl), C1-C3-haloalkyl (preferably trifluoromethyl), and C1-C3-alkoxy (preferably methoxy) as defined above.

[0038] The aryl, heteroaryl, cycloalkyl or heterocyclic groups defined herein specifically form one of the groups A and / or B as defined herein.

[0039] Wherein, group A represents one of the following groups (a-1), (a-2), (a-3), (a-4), and (a-5). (a-1) (a-2) (a-3) (a-4) (a-5)

[0040] Wherein, group (a-1) is pyridyl, which has 0 substituents (R1 / R2 represent hydrogen) or 1 or 2 identical or different substituents, R1 / R2 being independently selected from halogens as defined above (preferably F, Br and Cl), C1-C3-alkyl (preferably methyl), C1-C3-haloalkyl (preferably trifluoromethyl) as defined above and C1-C3-alkoxy (preferably methoxy) as defined above.

[0041] Groups (a-2), (a-3), and (a-4) represent fused (condensed) ring systems, wherein in formulas (a-2), (a-3), and (a-4), the fused aryl, heteroaryl, cycloalkyl, or heterocyclic rings defined above are present at one of the positions indicated by C1, C2, and C3, preferably forming a fused tricyclic ring system.

[0042] Group (a-5) represents a fused (condensed) ring system in which two identical or different fused rings selected from aryl, heteroaryl, cycloalkyl and heterocyclic rings as defined above are located at the positions indicated by C4 and C5.

[0043] Group B represents one of the following groups (b-1), (b-2), and (b-3). (b-1) (b-2) (b-3)

[0044] Wherein, group (b-1) may represent benzimidazolyl (Z 1=C) or azabenzimidazolyl (one Z 1=N), which has 0 substituents (R 3 represents hydrogen) or 1 or 2 identical or different substituents, preferably 1 substituent. R 3 is selected from aryl, heteroaryl, cycloalkyl, heterocyclic and fused bicyclic ring systems (including benzene rings with fused cycloalkyl or heterocyclic rings) as defined above, which are linked by direct bonding, corresponding to R 3 representing aryl, (monocyclic or bicyclic) heteroaryl, cycloalkyl, heterocyclic or fused bicyclic systems (including benzene rings with fused cycloalkyl or heterocyclic rings), or linked by a C 1-C 3-alkyl chain, preferably a C 1-alkyl chain or an alkynyl chain, preferably such as an ethynyl chain. If Z 1 represents N, the condition is that no more than one Z 1 represents N.

[0045] The aryl, heteroaryl, cycloalkyl, or heterocyclic rings linked through the C1-C3 alkyl chain preferably correspond to R3 representing: aralkyl, heteroaryl, cycloalkylalkyl, or heterocyclic alkyl, wherein "alkyl" preferably represents C1-C3 alkyl. Aryl (e.g., phenyl) and heterocyclic alkyl (e.g., piperazine) methyl methyl) or (P-linylmethyl) is preferred.

[0046] The aryl, heteroaryl, cycloalkyl, or heterocyclic group linked through an alkynyl chain, preferably an ethynyl chain, corresponds to R3 representing the following: arylynyl, heteroarylynyl, cycloalkynyl, or heterocyclic alkynyl, wherein "alkynyl" preferably represents ethynyl. Arylyl (e.g., benzoynyl) and heteroaryl (e.g., pyridineethynyl) are preferred. The aryl, heteroaryl, cycloalkyl, or heterocyclic ring may have 1, 2, or 3 identical or different substituents selected from halogens as defined above, preferably F, Br, and Cl; C1-C3-alkyl, preferably methyl; C1-C3-haloalkyl as defined above, preferably trifluoromethyl; C1-C3-alkoxy as defined above, preferably methoxy; aminohydroxyl as defined above, preferably dimethylamine carbonyl; and 5 or 6-membered heteroaryl as defined above, preferably... Azolium group.

[0047] These groups are also referred to herein as “unsubstituted or substituted aromatic ynyl group”, “unsubstituted or substituted heteroaromatic ynyl group”, “unsubstituted or substituted cycloalkynyl group” and “unsubstituted or substituted heterocyclic ynyl group”.

[0048] Groups (b-2) and (b-3) represent fused (condensed) ring systems, wherein, in formulas (b-2) and (b-3), the fused aryl, heteroaryl, cycloalkyl, or heterocyclic ring as defined above is present at one of the positions indicated by D1, D2, and D3, preferably forming a fused tricyclic system. In formula (b-2), preferably both Z2 and Z3 represent C. If either Z2 or Z3 is N, then Z2 can represent N when D2 is present, and Z3 can represent N when D3 is present. It is also possible that D1, D2, or D3 are present and both Z2 and Z3 represent C.

[0049] Groups (a-2), (a-3), (a-4), (a-5), (b-2), and (b-3) may optionally have 1, 2, or 3, preferably 1 or 2, identical or different substituents, independently selected from halogens, such as preferably Cl or F; straight-chain or branched C1-C3-alkyl groups, such as preferably methyl or ethyl; straight-chain or branched C1-C3-haloalkyl groups, such as preferably trifluoromethyl; straight-chain or branched C1-C3-alkoxy groups, such as preferably methoxy; alkoxyalkyl ether groups, such as preferably methoxyethyl ether groups [-O-CH2-CH2-O-CH3]; amine carbonyl groups, such as preferably dimethylamine carbonyl; and 5 or 6 heteroaryl groups, such as preferably The azole group is defined as above. This optional substituent is also indicated by Rx. The following formula includes possible unsubstituted groups, where Rx is absent or corresponds to hydrogen.

[0050] From group (a-1), unsubstituted pyridinyl groups (R1 and R2 represent hydrogen) and the following substituted pyridinyl groups are particularly preferred: From group (a-2), the following groups are particularly preferred: From group (a-3), the following groups are particularly preferred: From group (a-5), the following groups are particularly preferred: From group (b-1), the following groups are preferred, wherein R x may be absent (i.e., representing hydrogen) or may have the meaning defined above: From group (b-2), the following groups are particularly preferred: From group (b-3), the following groups are particularly preferred:

[0051] The compound of formula (I) of this invention is characterized in that at least one of groups A and B contains at least three rings. This means that one or two of groups A and B represent a ring system with at least three fused rings, wherein the individual fused ring can be independently selected from aryl, heteroaryl, cycloalkyl, and heterocyclic groups as defined above. The expression “at least one of groups A and B contains at least three rings” also includes compounds in which A is represented by group (a-1) and B by group (b-1), provided that in this case, R 3 does not represent hydrogen, but rather a (substituted or unsubstituted) aryl, heteroaryl, cycloalkyl, or heterocyclic ring, or a fused bicyclic ring system, including a benzene ring with a fused cycloalkyl or heterocyclic ring as defined above, which is bonded by direct bonding or by a C1-C3-alkyl chain or alkynyl chain as defined above. This means that the expression “at least one of groups A and B contains at least three rings” is not limited to a fused tricyclic ring system.

[0052] In equations (a-1), (a-2), (a-3), (a-4), (a-5), (b-1), (b-2), and (b-3), "*" indicates the binding position.

[0053] In equation (I), “l” represents an integer of 1 or 2, preferably l = 1.

[0054] In equation (I), “m” and “n” independently represent integers of 1, 2 or 3, preferably m = 2 and preferably n = 1 or 2.

[0055] In equation (I), X1, X2, and X3 are selected from: X 1 = N, S, or O; X 2 = N, S, O or CR 4; X 3 = C or N; However, the condition is that one of X1 and X2 is N, and if X3 is N, then X2 is CR4, forming one of the following groups: Wherein, * indicates the binding position with the amine carbonyl group in formula (I) and ** indicates the binding position with the -[(CH 2)] m-amine-[(CH 2)] n- group in formula (I).

[0056] R4 represents any substituent selected from halogens, straight-chain or branched C1-C3-alkyl groups, and straight-chain or branched C1-C3-haloalkyl groups, as defined above. If no substituent is present, R4 represents hydrogen.

[0057] The better one is azole-, isopropylamine azole-, thiazole-, and isothiazole- groups; , , , Azole and isopropylamine An azole group is preferred.

[0058] Other states relate to compounds of formula (I) as defined above, wherein l is an integer of 1 or 2; m and n are independent integers of 1, 2, or 3; X1 is N, S, or O; X 2 is N, S, O, or CR 4; X 3 is C or N; However, the condition is that one of X1 and X2 is N; And if X3 is N, then X2 is CR4; and where... R 4 represents H; A represents one of the groups (a-1), (a-2), (a-3), (a-4), and (a-5) as defined above; R1 and R2 represent independently - Hydrogen - Halogen, - Straight-chain or branched C1-C3-alkyl, - Straight-chain or branched C1-C3-haloalkyl, - Straight-chain or branched C1-C3-alkoxy groups; each as defined above. In equations (a-2), (a-3), and (a-4), one of C1, C2, and C3 exists; and in equation (a-5), both C4 and C5 exist; and C1, C2, C3, C4, and C5 represent fused benzene rings; and Groups (a-2), (a-3), (a-4), and (a-5) have 0 or 1 substituents, selected from... - Halogen, - Straight-chain or branched C1-C3-alkyl, - Straight-chain or branched C1-C3-haloalkyl, - Straight-chain or branched C1-C3-alkoxy groups; each as defined above. B represents one of the following groups (b-1), (b-2), and (b-3) as defined above; R 3 represents - H, - Unsubstituted or substituted phenyl, - Unsubstituted or substituted 5 or 6-membered heteroaryl groups, - Unsubstituted or substituted bicyclic heteroaryl groups, - 6-member heterocyclic group, - 6-membered heterocyclic alkyl, - Benzyl, - Unsubstituted or substituted phenylethynyl group or unsubstituted or substituted 6-membered heteroaryl ethynyl group, or - Phenyl, which forms a fused bicyclic ring having 5 or 6-membered cycloalkyl or heterocyclic groups; The definitions are as above, and for possible substituents, refer to the definitions of aryl, heteroaryl, cycloalkyl, and heterocyclic groups as above, and the possible substituents in each specific group; Z 1 represents N or C, However, the condition is that there is no more than one Z1 representing N; In equations (b-2) and (b-3), there exists one of D1, D2, and D3 that represents - Fused benzene ring, - Dysmerized 6-membered heteroaryl rings, - Fused 6-membered cycloalkyl rings, - Fused 5- or 6-membered heterocyclic rings; and Groups (b-2) and (b-3) have 0 or 1 substituents, which are selected from... - Halogen, - Straight-chain or branched C1-C3-alkyl, - Straight-chain or branched C1-C3-haloalkyl, - Straight-chain or branched C1-C3-alkoxy groups; each as defined above. Z2 and Z3 represent N or C, However, the condition is that Z2 can represent N when D2 exists, and Z3 can represent N when D3 exists; and The compound (I) is characterized in that at least one of groups A and B contains at least three rings; And its pharmaceutically acceptable salts.

[0059] In another embodiment of the invention, the compound of formula (I) as defined anywhere herein is characterized in that one of groups A and B contains three rings.

[0060] In another embodiment of the invention, preferably, group A in the compound of formula (I) as defined anywhere herein is group (a-1).

[0061] In another embodiment of the invention, preferably, group A in the compound of formula (I) as defined anywhere herein is group (a-2), (a-3), or (a-5).

[0062] In another embodiment of the invention, preferably, group A in the compound of formula (I) as defined anywhere herein is group (a-5).

[0063] In another embodiment of the invention, preferably, group B in the compound of formula (I) as defined anywhere herein is group (b-1) or (b-2).

[0064] In another embodiment of the invention, preferably, the possible substituent systems of the groups in the compound of formula (I) as defined anywhere herein are selected from the following groups. - Halogen substituents, representing F, Cl and Br, preferably F or Br, alternatively F or Cl, with F being the best; - Straight-chain or branched C1-C3-alkyl substituents, representing methyl or ethyl, with methyl being the most preferred. - Straight-chain or branched C1-C3 haloalkyl substituents, representing trifluoromethyl (CF3). - Straight-chain or branched C1-C3-alkoxy substituents, representing methoxy groups.

[0065] In another embodiment of the invention, preferably, group A in the compound of formula (I) as defined anywhere herein is selected from the following groups (a-1), (a-2), (a-3), and (a-5): (a-1): (a-2): (a-3): (a-5):

[0066] In another embodiment of the invention, preferably, group A in the compound of formula (I) as defined anywhere herein is selected from the following groups (a-1), (a-2), (a-3), and (a-5): In a particularly favorable state, the compounds of formula (I) as defined anywhere in this document are selected from the following compounds:

[0067] Pharmaceutically acceptable salts of the compounds according to the present invention include, for example, salts with suitable anions, such as carboxylates, sulfonates, sulfates, chlorides, bromides, iodides, phosphates, tartrates, methanesulfonates, hydroxyethanesulfonates, glycine salts, maleic acid salts, propionates, fumarates, toluenesulfonates, benzenesulfonates, trifluoroacetates, naphthalene disulfonates-1,5, salicylates, benzoates, lactates, malates, 3-hydroxy-2-naphthoic acid-2 salts, citrates, and acetates.

[0068] Pharmaceutically acceptable salts of the compounds according to the present invention further include, for example, salts with suitable pharmaceutically acceptable bases, such as, for example, salts with: alkali metal or alkaline earth metal hydroxides, such as NaOH, KOH, Ca(OH)₂, Mg(OH)₂, etc.; amine compounds, such as ethylamine, diethylamine, triethylamine, ethyl diisopropylamine, ethanolamine, diethanolamine, triethanolamine, methyl reduced glucosamine, dicyclohexylamine, dimethylaminoethanol, procaine, diphenylmethylamine, N-methyl Phosphoryl, arginine, lysine, ethylenediamine, N-methylpiperidine, 2-amino-2-methyl-propanol-(1), 2-amino-2-methyl-propanediol-(1,3), 2-amino-2-hydroxy-methyl-propanediol-(1,3) (TRIS), etc.

[0069] The novel compounds of this invention may exist in amorphous, crystalline or partially crystalline forms, or in hydrate form.

[0070] It has been surprisingly found that novel compounds of formula (I), as defined anywhere in this document, act as inhibitors of membrane iron transport proteins and are therefore suitable for use as pharmaceutical agents, particularly as inhibitors of membrane iron transport proteins.

[0071] As described above, membrane siderotransferrin is an iron transport protein responsible for absorbing released iron through the intestine and transferring it into the bloodstream, thereby delivering iron to appropriate tissues and organs. Deactivation or inhibition of membrane siderotransferrin prevents iron export, thus reducing intestinal iron absorption. Therefore, membrane siderotransferrin inhibition, in the context of this invention, includes inhibiting iron transport from cells into the bloodstream and inhibiting iron absorption in the intestine. In this document, inhibition of iron transport and / or iron reflux can be influenced by various mechanisms, including, for example, inhibiting the iron transport activity of membrane siderotransferrin, thus inhibiting iron reflux; triggering membrane siderotransferrin internalization, degradation, and / or reduction; administering hepcidin agonists, i.e., compounds that compete with hepcidin; or utilizing compounds that inhibit the binding of hepcidin to membrane siderotransferrin.

