Ferroportin inhibitors

Abstract

The invention relates to novel ferroportin inhibitors of the general formula (I) pharmaceutical compositions comprising them and the use thereof as medicaments, in particular for the prophylaxis and / or treatment of diseases caused by a lack of hepcidin or iron metabolism disorders, such as particularly iron overload states such as in particular thalassemia and hemochromatosis.

Description

NOVEL FERROPORTIN INHIBITORSDESCRIPTION INTRODUCTIONThe invention relates to novel ferroportin inhibitors of the general formula (I), pharmaceutical compositions comprising them and the use thereof as medicaments, in particular for the prophylaxis and / or treatment of diseases caused by a lack of hepcidin or iron metabolism disorders, such as particularly iron overload states such as in particular thalassemia and hemochromatosis.BACKGROUND AND PRIOR ARTIron is an essential trace element for almost all organisms and is relevant in particular with respect to growth and the formation of blood. The balance of the iron metabolism is in this case primarily regulated on the level of iron recovery from haemoglobin of ageing erythrocytes and the duodenal absorption of dietary iron. The released iron is taken up via the intestine, in particular via specific transport systems (DMT-1 , ferroportin), transferred into the blood circulation and thereby conveyed to the appropriate tissues and organs (transferrin, transferrin receptors).In the human body, the element iron is of great importance, inter alia for oxygen transport, oxygen uptake, cell functions such as mitochondrial electron transport, cognitive functions, etc. and ultimately for the entire energy metabolism.On average, the human body contains 4 to 5 g iron, with it being present in enzymes, in haemoglobin and myoglobin, as well as depot or reserve iron in the form of ferritin and hemosiderin. Approximately half of this iron, about 2 g, is present as heme iron, bound in the haemoglobin of the erythrocytes. Since these erythrocytes have only a limited lifespan (75-150 days), new ones have to be formed continuously and old ones degraded (over 2 million erythrocytes are being formed per second). This high regeneration capacity is achieved by macrophages phagocytizing the ageing erythrocytes, lysing them and thus recycling the iron thus obtained for the iron metabolism. The majority of the iron required for erythropoiesis, about 25 mg per day, is provided in this way.The daily iron requirement of a human adult is between 0.5 to 1 .5 mg per day, infants and women during pregnancy require 2 to 5 mg of iron per day. The daily iron loss, e.g. by desquamation of skin and epithelial cells, is low. Increased iron loss occurs, for example, during menstrual hemorrhage in women. Generally, blood loss can significantly reduce the iron level since about 1 mg iron is lost per 2 ml blood. In a healthy human adult, the normal daily loss of iron of about 1 mg is usually replaced via the daily food intake thus rebalancing the daily iron requirement to the adequate levelThe iron level is regulated by absorption, with the absorption rate of the iron present in food being between 6 and 12 %, and up to 25 % in the case of iron deficiency. The absorption rate is regulated by the organism depending on the iron requirement and the size of the iron store. In the process, the human organism utilizes both divalent as well as trivalent iron ions. Usually, iron(lll) compounds are dissolved in the stomach at a sufficiently acid pH value and thus made available for absorption. The absorption of the iron is carried out in the upper small intestine by mucosal cells. In the process, trivalent non-heme iron is first reduced in the intestinal cell membrane to Fe(ll) for absorption, for example by ferric reductase (membrane-bound duodenal cytochrome b), so that it can then be transported into the intestinal cells by means of the transport protein DMT1 (divalent metal transporter 1 ). In contrast, heme iron enters the enterocytes through the cell membrane without any change. In the enterocytes, iron is either stored in ferritin as depot iron, or released into the blood by the transport protein ferroportin. Hepcidin plays a central role in this process because it is the essential regulating factor of iron absorption. The divalent iron transported into the blood by ferroportin is converted into trivalent iron by oxidases (ceruloplasmin, hephaestin), the trivalent iron then being transported to the relevant places in the organism by transferrin (see for example "Balancing acts: molecular control of mammalian iron metabolism". M.W. Hentze, Cell 1 17,2004,285-297.). Mammalian organisms are unable to actively discharge iron. The iron metabolism is substantially controlled by hepcidin via the cellular release of iron from macrophages, hepatocytes and enterocytes.Hepcidin is a peptide hormone produced in the liver. The predominant active form has 25 amino acids (see for example: "Hepcidin, a key regulator of iron m etabolism and mediator of anaemia of inflammation". T. Ganz, Blood, 102, 2003, 783-8), although two forms which are shortened at the amino end, hepcidin-22 and hepcidin-20, have been found. Hepcidin acts on the absorption of iron via the intestine and via the placenta and on the release of iron from the reticuloendothelial system. In the body, hepcidin is synthesized in the liver from what is known as pro-hepcidin, pro-hepcidin being coded by the gene known as the HAMP gene. The formation of hepcidin is regulated in direct correlation to the organisms iron level, i.e. if the organism is supplied with sufficient iron and oxygen, more hepcidin is formed, if iron and oxygen levels are low, or in case of increased erythropoiesis less hepcidin is formed. In the small intestinal mucosal cells and in the macrophages hepcidin binds with the transport protein ferroportin, which conventionally transports the phagocytotically recycled iron from the interior of the cell into the blood.The transport protein ferroportin is a transmembrane protein consisting of 571 amino acids which is formed in the liver, spleen, kidneys, heart, intestine and placenta. In particular, ferroportin is localized in the basolateral membrane of intestinal epithelial cells. Ferroportin bound inthis way thus acts to export the iron into the blood. In this case, it is most probable that ferroportin transports iron as Fe2+. If hepcidin binds to ferroportin, ferroportin is transported into the interior of the cell, where its breakdown takes place so that the release of the phagocytotically recycled iron from the cells is then almost completely blocked. If the ferroportin is inactivated, for example by hepcidin, so that it is unable to export the iron which is stored in the mucosal cells, the stored iron is lost with the natural shedding of cells via the stools. The absorption of iron in the intestine is therefore reduced , when ferroportin is inactivated or inhibited , for example by hepcidin. In addition, ferroportin is markedly localized in the reticuloendothelial system (RES), to which the macrophages also belong. Hepcidin plays an important part here when iron metabolism is impaired by chronic inflammation. In case of inflammation in particular interleukin-6 is increased , triggering an increase in hepcidin levels. As a result, more hepcidin is bound to the ferroportin of the macrophages, thus blocking the release of stored iron, which ultimately leads to anemia of inflammation (ACD or Al).On the other hand, if the serum iron level decreases, hepcidin production in the hepatocytes of the liver is reduced so that less hepcidin is released and accordingly less ferroportin is inactivated, allowing a larger amount of stored iron to be transported into the serum.Therefrom it becomes apparent that the hepcidin-ferroportin system directly regulates the iron metabolism and that a disorder of the hepcidin regulation mechanism therefore has a direct effect on iron metabolism in the organism. In principle the hepcidin-ferroportin regulation mechanism acts via the two following opposite principles:On the one hand, an increase of hepcidin leads to inactivation of ferroportin, thus blocking the release of stored iron from the cells into the serum, thus decreasing the serum iron level. In pathological cases a decreased serum iron level leads to a reduced hemoglobin level, reduced erythrocyte production and thus to iron deficiency anemia.On the other hand , a decrease of hepcidin results in an increase of active ferroportin, thusallowing an enhanced release of stored iron and an enhanced iron uptake e.g. from the food , thus increasing the serum iron level. In pathological cases an increased iron level leads to iron overload.Iron overload states and diseases are characterized by excess iron levels. Therein, the problems arise from excess serum iron level which lead to non-transferrin bound iron (NTBI). The NTBI is rapidly taken up unspecifically by the organs, leading to an accumulation of iron in tissue and organs. Iron overload causes many diseases and undesired medical conditions, including cardiac, liver and endocrine damage. Further, iron accumulation in brain has been observed in patients suffering from neurodegenerative diseases such as for example Alzheimer's disease and Parkinson's disease. As a particular detrimental aspect of excess free iron the undesired formation of radicals must be mentioned. In particular iron(ll) ions catalyze the formation (inter alia via Fenton reaction) of reactive oxygen species (ROS). These ROS cause damage to DNA, lipids, proteins and carbohydrates which has far-reaching effects in cells, tissue and organs. The formation of ROS is well known and described in the literature to cause the so-called oxidative stress.A well-established hitherto existing method for treating iron overload is based on the concept to reduce the amount of iron in the serum by increased removal of the iron from the body. The eldest known and still routine treatment method in an otherwise-healthy person consists of regularly scheduled phlebotomies (bloodletting). When first diagnosed, the phlebotomies are usually scheduled fairly frequent, e.g. once a week, until iron levels are brought to within normal range, followed by phlebotomies which are then scheduled once a month or every three months depending upon the patient's rate of iron loading.For patients unable to tolerate routine blood draws, there are chelating agents available for use. For example, deferoxamine (also known as desferrioxamine B, N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5- ({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl} amino)pentyl]-N-hydroxysuccinamide or Desferal®), which is a bacterial siderophore, is an established drug used in chelation therapy. Deferoxamine binds iron in the bloodstream as an chelator and enhances its elimination via urine and faeces. Typical treatment of chronic iron overload requires subcutaneous injection over a period of 8 - 12 hours daily. Parenterally injectable compositions of desferrioxamine-B salts are described for example in WO 1998 / 25887.Two newer drugs, licensed for use in patients receiving regular blood transfusions to treat thalassemia, resulting in the development of iron overload, aredeferasirox and deferiprone.Deferasirox (Exjade®, 4-(3,5-bis(2-hydroxyphenyl)-1 H-1 ,2,4-triazol-1-yl)benzoic acid), being described for example in WO 1997 / 49395 and deferiprone (Ferriprox®, 3-hydroxy-1 ,2-dimethylpyridin- 4(1 H)-one) are similarly acting as an iron chelating agent, thus being suitable as a drug for iron chelation therapy.Further compounds acting as iron chelator for use in the treatment of iron overload have been described. For example WO 2013 / 142258 relates to encapsulated particles of diethylenetriaminepentaacetate (DTPA) and a zinc salt. WO 2003 / 041709 relates to 4-hydroxy-2- alkylquniolines such as 4-hydroxy-2-nonylqunioline as an iron chelator. WO 1998 / 09626 relates to chelating agents for treating iron overload states on the basis of dithiocarbamatecontaining compositions.for the use in the treatment of iron overload diseases. According to WO 2015 / 077655 said desferrithiocin derivatives have been found to act as iron chelating agents.WO 2005 / 05141 1 relates to novel antibiotics or antimycotics on the basis of oxachelin and derivatives thereof according to formulawhich are described to act as an iron chelator and to be used in the treatment of iron overload diseases.The disadvantage in the treatment of iron overload by chelation therapy is the removal of the chelated iron from the body when the iron overload has already occurred instead of preventing the occurrence of the disorder. Further, the established drugs for iron chelation therapy are known to exhibit a toxic potential.Modern approaches can be expected to supersede this method increasingly, in particular with increasing knowledge about the underlying mechanisms and development of appropriate treating methods on the basis of such knowledge. Hepcidin agonists or compounds which have an inhibiting or supporting effect on the biochemical regulatory pathways in the iron metabolism are basically known from the prior art.Iron overload may occur, for example, if hepcidin expression is prevented, for example due to a genetic defect, such as in the known iron overload disease haemochromatosis. Hemochromatosis is a disease of iron overload caused by mutations in genes that control hepcidin synthesis or in the hepcidin gene itself. Low or absent levels of hepcidin in these patients result in enhanced amounts of active ferroportin, allowing increased absorption of dietary iron, leading to severe iron overload, which causes cardiac, liver and endocrine damages. Hepcidin mimetic peptides, i.e. peptides which similarly bind and inactivate ferroportin, have been shown to effectively reverse the accumulation of tissue iron in the hepcidin knockout mouse, a model of Type 2 (juvenile) hemochromatosis. (Ramos et al , Blood 2012).In the known iron overload disease beta-thalassemia a mutation in the beta globin gene causes a reduction in hemoglobin production and ineffective erythropoiesis, the inability to produce adequate numbers of red cells because of damage to and death of developing red cells in the bone marrow. This causes upregulation of the rate of erythropoiesis and a reduction in hepcidin level to make more iron available for increased erythropoietic activity. This maladaptive response results in iron overloaddue to the reduced hepcidin levels, which lead to enhanced amounts of active ferroportin, allowing increased absorption of dietary iron, as described above. Red cells in thalassemia have a shortened half-life because of the toxicity of an imbalanced ratio of alpha- and beta- hemoglobin-subunits. Also in the treatment of beta-thalassemia the use of hepcidin mimetic peptides has been described , the therapeutic rationale being based on the increase of hepcidin activity leading to iron restriction and reduction of iron mediated damage in red cells. Administration of hepcidin mimetic peptides to the th3 / + mouse, a model of non-transfusion dependent beta-thalassemia resulted in relief of ineffective erythropoiesis, increased red cell survival time and improvement of anemia. In this model the prevention of iron overload due to reduction in the absorption of dietary iron turned out as an additional benefit of the hepcidin mimetic therapy (Gardenghi et al, 2010; Casu et al 2013).The described therapeutic approaches are based on a direct involvement into the disturbed iron metabolism pathway by directly acting via the primary regulator hepcidin by providing a hepcidin mimeticor a hepcidin agonist, i.e. acting in the sense of a kind of hepcidin substitute or supply. The approach is based on the therapeutic rationale to treat iron overload , i.e. excess serum iron level, by inhibiting ferroportin, via the hepcidin-inactivation mechanism, thus blocking excessive iron absorption.Further known iron overload related diseases are diseases associated with ineffective erythropoiesis such as the myelodysplastic syndromes (also known as MDS or myelodysplasia), polycythemia vera, etc.Further, mutations in genes involved in sensing the systemic iron stores, such as hepcidin (Hampl ), hemochromatosis protein (HFE), hemojuvelin (HJV) and transferrin receptor 2 (TFR2) cause iron overload in mice and men. Accordingly, diseases related to HFE and gene mutations, chronic hemolysis associated diseases, sickle cell diseases, red cell membrane disorders, as well as Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency), erythrpoietic porphyria and Friedrich's Ataxia can be mentioned. Further, subgroups of iron overload comprise transfusional iron overload , iron intoxication, pulmonary hemosiderosis, osteopenia, insulin resistense, African iron overload , Hallervordan Spatz disease, hyperferritinemia, ceruloplasmin deficiency, neonatal hemochromatosis and red blood cell disorders comprising thalassemia, alpha thalassemia, thalassemia intermedia, sickle cell disease and myelodyplastic syndrome are included .Further disease and / or disorders and / or diseased conditions associated with elevated iron levels include, but are not limited to, diseases with elevated iron level, comprising ataxia, Friedrich's ataxia, age- related macular degeneration, age-related cataract, age-related retinal diseases and neurodegenrative disease, whereby such neurodegenrative disease comprises Alzheimer's disease, Parkinson's disease, pantothenate kinase-associated neurodegeneration, restless leg syndrom and Huntington's disease,Hepcidin is a host defense peptide, representing a component of the innate immune system that responds to invading organisms. It has been described that many bacteria are highly dependent on a supply of iron from the host (so-called siderophilic organisms) and have evolved mechanisms to capture iron from the local tissues. The ability to limit the amount of iron available to such organisms by ferroportin- inhibitors may represent effective adjunctive therapy. One such siderophilic organism is Vibrio vulnificus, which causes rare but extremely severe infections in coastal communities, often in subjects with undiagnosed iron overload . Studies in animals that have been inoculated with a lethal dose of Vibrio vulnificus have demonstrated nearly 100% survival in response to treatment with hepcidin mimetic peptides, inactivating ferroportin, regardless of whether treatment is started before or after the infection is initiated (Arezes et al 2015).As known hepcidin mimetics the so-called minihepcidins can be mentioned, described for example in WO 2013 / 086143. Minihepcidins are small-sized synthetic peptide analogues of the hepcidin -terminus which is crucial for hepcidin interaction with ferroportin. Minihepcidins have been developed on the basis that the first 9 amino acids of hepcidin (DTHFPICIF) have been found to be sufficient for in vitro activity (measured as ferroportin-GFP degradation). Minihepcidins have a modified hepcidin-9 amino acid sequence to exhibit improved resistance to proteolysis and enhanced biophysical interaction with ferroportin. Minihepcidins are described to be useful for the treatment of human iron overload conditions caused by hepcidin deficiency.WO 2015 / 069660 describes methods for increasing hepcidin expression for treating iron overload disorders by decreasing non-transferrin bound iron (NTBI) by administering a modified iron binding / releasing transferrin.All the described compounds which act as hepcidin agonists, hepcidin mimetics or ferroportin inhibitor etc. are relatively high molecular weight compounds, in particular those which are obtainable predominantly by genetic engineering. Various further approaches on the basis of biomolecular interactions and biomolecules have been described . The disadvantage is the complex preparation and high sensitivity of such biomolecular compounds. In particular methods on the basis of ferroportin antibodies are not sufficiently efficient as the antibody-inhibited ferroportin is permanently reproduced by the organism and the inhibition is thus not sufficiently long-lasting to achieve the desired therapeutic effect. Low molecular weight compounds which play a part in iron metabolism and can have an inhibiting or promoting effect are also known.For example WO 2008 / 151288, WO 2008 / 1 18790, WO 2008 / 1 15999, and WO 2008 / 109840 describe compounds acting as divalent metal transporter-1 (DMT1 ) inhibitors and their use for the treatment of iron disorders such as thalassemia or hemochromatosis.WO 2008 / 123093 relates to an agent for prevention or treatment of iron overload disorders, comprising 22 beta-methoxyolean-12-ene-3 beta,24(4 beta)-diol.EP 1074254 and EP1072265 relate to the use of catechic- and flavonoid-structure plant polyphenols for treating iron overload.WO 201 1 / 029832 relates to thiazol and oxazol compounds, which act as hepcidin antagonists and are thus described to be suitable in the use for the treatment of iron deficiency diseases. Therein, hepcidin antagonistic activity is described to inhibit the inhibition of ferroportin by hepcidin, which is the opposite effect as has been found by the inventors of the present invention for the compounds as described herein.Chemical compounds based on the structures of the general formulae of the present invention have hitherto not been disclosed in connection with their activity as ferroportin inhibitors or for the use in the prophylaxis and treatment of iron metabolism disorders which are associated with increased iron levels such as iron overload.US 2004 / 0138268 A1 , US 201 1 / 0224136 A1 , CN 103508957, WO 2006 / 062224 A1 , WO 2015 / 051362 A1 , EP 1953145 A1 , WO 2009 / 154739 A2, GB 937878 A, WO 201 1 / 023722 A1 , WO 2010 / 020556 A1 , WO 2005 / 01 1685 A1 , WO 00 / 56724 A1 , WO 2010 / 036632 A1 , WO 2005 / 014576 A1 , WO 2013 / 067578 A1 , WO 2005 / 1 16355 A1 or in Zou Yiquan et al. "Discovery of pyrazole as C-terminus of selective BACE1 inhibitors"; Eur. J. of Medicinal Chemistry 68 (2013) 270-283, Tussing-Humphreys et al. "Rethinking Iron Regulation and Assessment in Iron Deficiency, Anemia of Chronic Disease, and Obesity: Introducing Hepcidin" J. Academy of Nutrition and Dietetics (2012), Vol. 122, No. 3, 391 -400, Riordan et al. "Bleomycin analogs. Synthesis and proton NMR spectral assignments of thiazole amides related to bleomycin A2 (1 )"; J. Heterocyclic Chem. 18, 1213 (1981 ), Hideaki Sasaki "Synthesis of a novel bis(2,4'-bithiazole) derivative as a Co(ll)-activated DNA cleaving agent"; Chem. Pharm. Bull. 42(8) 1685- 1687 (1994), and Ballell et al. "Fueling open-source drug discovery. 