[0072] Inhibition of membrane transport proteins can be determined by measuring the inhibition of membrane transport protein-mediated iron transport activity in an iron reaction assay (BLAzer-Assay), as described in more detail in the following examples. Furthermore, inhibition of membrane transport proteins can be determined by measuring membrane transport protein internalization and / or degradation in a membrane transport protein internalization and degradation assay (FACS), or by examining membrane transport protein ubiquitination and degradation, each described in more detail in the following examples. Additionally, inhibition of membrane transport proteins can be determined by measuring the activity of hepcidin as an agonist, for example by determining the binding affinity of hepcidin to membrane transport proteins in a hepcidin internalization assay (J774), as described in more detail in the following examples. Furthermore, inhibition of membrane transport proteins can be determined by confirming the inhibition of hepcidin binding to membrane transport proteins, for example, in a biophysical membrane transport protein-hepcidin binding assay (Hep Bind FP), as described in more detail in the following examples. Furthermore, inhibition of membrane iron transport proteins can be determined by measuring the activity of a compound in terms of its ability to block iron efflux via membrane iron transport proteins, for example using a test that measures the inhibition of iron efflux, which is described in more detail in the following examples.

[0073] In the context of this invention, membrane transfer protein inhibition can therefore be specifically defined by exhibiting inhibitory activity of membrane transfer proteins in at least one of the aforementioned test methods, specifically manifested as follows: In the Blazer Assay, inhibition of iron transport activity mediated by membrane iron transport proteins was achieved with an IC50 value [μM] not exceeding 100 (≤ 100), preferably not exceeding 50 (≤ 50), and more preferably below 50 (< 50).

[0074] Membrane iron transporter internalization and degradation analysis (FACS): EC 50 value [μM] not exceeding 100 (≤ 100), preferably not exceeding 50 (≤ 50), and more preferably below 50 (< 50).

[0075] Ubiquitination and degradation of membrane iron transport proteins: In the Western ink dot method, the visual effect is "+ equivalent to hepcidin", "+ / - medium effect" and "+ / + / - stronger than medium effect", with "+" or "+ / + / -" being better and "+" being the best.

[0076] Internal analysis of hepcidin (J774): IC50 value [μM] not exceeding 100 (≤ 100), preferably not exceeding 50 (≤ 50), and more preferably below 50 (< 50).

[0077] Biophysical membrane iron transporter-hepcidin binding analysis: IC50 value [μM] not exceeding 100 (≤ 100), preferably not exceeding 50 (≤ 50), and more preferably below 50 (< 50).

[0078] Suppression of iron efflux: IC50 value not exceeding 100 (≤ 100), preferably not exceeding 50 (≤ 50), and more preferably below 50 (< 50).

[0079] Inhibition of membrane iron transporters can be further determined in in vivo models, as detailed in the examples below. Suitable in vivo models may include, for example, examining hypoferemia in naïve mice by measuring decreased serum iron; examining the prevention of iron absorption in anemic rats by measuring serum iron inhibition; examining the correction of hyperferemia in β2-microglobulin-deficient mice by measuring decreased serum iron; examining the prevention of iron overload in β2-microglobulin-deficient mice by measuring total iron in the spleen or liver; and examining the improvement of anemia, ineffective erythropoiesis, and iron overload in an intermediate β-thalassemia mouse model.

[0080] The activity of the compounds of the present invention as inhibitors of membrane iron transport proteins can be determined, in particular, by the methods described in the following examples.

[0081] As further explained above, inhibition of membrane iron transport proteins can be influenced by, for example, hepcidin, which is an essential regulator of iron absorption. Hepcidin inhibits membrane iron transport proteins, thus blocking iron transport from cells to the bloodstream and iron absorption. Surprisingly, many of the compounds defined herein act as hepcidin mimics or hepcidin agonists, and in the context of this invention, also include membrane iron transport protein inhibition.

[0082] Accordingly, the compounds defined in this invention are also suitable for inhibiting iron transport from cells into the bloodstream and inhibiting iron absorption in the intestine, as well as for use as hepcidin mimics or hepcidin agonists.

[0083] Since the compounds defined herein are inhibitors of membrane iron transport proteins, the compounds of this invention are particularly suitable for inhibiting iron transport mediated by membrane iron transport proteins, thereby preventing and / or treating iron metabolism disorders leading to increased iron levels, diseases associated with or resulting from increased iron levels, increased iron absorption, or iron excess, such as, in particular, tissue iron excess, diseases associated with ineffective erythropoiesis, or diseases caused by decreased hepcidin levels. Furthermore, the compounds of this invention are suitable for use as adjunctive therapy to prevent or treat infections caused by pathogenic microorganisms such as Vibrio vulnificus through limiting the amount of iron available to them.

[0084] Diseases associated with, related to, caused by, or resulting from increased iron levels, increased iron absorption, iron excess (e.g., tissue iron excess), or ineffective erythropoiesis include thalassemia, heme disorders such as heme E disease (HbE), heme H disease (HbH), hemochromatosis, hemolytic anemia such as sickle cell anemia, and congenital erythropoiesis disorder anemia.

[0085] Diseases associated with, related to, or caused by increased iron levels, increased iron absorption, iron excess (e.g., tissue iron excess), and further including neurodegenerative diseases such as Alzheimer's and Parkinson's, in which the compound is thought to act by limiting or increasing iron deposition in tissues or cells.

[0086] The compounds of this invention are also applicable to the prevention and / or treatment of the formation of free radicals, reactive oxygen species (ROS) and oxidative stress caused by excessive iron or iron excess, as well as the prevention and / or treatment of cardiac, hepatic and endocrine damage caused by excessive iron or iron excess, and further the prevention and / or treatment of inflammation triggered by excessive iron or iron excess.

[0087] Diseases associated with ineffective erythropoiesis include, in particular, myelomectomy syndrome (MDS) and congenital dysplastic anemia, as well as myeloproliferative neoplasms such as polycythemia vera.

[0088] Further diseases, abnormalities, and / or symptoms include iron overload caused by mutations in genes involved in sensing systemic iron stores, such as hepcidin (Hamp1), hemochromatin (HFE), hemojuglin (HJV), and transferrin receptor 2 (TFR2), such as diseases particularly associated with mutations in the HFE and HJV genes, diseases associated with chronic hemolysis, sickle cell disease, erythrocyte membrane abnormalities, glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency), erythrocytic porphyria, Friedrich's ataxia, and subgroups of iron overload such as transfusion iron overload, iron poisoning, pulmonary hemosiderosis, osteopenia, insulin resistance, African iron overload, Hallervordans, etc. Spatz disease, ferritinemia, ceruloplasmin deficiency, neonatal hemochromatosis and erythrocyte disorders, including thalassemia, including α-thalassemia, β-thalassemia and δ-thalassemia, moderate thalassemia, sickle cell disease and bone marrow biochemical syndrome.

[0089] Other diseases and / or abnormalities and / or symptoms associated with elevated iron levels include, but are not limited to, diseases of elevated iron levels, including ataxia, Friedreich ataxia, age-related macular degeneration, age-related cataracts, age-related retinal diseases, and neurodegenerative diseases such as pantothenate kinase-related neurodegenerative diseases, restless legs syndrome, and Huntington's disease.

[0090] The compounds of this invention are also suitable for the prevention and treatment of diseases caused by hepcidin deficiency.

[0091] In view of this, another object of the present invention relates to a pharmaceutical agent containing one or more compounds as defined above, such as, in particular, an agent for the prevention and treatment of any indication, condition, abnormality or disease as defined above.

[0092] Another object of the present invention relates to a pharmaceutical composition and agent comprising one or more of the compounds of the present invention as defined above, and optionally one or more pharmaceutically acceptable carriers and / or excipients and / or solvents. Another object of the present invention relates to a pharmaceutical composition and agent comprising one or more of the compounds of the present invention as defined above, and optionally one or more other pharmaceutically effective compounds. The pharmaceutical composition contains, for example, up to 99% by weight, up to 90% by weight, up to 80% by weight, or up to 70% by weight of the compounds of the present invention, the remainder being formed from pharmaceutically acceptable carriers and / or excipients and / or solvents and / or optionally other pharmaceutically active compounds.

[0093] The pharmaceutically acceptable carrier, adjuvant, or solvent is a commonly used pharmaceutical carrier, adjuvant, or solvent, including various organic or inorganic carriers and / or auxiliary materials, which are typically used for pharmaceutical purposes, particularly for solid dosage forms. Examples include excipients such as sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, and calcium carbonate; binders such as cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, and starch; disintegrants such as starch, hydrolyzed starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, hydroxypropyl starch, sodium glycol starch, sodium bicarbonate, calcium phosphate, and calcium citrate; lubricants such as magnesium stearate, talc, and sodium lauryl sulfate; and flavorings such as citric acid and menthol. Glycine, orange powder; preservatives, such as sodium benzoate, sodium bisulfite, parabens (e.g., methylparaben, ethylparaben, propylparaben, butylparaben); stabilizers, such as citric acid, sodium citrate, acetic acid, and polycarboxylic acids from the titriplex series, such as diethylenetriaminepentaacetic acid (DTPA); suspending agents, such as methylcellulose, polyvinylpyrrolidone, aluminum stearate; dispersants; diluents, such as water, organic solvents; waxes, fats and oils, such as beeswax, cocoa butter; polyethylene glycol; white petrolatum, etc.

[0094] Liquid pharmaceutical formulations, such as solutions, suspensions, and gels, typically contain a liquid carrier, such as water, and / or a pharmaceutically acceptable organic solvent. In addition, such liquid formulations may contain pH adjusters, emulsifiers or dispersants, buffers, preservatives, wetting agents, gelling agents (e.g., methylcellulose), dyes, and / or fragrances, as defined above. The composition may be isotonic, meaning it can have the same osmotic pressure as blood. The isotonicity of the composition can be adjusted using sodium chloride and other pharmaceutically acceptable reagents, such as dextran, maltose, boric acid, sodium tartrate, propylene glycol, and other inorganic or organic soluble substances. The viscosity of the liquid composition can be adjusted using a pharmaceutically acceptable thickener, such as methylcellulose. Other suitable thickeners include, for example, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, etc. The optimal concentration of the thickener depends on the reagent chosen.

[0095] Pharmaceutically acceptable preservatives can be used to extend the shelf life of this liquid composition. While a variety of preservatives can be used, including, for example, parabens, sodium ethylmercuric thiosalicylate, chlorobutanol, and dimethyl chlorobenzyl ammonium, benzyl alcohol may be more suitable.

[0096] The above-mentioned pharmaceutical compositions are suitable for, for example, intravenous, intraperitoneal, intramuscular, intravaginal, buccal, transdermal, subcutaneous, mucocutaneous, oral, rectal, transdermal, topical, intradermal, gastric, or intracutaneous administration, and are provided in, for example, pills, tablets, enteric-coated tablets, film tablets, layer tablets; sustained-release dosage forms (especially as ointments), long-acting dosage forms, sugar-coated pills, suppositories, gels, ointments, syrups, granules, suppositories, emulsions, dispersants, microcapsules, microformulations, nanoformulations, liposome formulations, capsules, enteric-coated capsules, powders, inhalation powders, microcrystalline formulations, inhalation sprays, powders, drops, nasal drops, nasal sprays, aerosols, ampoules, solutions, juices, suspensions, infusions, or injectable solutions.

[0097] Another object of the present invention relates to a pharmaceutical preparation or combination thereof containing one or more of the compounds as defined above and at least one other pharmaceutically active compound, such as, in particular, compounds for the prevention and treatment of iron overdose and related symptoms, preferably iron chelating compounds, or compounds for the prevention and treatment of any state, abnormality or disease as defined above, such as, in particular, pharmaceutically active compounds for the prevention and treatment of thalassemia, hemochromatosis, neurodegenerative diseases (e.g., Alzheimer's disease or Parkinson's disease) and related symptoms.

[0098] Another object of the present invention relates to the use of the compound as defined above in combination therapy (fixed-dose or continuously administered free-dose combination) with one or two other active ingredients (medications). Such combination therapy involves co-administering the compound of the present invention with at least one additional pharmaceutically active compound (medication). Fixed-dose combination therapy involves administering the compound of the present invention with at least one additional pharmaceutically active compound in a fixed-dose formulation. Free-dose combination therapy involves co-administering the compound of the present invention with at least one additional pharmaceutically active compound at a free dose of each compound, either by simultaneous administration of the individual compounds or by sequential administration of the individual compounds over a period of time. The at least one additional pharmaceutically active compound (drug) contains a drug specifically for reducing iron excess (e.g., Tmprss6-ASO) or an iron chelator, especially curcumin, SSP-004184, deferitrin, deferasirox, deferoxamine, and / or deferiprone, or an antioxidant such as n-acetylcysteine, an antidiabetic drug such as a GLP-1 receptor agonist, or an antibiotic. Examples of antiviral drugs include vancomycin or tobramycin, antimalarial drugs, anticancer agents, antifungal drugs, drugs for treating neurodegenerative diseases such as Alzheimer's and Parkinson's (e.g., dopamine agonists, such as levodopa), antiviral drugs such as interferon-alpha or ribavirin, or immunosuppressants (cyclosporine A or cyclosporine A derivatives), iron supplements, vitamin supplements, erythropoiesis stimulants, anti-inflammatory biologics, anticoagulants, statins, vasopressins, and muscle-contracting compounds.

[0099] Other objects of the present invention relate to the use of the above-described combination in the prevention and / or treatment of diseases caused by hepcidin deficiency or abnormal iron metabolism, such as, in particular, iron excess states, such as, in particular, thalassemia and hemochromatosis and other abnormalities as described in this application.

[0100] Other objects of the invention relate to the use of the compounds defined herein or the combination therapies described above in conjunction with blood transfusion.

[0101] The compounds, pharmaceuticals, and / or combinations thereof according to the present invention can be administered orally, parenterally, and intravenously.

[0102] Therefore, the compounds of the present invention are preferably provided in pharmaceutical preparations or pharmaceutical compositions in the form of pills, tablets, such as casing tablets, film tablets and layer tablets, sustained-release formulations for oral administration, long-acting formulations, sugar-coated pills, granules, emulsions, dispersants, microcapsules, microformulations, nanoformulations, liposome formulations, capsules, such as casing capsules, powders, microcrystalline formulations, powders, drops, ampoules, solutions, suspensions, infusion solutions or injection solutions, or inhalation-suitable formulations.