177 small-molecule leads against tuberculosis"; ChemMedChem 2013, 8, 313-321 describe compounds for different medical uses and mechanisms of action.OBJECTThe object of the present invention was to provide, in particular, new therapeutically effective compounds that can be used for an effective therapy for the prophylaxis and treatment of iron metabolism disorders which are associated with increased iron levels, such as in particular iron overload. In a further object, the new compounds should exhibit few side effects and have a very low toxicity and good bioavailability and compatibility. Moreover, these new compounds, in contrast to the known iron chelating compounds, should be suitable to prevent the occurrence of increased iron levels and thus the related disorders, instead of removing excess iron from the body when the iron overload has already occurred. In a further object the new compounds should have a defined structure (stoichiometry) and should be preparable by simple synthesis processes, exhibit less sensitivity and improved long-lasting efficiency as compared to the known biomolecular compounds, such as antibodies.This goal was achieved by the development of the novel compounds according to the formulae as defined herein, such as in particularformula (I), which have been found to act as ferroportin inhibitors, thus being suitable for the use in the inhibition of iron transport, and thus being effective in the prophylaxis and treatment of iron metabolism disorders which are associated with increased iron levels, such as in particular iron overload, as well as in in the prophylaxis and treatment of diseases caused by a lack of hepcidin, diseases related to or caused by increased iron levels or iron overload and diseases associated with ineffective erythropoiesis.DESCRIPTION OF THE INVENTIONThe inventors have surprisingly found that specific compounds having the general structural formula (I) as defined herein, act as ferroportin inhibitors, thus effectively inhibiting iron transport and accordingly being particularly suitable for the use as medicaments, in particular for the use in the treatment and / or prophylaxis of diseases caused by a lack of hepcidin, diseases associated with ineffective erythropoiesis or iron metabolism disorders leading to increased iron levels, such as particularly iron overload states such as in particular thalassemia and hemochromatosis. Very particularly the new compounds turned out to be suitable for treating thalassemia and hemochromatosis. The new compounds are also suitable for the treatment of diseases caused by pathologically low hepcidin-levels and for the use in the inhibition of iron transport.Accordingly, the invention relates to compounds of general formula (I)or pharmaceutically acceptable salts thereof, for the use as ferroportin inhibitors, whereinR and R2 are the same or different and are independently selected from the group consisting of- hydrogen,- optionally substituted alkyl,- optionally substituted aryl,- optionally substituted heteroaryl,- optionally substituted heterocyclyl, or- R and R2 together with the nitrogen atom to which they are bonded form anoptionally substituted 3- to 6-membered ring, which may optionally contain further heteroatoms, or- one of R and R2 is an alkanoyl-group, which together with Z being an amino group (-NH-) forms a 5- or 6-membered heterocyclic diketone containing two nitrogen atoms;Z is a cyclic group or a linear group and is selected from- optionally substituted 5-or 6-membered heteroaryl- optionally substituted aryl,- optionally substituted 5- or 6-membered heterocyclyl,- amino (-NH-),- an alkylaminocarbonyl group [-(CH2)n-NI-l-(C=0)-], preferably with n = 1 , or- an alkylcarbonylamino group [-(CH2)n-(C=0)-NH-], preferably with n = 1 ;A1 is optionally substituted alkanediyi;A2 is- optionally substituted alkanediyi,- a direct bond, or - a sulfonyl group (-S02-);R3 is- hydrogen, or- optionally substituted alkyl; orA1 and R3 together with the nitrogen atom to which they are bonded form an optionally substituted 4 to 6- membered mono- or bicyclic ring; or R3 and A2 together with the nitrogen atom to which they are bonded form an optionally substituted 4 to 7- membered ring ; andAr is- optionally substituted aryl,- optionally substituted monocyclic heteroaryl, or- optionally substituted bicyclic heteroaryl, which may be fused with a ring formed byR3 and A2 together with the nitrogen atom to which they are bonded.Therein and throughout the invention, the above-mentioned substituent groups are defined as follows:Optionally substituted alkyl preferably includes:linear or branched alkyl preferably containing 1 to 8, more preferably 1 to 6 , more preferably 1 to 4, even more preferred 1 to 3 (C-|-C3-alkyl) or 1 , 2 or 3 carbon atoms.Optionally substituted alkyl further includes cycloalkyi containing preferably 3 to 8, more preferably 5 or 6 carbon atoms.Examples of alkyl residues containing 1 to 8 carbon atoms include: a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, an n-pentyl group, an i-pentyl group, a sec-pentyl group, a t-pentyl group, a 2-methylbutyl group, an n- hexyl group, a 1 -methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 1 -ethylbutyl group, a 2-ethylbutyl group, a 3-ethylbutyl group, a 1 , 1 -dimethylbutyl group, a 2,2- dimethylbutyl group, a 3,3-dimethylbutyl group, a 1 -ethyl-1 -methylpropyl group, an n-heptyl group, a 1 - methylhexyl group, a 2-methylhexyl group, a 3-methylhexyl group, a 4-methylhexyl group, a 5-methylhexyl group, a 1 -ethylpentyl group, a 2-ethylpentyl group, a 3-ethylpentyl group, a 4-ethylpentyl group, a 1 , 1 - dimethylpentyl group, a 2,2-dimethylpentyl group, a 3,3-dimethylpentyl group, a 4,4-dimethylpentyl group, a 1 -propylbutyl group, an n-octyl group, a 1 -methylheptyl group, a 2-methylheptyl group, a 3-methylheptyl group, a 4-methylheptyl group, a 5-methylheptyl group, a 6-methylheptyl group, a 1 -ethylhexyl group, a 2- ethylhexyl group, a 3-ethylhexyl group, a 4-ethylhexyl group, a 5-ethylhexyl group, a 1 , 1 -dimethylhexyl group, a 2,2-dimethylhexyl group, a 3,3-dimethylhexyl group, a 4,4-dimethylhexyl group, a 5,5- dimethylhexyl group, a 1 -propylpentyl group, a 2-propylpentyl group, etc. Those containing 1 to 6, preferably 1 to 4 carbon atoms, such as in particular methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec- butyl, and t-butyl are preferred . C-|-C3 alkyl, in particular, methyl, ethyl and i-propyl are more preferred . Most preferred are C-i and C2 alkyl, such as methyl and ethyl.Cycloalkyi residues containing 3 to 8 carbon atoms preferably include: a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and a cyclooctyl group. A cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group are preferred . A cyclopentyl group and a cyclohexyl group are particularly preferred .Substituents of the above-defined optionally substituted alkyl preferably include 1 to 3 of the same or different substituents, more preferably 1 or 2 of the same or different substituents, selected, for example, from the group consisting of: optionally substituted cycloalkyi, as defined above, hydroxy, an oxo-group (=0), carboxy, halogen, as defined below, cyano, alkoxy, as defined below, optionally substituted acyl, as defined below, optionally substituted acyloxy, as defined below, optionally substituted aryl, as defined below, optionally substituted heteroaryl, as defined below, optionally substituted heterocyclyl, as defined below, optionally substituted amino, as defined below, optionally substituted alkyl, aryl or heterocyclylsulfonyl (R-S02-), as defined below as well as an alkylene group such as in particular a methylene-group, forming for example a methylene-substituted ethyl-group (-CH3-(C=CH2)- or wherein * indicates the binding site). Preferably the 1 to 3 substituents of alkyl are selected from optionally substituted cycloalkyl, hydroxy, oxo (=0), carboxy, optionally substituted acyloxy, halogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino, optionally substituted alkyl, aryl or heterocyclylsulfonyl (R-S02-) and an alkylene group such as in particular a methylene-group. More preferred are 1 to 3 substituents of alkyl, selected from optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl and an alkylene group such as in particular a methylene-group. More preferred is one substituent of alkyl. Most preferred is one substituent of alkyl, which is optionally substituted aryl or optionally substituted heteroaryl as defined below.Within the meaning of the present invention, halogen includes fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine, most preferred is fluorine.Examples of a linear or branched alkyl residue substituted by halogen and containing 1 to 8 carbon atoms include:a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, a trichloromethyl group, a bromomethyl group, a dibromomethyl group, a tribromomethyl group, a 1-fluoroethyl group, a 1-chloroethyl group, a 1-bromoethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a difluoroethyl group such as a 1 ,2-difluoroethyl group, a 1 ,2-dichloroethyl group, a 1 ,2-dibromoethyl group, a 2,2-difluoroethyl group, a 2,2-dichloroethyl group, a2.2- dibromoethyl group a 2,2,2-trifluoroethyl group, a heptafluoroethyl group, a 1 -fluoropropyl group, a 1- chloropropyl group, a 1-bromopropyl group, a 2-fluoropropyl group, a 2-chloropropyl group, a 2- bromopropyl group, a 3-fluoropropyl group, a 3-chloropropyl group, a 3-bromopropyl group, a 1 ,2- difluoropropyl group, a 1 ,2-dichloropropyl group, a 1 ,2-dibromopropyl group, a 2,3-difluoropropyl group, a2.3- dichloropropyl group, a 2,3-dibromopropyl group, a 3,3,3-trifluoropropyl group, a 2,2,3,3,3- pentafluoropropyl group, a 2-fluorobutyl group, a 2-chlorobutyl group, a 2-bromobutyl group, a 4-fluorobutyl group, a 4-chlorobutyl group, a 4-bromobutyl group, a 4,4,4-trifluorobutyl group, a 2,2,3,3,4,4,4- heptafluorobutyl group, a perfluorobutyl group, a 2-fluoropentyl group, a 2-chloropentyl group, a 2- bromopentyl group, a 5-fluoropentyl group, a 5-chloropentyl group, a 5-bromopentyl group, a perfluoropentyl group, a 2-fluorohexyl group, a 2-chlorohexyl group, a 2-bromohexyl group, a 6-fluorohexyl group, a 6-chlorohexyl group, a 6-bromohexyl group, a perfluorohexyl group, a 2-fluoroheptyl group, a 2- chloroheptyl group, a 2-bromoheptoyl group, a 7-fluoroheptyl group, a 7-chloroheptyl group, a 7- bromoheptyl group, a perfluoroheptyl group, etc. Fluoroalkyl, difluoroalkyl and trifluoroalkyl are mentioned in particular, and trifluoromethyl and mono- and di-fluoroethyl is preferred. Particularly preferred is trifluoromethyl and 2,2-difluoroethyl.Examples of a cycloalkyl residue substituted by halogen and containing 3 to 8 carbon atoms include: a 2-fluorocyclopentyl group, a 2-chlorocyclopentyl group, a 2-bromocyclopentyl group, a 3- fluorocyclopentyl group, a 3-chlorocyclopentyl group, a 3-bromocyclopentyl group, a 2-fluorocyclohexyl group, a 2-chlorocyclohexyl group, a 2-bromocyclohexyl group, a 3-fluorocyclohexyl group, a 3- chlorocyclohexyl group, a 3-bromocyclohexyl group, a 4-fluorocyclohexyl group, a 4-chlorocyclohexyl group, a 4-bromocyclohexyl group, a di-fluorocyclopentyl group, a di-chlorocyclopentyl group, a di- bromocyclopentyl group, a di-fluorocyclohexyl group, a di-chlorocyclohexyl group, a di-bromocyclohexyl group, a tri-fluorocyclohexyl group, a tri-chlorocyclohexyl group, a tri-bromocyclohexyl group, etc.. Examples of a hydroxy-substituted alkyl residue include the above-mentioned alkyl residues which contain 1 to 3 hydroxyl residues such as, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, etc. Hydroxymethyl being preferred .Examples of an oxo-substituted alkyl residue includes the above-mentioned alkyl residues, wherein at least one carbon atom is substituted by an oxo-group forming a carbonyl group [-(C=0)-] in the alkyl chain or an alkanoyl-group [alkyl-(C=0)-)], such as C-i to C6 alkanoyl, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.. Preferred is an oxo-substitution of the alkyl residue in the form of a carbonyl-group [-(C=0)-] or an acetyl-group like [-(C=0)-CH3] or [-(C=0)-CH2-].Examples of an alkoxy-substituted alkyl residue include the above-mentioned alkyl residues which contain 1 to 3 alkoxy residues as defined below such as, for example, methoxymethyl, ethoxymethyl, 2- methoxyethylene, etc.Examples of an acyl-substituted alkyl residue include the above-mentioned alkyl residues which contain 1 to 3 acyl residues as defined below.Examples of an acyloxy-substituted alkyl residue include the above-mentioned alkyl residues which contain 1 to 3, preferably 1 acyloxy residues f-0-(C=0)-].Examples of a cycloalkyl-substituted alkyl group include the above-mentioned alkyl residues containing 1 to 3, preferably 1 (optionally substituted) cycloalkyl group such as, for example: cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl cyclohexylmethyl, 2-cyclopropylethyl, 2- cyclobutylethyl, 2-cyclopentylethyl 2-cyclohexylethyl, 2- or 3-cyclopropylpropyl, 2- or 3-cyclobutylpropyl, 2- or 3-cyclopentylpropyl, 2- or 3-cyclohexylpropyl, etc. Preferred are cyclopropylmethyl and cyclohexylmethyl.Examples of an aryl-substituted alkyl group include the above-mentioned alkyl residues containing 1 to 3, preferably 1 (optionally substituted) aryl group, as defined below, such as, for example, phenylmethyl, 1 - or 2-phenylethyl, 2- or 3-phenylpropyl, etc. , phenylmethyl, 1 -phenylethyl, 2-phenylethyl, and 2-phenylpropyl being preferred . Also particularly preferred are alkyl groups, as defined above, which are substituted by substituted aryl, as defined below, in particular by phenyl being substituted with 1 to 3, preferably 1 or 2 of the same of different substituents, preferably selected from halogen, such as preferably F and CI, cyano, optionally substituted alkyl, such as preferably methyl, ethyl, halogen-substituted alkyl such as trifluoromethyl, optionally substituted alkoxy, such as methoxy, ethoxy, halogen-substituted alkoxy such as difluoromethoxy, trifluoromethoxy, an optionally substituted amino group such as amino (NH2-) or mono- or di-alkylamino such as preferably dimethylamino, an optionally substituted heterocyclyl group, such as pyrrolidinyl, alkyl-substituted piperazinyl, or morpholinyl, or an optionally substituted heterocyclyl- sulfonyl group, such as N-morpholinyl-sulfonyl, forming in particular alkyl-groups, which are substituted with substituted aryl according to the formulaswhich are particularly preferred for R and / or R2.Examples of a heterocyclyl-substituted alkyl group include the above-mentioned alkyl residues containing 1 to 3, preferably 1 (optionally substituted) heterocyclyl group, as defined below, which may be substituted with 1 to 3, preferably with 1 substituent. Preferably the heterocyclyl group as a substituent of alkyl is for example a morpholinyl group, a piperazinyl group, a piperidinyl group etc.. As defined above, the heterocylcyl group may be substituted and a preferred substituent is an optionally substituted alkyl group, preferably a methyl or ethyl group or a trifluoromethyl group. Particularly preferred is a a piperidinyl group and a methyl-substituted morpholinyl group.Examples of a heteroaryl-substituted alkyl group include the above-mentioned alkyl residues containing 1 to 3, preferably 1 (optionally substituted) heteroaryl group, as defined below, such as, for example a pyridinyl, a pyridazinyl, a pyrimidinyl, a pyrazinyl, a pyrazolyl, an imidazolyl, a benzimidazolyl, a thiophenyl, or an oxazolyl group, such as pyridine-2-yl-methyl, pyridine-3-yl-methyl, pyridine-4-yl-methyl, 2- pyridine-2-yl-ethyl, 2-pyridine-1-yl-ethyl, 2-pyridine-3-yl-ethyl, pyridazine-3-yl-methyl, pyridazine-3-yl-ethyl pyrimidine-2-yl-methyl, pyrimidine-4-yl-methyl, pyrazine-2-yl-methyl, pyrazol-3-yl-methyl, pyrazol-4-yl- methyl, pyrazol-5-yl-methyl, imidazole-2-yl-methyl, imidazole-5-yl-methyl, benzimidazol-2-yl-methyl, thiophen-2-yl-methyl, thiophen-3-yl-methyl, 1 ,3-oxazole-2-yl-methyl.Preferred is an alkyl group which is substituted with optionally substituted pyridazinyl, such as in particular pyridazin-3-yl-methyl and pyridazin-3-yl-ethyl, optionally substituted pyridinyl, such as in particular optionally substituted pyridine-2-yl-methyl, pyridine-3-yl-methyl, pyridine-4-yl-methyl, 2-pyridine- 2-yl-ethyl, 2-pyridine-1-yl-ethyl, 2-pyridine-3-yl-ethyl, very particularly optionally substituted pyridine-2-yl- methyl and 2-pyridin-2-yl-ethyl, optionally substituted pyrazol-3-yl-methyl, pyrazol-4-yl-methyl, pyrazol-5-yl- methyl, pyrazol-3-yl-ethyl, pyrazol-4-yl-ethyl, pyrazol-5-yl-ethyl. Particularly preferred is substituted pyridinyl-alkyl, such as substituted pyridinyl-methyl or substituted pyridinyl-ethyl, wherein the 1 , 2 or 3 substituents are selected from halogen, such as fluorine, Ci-C3-alkyl, such as methyl, and trifluoromethyl. Particularly preferred is fluorine substituted pyridinyl-alkyl, such as fluorine substituted pyridinyl-methyl or fluorine substituted pyridinyl-ethyl. Most preferred is fluorine substituted pyridinyl-methyl according to formulaExamples of a heteroaryl-substituted alkyl group includes further in particular a cyclo-alkyl residue as defined above, which is bound to the heteroaryl-substituent by forming a fused ring with the heteroaryl- substituent as defined above, preferably the fused cyclo-alkyl- residue is cyclopentyl or cyclohexyl. Further, preferably the fused heteroaryl-subsituten is pyridinyl, forming for example fused rings such as cyclopenta- pyridinyl and c clohexa-pyridinyl, according to the formulas, which are particularly preferred for R and / or R2 or a group Cycl-[CQ]n, wherein Q is Ci-C4-alkyl, which forms a fused 5- or 6-membered ring with Cycl.In each case the heterocyclyl-substituent of an alkyl-residue as defined herein may be substituted with 1 to 3, preferably 1 or 2 of the same or different substituents, which are preferably selected from halogen, such as preferably F and CI, cyano, optionally substituted alkyl, such as preferably methyl, ethyl, halogen-substituted alkyl such as trifluoromethyl and hydroxy-substituted alkyl such as hydroxymethyl, optionally substituted alkoxy, such as preferably methoxy and ethoxy, an oxo-group (=0), a heterocyclyl group as defined below, such as an N-morpholinyl group, an aminocarbonyl group, an optionally substituted amino group, such as preferably amino (NH2-) or mono- or di-alkylamino such as preferably dimethylamino.Examples of an amino-substituted alkyl residue include the above-mentioned alkyl residues containing 1 to 3, preferably 1 (optionally substituted) amino group, as defined below, such as, for example, aminoalkyl (NH2-alkyl) or mono- or dialkylamino-alkyl, such as aminomethyl, 2-aminoethyl, 2- or 3-aminopropyl, methylaminomethyl, methylaminoethyl, methylaminopropyl, 2-ethylaminomethyl, 3- ethylaminomethyl, 2-ethylaminoethyl, 3-ethylaminoethyl, etc. or an alkyl group, which may be substituted with an optionally substituted alkyloxycarbonylamino group such as a group according to formula, wherein R defines a substituent of alkyl as defined above, preferably a phenyl group, such group being particularly preferred for R3.Throughout the invention, optionally substituted aryl preferably includes:aromatic hydrocarbon residues containing 6 to 14 carbon atoms (excluding the carbon atoms of the possible substituents), which may be monocyclic or bicyclic, including, for example: phenyl, naphthyl, phenanthrenyl and anthracenyl, which may optionally be substituted preferably by 1 to 3 of the same or different substituents selected from hydroxy, halogen, as defined above, cyano, optionally substituted amino, as defined below, optionally substituted alkyl, as defined above, optionally substituted acyl, as defined below, and optionally substituted alkoxy, as defined below, optionally substituted aryloxy, as defined below, optionally substituted heterocyclyloxy, as defined below, optionally substituted aryl, as defined herein, optionally substituted heterocyclylyl, as defined below. Optionally substituted phenyl is preferred, such as unsubstituted phenyl and phenyl which is substituted with 1 to 3, more preferably with 1 or 2 substituents, which may be the same or different. The 1 to 3 phenyl substituents are in particular selected from the group consisting of heterocyclyl as defined below, halogen as defined above such as in particular F, optionally substituted amino as defined below such as in particular (-NH2) or mono- or dialkylamino with dimethylamino being preferred, cyano, optionally substituted alkoxy as defined below such as in particular di-fluoromethoxy and trifluoromethoxy, and an optionally substituted sulfonyl-group which may form in particular a groupwith * indicating the binding site of the substituted phenyl substituent. Most preferred is halogen-substituted phenyl, alkoxy substituted phenyl and hydroxyl-substituted phenyl. The aforementioned substituents of phenyl are particularly preferred for the group "Cycl" in the formulae as defined herein with the meaning of a substituted aryl group being substituted phenyl. Further preferred is unsubstituted phenyl.Examples of an alkyl-substituted aryl group preferably include: aryl, as described above which is substituted by straight-chain or branched alkyl containing 1 to 8, preferably 1 to 4 carbon atoms, as described above. Toluoyl is the preferred alkylaryl.Examples of a hydroxy-substituted aryl group preferably include: aryl, as described above, which is substituted by 1 to 3 hydroxyl residues such as, for example 2-hydroxyphenyl, 3-hydroxyphenyl, 4- hydroxyphenyl, 2,4-di-hydroxyphenyl, 2,5-di-hydroxyphenyl, 2,6-di-hydroxyphenyl, 3,5-di-hydroxyphenyl, 3,6-di-hydroxyphenyl, 2,4,6-tri-hydroxyphenyl, etc..Examples of a halogen-substituted aryl group preferably include: aryl, as described above, which is substituted by 1 to 3 halogen atoms such as, for example 2-chloro- or fluorophenyl, 3-chloro- or fluorophenyl, 4-chloro- or fluorophenyl, 2,4-di-(chloro- and / or fluorophenyl, 2,5-di-(chloro- and / or fluorophenyl, 2,6-di-(chloro- and / or fluorophenyl, 3,5-di-(chloro- and / or fluorophenyl, 3,6-di-(chloro- and / or fluorophenyl, 2,4,6-tri-(chloro- and / or fluorophenyl, etc.. Examples of an alkoxy-substituted aryl group preferably include: aryl, as described above, which is substituted by 1 to 3 alkoxy residues, as described below, such as preferably 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2,4-di-methoxyphenyl, etc., as well as di-fluoromethoxyphenyl and trifluoromethoxyphenyl.Throughout the invention, optionally substituted heterocyclyl preferably includes:Saturated or unsaturated mono- or bicyclic 4- to 8-membered heterocyclic residues containing 1 to 3, preferably 1 to 2 same or different hetero atoms, selected from N, O and S and which may optionally be substituted preferably by 1 to 3 substituents, wherein reference may be made to the definition of possible substituents for optionally substituted heterocyclyl. 4-, 5- and 6-membered saturated or unsaturated, mono- or bicyclic optionally substituted heterocyclic residues are preferred, and examples comprise azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, etc., such as azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, tetrahydrofuran-2- yl, tetrahydrofuran-3-yl, tetrahydro-thiophen-2-yl, tetrahydro-thiophen-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, morpholin-1-yl, morpholin-2-yl, morpholin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4- yl, etc., which may optionally be condensed with aromatic rings. Particularly preferred are azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl residues. Particularly preferred are the following heterocyclic residues, which may be substituted as defined above:and(with X being N, O or S, preferably S), which are particularly preferred for , and, being particularly preferred for R and / or R2, and which is particularly preferred as a substituent for an aryl group.Preferred substituents of heterocyclyl-residues comprise an alkyl-group such as preferably methyl and ethyl, a hydroxyl-group, and an oxo-group (=0).Throughout the invention, optionally substituted heteroaryl includes:heteroaromatic hydrocarbon residues containing 4 to 9 ring carbon atoms, which additionally preferably contain 1 to 3 of the same or different heteroatoms from the series S, O, N in the ring and therefore preferably form 5- to 12-membered heteroaromatic residues which may preferably be monocyclic but also bicyclic. Preferred aromatic heterocyclic residues include: pyridyl (pyridinyl), pyridyl-N-oxide, pyridazinyl, pyrimidyl, pyrazinyl, thienyl (thiophenyl), furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl or isoxazolyl, indolizinyl, indolyl, benzo[b]thienyl, benzo[b]furyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolinyl, quinoxalinyl. 