[0103] In a preferred embodiment of the invention, the compound is administered in the form of tablets or capsules as defined above. These may be present, for example, in an acid-resistant form or in a form with a pH-dependent coating.

[0104] The compounds of this invention, as active substances, can be administered in unit doses, for example, from 0.001 mg / kg to 500 mg / kg body weight, for example, once to four times a day. However, the dose may be increased or decreased depending on age, weight, patient condition, disease severity, or type of administration.

[0105] Accordingly, other objects of the present invention relate to compounds, pharmaceuticals, compositions and combinations as defined above, for the preparation of pharmaceuticals, particularly for the prevention and treatment of any indication, condition, abnormality or disease as defined above, particularly for oral or parenteral administration.

[0106] Other objects of the present invention relate to a method for prevention and treatment as defined above, such particularly for the prevention and / or treatment of iron metabolism disorders (especially iron excess) associated with or causing iron excess, diseases associated with or caused by iron excess, iron storage diseases associated with or causing iron excess, and diseases associated with ineffective red blood cell production, the method comprising administering, to a patient (human or animal) in need, a compound, drug, composition, or combination of preparations as defined above.

[0107] Diseases associated with, related to, caused by, or resulting from increased iron levels or iron excess are as defined above.

[0108] Other objects of the invention relate to the use of the compounds as defined above in the preparation of medicaments, particularly for the prevention and treatment of any of the indications, conditions, abnormalities or diseases as defined above.

[0109] The compound of general formula (I) according to the present invention can be prepared substantially by the method described in unpublished international application PCT / EP2021 / 057424, which is incorporated herein by reference.

[0110] In particular, the following general procedure describes a suitable preparation process: [Step 1:] [] [] [Step 2:] [step] [3:] [, , ] Wherein X1, X2, X3 and groups A and B, as well as l, m and n, have the meanings defined anywhere in this document.

[0111] In other respects, this invention covers intermediate compounds obtained by the preparation methods described herein, particularly those generated in individual steps of the general reaction scheme described above and those further described herein. Details of the preparation conditions are provided in the following examples. [example]

[0112] The invention is illustrated in more detail by way of the following examples. These examples are merely illustrative, and those skilled in the art can extend the specific examples to further claimed compounds. [Pharmacological Analysis] [] [1.] [Internalization analysis of hepcidin (J774)] []

[0113] This cellular assay allows for the quantification of hepcidin binding to the membrane iron transport protein (Fpn) by detecting fluorescently labeled hepcidin internalized into J774 cells under a microscope. J774 is a mouse macrophage cell line that exhibits endogenous Fpn when cultured with iron (Knutson et al., 2005). The binding of hepcidin to Fpn triggers the internalization and degradation of both hepcidin and Fpn. However, even after the degradation of the hepcidin peptide backbone, the TMR (6-carboxytetramethylrhodamine) fluorophore attached to hepcidin remains attached to the cell. Therefore, the microscopic detection of cell-attached TMR fluorescence is a measure of hepcidin-Fpn binding and the internalization of both hepcidin and Fpn. If the binding of TMR-hepcidin to Fpn is impaired, the cellular TMR fluorescence remains at a low level (Dürrenberger et al., 2013). The role of low molecular weight Fpn inhibitor compounds in this assay is evaluated in vitro, as described below.

[0114] J774 cells were collected from approximately 80% confluence cultures and seeded at 8 x 10⁵ cells / ml in complete medium (DMEM, 10% FBS, 1% penicillin-streptomycin) containing 200 μM Fe(III) NTA (nitroglycerin), 100 μl per well in a 96-well MicroClear dish (Greiner; catalog number 655090). The cells were grown at 37°C and 5% CO₂. After overnight culture, the cells were washed three times with pre-warmed phenol red-free DMEM. After the final wash, 30 μl / well of phenol red-free DMEM and 10 μl / well of serially diluted test compound were added, in triplicate. J774 cells were pre-cultured with the test compound at 37°C and 5% CO₂ for 15 minutes, and then TMR-hepcidin was added at a final concentration of 25 nM. Cells were incubated in 50 μl of water at 37°C and 5% CO2 for 2 hours. Hoechst 33342 dye was then added to a final concentration of 0.5 μg / ml for nucleus staining, followed by incubation at 37°C and 5% CO2 for 10 minutes. Cells were washed three times with PBS, and then fixed in 100 μl of 4% polyoxymethylene (POM) in PBS at room temperature for 15 minutes. After removing the POM solution, cells were washed three times with PBS, leaving 100 μl in each well. The wells were then sealed with foil. TMR (530-550 nm excitation / 575-625 nm emission / 400 ms exposure time) and Hoechst 33342 (360-370 nm excitation / 420-460 nm emission / 10 ms exposure time) fluorescence images were captured using a ScanR disc imager (Olympus) with a 20x high-NA objective lens. Four images were captured from each well, with each well's fluorescence channel covering approximately 1500 cells. The captured images were analyzed using ScanR image analysis software. Image analysis included nucleus detection (Hoechst 33342 fluorescence), identification of cell-associated regions, application of virtual channels and confinement to reduce rolling background, followed by a summative (average) algorithm to measure cell-associated TMR fluorescence as a quantification of internalized TMR-hepcidin. IC50 values ​​were calculated using the "log(inhibitor) vs. response" curve fitting method in Prism 5 software (GraphPad Software Inc., version 5.02) with the summative (average) raw data. For each dataset, the fit of the "log(inhibitor) vs. response (three parameters)" model was compared to the fit of the "log(inhibitor) vs. response – Variable slope (four parameters)" model, and the IC50 data using the better model were analyzed.The IC50 data for Fpn inhibitors tested in the hepcidin internalization assay are listed in Table 1. The IC50 for unlabeled hepcidin in this analysis was 0.015 ± 0.011 μM. [Table 1] [, indicating the analysis of hepcidin internalization for Fpn] [Average of measurements from multiple inhibitor tests (AVE) IC,] 50 , ] [data. ] [Table 1] [2.] [Biophysical membrane iron transport protein-] [Hepcidin binding analysis]

[0115] This biophysical analysis was developed to more directly confirm the inhibition of hepcidin binding to membrane iron transporter (Fpn). Culture of TMR-hepcidin and purified human Fpn isolated from Pichia pastoris yeast cells, exhibiting human Fpn with a C-terminal FLAG affinity tag (Bonaccorsi di Patti, 2014), induced an increase in the fluorescence polarization (FP) of the TMR-hepcidin ligand. The inhibition of TMR-hepcidin binding to Fpn by low molecular weight Fpn inhibitors was tested by detecting a dose-dependent decrease in the TMR FP signal, as detailed below.

[0116] A mixture of 1.3 μM human Fpn and 30 nM TMR-hepcidin, prepared in FP analysis buffer containing 50 mM Tris-HCl pH 7.3, 200 mM NaCl, 0.02% DDM, and 0.1% BSA, was seeded at 16 μl per well into a 384-well black low-volume round-bottom dish (Corning, catalog number 3677). 8 μl of serially diluted test compound (in duplicate) was added to the Fpn and TMR-hepcidin to final concentrations of 1 μM and 20 nM, respectively. The dishes were incubated at room temperature for 90 minutes, and then the horizontal (S) and vertical (P) fluorescence were measured using a Synergy H1 fluorescence reader (BioTek). The FP value was calculated using the following formula, in mP.

[0117] As described in the hepcidin internalization analysis, the IC50 value was determined using the calculated mP value. In this analysis, the IC50 for unlabeled hepcidin was approximately 0.37 ± 0.067 μM. [3.] [Inhibition of iron export activity mediated by membrane iron transport proteins in iron reaction analysis]

[0118] In this assay, intracellular iron levels were indirectly measured by monitoring the activity of the β-endoramisase (BLA) receptor gene fused to the human ferritin promoter and associated iron regulatory element (IRE) within the 5' untranslated region of the human ferritin mRMA. Lower reporter gene activity reflected iron efflux and lower iron levels in this cell line, as indicated by the expression of the membrane iron transporter (Fpn). Conversely, inhibition of Fpn-mediated iron efflux led to an increase in cellular iron levels, as detected by increased reporter gene activity. The dose-dependent effects of low molecular weight Fpn inhibitor compounds in this in vitro iron response assay were tested, as described below.

[0119] HEK-293 cell line #354 was generated by stable integration of the following: (i) insertion of a human Fpn-GFP fusion construct into a derivative of deoxytetracycline-inducible pTRE-Tight-BI plastid (Clontech, catalog number 631068) and (ii) introduction of a human ferritin promoter-BLA reporter gene into a derivative of HEK-293 Tet-ON Advanced cell line (Clontech). To generate the ferritin-BLA reporter gene construct, a 1.4 kb human ferritin H promoter fragment (forward primer 5'-CAGGTTTGTGAGCATCCTGAA-3'; reverse primer 5'-GGGCGGCGACTAAGGAGAGG-3') was amplified from human genomic DNA by PCR and inserted before the BLA gene present in the pcDNA™ 6.2 / cGeneBLAzer™-DEST plasmid (Invitrogen, catalog number 12578-043), thereby replacing the original CMV promoter and placing an IRE that regulates ferritin gene translation approximately 170 bp upstream of the reporter gene start codon. #354 cells were collected from approximately 80% confluence cultures and seeded at 1.8 x 10⁵ cells / mL in DMEM / F12 GlutaMAX™ medium (Invitrogen, catalog 31331-028) containing 10% FBS (Clontech, catalog 631106), 1% penicillin-streptomycin, 200 μg / mL hygromycin B (Invitrogen, catalog 10687-010), 5 μg / mL blastomycin (Invitrogen, catalog R210-01), and 4 μg / mL deoxytetracycline (Clontech, catalog 631311), 50 μL per well in a 384-well PDL spreader, and grown at 37°C and 5% CO₂. After incubation overnight, serially diluted test compounds (quadruple doses) were added at 10 μl / well, and the dish was incubated overnight again at 37°C and 5% CO2. Cells were washed three times with HBSS, leaving 25 μl in each well. BLA activity was detected by adding 5 μl / well of GeneBlazer reagent CCF4-AM (Invitrogen, catalog number K1085) to the cells. After incubation in the dark at 18°C ​​for 60 minutes, blue and green fluorescence signals were measured using a Safire 2 Tecan fluorescence optical disc reader, with an excitation wavelength of 410 nm and emission wavelengths of 458 nm (blue) and 522 nm (green). The blue / green fluorescence ratio was calculated as a measure of BLA activity, and the EC50 value was determined using the calculated blue / green fluorescence ratio, as described in the hepcidin internalization assay. The EC50 of hepcidin in this analysis was approximately 0.096 ± 0.063 μM (n = 37). [4.] [Analysis of Internalization and Degradation of Membrane Iron Transport Proteins]

[0120] Using flow cytometry sorting (FACS), the ability of compounds to induce the internalization and degradation of membrane iron transporter (Fpn) was measured in HEK-293 cell line #354 (described in Example 3). HEK-293 #354 cells were grown in deoxytetracycline containing a medium that induces the expression of human Fpn-GFP fusion protein on the cell surface. Data from 10 independent experiments showed that culturing HEK#354 cells at 4 μg / ml deoxytetracycline for 48 hours induced an average of 42.6% ± 6.4% of Fpn-GFP positive cells. The dose-dependent effect of low molecular weight Fpn inhibitor compounds on the mean fluorescence intensity (MFI) of Fpn-GFP in HEK-293 cell line #354 was tested as follows.

[0121] HEK#354 cells were obtained from approximately 80% confluence cultures and seeded at 0.6 x 10⁶ cells / mL in DMEM / F12 GlutaMAX™ medium (Invitrogen, catalog 31331-028) containing 10% FBS (Clontech, catalog 631106), 1% penicillin-streptomycin (Invitrogen, catalog 15140-122), 200 μg / mL hygromycin B (Invitrogen, catalog 10687-010), 5 μg / mL blastomycin (Invitrogen, catalog R210-01), and 4 μg / mL deoxytetracycline (Clontech, catalog 631311), 50 μL per well in a 384-well dish (Greiner; catalog 781091), and grown at 37°C and 5% CO₂. After incubating overnight, serially diluted test compounds (quadruple doses) were added at 10 μl / well, and the plates were incubated overnight at 37°C and 5% CO2. Cells were washed once with FACS buffer (PBS containing 1% FBS, 2 mM EDTA, and 0.05% NaN3), collected in FACS buffer containing 0.5 μg / ml propidium iodide (Sigma, catalog number P4864), and analyzed in a flow cytometer (CANTO tmII, BD Biosciences) equipped with a high-throughput sampler. Propidium iodide-negative cells were selected as viable HEK#354 cells, and Fpn-GFP expression was analyzed. The MFI of Fpn-GFP for each compound dilution >2000 viable cells was calculated using FlowJo (Tree Star's, Oregon), and the intensity of Fpn inhibitor-induced Fpn-GFP internalization and degradation was calculated according to the hepcidin internalization analysis. The mean EC50 value of hepcidin in this analysis was approximately 0.004 ± 0.002 μM. [5.] [Ubiquitination and Degradation of Membrane Iron Transport Proteins]

[0122] Exposing cells expressing the membrane iron transport protein (Fpn) to hepcidin is known to trigger Fpn ubiquitination and subsequent internalization and degradation (Qiao, 2012). Immunoprecipitation analysis of J774 mouse macrophages, which express Fpn after iron treatment, was used to investigate the potential of Fpn inhibitors to induce Fpn ubiquitination and degradation.

[0123] J774 cells (DSMZ, catalog number ACC170) were seeded at 0.8 x 10⁶ cells / mL in 15 mL of medium containing 200 μM Fe(III)-NTA (DMEM, catalog number 11971-025; 10% heat-inactivated FBS, catalog number 10500-064; 1% penicillin-streptomycin, catalog number 15140-122) and placed in 10 cm tissue culture dishes (Greiner catalog number 664160) and grown overnight at 37°C and 5% CO₂. The cells were then incubated with synthetic human hepcidin (Bachem, catalog number H-5926) or an Fpn inhibitor compound for 10 min or 120 min. Cells were washed and lysed with ice-cold lysis buffer (Pierce, Life Technologies, catalog 87787) containing a mixture of 1X HALT protease inhibitors (Life Technologies, catalog 78429) and 10 mM iodoacetamide (Sigma, catalog 16125) to stabilize ubiquitinated proteins. Immunoprecipitation was performed using the Pierce Classic IP kit (Life Technologies, catalog 26146) according to the manufacturer's instructions. Briefly, 2 mg of protein in 1.25 ml of IP lysis buffer was mixed with control agarose beads and incubated at 4°C for 1 hour to pre-clear lysates and reduce nonspecific signals. Unbound lysates were then incubated overnight with 12 μg of affinity-purified anti-Fpn antibody F308 per reaction, which is generated from the GST fusion protein of mouse Fpn amino acids 224-308. Immune complexes were captured by transferring 14 μl of the precipitated Pierce Protein A / G Plus agar beads (Life Technologies, catalog 20423) for each reaction and incubating the slurry at 4°C for 1.5 h while gently inverting to mix. The beads were washed and the immune complexes were directly extracted with 75 μl of SDS NuPAGE LDS sample buffer (Life Technologies, catalog NP0007) containing DTT (Life Technologies, catalog NP0009).