5- or 6-membered aromatic heterocycles are preferred, such as from the group of 5-membered heteroaryl, for example thiazolyl such as thiazol-2-yl, 2-thiazol-2-yl, 2- thiazol-4-yl, thienyl (thiophenyl) such as thien-3-yl, pyrazolyl such as 1-pyrazol-4-yl, 3-pyrazol-5-yl, imidazolyl such as imidazole-2-yl, 2-imidazol-4-yl, 1-imidazol-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, oxazolyl such as 2-oxazol-4-yl, 2-oxazol-5-yl, oxadiazolyl such as 1 ,2,4-oxadiazol-3-yl and from the group of 6-membered heteroaryl, for example pyridyl (pyridinyl) such as pyrid-1 -yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 2-pyrid-4-yl, 2-pyrid-6-yl, 3-pyrid-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, and from the group of bicyclic heteroaromatic residues in particular benzimidazolyl such as benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, as well as benzimidazol- ridinyl according to formula ; or benzoxazol-2-yl according to formula , or benzimidazol forming a fused ring with a heterocyclyl residue, as defined above.The aforementioned heteroaryl-g roups may have one or more, preferably 1 to 3, more preferably 1 or 2 same or different substituents, which are in particular selected from halogen, such as preferably F and CI, cyano, optionally substituted alkyl as defined above, such as preferably methyl, ethyl, n-propyl, i-propyl, halogen-substituted alkyl such as difluoromethyl or trifluoromethyl, hydroxy-substituted alkyl such as hydroxymethyl, aminocarbonyl-substituted alkyl such as aminocarbonylmethyl, carboxyl-substituted alkyl such as carboxylmethyl, an alkenyl group such as propenyl, optionally substituted alkoxy, such as preferably methoxy and ethoxy, a hydroxyl group (-OH), an oxo-group (=0), a carboxyl group [-(C=0)-OH], a heterocyclyl group as defined above, such as a N-morpholinyl group, an aminocarbonyl group, such as NH2-(C=0)-, an optionally substituted amino group, such as preferably amino (NH2-) or mono- or di- alkylamino such as preferably dimethylamino.In particular, examples of an alkyl-substituted heteroaryl group preferably include: heteroaryl, as described above, which is substituted by linear or branched , optionally substituted alkyl containing 1 to 8, preferably 1 to 4 carbon atoms, as described above, such as in particular methylimidazolyl such as in particular N-methylimidazolyl, methylbenzimidazolyl such as in particular N-methylbenzimidazolyl, 5- methylbenzimidazolyl, 4-trifluoromethylbenzimidazolyl, 5-trifluoromethylbenzimidazolyl, N- aminocarbonylmethylbenzimidazolyl, N-carboxylmethylaminocarbonyl, N-methylpyrazolyl, 1 (N),5- dimethylpyrazolyl, methylpyridinyl such as 2-methylpyridin-3-yl, 2-methylpyridin-4-yl, 3-methylpyridin-2-yl, 3-methylpyridin-3-yl, 3-methylpyridin-4-yl, 4-methylpyridin-2-yl, 5-methylpyridin-2-yl, 6-methylpyridin-2-yl etc. , dimethylpyridinyl such as 3,5-dimethylpyridin-2-yl, 4,6-dimethylpyridin-3-yl, trifluoromethylpyridinyl, in particular 3- or 4- trifluoromethylpyridin-2-yl, 6-trifluoromethylpyridin-3-yl, 3-hydroxymethylpyridin-2-yl, 5- methylpyrimidin-2-yl, etc..Examples of a halogen-substituted heteroaryl group preferably include: heteroaryl, as described above, which is substituted by 1 to 3, preferably 1 or 2 halogen atoms such as preferably by F and / or CI, including in particular fluoropyridinyl such as 3-fluoro-pyridin-2-yl, 4-fluoro-pyridin-2-yl, 5-fluoro-pyridin-2-yl, 6-fluoro-pyridin-2-yl, 3-chloro-pyridin-2-yl, 4-chloro-pyridin-2-yl, 5-chloro-pyridin-2-yl, 6-chloro-pyridin-2-yl,2- fluoro-pyridin-3-yl, 4-fluoro-pyridin-3-yl, 5-fluoro-pyridin-3-yl, 6-fluoro-pyridin-3-yl, 2-chloro-pyridin-3-yl, 4- chloro-pyridin-3-yl, 5-chloro-pyridin-3-yl, 6-chloro-pyridin-3-yl, 2-fluoro-pyridin-4-yl, 3-fluoro-pyridin-4-yl, 5- fluoro-pyridin-4-yl, 6-fluoro-pyridin-4-yl, 2-chloro-pyridin-4-yl, 3-chloro-pyridin-4-yl, 5-chloro-pyridin-4-yl, 6- chloro-pyridin-4-yl, etc. , di-fluoropyridinyl such as 3 , 5-d i-f I u o ro py rid i n-2-y I , fluoro-chloro-pyridinyl such as 3- chloro-5-f I uoro-py rid i n-2-y I , etc..Examples of a halogen- and alkyl-substituted heteroaryl group preferably include: heteroaryl, as described above, which is substituted by 1 to 3 halogen atoms such as preferably by F and / or CI, and 1 to 3 linear or branched, optionally substituted alkyl-residues as described above, such as in particular 3- fluoro-6-methylpyridin-2-yl, 3-chloro-5-trifluoromethylpyridin-2-yl.Further preferred examples of substituted heteroaryl-groups include:methoxypyridinyl such as 3-, 4-, 5- or 6-methoxypyridin-2-yl, 2-, 4-, 5- or 6-methoxypyridin-3-yl, 2-,3- , 5- or 6-methoxypyridin-4-yl, etc., hydroxy pyridinyl such as 3-, 4-, 5- or 6-hydroxypyridin-2-yl, 2-, 4-, 5- or 6-hydroxypyridin-3-yl, 2-, 3-, 5- or 6-hydroxypyridin-4-yl, etc. , oxo-pyridinyl such as 6-oxo-1 ,6- dihydropyridin-2-yl, 2-oxo-1 ,2-dihydropyridin-3-yl etc., aminopyridinyl such as 6-dimethylaminopyridin-3-yl, aminocarbonylpyridinyl such as 6-aminocarbonylpyridin-3-yl, cyanopyridinyl such as 3-, 4-, 5- or 6- cyanopyridin-2-yl, 2-, 4-, 5- or 6-cyanopyridin-3-yl, 2-, 3-, 5- or 6-cyanopyridin-4-yl, etc., as well as 2- morpholin-4-yl-pyridin-4-yl.With respect to 1 to 3, preferably 1 or 2 same or different optional substituents of a bicyclic heteroaryl group Ar or Het-2 according to any of the formulae as defined herein said heteroaryl- substituents are preferably selected from halogen, such as preferably F and CI, cyano, optionally substituted alkyl as defined above, such as preferably methyl, ethyl, n-propyl, i-propyl, halogen-substituted alkyl such as difluoromethyl or trifluoromethyl, aminocarbonyl-substituted alkyl such as aminocarbonylmethyl, carboxyl-substituted alkyl such as carboxylmethyl, optionally substituted alkoxy, such as preferably methoxy and ethoxy and a carboxyl graup [-(C=0)-OH]. It is most preferred, that such a substituted Ar or Het-2 group comprises 1 or 2 same or different substituents selected from F, CI, cyano, optionally substituted alkyl such as methyl and trifluoromethyl, aminocarbonyl-substituted alkyl such as aminocarbonylmethyl, carboxyl-substituted alkyl such as carboxylmethyl, optionally substituted alkoxy, such as methoxy and a carboxyl group [-(C=0)-OH].With respect to 1 to 4, preferably 1 to 3, more preferably 1 or 2 same or different substituents of a heteroaryl group Cycl according to any of the formulae as defined herein said heteroaryl-substituents are preferably selected from halogen, such as preferably F and CI, cyano, optionally substituted alkyl as defined above, such as preferably methyl, ethyl, n-propyl, i-propyl, halogen-substituted alkyl such as difluoromethyl or trifluoromethyl, hydroxy-substituted alkyl such as hydroxymethyl, optionally substituted alkoxy, such as preferably methoxy and ethoxy, an oxo-group (=0), a heterocyclyl group as defined above, such as a N-morpholinyl group, an aminocarbonyl group such as NH2-(C=0)-, an optionally substituted amino group, such as preferably amino (NH2-) or mono- or di-alkylamino such as preferably dimethylamino. It is most preferred, that such a substituted heteroaryl group Cycl comprises 1 or 2 same or different substituents selected from F, CI, cyano, optionally substituted alkyl such as methyl, trifluoromethyl, and hydroxymethyl, optionally substituted alkoxy, such as methoxy, an oxo-group (=0), forming for example an oxo-substituted heteroaryl of the formulaor , a heterocyclyl group such as a N-morpholinyl group, an aminocarbonyl group such as NH2-(C=0)-, an optionally substituted amino group, such as di-alkylamino such as dimethylaminoOptionally substituted acyl here and hereinafter includes: formyl (-CH(=0)), optionally substituted aliphatic acyl (alkanoyl = alkyl-CO, wherein reference may be made to the foregoing definition of optionally substituted alkyl with respect to the alkyl group), optionally substituted aromatic acyl (aroyl = aryl-CO-, wherein reference may be made to the foregoing definition of optionally substituted aryl with respect to the aryl group), optionally substituted heteroaromatic acyl (heteroaroyl = heteroaryl-CO-, wherein reference may be made to the foregoing definition of optionally substituted heteroaryl with respect to the heteroaryl group), or heterocyclic acyl (heterocycloyl = heterocyclyl-CO-, wherein reference may be made to the foregoing definition of optionally substituted heterocyclyl with respect to the heterocyclyl group). Aliphatic acyl = alkanoyl = alkyl-CO- is preferred.Optionally substituted amino according to the invention preferably includes: amino (-NH2), optionally substituted mono- or dialkylamino (alkyl-NH-, (alkyl)2N-), wherein with respect to "alkyl" reference can be made to the definition of optionally substituted alkyl above. Further included are optionally substituted mono- or diarylamino, mono- or diheteroarylamino and mono- or diheterocyclylamino radicals or mixed optionally substituted alkylarylamino, alkylheteroarylamino and alkylheterocyclylamino radicals, wherein reference can be made to the above definitions of optionally substituted alkyl, aryl, heteroaryl and heterocyclyl. According to the present invention an amino group further includes a group - NH-, such as in particular in the definition of the substituent Z, wherein the amino group -NH- is bound to the R R2N-(C=0)- group and to the A1 substiuent as shown for example in the general formula (I).Optionally substituted amino is preferably optionally substituted mono- or dialkylamino (alkyl-NH-, (alkyl)2N-), in particular with 1 to 8, preferably 1 to 6, more preferably 1 to 3 carbon atoms, as previously mentioned. Most preferred optionally substituted amino is mono- or dimethylamino and mono- or diethylamino. Most preferred is an amino group (-NH2) or (-NH-) and a dimethylamino group.As a further substituted amino group of the present invention an alkylcarbonylamino group [- (CH2)n-(C=0)-NH-] or alkylaminocarbonyl group [-(CH2 )n-NH-(C=0)-] may be mentioned, which are both included in and preferred for the definition of the substituent Z of the present invention. Therein n is an integer of 1 to 6, preferably 1 to 3, more preferably 1 or 2. Most preferred is an alkylcarbonylamino group or alkylaminocarbonyl group Z with the meaning [-(CH2)-(C=0)-NH-] or [-(CH2 )-NH-(C=0)-], respectively.It is further possible that an amino group (-NH-) forms a 5- or 6-membered heterocyclic ring together with an optionally substituted alkyl-group (such as an oxo-substituted alkyl group) or alkanoyl- group, such as preferably with an alkanoyl group. It is accordingly possible that, for example, one of the substituents R and R2 is an oxo-substituted alkyl group or alkanoyl-group (alkyl-(C=0)-), as defined above, which together with Z being an amino group (-NH-) forms a 5- or 6-membered heterocyclic diketone containing two nitrogen atoms, for example according to the following formulaThroughout the invention, optionally substituted alkanediyl is preferably a divalent straight-chained or branched alkanediyl radical having from 1 to 7, preferably from 1 to 6, more preferably from 1 to 4, carbon atoms, which can optionally carry from 1 to 3, preferably 1 or 2 substituents selected from the group consisting of halogen, hydroxy, an oxo group (forming a carbonyl or acyl group)and an amino group as defined above. The following may be mentioned as preferred examples: methylene, ethane-1 ,2-diyl, ethane-1 ,1 -diyl, propane-1 ,3-diyl, propane-1 ,1 -diyl, propane-1 ,2-diyl, propane-2,2-diyl, butane-1 ,4-diyl, butane-1 ,2-diyl, butane-1 ,3-diyl, butane-2,3-diyl, butane-1 ,1 -diyl, butane-2,2-diyl, butane-3,3-diyl, pentane- 1 ,5-diyl, etc. Particularly preferred is methylene, ethane-1 ,2-diyl, ethane-1 ,1-diyl, propane-1 ,3-diyl, propane-2,2-diyl, and butane-2,2-diyl. Most preferred are methylene and ethane-1 ,2-diyl.A preferred substituted alkanediyl radical is a hydroxy-substituted alkanediyl such as a hydroxyl- substituted ethanediyl, an oxo-substituted alkanediyl such as an oxo-substituted methylene or ethanediyl radical, forming a carbonyl or an acyl (acetyl) group, a halogen substituted alkanediyl group such as an alkanediyl group being substituted with one or two halogen atoms selected from F and CI, preferably 2,2- di-fluoro-ethanediyl, or an alkanediyl group which is substituted with an oxo and an amino group, forming an aminocarbonyl group such as preferably a group E-(C=0)-NH-].According to the present invention the substituents R and R2 or a respective group -[CQ]n-, wherein Q is C-|-C4-alkyl, may together with the nitrogen atom to which they are bonded form an optionally substituted 3- to 6-membered ring, which may optionally contain further heteroatoms. Therein, R and R2 (or the group -[CQ]n-, wherein Q is Ci-C4-alkyl) may preferably together with the nitrogen atom to which they are bonded form a 5- or 6-membered ring, which may contain further heteroatoms, preferably one further heteroatom selected from N and O. Therein it is most preferred that R and R2 (or the group -[CQ]n-, wherein Q is C-|-C4-alkyl) together with the nitrogen atom to which they are bonded form a 6-membered ring, which contains no further heteroatom, forming an N-piperidinyl ring or a 6-membered ring, which contains one further heteroatom O, forming an N-morpholinyl ring. In particular such N-piperidinyl ring may be substituted with aryl or heteroaryl as defined above, preferably with phenyl or piperidinyl, forming a biciclyc ring according to the formulaorAs explained above in context with the definition of amino it is further possible that one of R and R2 is an optionally substituted alkyl-group (preferably an oxo-substituted alkyl group) or alkanoyl- group (alkyl-(C=0)-), each as defined above, which together with Z being an amino group (-NH-) forms a 5- or 6- membered heterocyclic diketone containing two nitrogen atoms, as shown above.According to the present invention it is further possible that A1 , having the meaning of a linear or branched alkanediyl group as defined above, and R3, having the meaning of an optionally substituted alkyl group as defined above, together with the nitrogen atom to which they are bonded form an optionally substituted 4- to 6-membered mono- or bicyclic ring, which may be fused with Z, being a heteroaryl group, and which may be substituted with 1 to 3 substituents as defined above, such as for example according to the following formulasIn the context of the present invention it is further possible that R3 and A2 together with the nitrogen atom to which they are bonded form an optionally substituted 4- to 7-membered ring, wherein optional substituents are preferably selected from heteroaryl as defined above and an oxo group. A heteroaryl substituent may then also form a fused ring with the 4- to 7-membered ring formed by R3 and A2 together with the nitrogen atom to which they are bonded. Examples include residues according to the following formulas:It is particularly preferred that the subsitutents in the formula (I) above have the meaning as follows: R and R2 are the same or different and are independently selected from the group consisting of- hydrogen,- optionally substituted alkyl, or- R and R2 (or a respective group -[CQ]n-, wherein Q is Ci-C4-alkyl) together with the nitrogen atom to which they are bonded form an optionally substituted 3- to 6-membered ring, which may optionally contain further heteroatoms;Z is a cyclic group or a linear group and is selected from- optionally substituted 5-or 6-membered heteroaryl- optionally substituted aryl,- optionally substituted 5- or 6-membered heterocyclyl,- amino (-NH-),- an alkylaminocarbonyl group [-(CH2)-NH-(C=0)-], or- an alkylcarbonylamino group [-(CH2)-(C=0)-NH-];A1 is optionally substituted alkanediyi; A2 is- optionally substituted alkanediyi, or- a direct bond;R3 is- hydrogen, or- Ci-C3-alkyl; such as preferably methyl or ethyl, more preferably methyl; orA1 and R3 together with the nitrogen atom to which they are bonded form an optionally su bstituted 4- membered monocyclic ring; orR3 and A2 together with the nitrogen atom to which they are bonded form an optionally substituted 4- to 7- membered ring; andAr is optionally substituted bicyclic heteroaryl.Further preferred embodiment 2:A further preferred embodiment of the present invention relates tocompounds according to formula (I) as defined above, wherein Z is an optionally substituted cyclic group Z-Cycl, forming compounds according to formula (II):wherein Z-Cycl is selected from- an optionally substituted 5-or 6-membered heteroaryl, as defined above,- an optionally substituted aryl, as defined above, and- an optionally substituted 5- or 6-membered heterocyclyl, as definedabove; and wherein R , R2, R3, A1 , A2 and Ar have the meaning as defined above.Preferred are compounds, wherein Z-Cycl is selected from an optionally substituted aromatic group, preferably comprising an optionally substituted 5-or 6-membered heteroaryl, as defined above, and an optionally substituted aryl, as defined above.Also preferred are compounds, wherein Z-Cycl is selected from an optionally substituted 5-or 6- membered heterocyclic group, preferably comprising an aromatic heteroaryl and a heterocyclyl, each as defined above.Preferably Z-Cycl is selected from- a phenyl group as defined above,- an optionally substituted 5-membered heteroaryl, as defined above,- an optionally substituted 6-membered heteroaryl, as defined above, preferably a pyridinyl group as defined above, or- a 5- or 6-membered heterocylyl selected from a pyrrolidinyl and a piperidinyl group.More preferably Z-Cycl is selected from an optionally substituted 5-membered heteroaryl as defined above. In particular said 5-membered heteroaryl for Z is selected from- an oxazolyl group,- a thiazolyl group,- a triazolyl group,- an oxadiazolyl group,- a pyrazolyl group,- an imidazolyl group, and- a thiophenyl (thienyl) group; each as defined above.More preferred is- an oxazolyl group,- a thiazolyl group,- a triazolyl group, and- an oxadiazolyl group,- a pyrazolyl group; each as defined above.Even more preferred is- an oxazolyl group,- a thiazolyl group, and- a triazolyl group; each as defined above.Even more preferred is- an oxazolyl group, and- a thiazolyl group; each as defined above.Most preferred is- an oxazolyl group, as defined above.Embodiment 2a:A particularly preferred embodiment (2a) relates to compounds, wherein Z is a cyclic group Z-Cycl, which is selected from an optionally substituted 5-membered heteroaryl, forming a compound of the formula (Ma)wherein 1 to 3 heteroatoms X (X1 , X2, X3 and / or X4) are present, wherein X1 to X4 may be the same or different and are independently selected from the group consisting of C, N, S and O. Preferably in formula (Ma) 1 to 3 heteroatoms X are present, whereinX1 is C, N, S or O;X2 is C or N;X3 is C, N, S or O; andX4 is C, N, S or O, preferably X4 is C, N or S,and wherein X1, X3 and X4 with the meaning of C or N may carry hydrogen or a further substituent, such as preferably a substituent as defined above for substituted heteroarylEmbodiment 2b:Another particularly preferred embodiment (2b) relates to compounds, wherein Z is a cyclic group Z-Cycl, which is selected from an optionally substituted 6-membered heteroaryl, forming a compound of the formula (lib)wherein Y is N or C, with the proviso that at least one Y is N.Preferably only one Y is N and the remaining Y are C.Therein, any Y with the meaning of C may carry hydrogen and / or a further substituent, preferably substituents as defined above for optionally substituted heteroarylIn formula (Ma) and / or (Mb) R , R2, R3, A1 , A2 and Ar have the meaning as defined in any one of the above or the following embodiments described hereinEmbodiment 2a-a:Another particularly preferred embodiment (2a-a) relates to compounds, wherein Z is a cyclic group Z-Cycl, which is selected from an optionally substituted 5-membered heteroaryl, as defined above and according to formula (I la) above, wherein X1 is N, forming a compound of the formula (lla-a)wherein one or two further heteroatoms X (X2, X3, X4) are present, and whereinX2 is C or N;X3 is C, N, S or O; andX4 is C or N;with the proviso that in case of two further heteroatoms both are selected to be N or one is N and one (except X2) is O; andwherein X3 and X4 with the meaning of C or N may carry a further substituent, such as preferably hydrogen or a substituent as defined above for substituted heteroarylEmbodiment 2a-b: Another particularly preferred embodiment (2a-b) relates to compounds, wherein Z is a cyclic group Z-Cycl, which is selected from an optionally substituted 5-membered heteroaryl, as defined above and according to formula (I la) above, wherein X2 and X3 are both N, forming a compound of the formula (lla-b)with X1 and X4 being C; and wherein X1 and / or X4 may carry hydrogen or a further substituent, such as preferably a substituent as defined above for substituted heteroarylEmbodiment 2a-c:Another particularly preferred embodiment (2a-c) relates to compounds, wherein Z is a cyclic group Z-Cycl, which is selected from an optionally substituted 5-membered heteroaryl, as defined above and according to formula (Ma) or (lla-a) above, wherein X1 is N, X2 is C and X3 is S, forming a compound of the formula (lla-c)wherein X is C or N, preferably C, which may carry a further substituent, such as preferably hydrogen or a substituent as defined above for substituted heteroarylEmbodiment 2a-d:Another particularly preferred embodiment (2a-d) relates to compounds, wherein Z is a cyclic group Z-Cycl, which is selected from an optionally substituted 5-membered heteroaryl, as defined above and according to formula (Ma) or (lla-a) above, wherein X1 is N, X2 is C and X3 is O, forming a compound of the formula (lla-d)wherein X4 is C or N, and which may carry a further substituent, such as preferably hydrogen or a substituent as defined above for substituted heteroaryl forming compounds according to formula (lla-d-1 )wherein X4 being C may carry a hydrogen or a further substituent, and which is preferred; or forming compounds according to formula (lla-d-2)wherein X being N may carry a further substituent.Embodiment 2a-e:Another particularly preferred embodiment (2a-e) relates to compounds, wherein Z is a cyclic group Z-Cycl, which is selected from an optionally substituted 5-membered heteroaryl, as defined above and according to formula (lla) above, wherein X2, X3 and X4 are N, forming a compound of the formula (lla- e)with X1 being C, which may carry a further substituent.Embodiment 2b-a:Another particularly preferred embodiment (2b-a) relates to compounds, wherein Z is a cyclic group Z-Cycl, which is selected from an optionally substituted 6-membered heteroaryl, as defined above and according to formula (Mb) above, containing one heteroatom N, being selected from compounds according to formula (llb-a)Embodiment 2b-b:Another particularly preferred embodiment (2b-b) relates to compounds, wherein Z is a cyclic group Z-Cycl, which is selected from an optionally substituted 6-membered heteroaryl, as defined above and according to formula (Mb) above, containing one heteroatom N, being selected from compounds according to formula (llb-b)Embodiment 2b-c:Another particularly preferred embodiment (2b-c) relates to compounds, wherein Z is a cyclic group Z-Cycl, which is selected from an optionally substituted 6-membered heteroaryl, as defined above and according to formula (Mb) above, containing one heteroatom N, being selected from compounds according to formula (llb-c)Embodiment 2b-d:Another particularly preferred embodiment (2b-d) relates