[0124] After analyzing immunoprecipitated samples using Western ink dot assay with rabbit anti-mouse MTP1 antiserum (Alpha Diagnostic International, catalog number MTP11-A) and mouse anti-mono- and polyubiquitinated conjugate monoclonal antibody (Enzo Lifesciences, catalog number BML-PW8810), which are used to detect membrane iron transport proteins and ubiquitin respectively, mouse monoclonal anti-rabbit IgG light chain (Abcam, catalog number ab99697) and anti-mouse IgG H&L (Abcam, catalog number ab6789) HRP conjugate were used as secondary antibodies. [6.] [Using membrane iron transport protein inhibitors to suppress iron efflux]

[0125] As described below, the activity of hepcidin and membrane iron transporter inhibitor compounds in T47D cells (ECACC, catalog number 85102201) was tested to assess their ability to block iron export through membrane iron transporters.

[0126] Cells were seeded in 24-well plates (Greiner, catalog number 662160) with 350,000 cells per well and incubated overnight in 100 μM 58Fe (58Fe(II)-sulfate, Vifor Pharma batch number ROR 3085) in 500 μM ascorbic acid (Sigma Aldrich, catalog number 795437) containing growth medium. Cells were washed once with 500 μl of iron absorption buffer (IUB; PIPES 40 mM, catalog number P1851, glucose monohydrate 10 mM, catalog number 49158, sodium chloride 260 mM, catalog number 71379, potassium chloride 20 mM, catalog number P9541, magnesium sulfate 2 mM, catalog number 63138, Sigma Aldrich), then washed once with removal buffer (incubated for 2 minutes, BPDS 100 μM, catalog number 11890 and Na₂S₂O 4500 μM, catalog number 157953, Sigma Aldrich, in IUB), and then washed twice more with IUB. Serially diluted hepcidin (Bachem) or a membrane iron transporter inhibitor (4 μM–0.0064 μM, 5-fold dilution) was added to a total volume of 0.6 ml per well. Cells were incubated at 37°C and 5% CO₂ for 20 hours. Supernatant was collected and 58Fe was measured using inductively coupled plasma mass spectrometry (ICP-MS, Thermo Scientific, Element 2). Precipitated pellets were collected for protein concentration measurement. Results were plotted as 58Fe (ng) in supernatant / mg protein in cell lysate. [Preparation of Exemplary Compounds] [General Experimental Details]

[0127] Commercially available reagents and solvents (HPLC grade) were used, without further purification. 1H NMR spectra were recorded in deuterated solvents on a Bruker DRX 500 MHz spectrometer, a Bruker DPX 250 MHz spectrometer, or a Bruker Avance spectrometer at 400 MHz. Chemical shifts (δ) are expressed in parts per million.

[0128] The compound was purified by rapid column chromatography on normal-phase silica using a suitable SNAP cartridge and gradient on a Biotage Isolera system. Alternatively, the compound was purified on reverse-phase using a Biotage Isolera system with a suitable C18 SNAP cartridge and reverse-phase extraction buffer, or by preparative HPLC (if otherwise specified). [abbreviation] [] EtOAc ethyl acetate CH₂Cl₂ dichloromethane Et 2O diethyl ether MeOH (methanol) EtOH (ethanol) brine saturated sodium chloride aqueous solution Chloroform-d-deuterated chloroform DMSO-d6-deuterated dimethyl sulfoxide s Single peak br s bright single peak d Bimodal dd Two double peaks dt Two triple peaks td Three bimodal peaks hept. Seven Peaks m multiplet q Quadruple Peak δ chemical shift ppm (parts per million) M molar concentration mm millimolar umol (micromollium) g gram mg l rise mL h hours min minutes %-w / w (percentage of mass) TLC (Thin Layer Chromatography) UHPLC (Ultra-high Pressure Liquid Chromatography) MS mass spectrometry ESI Electrospray Ionization m / z mass-to-charge ratio H+protons MHz (million hertz) sm starting materials Jones' reagent is prepared in H₂SO₄ with CrO₃. CrO3 Chromium trioxide HCl hydrochloric acid H₂SO₄ sulfuric acid NH4Cl ammonium chloride Sodium sulfate (Na₂SO₄) NaOH (sodium hydroxide) Bn benzyl MS mass spectrometry ESI Electrospray Ionization SNAP is a brand name for Biotage columns used in rapid column chromatography. R f retention factor TLC (Thin Layer Chromatography) [Chemical Nomenclature] []

[0129] The chemical names of the intermediates and the final example compound were generated using Chem Draw Professional 17.0.

[0130] All Rf values ​​were determined using the following TLC plates: Merck, TLC Silcagel 60 F 254. [Intermediate] [] [A.] [, N , -( ] [Benzo[f]] [Quinoline-3-] [methyl)-2- [Vinyl] [ ] [azole-4-] [Methionine] [(] [Example Compound No. 6 –] [Step 1)]

[0131] 4-methyl 0.3 ml (2.5 mmol) of linyl group and ethyl chloroformate (0.1 g, 0.89 mmol) were added to 2-vinyl group. Azoxyl-4-carboxylic acid (0.1 g, 0.7 mmol) was prepared in 10 mL of dichloromethane at 0 °C. After stirring at 0 °C for 1 hour, benzo[f]quinoline-3-ylmethylamine dihydrochloride (0.2 g, 0.7 mmol) (purchased from Chemspace) was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with saturated NH4Cl aqueous solution (1 x 10 mL) and brine (1 x 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH2Cl2 / MeOH) to obtain a white solid, title compound A (0.13 g, 0.4 mmol, 55%). UHPLC / MS (ESI): [m / z]: 330 [M+H]+. [B.] [, N , -( ] [Phenyridine-6-] [methyl)-2- [Vinyl] [ ] [azole-4-] [Methionine] [(] [Example Compound No. 7 -] [Step 1)]

[0132] 4-methyl 0.3 ml (2.5 mmol) of linyl group and ethyl chloroformate (0.1 g, 0.89 mmol) were added to 2-vinyl group. Azoxyl-4-carboxylic acid (0.1 g, 0.7 mmol) was prepared in 10 mL of dichloromethane at 0 °C. After stirring at 0 °C for 1 hour, phenidyl-6-ylmethylamine dihydrochloride (Chemspace) (0.2 g, 0.7 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with saturated aqueous NH4Cl solution (1 x 10 mL) and brine (1 x 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH2Cl2 / MeOH) to obtain a white solid, title compound B (0.164 g, 0.5 mmol, 71%). UHPLC / MS (ESI): [m / z]: 330 [M+H]+. [C.] [, N , ] [-((3-] [Methylpyridine] [-2-] [base] [)] [methyl] [)-2-] [Vinyl] [ ] [azole] [-4-] [Methionine] [] [(] [Example Compound No. 13 -] [Step 1)]

[0133] 4-methyl 0.5 ml (4.4 mmol) of linyl group and ethyl chloroformate (0.5 ml, 4.5 mmol) were added to 2-vinyl group. Azoxyl-4-carboxylic acid (0.5 g, 3.6 mmol) was prepared in 10 mL of dichloromethane at 0 °C. After stirring at 0 °C for 1 hour, (3-methylpyridin-2-yl)methylamine (Chemspace) (0.5 g, 3.5 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with saturated aqueous solution of NH4Cl (1 x 10 mL) and brine (1 x 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH2Cl2 / MeOH) to obtain the title compound C (0.432 g, 1.8 mmol, 49%) as a white solid. UHPLC / MS (ESI): [m / z]: 244 [M+H]+. [D.] [, N , -((3- ] [Clopyridine-2-] [base)] [Methyl)-2- [Vinyl] [ ] [azole-4-] [Methionine] [(] [Example Compound No. 14 -] [Step 1)]

[0134] 4-methyl 0.4 ml (3.6 mmol) of linyl group and ethyl chloroformate (0.3 ml, 3.2 mmol) were added to 2-vinyl group. Azoxyl-4-carboxylic acid (0.4 g, 2.9 mmol) was prepared in 10 mL of dichloromethane at 0 °C. After stirring at 0 °C for 1 hour, (3-chloropyridin-2-yl)methylamine (Chemspace) (0.4 g, 2.9 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with saturated NH4Cl aqueous solution (1 x 10 mL) and brine (1 x 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH2Cl2 / MeOH) to obtain the title compound D (0.3 g, 1.14 mmol, 39%) as a white solid. UHPLC / MS (ESI): [m / z]: 264 [M+H]+. [E.] [, N , -((3- ] [Methoxypyridine-2-] [base)] [Methyl)-2- [Vinyl] [ ] [azole-4-] [Methionine] [(] [Example Compound No. 15 -] [Step 1)]

[0135] 4-methyl 0.5 ml (4.5 mmol) of linyl group and ethyl chloroformate (0.5 ml, 4.5 mmol) were added to 2-vinyl group. Azoxyl-4-carboxylic acid (0.5 g, 3.6 mmol) was prepared in 10 mL of dichloromethane at 0 °C. After stirring at 0 °C for 1 hour, (3-methoxypyridin-2-yl)methylamine (Chemspace) (0.5 g, 3.6 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with saturated NH4Cl aqueous solution (1 x 10 mL) and brine (1 x 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH2Cl2 / MeOH) to obtain the title compound E (0.75 g, 2.9 mmol, 80%) as a off-white solid. UHPLC / MS (ESI): [m / z]: 260 [M+H]+. [F.] [, N , -((3-( ] [Trifluoromethyl] [Pyridine-2-] [base)] [Methyl)-2- [Vinyl] [ ] [azole-4-] [Methionine] [(] [Example Compound No. 16 -] [Step 1)]

[0136] 4-methyl 0.4 ml (3.6 mmol) of linyl group and ethyl chloroformate (0.3 ml, 3.2 mmol) were added to 2-vinyl group. Azoxyl-4-carboxylic acid (0.4 g, 2.8 mmol) was prepared in 10 mL of dichloromethane at 0 °C. After stirring at 0 °C for 1 hour, (3-(trifluoromethyl)pyridin-2-yl)methylamine (Chemspace) (0.5 g, 2.8 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with saturated NH4Cl aqueous solution (1 x 10 mL) and brine (1 x 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH2Cl2 / MeOH) to obtain the title compound F (0.51 g, 1.7 mmol, 61%) as a off-white solid. UHPLC / MS (ESI): [m / z]: 298 [M+H]+. [G.] [, N , -( ] [Pyridine-2-] [methyl)-2- [Vinyl] [ ] [azole-4-] [Methionine] []

[0137] 4-methyl 0.5 ml (4.4 mmol) of linyl group and ethyl chloroformate (0.35 g, 3.3 mmol) were added to 2-vinyl group. Azoxyl-4-carboxylic acid (0.5 g, 3.6 mmol) was prepared in 10 mL of dichloromethane at 0 °C. After stirring at 0 °C for 1 hour, pyridin-2-methylamine (Chemspace) (0.39 g, 3.6 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with saturated aqueous NH4Cl solution (1 x 10 mL) and brine (1 x 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH2Cl2 / MeOH) to obtain the title compound (0.44 g, 1.9 mmol, 53%) as a off-white solid. UHPLC / MS (ESI): [m / z]: 230 [M+H]+. [Example Compound] [1.] [Example Compound Number] [1] [:] 2-(2-(((1H-naphtho[2,3-d]imidazol-2-yl)methyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl) 4-Azoxyl-methylamine

[0138] (1H-naphtho[2,3-d]imidazol-2-yl)methylamine dihydrochloride (purchased from Chemspace) (100 mg, 0.37 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (92 mg, 0.37 mmol) was added to a solution of NaOH (31 mg, 0.78 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give a white solid, namely, title compound 1 (6.9 mg, 0.016 mmol, 4%). 1H NMR (400 MHz, DMSO- d 6) δ 8.50 (m, 2H), 8.35 (m, 1H), 7.95 (m, 4H), 7.65 (m, 1H), 7.35 (m, 3H), 4.60 (m, 2H), 4.00 (m, 2H), 3.00 (m, 2H) ppm. UHPLC / MS (ESI): [ m / z]: 445 [M+H] +. [2.] [Example Compound Number] [2:] [] 2-(2-(((3H-imidazol[4,5-c]quinoline-2-yl)methyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl) 4-Azoxyl-methylamine

[0139] (3H-imidazolium[4,5-c]quinoline-2-yl)methylamine dihydrochloride (purchased from Chemspace) (100 mg, 0.37 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (92 mg, 0.37 mmol) was added to a solution of NaOH (31 mg, 0.78 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 2 (8 mg, 0.018 mmol, 5%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 9.10 (m, 1H), 8.50 (m, 1H), 8.40 (m, 2H), 8.05 (m, 1H), 7.65 (m, 3H), 7.4 (m, 1H), 4.60 (m, 2H), 4.10 (m, 2H), 3.00 (m, 4H) ppm. UHPLC / MS (ESI): [m / z]: 446 [M+H]+. [3.] [Example Compound Number] [3:] 2-(2-((2-(3H-imidazol[4,5-c]quinoline-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl) 4-Azoxyl-methylamine

[0140] 2-(3H-imidazolium[4,5-c]quinolin-2-yl)ethane-1-amine dihydrochloride (purchased from Chemspace) (100 mg, 0.35 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (87 mg, 0.35 mmol) was added to a solution of NaOH (30 mg, 0.74 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 3 (45.8 mg, 0.1 mmol, 28%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 9.1 (s, 1H), 8.5 (m, 1H), 8.3 (m, 2H), 8.2 (s, 1H), 8.1 (m, 1H), 7.6 (m, 3H), 7.4 (m, 1H), 4.6 (d, 2H), 3.2 (m, 4H), 3.0 (m, 4H) ppm. UHPLC / MS (ESI): [m / z]: 460 [M+H]+. [4.] [Example Compound Number] [4] [:] [] 2-(2-(((3H-naphtho[1,2-d]imidazol-2-yl)methyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl) 4-Azoxyl-methylamine

[0141] (3H-naphtho[1,2-d]imidazol-2-yl)methylamine dihydrochloride (purchased from Chemspace) (100 mg, 0.37 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (92 mg, 0.37 mmol) was added to a solution of NaOH (31 mg, 0.78 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 4 (5 mg, 0.011 mmol, 3%) as a white solid. UHPLC / MS (ESI): [m / z]: 445 [M+H]⁺. UHPLC / MS (ESI): [m / z]: 445 [M+H] +, 265 [C 12H 14FN 4O 2] +, 181 [C 12H 9N 2] +, 110 [C 6H 5FN] +. [5.] [Example Compound Number] [5:] 2-(2-((2-(3H-naphtho[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl) 4-Azoxyl-methylamine

[0142] 2-(3H-naphtho[1,2-d]imidazol-2-yl)ethane-1-amine dihydrochloride (purchased from Chemspace) (100 mg, 0.35 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (87 mg, 0.35 mmol) was added to a solution of NaOH (30 mg, 0.74 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 5 (40.6 mg, 0.09 mmol, 25%) as a off-white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.50 (m, 2H), 8.30 (m, 2H), 7.95 (d, 1H), 7.60 (m, 4H), 7.40 (m, 2H), 4.60 (d, 2H), 3.00 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 459 [M+H]+. [6.] [Example Compound Number] [6:] 2-(2-((2-(1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-(benzo[f]quinoline-3-ylmethyl) 4-Azoxyl-methylamine

[0143] 2-(1H-benzo[d]imidazol-2-yl)ethane-1-amine (49 mg, 0.3 mmol) and N-(benzo[f]quinoline-3-ylmethyl)-2-vinyl Azoxyl-4-methoxylamine (100 mg, 0.3 mmol) was added to a solution of NaOH (1.2 mg, 0.03 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 6 (56 mg, 0.11 mmol, 38%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 9.2 (m, 1H), 9.05 (m, 1H), 8.8 (m, 1H), 8.65 (s, 1H), 8.1 (m, 2H), 7.9 (m, 1H), 7.7 (m, 2H), 7.6 (m, 1H), 7.45 (m, 2H), 7.15 (m, 2H), 4.8 (m, 2H), 3.6 (m, 2H), 3.45 (m, 2H), 3.2 (m, 2H), 3.15 (m, 2H) ppm. UHPLC / MS (ESI): [m / z]: 491 [M+H]+. [7.] [Example Compound Number] [11:] 2-(2-((2-(3H-naphtho[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)-N-(benzo[f]isoquinoline-2-ylmethyl) 4-Azoxyl-methylamine

[0144] 2-(3H-naphtho[1,2-d]imidazol-2-yl)ethane-1-amine dihydrochloride (purchased from Chemspace) (130 mg, 0.46 mmol) and N-(benzo[f]quinoline-3-ylmethyl)-2-vinyl Azoxyl-4-methoxylamine (150 mg, 0.46 mmol) was added to a solution of NaOH (55 mg, 1.37 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 11 (7 mg, 0.013 mmol, 3%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 9.1 (m, 1H), 8.9 (m, 1H), 8.8 (m, 1H), 8.6 (s, 1H), 8.3 (m, 1H), 8.1 (m, 2H), 8.0 (m, 1H), 7.9 (m, 1H), 7.8 – 7-5 (m, 7H), 7.4 (m, 1H), 4.7 (m, 2H), 3.2 – 3.1 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 541 [M+H] +. [8.] [Example Compound Number] [12:] 2-(2-((2-(3H-imidazol[4,5-c]quinoline-2-yl)ethyl)amino)ethyl)-N-(benzo[f]isoquinoline-2-ylmethyl) 4-Azoxyl-methylamine

[0145] 2-(3H-imidazolium[4,5-c]quinoline-2-yl)ethane-1-amine dihydrochloride (purchased from Chemspace) (130 mg, 0.46 mmol) and N-(benzo[f]quinoline-3-ylmethyl)-2-vinyl Azoxyl-4-methoxylamine (150 mg, 0.46 mmol) was added to a solution of NaOH (55 mg, 1.37 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 12 (30.1 mg, 0.056 mmol, 12%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 9.2 (m, 1H), 9.1 (s, 1H), 9.0 (m, 1H), 8.8 (m, 1H), 8.6 (s, 1H), 8.3 (m, 1H), 8.1 (m, 3H), 7.9 (m, 1H), 7.8 – 7-6 (m, 5H), 4.7 (m, 2H), 3.2 – 3.1 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 542 [M+H] +. [9.] [Example Compound Number] [7:] 2-(2-((2-(1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-(phenidin-6-ylmethyl) 4-Azoxyl-methylamine

[0146] 2-(1H-benzo[d]imidazol-2-yl)ethane-1-amine (49 mg, 0.3 mmol) and N-(phenidin-6-ylmethyl)-2-vinyl Azoxyl-4-methoxylamine (100 mg, 0.3 mmol) was added to a solution of NaOH (1.2 mg, 0.03 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 7 (6 mg, 0.012 mmol, 4%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.9 – 8.8 (m, 3H), 8.6 (s, 1H), 8.4 (m, 1H), 8.1 – 7.9 (m, 2H), 7.8 – 7.7 (m, 3H), 7.4 (m, 2H), 7.1 (m, 2H), 5.2 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 491 [M+H]+. [10.] [Example Compound Number] [8:] 2-(2-((2-(3H-naphtho[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)-N-(phenidin-6-ylmethyl) 4-Azoxyl-methylamine

[0147] 2-(3H-naphtho[1,2-d]imidazol-2-yl)ethane-1-amine dihydrochloride (purchased from Chemspace) (130 mg, 0.46 mmol) and N-(phenidin-6-ylmethyl)-2-vinyl Azoxyl-4-methoxylamine (150 mg, 0.46 mmol) was added to a solution of NaOH (55 mg, 1.37 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 8 (31 mg, 0.057 mmol, 13%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.9 (m, 2H), 8.8 (m, 1H), 8.6 (s, 1H), 8.4 (d, 1H), 8.3 (d, 1H), 8.0 – 7.9 (m, 3H), 7.8 – 7.7 (m, 3H), 7.6 – 7.5 (m, 3H), 7.4 (m, 1H), 5.2 (d, 2H), 3.2 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 541 [M+H] +. [11.] [Example Compound Number]

[13] [:] [] 2-(2-((2-(3H-naphtho[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-methylpyridin-2-yl)methyl) 4-Azoxyl-methylamine

[0148] 2-(3H-naphtho[1,2-d]imidazol-2-yl)ethane-1-amine dihydrochloride (purchased from Chemspace) (100 mg, 0.35 mmol) and N-((3-methylpyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (87 mg, 0.35 mmol) was added to a solution of NaOH (30 mg, 0.74 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 13 (21 mg, 0.046 mmol, 13%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.50 (m, 2H), 8.30 (m, 2H), 7.95 (d, 1H), 7.60 (m, 4H), 7.40 (m, 2H), 4.60 (d, 2H), 3.00 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 455 [M+H]+. [12.] [Example Compound Number]

[14] [:] [] 2-(2-((2-(3H-naphtho[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-chloropyridin-2-yl)methyl) 4-Azoxyl-methylamine

[0149] 2-(3H-naphtho[1,2-d]imidazol-2-yl)ethane-1-amine dihydrochloride (purchased from Chemspace) (100 mg, 0.35 mmol) and N-((3-chloropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (93 mg, 0.35 mmol) was added to a solution of NaOH (30 mg, 0.74 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 14 (33.7 mg, 0.071 mmol, 20%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.50 (m, 3H), 8.30 (m, H), 7.95 (m, 2H), 7.60 – 7.40 (m, 5H), 4.60 (m, 2H), 3.00 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 471 [M+H] +. [13.] [Example Compound Number]

[15] [:] [] 2-(2-((2-(3H-naphtho[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-methoxypyridin-2-yl)methyl) 4-Azoxyl-methylamine

[0150] 2-(3H-naphtho[1,2-d]imidazol-2-yl)ethane-1-amine dihydrochloride (purchased from Chemspace) (100 mg, 0.35 mmol) and N-((3-methoxypyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (91 mg, 0.35 mmol) was added to a solution of NaOH (30 mg, 0.74 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 15 (70 mg, 0.15 mmol, 42%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.50 (s, 1H), 8.3 (m, 2H), 8.1 (m, 1H), 7.95 (m, 1H), 7.6 (m, 3H), 7.4 (m, 2H), 7.3 (m, 1H), 4.5 (d, 2H), 3.95 (s, 3H), 3.1 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 471 [M+H] +. [14.] [Example Compound Number]

[16] [:] [] 2-(2-((2-(3H-naphtho[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-(trifluoromethyl)pyridin-2-yl)methyl) 4-Azoxyl-methylamine

[0151] 2-(3H-naphtho[1,2-d]imidazol-2-yl)ethane-1-amine dihydrochloride (purchased from Chemspace) (100 mg, 0.35 mmol) and N-((3-(trifluoromethyl)pyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (105 mg, 0.35 mmol) was added to a solution of NaOH (30 mg, 0.74 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 16 (43.6 mg, 0.086 mmol, 24%) as a off-white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.8 (d, 1H), 8.5 (m, 2H), 8.3 (d, 1H), 8.2 (d, 1H), 7.9 (d, 1H), 7.6 (m, 3H), 7.4 (m, 1H), 4.7 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 509 [M+H]+. [] [15.] [Example Compound Number]

[19] [:] [] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-((2-(5-phenyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0152] 2-(5-phenyl-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.32 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (80 mg, 0.32 mmol) was added to a solution of NaOH (32 mg, 0.81 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 19 (22 mg, 0.045 mmol, 14%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.3 (m, 1H), 7.7 (m, 4H), 7.5 (d, 1H), 7.4 (m, 4H), 7.3 (m, 1H), 4.6 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 485 [M+H]+. [16.] [Example Compound Number]

[30] [:] [] 2-(2-((2-(5-(4-fluorophenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl) 4-Azoxyl-methylamine []

[0153] 2-(5-(4-fluorophenyl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.31 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (70 mg, 0.31 mmol) was added to a solution of NaOH (31 mg, 0.77 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 30 (26 mg, 0.052 mmol, 17%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.3 (m, 1H), 7.7 (m, 4H), 7.5 (m, 1H), 7.4 (m, 2H), 7.2 (m, 2H), 4.6 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 503 [M+H] +. [17.] [Example Compound Number]

[32] [:] [] 2-(2-((2-(5-(1H-pyrrolo-1-yl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl) 4-Azoxyl-methylamine []

[0154] 2-(5-(1H-pyrrolo-1-yl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.33 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (83 mg, 0.33 mmol) was added to a solution of NaOH (34 mg, 0.84 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 32 (54 mg, 0.11 mmol, 35%) as a off-white solid. [. ] 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.35 (m, 1H), 7.7 (m, 1H), 7.55 (m, 1H), 7.5 (m, 1H), 7.4 (m, 1H), 7.3 (m, 3H), 6.2 (m, 2H), 4.6 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 474 [M+H]+. [18.] [Example Compound Number]

[33] [:] [] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-((2-(5,6,7,8-tetrahydro-1H-naphtho[2,3-d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0155] 2-(5,6,7,8-tetrahydro-1H-naphtho[2,3-d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.35 mmol) and N-((3-methoxypyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (86 mg, 0.35 mmol) was added to a solution of NaOH (35 mg, 0.87 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 33 (57 mg, 0.12 mmol, 36%) as a off-white solid. [. ] 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.35 (m, 1H), 7.7 (m, 1H), 7.4 (m, 1H), 7.1 (m, 2H), 4.6 (d, 2H), 3.0 (m, 12H), 1.8 (m, 4H) ppm. UHPLC / MS (ESI): [m / z]: 463 [M+H] +. [19.] [Example Compound Number]

[34] [:] [] 2-(2-((2-(6,7-dihydro-1H-[1,4]di) [2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl) 4-Azoxyl-methylamine []

[0156] 2-(6,7-dihydro-1H-[1,4]di (2',3':4,5)Benzo[1,2-d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.34 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-ethenyl oxazole-4-carboxamide (85 mg, 0.34 mmol) were added to a solution of NaOH (35 mg, 0.86 mmol) prepared in 10 ml of water. The resulting mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 34 as a beige solid (25.3 mg, 0.054 mmol, 16%). 1H NMR (400 MHz, DMSO-d6) δ 8.5 (m, 2H), 8.3 (m, 1H), 7.7 (m, 1H), 7.4 (m, 1H), 6.9 (m, 3H), 4.6 (d, 2H), 4.2 (m, 6H), 3.1 (m, 6H) ppm. UHPLC / MS (ESI): [m / z]: 467 [M+H]+. [20.] [Example Compound Number]

[36] [:] [] 2-(2-((2-(5H-[1,3]di benzo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl) oxazole-4-carboxamide []

[0157] 2-(5H-[1,3]di [4',5':4,5]benzo[1,2-d]imidazol-6-yl)ethane-1-amine hydrochloride (Chemspace) (100 mg, 0.41 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (102 mg, 0.41 mmol) was added to a solution of NaOH (25 mg, 0.62 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 36 (13 mg, 0.029 mmol, 7%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.6 (m, 2H), 8.4 (m, 1H), 7.7 (m, 1H), 7.4 (m, 1H), 7.0 (m, 2H), 6.0 (s, 2H), 4.6 (d, 2H), 3.2 – 3.1 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 453 [M+H] +. [twenty one.] [Example Compound Number]

[37] [:] [] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-((2-(7-(phenylethynyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0158] 2-(2-(12-azalkyl)ethyl)-7-(phenylethynyl)-1H-benzo[d]imidazolium dihydrochloride (Chemspace) (105 mg, 0.31 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (77 mg, 0.31 mmol) was added to a solution of NaOH (25 mg, 0.63 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 37 (49 mg, 0.1 mmol, 31%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.6 (m, 2H), 8.35 (m, 1H), 7.7 – 7.3 (m, 8H), 7.15 (m, 1H), 4.6 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 509 [M+H]+. [twenty two.] [Example Compound Number]

[39] [:] [] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-((2-(6,7,8,9-tetrahydro-3H-naphtho[1,2-d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0159] 2-(6,7,8,9-tetrahydro-3H-naphtho[1,2-d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.35 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (86 mg, 0.35 mmol) was added to a solution of NaOH (35 mg, 0.87 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 39 (54 mg, 0.12 mmol, 33%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.3 (m, 1H), 7.7 (m, 1H), 7.4 (m, 1H), 7.1 (d, 1H), 6.8 (d, 1H), 4.6 (d, 2H), 3.0 (m, 8H), 2.85 (m, 2H), 2,75 (m, 2H), 1.8 (m, 4H) ppm. UHPLC / MS (ESI): [m / z]: 463 [M+H] +. [twenty three.] [Example Compound Number]

[43] [:] [] 2-(2-((2-(1H-naphtho[2,3-d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl) 4-Azoxyl-methylamine []