to compounds, wherein Z is a cyclic group Z-Cycl, which is selected from an optionally substituted 6-membered heteroaryl, as defined above and according to formula (Mb) above, containing one heteroatom N, being selected from compounds according to formula (llb-d)Among the embodiments 2b-a to 2b-d the embodiment 2b-c, referring to compounds according to formula (llb-c), is most preferred.In the embodiments 2b-a to 2b-d it is further possible that the pyridinyl-ring (Z-Cycl) may carry further substituents as defined above for substituted heteroaryl.Embodiment 2c:Another particularly preferred embodiment (2c) relates to compounds, wherein Z is a cyclic group Z-Cycl, which is selected from an optionally substituted 6-membered aryl, as defined above, such as preferably an optionally substituted phenyl group. Very particularly Z-Cycl is a phenyl group, forming a compound of the formula (lie)wherein the phenyl-ring may be substituted with 1 to 3, preferably 1 or 2, preferably 1 substituents as defined above.Embodiment 2c-a:Another particularly preferred embodiment (2c-a) relates to compounds, wherein Z is a cyclic group Z-Cycl, which is selected from the group of optionally substituted 6-membered aryl and has the meaning of phenyl, according to formula (lie) above, and is further selected from compounds according to formula (llc- a)wherein the phenyking (Z-Cycl) may optionally be substituted with 1 to 3, preferably 1 or 2, preferably 1 substituents as defined above.Embodiment 2c-b:Another particularly preferred embodiment (2c-b) relates to compounds, wherein Z-Cycl is selected from the group of optionally substituted 6-membered aryl and has the meaning of phenyl, according to formula (lie) above, and is further selected from compounds accordng to formula (llc-b)wherein the phenyl-ring (Z-Cycl) may optionally be substituted with 1 to 3, preferably 1 or 2, preferably 1 substituents as defined above.Embodiment 2d:Another particularly preferred embodiment (2d) relates to compounds, wherein Z is an optionally substituted 5- or 6-membered heterocyclic group N-Cycl, forming compounds according to formula (lid):wherein N-Cycl is a 5- or 6-membered heterocyclyl group as defined above, which contains at least one N atom. For reasons of clarification it is noted that the abbreviation "N-Cycl" used in formula (lid) is not limited to indicate a specific binding position of N in "N-Cycl", in particular the abbreviation "N-Cycl" is not limited to nitrogen containing heterocycles, wherein the binding to the R R2N-(C=0)-group takes place via the cyclic nitrogen atom.Embodiment 2d-a: Another particularly preferred embodiment (2d-a) relates to compounds according to formula (lid) above, wherein Z is a nitrogen containing 6-membered heterocyclic group N-Cycl as defined above, which is preferably a piperidinyl group, preferably forming compounds according to formula (lld-a)wherein the piperidinyl-ring may optionally be substituted with 1 to 3, preferably 1 or 2, preferably 1 substituents as defined above for substituted heterocyclyl.Embodiment 2d-b:Another particularly preferred embodiment (2d-b) relates to compounds according to formula (lid) above, wherein Z is a nitrogen containing 5-membered heterocyclic group N-Cycl as defined above, which is preferably a pyrrolidinyl-group, preferably forming compounds according to formula (lld-b)wherein the pyrrolid inyl-ring may optionally be substituted with 1 to 3, preferably 1 or 2, preferably 1 substituents as defined above for substituted heterocyclyl.Embodiment 2e and 2f:Another embodiment of the present invention relates to compounds, wherein Z is a linear group of the formulawherein, * indicates the possible binding sites to A1 in formula (I) above, and whereinm is 0 or 1 , with the proviso that m is 1 on the binding site *, which binds to the [NR R2-(C=0)-] group in formula (I) above. Examples include compounds of formula (I) above, wherein Z is an alkylaminocarbonyl group [-(CH2)-NH-(C=0)-] according to embodiment 2e and as shown in thefollowing formula (Me)compounds of formula (I) above, wherein Z is an acetamide-group [-(CH2)-(C=0)-NH-] according to embodiment 2f and as shown in the following formula (l lf)In each of the above mentioned embodiments 2a, 2a-a, 2a-b, 2a-c and 2a-d , 2a-d-1 and 2a-d-2, as well as 2b, 2b-a, 2b-b, 2b-c and 2b-d, as well as 2c, 2c-a and 2c-b, as well as 2d , 2d-a and 2d-b, as well as 2e and 2f the substituents R , R2, R3, A1 , A2 and Ar have the meaning as defined in context with any one of the embodiments described herein, in particular as defined for formula (I) and as defined in context with embodiments 3, 3a, 3b, 3b-a, 3b-b, 3b-c, 3b-d, 3b-e, 4, 4a, 4b, 4c and 4d below.Further preferred embodiment 3:A further preferred embodiment of the present invention relates to any one of the compounds as defined above, wherein at least one of R and R2 is a linear or branched alkyi group -[CQ]n- with Q = H or C1-C4- alkyl, which is substituted with a cyclic group "Cycl", designated as R2*, whereinCycl is selected from- optionally substituted aryl, and- optionally substituted heteroaryl,and wherein n is an integer of 1 to 3;the remaining of R or R2, designated as R , is selected from- hydrogen, and- optionally substituted alkyi; andZ, R3, A1 , A2 and Ar have the meaning as defined in any one of the preceding embodiments.In particular when one of R and R2 is a branched alkyi group -[CQ]n- with Q = C-|-C4-alkyl, it is possible and preferred that the alkyl-group of Q forms a fused ring with the cycle group "Cycl".A further preferred embodiment of the present invention relates to any one of the compounds as defined above, wherein at least one of R and R2 is a linear, branched or cyclic alkyi group (a cyclic alkyi group meaning in particular a cycloalkyl fused with the group Cycl), as defined above, which is substituted with a cyclic group "Cycl", designated as R2 ; forming compounds according to formula (A- II I):wherein in the group -[CQ]n- Q = H or C-|-C4-alkyl, preferably Q = H resulting in formula (I I I)wherein "Cycl" is selected from- optionally substituted aryl, as defined above,- optionally substituted heteroaryl, as defined above, and- optionally substituted heterocyclyl, as defined above;preferably optionally substituted aryl or heteroaryl, as defined above, n is an integer of 1 to 8, preferably 1 to 4, preferably 1 to 3, such as 1 , 2 or 3, more preferred 1 (in particular in embodiments with Q = Ci-C4-alkyl); andthe remaining of R or R2 (designated as R ) is selected from- hydrogen,- optionally substituted alkyl, as defined above, and- an alkanoyl group, such as preferably an acetyl-group, which together with Z, being an amino group (-NH-), forms a 5- or 6-membered, preferably a 5-membered heterocyclic diketone containing two nitrogen atoms, as defined above;preferably hydrogen and optionally substituted alkyl, as defined above;andZ, R3, A , A2 and Ar have the meaning as defined in context with any one of the embodiments described herein. Embodiment 3a:Another particularly preferred embodiment (3a) of the present invention relates to compounds as defined herein and in particular to compounds according to formula (II I) above, wherein at least one of R and R2 is a linear, branched or cyclic alkyl group, as defined above, which is substituted with a cyclic group "Cycl", designated as R2 ; which is selected from optionally substituted aryl, as defined above, such as in particular an optionally substituted phenyl group forming compounds according to formula (A-ll la)wherein in the group -[CQ]n- Q = H or C-|-C4-alkyl, preferably Q = H resulting in formula (I l ia)wherein n is an integer of 1 to 8, preferably 1 to 4, preferably 1 to 3 such as 1 , 2 or 3, more preferred 1 (in particular in embodiments with Q = C-|-C4-alkyl); and the phenyl-ring may optionally be substituted with 1 to 3, preferably 1 or 2, preferably 1 substituents as defined above, preferably the substituents of the phenyl ring are selected from halogen and hydroxy; andthe remaining of R or R2 (designated as R ) has the meaning as defined above, particularly as defined for formula (I) and as defined in context with embodiment 3 above; andZ, R3, A1 , A2 and Ar have the meaning as defined in context with any one of the embodiments described herein.Embodiment 3b:Another preferred embodiment (3b) of the present invention relates to compounds as defined herein and in particular to compounds according to formula (III) above, whereinat least one of R and R2 is a linear, branched or cyclic alkyl group, as defined above, which is substituted with a cyclic group "Cycl" being an optionally substituted heterocyclic group as defined above, "Het-1 ", forming compounds according to formula (A-lllb)wherein in the group -[CQ]n- Q = H or Ci-C4-alkyl, preferably Q = H resulting in formula (Mb)with Het-1 being selected from- an optionally substituted, optionally fused 5- to 6-membered heteroaryl, as defined above, or- an optionally substituted 5- or 6-membered aliphatic heterocyclyl, preferably a 6-membered aliphatic heterocyclyl, each as defined abovewherein the Het-1 group contains 1 or 2 identical or different heteroatoms selected from N, Oand S, preferably selected from N and O, more preferably N; andthe Het-1 group may carry 1 to 3, preferably 1 or 2, preferably 1 substituents as defined above, preferably selected from halogen, cyano, optionally substituted alkyl as defined above, optionally substituted alkoxy, a hydroxyl group (-OH), an oxo-group (=0), a carboxyl group [-(C=0)-OH], a heterocyclyl group as defined above, an aminocarbonyl group, an optionally substituted amino group;n is an integer of 1 to 8, preferably 1 to 4, preferably 1 to 3 such as 1 , 2 or 3, more preferred 1 (in particular in embodiments with Q = C-|-C4-alkyl);andthe remaining of R or R2 (designated as R ) has the meaning as defined above, particularly as defined for formula (I) and as defined in context with embodiment 3 above; andZ, R3, A1 , A2 and Ar have the meaning as defined in context with any one of the embodiments described herein.Embodiment 3b-a: Another preferred embodiment (3b-a) of the present invention relates to compounds according to formula (lllb) above, wherein Het-1 is selected from an optionally substituted 5- membered heteroaryl, as defined above, preferably an optionally substituted pyrazolyl, forming for example compounds according to formula (A-lllb-a)wherein in the group -[CQ]n- Q = H or Ci-C4-alkyl, preferably Q = H resulting in formula (lllb-a)wherein R4 is hydrogen or alkyl as defined above, preferably Ci-C3-alkyl,n is an integer of 1 to 8, preferably 1 to 4, preferably 1 to 3, such as 1 , 2 or 3, more preferred 1 (in particular in embodiments with Q = C-|-C4-alkyl); andthe remaining of R or R2 (designated as R ) has the meaning as defined above, particularly as defined for formula (I) and as defined in context with embodiment s and 3b above, and wherein the pyrazolyl ring may carry 1 or 2 further substituents as defined above; andZ, R3, A1 , A2 and Ar have the meaning as defined in context with any one of the embodiments described herein.Embodiment 3b-b:Another preferred embodiment (3b-b) of the present invention relates to compounds according to formula (lllb) above, wherein Het-1 is selected from an optionally substituted 5- membered heteroaryl, as defined above, preferably an optionally substituted imidazolyl, forming for example compounds according to formul -lllb-b)wherein in the group -[CQ]n- Q = H or Ci-C4-alkyl, preferably Q = H resulting in formula (lllb-b) wherein R4 is hydrogen or alkyl as defined above, preferably Ci-C3-alkyl,n is an integer of 1 to 8, preferably 1 to 4, preferably 1 to 3 such as 1 , 2 or 3 more preferred 1 (in particular in embodiments with Q = C-|-C4-alkyl); andthe remaining of R or R2 (designated as R ) has the meaning as defined above, particularly as