[0160] 2-(1H-naphtho[2,3-d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.35 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (87 mg, 0.35 mmol) was added to a solution of NaOH (35 mg, 0.88 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 43 (37.6 mg, 0.082 mmol, 23%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.3 (m, 1H), 7.9 (m, 4H), 7.7 (m, 1H), 7.3 (m, 3H), 4.6 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 459 [M+H]+. [twenty four.] [Example Compound Number]

[44] [:] [] 2-(2-((2-(5-(2-chlorophenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl) 4-Azoxyl-methylamine []

[0161] 2-(5-(2-chlorophenyl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.29 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (72 mg, 0.29 mmol) was added to a solution of NaOH (29 mg, 0.73 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 44 (32 mg, 0.062 mmol, 21%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.3 (m, 1H), 7.7 (m, 1H), 7.6 (s, 1H), 7.5 (m, 2H), 7.4 (m, 2H), 7.3 (m, 3H), 4.6 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 520 [M+H]+. [25.] [Example Compound Number]

[45] [:] [] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-((2-(5-(2-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0162] 2-(5-(2-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.29 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (73 mg, 0.29 mmol) was added to a solution of NaOH (29 mg, 0.73 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 45 (64 mg, 0.12 mmol, 42%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.3 (m, 1H), 7.7 (m, 1H), 7.5 (s, 1H), 7.45 (d, 1H), 7.35 (m, 1H), 7.3 (m, 2H), 7.2 (dd, 1H), 7.1 (d, 1H), 7.0 (t, 1H), 4.6 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 515 [M+H] +. [26.] [Example Compound Number]

[46] [:] [] 2-(2-((2-(5-(2-fluorophenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl) 4-Azoxyl-methylamine []

[0163] 2-(5-(2-fluorophenyl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.3 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (75 mg, 0.3 mmol) was added to a solution of NaOH (31 mg, 0.76 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 46 (49.1 mg, 0.098 mmol, 32%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.3 (m, 1H), 7.7 (m, 1H), 7.6 (s, 1H), 7.5 (m, 2H), 7.4 (m, 2H), 7.3 (m, 3H), 4.6 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 503 [M+H] +. [27.] [Example Compound Number]

[47] [:] [] 2-(2-((2-(6,7-dihydro-1H-[1,4]di) [2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-methylpyridin-2-yl)methyl) 4-Azoxyl-methylamine []

[0164] 2-(6,7-dihydro-1H-[1,4]di [2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.34 mmol) and N-((3-methylpyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (84 mg, 0.34 mmol) was added to a solution of NaOH (35 mg, 0.86 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 47 (18 mg, 0.039 mmol, 12%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.3 (m, 1H), 7.7 (m, 1H), 7.4 (m, 1H), 6.9 (m, 3H), 4.6 (d, 2H), 4.2 (m, 6H), 3.1 (m, 6H) ppm. UHPLC / MS (ESI): [m / z]: 463 [M+H] +. [28.] [Example Compound Number]

[48] [:] [] 2-(2-((2-(6,7-dihydro-1H-[1,4]di) [2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-methoxypyridin-2-yl)methyl) 4-Azoxyl-methylamine []

[0165] 2-(6,7-dihydro-1H-[1,4]di [2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.34 mmol) and N-((3-methoxypyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (89 mg, 0.34 mmol) was added to a solution of NaOH (35 mg, 0.86 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 48 (33 mg, 0.069 mmol, 20%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 1H), 8.3 (m, 1H), 8.1 (m, 1H), 7.4 (m, 1H), 7.3 (m, 1H), 6.85 (m, 2H), 4.5 (d, 2H), 4.2 (m, 4H), 3.9 (m, 3H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 479 [M+H]+. [29.] [Example Compound Number]

[49] [:] [] 2-(2-((2-(5-(2-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-methylpyridin-2-yl)methyl) 4-Azoxyl-methylamine []

[0166] 2-(5-(2-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.29 mmol) and N-((3-methylpyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (72 mg, 0.29 mmol) was added to a solution of NaOH (29 mg, 0.74 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 49 (53 mg, 0.11 mmol, 38%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.35 (m, 1H), 7.6 (d, 1H), 7.5 (s, 1H), 7.4 (d, 1H), 7.3 (m, 2H), 7.2 (m, 2H), 7.1 (m, 1H), 7.0 (m, 1H), 4.5 (d, 2H), 3.7 (s, 3H), 3.0 (m, 8H), 2.3 (s, 3H) ppm. UHPLC / MS (ESI): [m / z]: 481 [M+H] +. [30.] [Example Compound Number]

[50] [:] [] (3-Methoxypyridin-2-yl)methyl 2-(2-((2-(6,7,8,9-tetrahydro-3H-naphtho[1,2-d]imidazol-2-yl)ethyl)amino)ethyl) azole-4-carboxylate []

[0167] 2-(6,7,8,9-tetrahydro-3H-naphtho[1,2-d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.35 mmol) and N-((3-methoxypyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (90 mg, 0.35 mmol) was added to a solution of NaOH (35 mg, 0.87 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 50 (58 mg, 0.12 mmol, 35%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 1H), 8.3 (m, 1H), 8.1 (m, 1H), 7.4 (d, 1H), 7.3 (m, 1H), 7.1 (d, 2H), 6.8 (d, 1H), 4.5 (d, 2H), 3.9 (s, 3H), 3.0 (m, 8H), 2.85 (m, 2H), 2,75 (m, 2H), 1.8 (m, 4H) ppm. UHPLC / MS (ESI): [m / z]: 475 [M+H]+. [31.] [Example Compound Number]

[51] [:] [] 2-(2-((2-(5-(2-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-methoxypyridin-2-yl)methyl) 4-Azoxyl-methylamine []

[0168] 2-(5-(2-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.29 mmol) and N-((3-methoxypyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (76 mg, 0.29 mmol) was added to a solution of NaOH (29 mg, 0.74 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 51 (66 mg, 0.13 mmol, 43%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (s, 1H), 8.3 (m, 1H), 8.1 (m, 1H), 7.5 (d, 1H), 7.4 (m, 2H), 7.3 (m, 3H), 7.2 (m, 1H), 7.1 (m, 1H), 7.0 (m, 1H), 4.5 (d, 2H), 3.9 (s, 3H), 3.7 (s, 3H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 527 [M+H] +. [32.] [Example Compound Number]

[52] [:] [] N-((3-methylpyridin-2-yl)methyl)-2-(2-((2-(5-phenyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0169] 2-(5-phenyl-1H-benzimidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.30 mmol) and N-((3-methylpyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (75 mg, 0.30 mmol) was added to a solution of NaOH (30 mg, 0.75 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 52 (58 mg, 0.12 mmol, 40%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.35 (m, 1H), 7.65 (m, 2H), 7.6 (m, 1H), 7.5 (m, 1H), 7.4 (m, 3H), 7.3 (m, 1H), 7.2 (m, 1H), 4.5 (d, 2H), 3.0 (m, 8H), 2.3 (s, 3H) ppm. UHPLC / MS (ESI): [m / z]: 481 [M+H] +. [33.] [Example Compound Number]

[53] [:] [] N-((3-methoxypyridin-2-yl)methyl)-2-(2-((2-(5-phenyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0170] 2-(5-phenyl-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.33 mmol) and N-((3-methoxypyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (84 mg, 0.32 mmol) was added to a solution of NaOH (32 mg, 0.81 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 53 (87 mg, 0.18 mmol, 55%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 1H), 8.35 (m, 1H), 8.1 (m, 1H), 7.7 (m, 2H), 7.5 (m, 1H), 7.4 (m, 3H), 7.3 (m, 2H), 4.5 (d, 2H), 3.8 (s, 3H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 497 [M+H]+. [34.] [Example Compound Number]

[54] [:] [] 2-(2-((2-(5-(1H-pyrrolo-1-yl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-methoxypyridin-2-yl)methyl) 4-Azoxyl-methylamine []

[0171] 2-(5-(1H-pyrrolo-1-yl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.33 mmol) and N-((3-methoxypyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (87 mg, 0.33 mmol) was added to a solution of NaOH (34 mg, 0.84 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 54 (63 mg, 0.13 mmol, 39%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 1H), 8.35 (m, 1H), 8.1 (m, 1H), 7.55 (m, 1H), 7.5 (m, 1H), 7.4 (m, 1H), 7.3 (m, 4H), 6.2 (m, 2H), 4.6 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 486 [M+H]+. [35.] [Example Compound Number]

[55] [:] [] N-((3-chloropyridin-2-yl)methyl)-2-(2-((2-(6,7-dihydro-1H-[1,4]di) [2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0172] 2-(6,7-dihydro-1H-[1,4]di [2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.34 mmol) and N-((3-chloropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (90 mg, 0.34 mmol) was added to a solution of NaOH (35 mg, 0.86 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 55 (61 mg, 0.13 mmol, 37%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 3H), 7.9 (m, 1H), 7.4 (m, 1H), 6.9 (m, 2H), 4.6 (d, 2H), 4.2 (m, 4H), 3.0 – 2.8 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 483 [M+H] +. [36.] [Example Compound Number]

[56] [:] [] 2-(2-((2-(6,7-dihydro-1H-[1,4]di) [2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-(trifluoromethyl)pyridin-2-yl)methyl) 4-Azoxyl-methylamine []

[0173] 2-(6,7-dihydro-1H-[1,4]di [2',3':4,5]Benzo[1,2-d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.34 mmol) and N-((3-(trifluoromethyl)pyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (102 mg, 0.34 mmol) was added to a solution of NaOH (35 mg, 0.86 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 56 (13 mg, 0.025 mmol, 7%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.8 (m, 1H), 8.5 (m, 2H), 8.2 (m, 1H), 7.5 (m, 1H), 6.9 (m, 1H), 4.6 (d, 2H), 4.2 (m, 4H), 3.0 – 2.8 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 517 [M+H] +. [37.] [Example Compound Number]

[57] [:] [] 2-(2-((2-(5-(4-chlorophenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl) 4-Azoxyl-methylamine []

[0174] 2-(5-(4-chlorophenyl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.31 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (75 mg, 0.31 mmol) was added to a solution of NaOH (31 mg, 0.77 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 57 (11 mg, 0.02 mmol, 3%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.35 (m, 1H), 7.7 (m, 4H), 7.5 - 7.3 (m, 5H), 4.6 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 520 [M+H]+. [38.] [Example Compound Number]

[58] [:] [] 2-(2-((2-(5-(1H-pyrrolo-1-yl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-(trifluoromethyl)pyridin-2-yl)methyl) 4-Azoxyl-methylamine []

[0175] 2-(5-(1H-pyrrolo-1-yl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.33 mmol) and N-((3-trifluoromethylpyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (100 mg, 0.33 mmol) was added to a solution of NaOH (34 mg, 0.84 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 58 (63 mg, 0.12 mmol, 37%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.8 (m, 1H), 8.5 (m, 2H), 8.1 (m, 1H), 7.5 (m, 3H), 7.3 (m, 3H), 6.2 (m, 2H), 4.6 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 524 [M+H]+. [39.] [Example Compound Number]

[59] [:] [] 2-(2-((2-(5-(1H-pyrrolo-1-yl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-chloropyridin-2-yl)methyl) 4-Azoxyl-methylamine []

[0176] 2-(5-(1H-pyrrolo-1-yl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.33 mmol) and N-((3-chloropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (100 mg, 0.33 mmol) was added to a solution of NaOH (34 mg, 0.84 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 59 (66 mg, 0.14 mmol, 41%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 3H), 7.9 (m, 1H), 7.55 (m, 1H), 7.5 (m, 1H), 7.4 (m, 1H), 7.3 (m, 3H), 6.2 (m, 2H), 4.6 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 491 [M+H]+. [40.] [Example Compound Number]

[60] [:] [] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-((2-(5-(p-tolyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0177] 2-(5-(p-tolyl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.31 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (77 mg, 0.31 mmol) was added to a solution of NaOH (31 mg, 0.77 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 60 (36 mg, 0.07 mmol, 23%) as a off-white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.35 (m, 1H), 7.7 (m, 2H), 7.5 (m, 3H), 7.4 (m, 2H), 7.2 (m, 2H), 4.6 (d, 2H), 3.0 (m, 8H), 2.3 (s, 3H) ppm. UHPLC / MS (ESI): [m / z]: 499 [M+H]+. [41.] [Example Compound Number]

[61] [:] [] 2-(2-((2-(5-(3-fluorophenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl) 4-Azoxyl-methylamine []

[0178] 2-(5-(3-fluorophenyl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.31 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (77 mg, 0.31 mmol) was added to a solution of NaOH (31 mg, 0.77 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 61 (44 mg, 0.088 mmol, 28%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.3 (m, 1H), 7.7 (m, 2H), 7.5 (m, 5H), 7.1 (m, 1H), 4.6 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 503 [M+H] +. [42.] [Example Compound Number]

[62] [:] [] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-((2-(5-(o-tolyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0179] 2-(5-(o-tolyl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.31 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (77 mg, 0.31 mmol) was added to a solution of NaOH (31 mg, 0.77 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 62 (34 mg, 0.068 mmol, 22%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.3 (m, 1H), 8.1 (s, 1H), 7.7 (m, 1H), 7.5 (m, 1H), 7.4 (m, 2H), 7.2 (m, 4 H), 7.0 (m, 1H), 4.6 (d, 2H), 3.0 (m, 8H), 2.2 (s, 3H) ppm. UHPLC / MS (ESI): [m / z]: 499 [M+H]+. [43.] [Fan] [Example: Compound number]

[63] [:] [] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-((2-(5-(3-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0180] 2-(5-(3-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.31 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (70 mg, 0.31 mmol) was added to a solution of NaOH (31 mg, 0.77 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 63 (23 mg, 0.045 mmol, 15%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.3 (m, 1H), 7.7 (m, 2H), 7.5 (m, 1H), 7.4 (m, 3H), 7.2 (m, 2H), 6.9 (m, 1H), 4.6 (d, 2H), 3.8 (s, 3H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 515 [M+H] +. [44.] [Example Compound Number]

[64] [:] [] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-((2-(5-(4-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0181] 2-(5-(4-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.31 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (70 mg, 0.31 mmol) was added to a solution of NaOH (31 mg, 0.77 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 64 (41 mg, 0.08 mmol, 26%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.3 (m, 1H), 7.7 (m, 1H), 7.6 (m, 3H), 7.5 (m, 1H), 7.4 (m, 2H), 7.0 (m, 2H), 4.6 (d, 2H), 3.8 (s, 3H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 515 [M+H] +. [45.] [Fan] [Example: Compound number]

[65] [:] [] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-((2-(5-(m-tolyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0182] 2-(5-(m-tolyl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.31 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (70 mg, 0.31 mmol) was added to a solution of NaOH (31 mg, 0.77 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 65 (10 mg, 0.02 mmol, 7%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.3 (m, 1H), 7.7 (m, 2H), 7.5 – 7.3 (m, 5H), 7.1 (m, 1H), 4.6 (d, 2H), 3.0 (m, 8H), 2.3 (s, 3H) ppm. UHPLC / MS (ESI): [m / z]: 499 [M+H]+. [46.] [Fan] [Example: Compound number]

[66] [:] [] 2-(2-((2-(5-(4-fluorophenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-(pyridin-2-ylmethyl) 4-Azoxyl-methylamine []

[0183] 2-(5-(4-fluorophenyl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.31 mmol) and N-(pyridin-2-ylmethyl)-2-vinyl Azoxyl-4-methoxylamine (70 mg, 0.31 mmol) was added to a solution of NaOH (31 mg, 0.77 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 66 (27 mg, 0.056 mmol, 18%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.8 (m, 1H), 8.5 (m, 2H), 7.7 (m, 4H), 7.5 (m, 1H), 7.4 (m, 1H), 7.2 (m, 5H), 4.5 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 485 [M+H]+. [47.] [Example Compound] [serial number]

[68] [:] [] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-((2-(6-(2-methoxyethoxy)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0184] 2-(6-(2-methoxyethoxy)-1H-benzo[d]imidazol-2-yl)ethane-1-amine hydrochloride (Chemspace) (100 mg, 0.37 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (91 mg, 0.37 mmol) was added to a solution of NaOH (22 mg, 0.55 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 68 (40 mg, 0.072 mmol, 19%) as a off-white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.4 (m, 1H), 7.7 (m, 1H), 7.6 (s, 1H), 7.5 – 7.2 (m, 5H), 7.1 – 7.0 (m, 2H), 4.6 (d, 2H), 4.1 (d, 2H), 3.6 (d, 2H), 3.4 – 3.3 (m, 5H), 3.2 (s, 3H), 3.0 (m, 7H) ppm. UHPLC / MS (ESI): [m / z]: 559 [M+H]+. [48.] [Example Compound Number]

[69] [:] [] 2-(2-((2-(5-(3-fluorophenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-(pyridin-2-ylmethyl) 4-Azoxyl-methylamine []

[0185] 2-(5-(3-fluorophenyl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.31 mmol) and N-(pyridin-2-ylmethyl)-2-vinyl Azoxyl-4-methoxylamine (70 mg, 0.31 mmol) was added to a solution of NaOH (31 mg, 0.76 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 69 (19 mg, 0.039 mmol, 13%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.8 (m, 1H), 8.5 (s, 1H), 8.45 (m, 2H), 7.8 (m, 2H), 7.5 (m, 5H), 7.3 (m, 2H), 7.1 (m, 1H), 4.5 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 485 [M+H]+. [49.] [Example Compound Number]

[70] [:] [] 2-(2-((2-(5-(3-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-(pyridin-2-ylmethyl) 4-Azoxyl-methylamine []

[0186] 2-(5-(3-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.30 mmol) and N-(pyridin-2-ylmethyl)-2-vinyl Azoxyl-4-methoxylamine (70 mg, 0.30 mmol) was added to a solution of NaOH (31 mg, 0.76 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 70 (40 mg, 0.08 mmol, 27%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.7 (m, 1H), 8.55 (s, 1H), 8.5 (m, 1H), 7.7 (m, 2H), 7.5 (m, 1H), 7.4 (m, 2H), 7.2 (m, 3H), 7.15 (m, 1H), 6.9 (m, 1H), 4.5 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 497 [M+H]+. [50.] [Example Compound Number]

[71] [:] [] 2-(2-((2-(5-(2-ethylphenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl) 4-Azoxyl-methylamine []

[0187] 2-(5-(2-ethylphenyl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.30 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (73 mg, 0.31 mmol) was added to a solution of NaOH (30 mg, 0.74 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 71 (65 mg, 0.13 mmol, 42%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.4 (m, 1H), 7.7 (m, 1H), 7.5 (m, 1H), 7.4 – 7.2 (m, 6H), 7.0 (m, 1H), 4.6 (d, 2H), 3.0 (m, 8H), 2.6 (m, 2H), 1.0 (t, 3H) ppm. UHPLC / MS (ESI): [m / z]: 513 [M+H] +. [51.] [Example Compound Number]

[72] [:] [] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-((2-(5-(phenylethynyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0188] 2-(5-(phenylethynyl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.30 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (74 mg, 0.26 mmol) was added to a solution of NaOH (30 mg, 0.75 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 72 (56 mg, 0.11 mmol, 37%) as a off-white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.4 (m, 1H), 7.7 (m, 2H), 7.6 (m, 2H), 7.5 (m, 1H), 7.4 (m, 4H), 7.3 (m, 1H), 4.6 (d, 2H), 4.1 (d, 2H), 3.0 (m, 8H), 3.2 (s, 3H), 3.0 (m, 7H) ppm. UHPLC / MS (ESI): [m / z]: 509 [M+H]+. [52.] [Example Compound Number]

[73] [:] [] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-((2-(5-(pyridin-3-ylethynyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0189] 2-(5-(pyridin-3-ylethynyl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine trihydrochloride (Chemspace) (100 mg, 0.27 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (67 mg, 0.27 mmol) was added to a solution of NaOH (38 mg, 0.94 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 73 (42 mg, 0.083 mmol, 30%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.8 (s, 1H), 8.6 (m, 1H), 8.5 (m, 2H), 8.4 (m, 1H), 8.0 (m, 1H), 7.7 (m, 2H), 7.5 - 7.3 (m, 4H), 4.5 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 510 [M+H] +. [53.] [Example Compound Number]

[74] [:] [] N-((3-methoxypyridin-2-yl)methyl)-2-(2-((2-(5-(p-tolyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0190] 2-(5-(p-tolyl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.31 mmol) and N-((3-methoxypyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (79 mg, 0.31 mmol) was added to a solution of NaOH (31 mg, 0.76 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 74 (48 mg, 0.09 mmol, 30%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (s, 1H), 8.3 (m, 1H), 8.1 (m, 1H), 7.65 (s, 1H), 7.5 - 7.2 (m, 8H), 4.5 (d, 2H), 3.9 (s, 3H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 510 [M+H] +. [54.] [Example Compound Number]

[75] [:] [] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-((2-(5-phenylethyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0191] 2-(5-phenylethyl-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.3 mmol) and N-((3-methoxypyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (73 mg, 0.3 mmol) was added to a solution of NaOH (30 mg, 0.74 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 75 (65 mg, 0.13 mmol, 42%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.35 (m, 1H), 7.7 (m, 1H), 7.4 (m, 1H), 7.3 (m, 1H), 7.2 (m, 5H), 7.1 (m, 1H), 7.0 (m, 1H), 4.6 (d, 2H), 3.0 (m, 12H) ppm. UHPLC / MS (ESI): [m / z]: 513 [M+H] +. [55.] [Example Compound Number]

[76] [:] [] 2-(2-((2-(5-((3-(dimethylaminomethyl)phenyl)ethynyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl) 4-Azoxyl-methylamine []

[0192] 3-((2-(2-aminoethyl)-1H-benzo[d]imidazol-5-yl)ethynyl)-N,N-dimethylbenzylamine dihydrochloride (Chemspace) (100 mg, 0.25 mmol) and N-((3-methoxypyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (61 mg, 0.25 mmol) was added to a solution of NaOH (25 mg, 0.62 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 76 (21 mg, 0.036 mmol, 15%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.35 (m, 1H), 7.7 (m, 2H), 7.6 (m, 1H), 7.55 (s, 1H), 7.45 (m, 2H), 7.4 (m, 2H), 7.3 (m, 1H), 4.6 (d, 2H), 3.0 (m, 14H) ppm. UHPLC / MS (ESI): [m / z]: 580 [M+H]+. [56.] [Example Compound Number]

[78] [:] [] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-((2-(7-(((3-methoxyphenyl)ethynyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0193] 2-(2-(12-azalkyl)ethyl)-7-((3-methoxyphenyl)ethynyl)-1H-benzo[d]imidazolium dihydrochloride (Chemspace) (100 mg, 0.28 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (68 mg, 0.28 mmol) was added to a solution of NaOH (27 mg, 0.69 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 78 (78 mg, 0.15 mmol, 52%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.6 (m, 2H), 8.35 (m, 1H), 7.7 – 7.0 (m, 9H), 4.6 (d, 2H), 3.8 (s, 3H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 539 [M+H]+. [57.] [Example Compound Number]

[79] [:] [] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-((2-(7-((3-( (azol-2-yl)phenyl)ethynyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0194] 2-(3-((2-(2-(l2-azalkyl)ethyl)-1H-benzo[d]imidazol-7-yl)ethynyl)phenyl) Chemspace (100 mg, 0.25 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (62 mg, 0.25 mmol) was added to a solution of NaOH (25 mg, 0.62 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 79 (34 mg, 0.06 mmol, 24%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.35 (m, 1H), 8.25 (m, 1H), 8.2 (m, 1H), 8.0 (m, 1H), 7.7 – 7.1 (m, 8H), 4.6 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 576 [M+H]+. [58.] [Example Compound Number]

[80] [:] [] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-((2-(7-(pyridin-3-ylethynyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0195] 2-(2-(12-azalkyl)ethyl)-7-(pyridin-3-ylethynyl)-1H-benzo[d]imidazolium trihydrochloride (Chemspace) (100 mg, 0.27 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (67 mg, 0.27 mmol) was added to a solution of NaOH (38 mg, 0.94 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 80 (102 mg, 0.2 mmol, 74%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.8 (s, 1H), 8.6 – 8.3 (m, 4H), 8.0 (m, 1H), 7.7 – 7.1 (m, 6H), 4.6 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 510 [M+H] +. [59.] [Example Compound Number]

[81] [:] [] 2-(2-((2-(5-(2,3-dihydrobenzo[b][1,4]di) -5-yl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl) 4-Azoxyl-methylamine []

[0196] 2-(5-(2,3-dihydrobenzo[b][1,4]di) -5-yl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.27 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (68 mg, 0.27 mmol) was added to a solution of NaOH (27 mg, 0.69 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 81 (58 mg, 0.1 mmol, 36%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.55 (m, 2H), 8.35 (m, 1H), 7.7 (m, 1H), 7.55 (m, 1H), 7.45 (m, 1H), 7.3 (m, 1H), 7.2 (m, 1H), 6.85 (m, 3H), 4.6 (d, 2H), 4.3 (m, 4H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 543 [M+H] +. [60.] [Example Compound Number]

[82] [:] [] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-((2-(5-(5,6,7,8-tetrahydronaphthyl-1-yl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0197] 2-(5-(5,6,7,8-tetrahydronaphthyl-1-yl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.27 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (68 mg, 0.27 mmol) was added to a solution of NaOH (27 mg, 0.69 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 82 (52 mg, 0.1 mmol, 36%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.35 (m, 1H), 7.7 (m, 1H), 7.5 (m, 1H), 7.4 (m, 1H), 7.3 (m, 1H), 7.1 – 7.0 (m, 4H), 4.6 (d, 2H), 3.0 (m, 8H), 2.8 (m, 2H), 1.7 (m, 4H), 1.2 (m, 2H) ppm. UHPLC / MS (ESI): [m / z]: 539 [M+H]+. [61.] [Example Compound Number]

[83] [:] [] 2-(2-((2-(5-(2,3-dimethoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl) 4-Azoxyl-methylamine []

[0198] 2-(5-(2,3-dimethoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.27 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (67 mg, 0.27 mmol) was added to a solution of NaOH (27 mg, 0.68 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 83 (28 mg, 0.05 mmol, 19%) as a off-white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.35 (m, 1H), 7.7 (m, 1H), 7.5 (m, 2H), 7.4 (m, 1H), 7.2 (m, 1H), 7.1 (m, 1H), 7.0 (m, 1H), 6.9 (m, 1H), 4.6 (d, 2H), 3.8 (s, 3H), 3.5 (s, 3H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 545 [M+H] +. [62.] [Example Compound Number]

[84] [:] [] 2-(2-((2-(5-(2,3-dimethylphenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl) 4-Azoxyl-methylamine []

[0199] 2-(5-(2,3-dimethylphenyl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.3 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (73 mg, 0.3 mmol) was added to a solution of NaOH (30 mg, 0.74 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 84 (46 mg, 0.09 mmol, 30%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.35 (m, 1H), 7.7 (m, 1H), 7.5 (m, 1H), 7.4 (m, 1H), 7.3 (s, 1H), 7.1 – 7.0 (m, 4H), 4.6 (d, 2H), 3.0 (m, 8H), 2.3 (s, 3H), 2.1 (s, 3H) ppm. UHPLC / MS (ESI): [m / z]: 513 [M+H] +. [63.] [Example Compound Number]

[85] [:] [] 2-(2-((2-(5-(3-chlorophenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl) 4-Azoxyl-methylamine []

[0200] 2-(5-(3-chlorophenyl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.29 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (72 mg, 0.29 mmol) was added to a solution of NaOH (29 mg, 0.73 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 85 (108 mg, 0.2 mmol, 72%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.35 (m, 1H), 7.75 – 7.6 (m, 4), 7.55 – 7.35 (m, 5H), 4.6 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 520 [M+H]+. [64.] [Example Compound Number]

[86] [:] [] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-((2-(5-(2-( (2-yl)phenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0201] 2-(5-(2-( (Chemspace) (100 mg, 0.33 mmol) and N-((3-methoxypyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (81 mg, 0.33 mmol) was added to a solution of NaOH (7 mg, 0.2 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 86 (50 mg, 0.09 mmol, 27%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.35 (m, 1H), 7.9 (s, 1H), 7.8 – 7.2 (m, 8H), 6.9 (m, 1H), 4.6 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 552 [M+H]+. [65.] [Example Compound Number]

[87] [:] [] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-((2-(5-(3-( (2-yl)phenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0202] 2-(5-(3-( (Chemspace) (100 mg, 0.33 mmol) and N-((3-methoxypyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (81 mg, 0.33 mmol) was added to a solution of NaOH (7 mg, 0.2 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 87 (54 mg, 0.1 mmol, 30%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.35 (m, 1H), 8.2 (m, 2H), 7.95 (m, 1H), 7.8 (m, 2H), 7.7 – 7.55 (m, 3H), 7.45 – 7.35 (m, 3H), 4.6 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 552 [M+H]+. [66.] [Example Compound Number]

[88] [:] [] 2-(2-((2-(5-(2,3-dihydrobenzo[b][1,4]di) -6-yl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl) 4-Azoxyl-methylamine []

[0203] 2-(5-(2,3-dihydrobenzo[b][1,4]di) -6-yl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.27 mmol) and N-((3-methoxypyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (67 mg, 0.27 mmol) was added to a solution of NaOH (27 mg, 0.68 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 88 (10 mg, 0.02 mmol, 7%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.35 (m, 1H), 7.7 (m, 1H), 7.6 (s, 1H), 7.45 – 7.3 (m, 3H), 7.1 (m, 2H), 6.9 (m, 1H), 4.6 (d, 2H), 4.3 (s, 4H), 3.0 (m, 8H), 2.7 (m, 4H), 1.7 (m, 4H) ppm. UHPLC / MS (ESI): [m / z]: 543 [M+H] +. [67.] [Example Compound Number]

[89] [:] [] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-((2-(5-(5,6,7,8-tetrahydronaphthyl-2-yl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0204] 2-(5-(5,6,7,8-tetrahydronaphthyl-2-yl)-1H-benzo[d]imidazol-2-yl)ethane-1-amine dihydrochloride (Chemspace) (100 mg, 0.27 mmol) and N-((3-methoxypyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (68 mg, 0.27 mmol) was added to a solution of NaOH (27 mg, 0.69 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 89 (30 mg, 0.06 mmol, 20%) as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.35 (m, 1H), 7.65 (m, 2H), 7.5 (m, 1H), 7.3 (m, 4H), 7.1 (m, 1H), 4.6 (d, 2H), 3.0 (m, 8H), 2.7 (m, 4H), 1.7 (m, 4H) ppm. UHPLC / MS (ESI): [m / z]: 539 [M+H]+. [68.] [Example Compound Number]

[90] [:] [] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-((2-(5-(4-( (2-yl)phenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl) 4-Azoxyl-methylamine []

[0205] 2-(5-(4-( (Chemspace) (100 mg, 0.29 mmol) and N-((3-methoxypyridin-2-yl)methyl)-2-vinyl Azoxyl-4-methoxylamine (73 mg, 0.29 mmol) was added to a solution of NaOH (29 mg, 0.73 mmol) in 10 mL of water. The mixture was heated and stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with 2N HCl and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (CH₂Cl₂ / MeOH) to give the title compound 90 (30 mg, 0.05 mmol, 19%) as a off-white solid. 1H NMR (400 MHz, DMSO- d 6) δ 8.5 (m, 2H), 8.35 (m, 1H), 8.25 (m, 1H), 8.05 (m, 2H), 7.85 (m, 3H), 7.7 (m, 1H), 7.5 (m, 2H), 7.35 (m, 2H), 4.6 (d, 2H), 3.0 (m, 8H) ppm. UHPLC / MS (ESI): [m / z]: 552 [M+H]+.

[0206] Sequence List <![CDATA[ <110> VIFOR (INTERNATIONAL) AG, a Swiss company. <![CDATA[ <120> Modified FERROPORTIN inhibitor <![CDATA[ <140> TW 111113855]]> <![CDATA[ <141> 2022-04-12 <![CDATA[ <150> EP 21169916.0 <![CDATA[ <151> 2021-04-22 <![CDATA[ <160> 2]]> <![CDATA[ <170> BiSSAP 1.3.6 <![CDATA[ <210> 1]]> <![CDATA[ <211> 21]]> <![CDATA[ <212> DNA <![CDATA[ <213> People <![CDATA[ <220> ]]> <![CDATA[ <223> Forward introduction <![CDATA[ <400> 1]]> caggtttgtg agcatcctga a 21 <![CDATA[ <210> 2]]> <![CDATA[ <211> 19]]> <![CDATA[ <212> DNA <![CDATA[ <213> People <![CDATA[ <220> ]]> <![CDATA[ <223> Reverse pull <![CDATA[ <400> 2]]> ggcggcgact aaggagagg 19

[0207]

Claims

1. A compound according to formula (I) or a pharmaceutically acceptable salt thereof, (I) wherein l is an integer of 1 or 2; m and n are independently integers of 1, 2 or 3; X1 is N, S or O; X2 is N, S, O or CR4; X3 is C or N; provided that one of X1 and X2 is N and if X3 is N, then X2 is CR4; and wherein R4 represents H, halogen, straight-chain or branched C1-C3-alkyl, or straight-chain or branched C1-C3-haloalkyl; A represents one of the following groups (a-1), (a-2) and (a-5), (a-1) (a-2) (a-5) wherein * indicates the binding position; R1 and R2 independently represent H, halogen, straight-chain C1-C3-alkyl, straight-chain C1-C3-haloalkyl, or straight-chain C1-C3-alkoxy; In formula (a-2), one of C1, C2, and C3 is present, and in formula (a-5), both C4 and C5 are present, and C1, C2, C3, C4, and C5 independently represent a fused 6-membered aryl ring; B represents one of the following groups (b-1) and (b-2) (b-1) (b-2) where * indicates the bonding position; R3 represents H, an unsubstituted or substituted 6-membered aryl, an unsubstituted 5- or 6-membered heteroaryl, wherein the heteroatom is one to three identical or different heteroatoms selected from S, O, and N, an unsubstituted bicyclic heteroaryl, a 6-membered heterocyclic group, a 6-membered heterocyclic alkyl, wherein "alkyl" represents C1-C3-alkyl, a 6-membered arylalkyl, wherein "alkyl" represents C1-C3-alkyl, an unsubstituted or substituted 6-membered arylethynyl, An unsubstituted 6-membered heteroarylethynyl or phenyl group, which forms a fused bicyclic ring with a 6-membered cycloalkyl or heterocyclic group; Z1 represents N or C, provided that no more than one Z1 represents N; In formula (b-2), one of D1, D2 and D3 is present and represents a fused 6-membered aryl ring, a fused 6-membered heteroaryl ring, a fused 6-membered cycloalkyl ring, or a fused 5- or 6-membered heterocyclic ring; and wherein group (b-2) has 0 or 1 substituent independently selected from the following: halogen, and straight-chain C1-C3-alkoxy; Z2 and Z3 represent N or C, provided that Z2 can represent N when D2 is present, and Z3 can represent N when D3 is present; and wherein the compound (I) is characterized in that at least one of groups A and B contains at least 3 rings.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 represents H, an unsubstituted or substituted 6-membered aryl, an unsubstituted 5- or 6-membered heteroaryl, an unsubstituted bicyclic heteroaryl, wherein the heteroatom is one to three identical or different heteroatoms selected from S, O and N, a 6-membered heterocyclic group, a 6-membered heterocyclic alkyl group, wherein "alkyl" represents C1-C3-alkyl, or a 6-membered arylethynyl group.

3. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein l is an integer of 1 or 2; m and n are independently integers of 1, 2 or 3; X1 is N, S or O; X2 is N, S, O or CR4; X3 is C or N; provided that one of X1 and X2 is N and if X3 is N, then X2 is CR4; and R4 represents H; A represents one of the following groups (a-1), (a-2) and (a-5) (a-1) (a-2) (a-5) where * indicates the binding position; R1 and R2 independently represent hydrogen, halogen, straight-chain C1-C3-alkyl, straight-chain C1-C3-haloalkyl, or straight-chain C1-C3-alkoxy; In formula (a-2), one of C1, C2, and C3 is present, and in formula (a-5), both C4 and C5 are present, and C1, C2, C3, C4, and C5 represent a fused benzene ring; B represents one of the following groups (b-1) and (b-2) (b-1) (b-2) where * indicates the bonding position; R3 represents H, unsubstituted or substituted phenyl, unsubstituted 5- or 6-membered heteroaryl, unsubstituted bicyclic heteroaryl, wherein the heteroatom is 1 to 3 identical or different heteroatoms selected from S, O, and N, 6-membered heterocyclic group, 6-membered heterocyclic alkyl, wherein "alkyl" represents C1-C3-alkyl, phenylalkyl, wherein "alkyl" represents C1-C3-alkyl, unsubstituted phenylethynyl or unsubstituted 6-membered heteroarylethynyl, or a phenyl group that forms a fused bicyclic ring with a 6-membered cycloalkyl or heterocyclic group; Z1 represents N or C, provided that no more than one Z1 represents N; In formula (b-2), one of D1, D2, and D3 is present and represents a fused benzene ring, a fused 6-membered heteroaryl ring, a fused 6-membered cycloalkyl ring, or a fused 5- or 6-membered heterocyclic ring; and wherein group (b-2) has 0 or 1 substituent selected from the following: halogen, and straight-chain C1-C3-alkoxy; Z2 and Z3 represent N or C, provided that Z2 can represent N when D2 is present, and Z3 can represent N when D3 is present; and wherein the compound (I) is characterized in that at least one of groups A and B contains at least 3 rings.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 and R2 independently represent a halogen, a straight-chain C1-C3-alkyl, a straight-chain C1-C3-haloalkyl, or a straight-chain C1-C3-alkoxy; and R3 represents H, an unsubstituted or substituted phenyl, an unsubstituted 5- or 6-membered heteroaryl, an unsubstituted bicyclic heteroaryl, wherein the heteroatom is one to three identical or different heteroatoms selected from S, O and N, a 6-membered heterocyclic group, a 6-membered heterocyclic alkyl, wherein "alkyl" represents a C1-C3-alkyl or phenylethynyl.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that one of groups A and B contains three rings.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the substituents are selected from the following groups: halogen substituents representing F or Cl; straight-chain or branched C1-C3-alkyl substituents representing methyl or ethyl; straight-chain or branched C1-C3-haloalkyl substituents representing trifluoromethyl (CF3); straight-chain or branched C1-C3-alkoxy substituents representing methoxy; 5 or 6-membered heteroaryl substituents representing azole; alkoxyalkyl ether substituents representing methoxyethyl ether groups; and dialkylamine carbonyl substituents representing dimethylamine carbonyl.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the substituents are selected from the following groups: halogen substituents representing F or Cl, straight-chain or branched C1-C3-alkyl substituents representing methyl, straight-chain or branched C1-C3-haloalkyl substituents representing trifluoromethyl (CF3), and straight-chain or branched C1-C3-alkoxy substituents representing methoxy.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X1, X2 and X3 are selected to form one of the following groups: , , , or wherein * indicates the binding position with the amine carbonyl group and ** indicates the binding position with the –[(CH2)]m-amine-[(CH2)]n- group; and wherein R4 represents H, halogen, straight-chain or branched C1-C3-alkyl, or straight-chain or branched C1-C3-haloalkyl.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X1, X2 and X3 are selected to form one of the following groups: , , or.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein group A is selected from the following groups (a-1), (a-2) and (a-5): (a-1): (a-2): (a-5): , or.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: .

12. The compound or its pharmaceutically acceptable salt thereof, as claimed in any of claims 1 to 11, may be used as a pharmaceutical preparation.

13. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 11, used as an inhibitor of ferroportin or for inhibiting ferroportin-mediated iron transport.

14. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 11, used for the prevention and / or treatment of iron metabolism disorders resulting in increased iron levels or increased iron absorption and / or iron excess.

15. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 11, used for the prevention and / or treatment of diseases related to or caused by increased iron levels, increased iron absorption or iron excess, selected from thalassemia, heme disorders, heme E diseases, heme H diseases, hemochromatosis and hemolytic anemia.

16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein thalassemia includes α-thalassemia, β-thalassemia or δ-thalassemia; and wherein hemolytic anemia includes sickle cell anemia or congenital erythropoiesis-related anemia.

17. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 11, used for the prevention and / or treatment of: diseases associated with ineffective erythropoiesis; and / or diseases caused by a decrease in hepcidin levels; and / or infections caused by pathogenic microorganisms, as adjunctive therapy by limiting the amount of iron available to the pathogenic microorganisms; and / or neurodegenerative diseases, by limiting or increasing iron deposition in tissues or cells; and / or the formation of free radicals, reactive oxygen species (ROS) and oxidative stress; and / or cardiac, hepatic and endocrine damage caused by iron excess; and / or inflammation triggered by excessive iron.

18. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein: Diseases associated with ineffective erythropoiesis are selected from the following groups: myelomectomy syndrome, congenital erythropoietic anemia and myeloproliferative neoplasms; and / or neurodegenerative diseases are selected from Alzheimer's disease and Parkinson's disease.

19. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein myeloproliferative neoplasms include polycythemia vera.

20. A pharmaceutical agent comprising one or more of the compounds of any one of claims 1 to 11 or pharmaceutically acceptable salts thereof, further comprising one or more of the following: one or more pharmaceutically acceptable carriers and / or adjuvants and / or solvents, and / or at least one additional pharmaceutically active compound selected from active compounds for the prevention and treatment of iron overdose, thalassemia or hemochromatosis; active compounds for the prevention and treatment of neurodegenerative diseases and related symptoms; and iron chelating compounds.

21. The medicine requested in item 20 is in the form of a formulation for oral and external administration.

22. A compound or a pharmaceutically acceptable salt thereof from any of claims 1 to 11, used in a combination therapy comprising co-administering a compound or a pharmaceutically acceptable salt thereof from any of claims 1 to 11, and at least one additional pharmaceutically active compound, wherein the co-administration in the combination therapy is performed in a fixed-dose combination therapy by co-administering a compound or a pharmaceutically acceptable salt thereof from any of claims 1 to 11, and at least one additional pharmaceutically active compound in a fixed-dose formulation; or the co-administration in the combination therapy is performed in a free-dose combination therapy by co-administering a compound or a pharmaceutically acceptable salt thereof from any of claims 1 to 11 at a free dose. The compound or its pharmaceutically acceptable salt, together with at least one additional pharmaceutically active compound, which is administered simultaneously with the individual compounds or sequentially over a period of time; and wherein the one or more other pharmaceutically active compounds are active compounds for reducing iron excess, and / or selected from the following pharmaceutically active compounds: antioxidants, antidiabetic drugs, antibiotics, drugs for treating malaria, anticancer agents, antifungal drugs, drugs for treating neurodegenerative diseases, antiviral drugs, immunosuppressants, iron supplements, vitamin supplements, erythropoiesis stimulants, anti-inflammatory biological agents, anticoagulants, statins, vasopressins and muscle contraction compounds.

23. The compound of claim 22 or a pharmaceutically acceptable salt thereof, wherein, In this combination therapy, the active compound for reducing iron excess is selected from Tmprss6-ASO, iron chelators, curcumin, SSP-004184, deferitrin, deferasirox, deferoxamine, and / or deferiprone; the antioxidant is selected from n-acetylcysteine; the antidiabetic drug is selected from GLP-1 receptor agonists; the antibiotic is selected from vancomycin and tobramycin; the drug for treating neurodegenerative diseases is selected from drugs used to treat Alzheimer's disease and Parkinson's disease; the antiviral drug is selected from interferon-α and ribavirin; and the immunosuppressant is selected from cyclosporine A and cyclosporine A derivatives.