defined for formula (I) and as defined in context with embodiment 3 and 3b above, and wherein the imidazolyl ring may carry 1 or 2 further substituents as defined above; andZ, R3, A1 , A2 and Ar have the meaning as defined in context with any one of the embodiments described herein.Embodiment 3b-c:Another preferred embodiment (3b-c) of the present invention relates to compounds according to formula (1Mb) above, wherein Het-1 is selected from an optionally substituted 6- membered heteroaryl, as defined above, preferably an optionally substituted pyrimidinyl, forming for example compounds according to formula A-lllb-c)wherein in the group -[CQ]n- Q = H or C-|-C4-alkyl, preferably Q = H resulting in formula (lllb-c)wherein n is an integer of 1 to 8, preferably 1 to 4, preferably 1 to 3 such as 1 , 2 or 3, more preferred 1 (in particular in embodiments with Q = C-|-C4-alkyl); and the remaining of R or R2 (designated as R ) has the meaning as defined above, particularly as defined for formula (I) and as defined in context with embodiment 3 and 3b above, and wherein the pyrimidinyl ring may carry 1 to 3, preferably 1 or 2 further substituents as defined above; andZ, R3, A1 , A2 and Ar have the meaning as defined in context with any one of the embodiments described herein.Embodiment 3b-d:Another preferred embodiment (3b-d) of the present invention relates to compounds according to formula (1Mb) above, wherein Het-1 is selected from an optionally substituted 6- membered heteroaryl, as defined above, preferably an optionally substituted pyridazinyl, forming for example compounds according to formula (A-lllb-d)wherein in the group -[CQ]n- Q = H or Ci-C4-alkyl, preferably Q = H resulting in formula (lllb-d)wherein n is an integer of 1 to 8, preferably 1 to 4, preferably 1 to 3 such as 1 , 2 or 3, more preferred 1 (in particular in embodiments with Q = Ci-C4-alkyl); and the remaining of R or R2 (designated as R ) has the meaning as defined above, particularly as defined for formula (I) and as defined in context with embodiment 3 and 3b above, and wherein the pyridazinyl ring may carry 1 to 3, preferably 1 or 2 further substituents as defined above; andZ, R3, A1 , A2 and Ar have the meaning as defined in context with any one of the embodiments described herein.Embodiment 3b-e:Another particularly preferred embodiment (3b-e) of the present invention relates to compounds according to formula (1Mb) above, wherein Het-1 is selected from an optionally substituted 6- membered heteroaryl, as defined above, preferably an optionally substituted pyridinyl, forming for example compounds accordin to formula (A-lllb-e)wherein in the group -[CQ]n- Q = H or C-|-C4-alkyl, preferably Q = H resulting in formula (lllb-e)wherein n is an integer of 1 to 8, preferably 1 to 4, preferably 1 to 3 such as 1 , 2 or 3, more preferred 1 (in particular in embodiments with Q = Ci-C4-alkyl); and the remaining of R or R2 (designated as R ) has the meaning as defined above, particularly as defined for formula (I) and as defined in context with embodiment 3 and 3b above, and wherein the pyridinyl ring may carry 1 to 3, preferably 1 or 2 further substituents as defined above, andZ, R3, A1 , A2 and Ar have the meaning as defined in context with any one of the embodiments described herein.Embodiment 3b-f:Another particularly preferred embodiment (3b-f) of the present invention relates to compounds according to formula (1Mb) above, wherein Het-1 is selected from a substituted pyridinyl, forming compounds according to formula (A-lllb-f)wherein in the group -[CQ]n- Q = H or Ci-C4-alkyl, preferably Q = H resulting in formula (lllb-f)wherein n is an integer of 1 to 8, preferably 1 to 4, preferably 1 to 3 such as 1 , 2 or 3, more preferred 1 (in particular in embodiments with Q = C-|-C4-alkyl); and the remaining R or R2 (designated as R ) has the meaning as defined above, particularly as defined for formula (I) and as defined in context with embodiment 3 and 3b above, andwherein R5 indicates 1 to 4, preferably 1 to 3, preferably 1 or 2, more preferably 1 optional substituents, which may idenpendently be selected fromhalogen, preferably CI or F, more preferably F,optionally substituted alkyl, preferably C-|-C3-alkyl, such as preferably methyl, or trifluoromethylhydroxy,alkoxy, preferably methoxy;preferably R5 is selected from- halogen, preferably CI or F, more preferably F, and- Ci-C3-alkyl, such as preferably methyl, or trifluoromethyl; andZ, R3, A1 , A2 and Ar have the meaning as defined in context with any one of the embodiments described herein.Embodiment 3b-q:Another very particularly preferred embodiment (3b-g) of the present invention relates to compounds according to formula (1Mb) above, wherein Het-1 is selected from a substituted pyridinyl, forming compounds according to formula (A-lllb-g) wherein in the group -[CQ]n- Q = H or Ci-C4-alkyl, preferably Q = H resulting in formula (lllb-g)wherein n and the remaining of R or R2 (designated as R ) has the meaning as defined for embodiment 3b-f, and wherein R5 is selected fromhalogen, preferably CI or F, more preferably F,optionally substituted alkyl, preferably Ci-C3-alkyl, such as preferably methyl, or trifluoromethylhydroxy,alkoxy, preferably methoxy;more preferably R5 is selected from- halogen, preferably CI or F, more preferably F, and- Ci-C3-alkyl, such as preferably methyl, or trifluoromethyl; andZ, R3, A1 , A2 and Ar have the meaning as defined in context with any one of the embodiments described herein.It is further very particularly preferred that in the compounds as defined in embodiments 3, 3a, 3b, 3b-a, 3b-b, 3b-c, 3b-d, 3b-e, 3b-f and 3b-g the at least one of R and R2 being a linear, branched or cyclic alkyl group substituted with a cyclic group "Cycl". Such linear, branched or cyclic alkyl group means a linear or branched alkyl group -[CQ]n- with Q = H or Ci-C4-alkyl, which is substituted with said cyclic group "Cycl". In particular when one of R and R2 is a branched alkyl group -[CQ]n- with Q = Ci-C4-alkyl, it is possible and preferred that the alkyl-group of Q forms a forms a cyclic alkyl residue in the form of a fused ring with the cyclic group "Cycl". Accordingly said "linear, branched or cyclic alkyl residue (which is substituted with a cyclic group "Cycl") is selected from- an optionally substituted linear or branched alkanediyl group, as defined above, which is preferably selected from- methylene,- ethane-1 ,2-diyl,- ethane-1 ,1-diyl,- propane-1 ,3-diyl,- propane-1 , 1-diyl,- propane-1 ,2-diyl, and- propane-2,2-diyl; or - (in particular with Q being a Ci-C4-alkyl forming) an optionally substituted cycloalkyl group, as defined above, which is preferably selected from- cyclopropane and- cyclohexane;which in a further preferred embodiment may preferably form a fused bicyclic ring with Cycl being a Het-1 group selected from a 6-membered heteroaryl as defined above.More preferred is an optionally substituted linear or branched alkanediyl residue, as defined above. Even more preferably such optionally substituted alkanediyl residue is selected from the group consisting of methylene, ethane-1 ,2-diyl, ethane-1 , 1 -diyl and propane-2,2-diyl; more preferably methylene or ethane- 1 ,2-diyl; most preferred is methylene.In each of the above mentioned embodiments 3, 3a, 3b, 3b-a, 3b-b, 3b-c, 3b-d, 3b-e, 3b-f and 3b-g the remaining of R or R2, designated as R , Z, R3, A1 , A2 and Ar may have the meaning as defined for formula (I) and as defined in context with any one of the embodiments described herein, in particular as defined in context with embodiments 2a, 2a-a, 2a-b, 2a-c and 2a-d, as well as 2b, 2b-a, 2b-b, 2b-c and 2b- d, as well as 2c, 2c-a and 2c-b, as well as 2d, 2d-a and 2d-b, as well as 2e and 2f above and 4, 4a, 4b, 4c and 4d below.Further preferred embodiment 4:A further preferred embodiment of the present invention relates to any one of the compounds as defined above, wherein Ar is an optionally substituted mono- or bicyclic heteroaryl, as defined above, "Het- 2", forming compounds according to formula (IV)with Het-2 being selected from- an optionally substituted 5- or 6-membered monocyclic heteroaryl, as defined above, and- an optionally substituted bicyclic heteroaryl, as defined above, which may be fused with a ring formed by R3 and A2 together with the nitrogen atom to which they are bonded.Embodiment 4a:Another preferred embodiment (4a) relates to compounds as defined herein and in particular to compounds according to formula (IV) above, wherein Ar being an optionally substituted mono- or bicyclic heteroaryl "Het-2" is selected from an optionally substituted 5-membered monocyclic heteroaryl, as defined above, forming for exwherein X5 is S or N-R4 with R4 having the meaning as defined above, in particular in context with embodiments 3b-a and 3b-b, and wherein the 5-membered heteroaryl ring of Het-2 may carry 1 to 3 further substituents, preferably 1 or 2 further substituents, more preferably 1 further substituent, as defined above. Embodiment 4b:Another preferred embodiment (4b) relates to compounds as defined herein and in particular to compounds according to formula (IV) above, wherein Ar being an optionally substituted mono- or bicyclic heteroaryl "Het-2" is selected from an optionally substituted 6-membered monocyclic heteroaryl, as defined above, forming for exam le compounds according to formula (IVb)wherein Y2 is C or N, and wherein the 6-membered heteroaryl ring of Het-2 may carry 1 to 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent, as defined above.Embodiment 4c:Another particularly preferred embodiment (4c) relates to compounds as defined herein and in particular to compounds according to formula (IV) above, wherein Ar being an optionally substituted mono or bicyclic heteroaryl "Het-2" is selected from an optionally substituted bicyclic heteroaryl, as defined above, forming for example compounds according to formula (IVc)with- both Y2 being C or- one Y2 being N and one Y2 being C, andwherein the bicyclic heteroaryl ring of Het-2 may carry 1 to 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent, as defined above, and wherein the optionally substituted bicyclic heteroaryl ring of Het-2 may be fused with a ring formed by R3 and A2 together with the nitrogen atom to which they are bonded. Embodiment 4d:Another very particularly preferred embodiment (4d) relates to compounds as defined herein and in particular to compounds according to formula (IV) and (IVc) above, wherein Ar being an optionally substituted mono- or bicyclic heteroaryl "Het-2" is selected from an optionally substituted bicyclic heteroaryl, which is selected from benzimidazolyl, as defined above, forming compounds according to formula (IVdwherein the benzimidazolyl ring of Het-2 may carry 1 to 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent, as defined above, andwherein the benzimidazolyl ring of Het-2 may be fused with a ring formed by R3 and A2 together with the nitrogen atom to which they are bonded.Further preferred embodiment 5:A further particularly preferred embodiment of the present invention relates to any one of the compounds as defined above, wherein Ar is an optionally substituted bicyclic heteroaryl, as defined above in embodiment 4c and 4d and wherein Het-1 is selected from an optionally substituted 6- membered heteroaryl, as defined above in embodiments 3b-e, 3b-f and 3b-g, forming for example compounds according to formula Va-1 ), (Vb-1 ) or (Vc-1 ) or (Va-2), (Vb-2) or (Vc-2):wherein Q, n, R5, Y2, as well as R1*, Z, R3, A1 and A2 have the meaning as defined in context with any one of the embodiments described herein and wherein the pyridinyl ring may carry 1 to 3, preferably 1 or 2 further substituents as defined above and wherein the benzimidazolyl ring of Het-2 may carry 1 to 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent, as defined above, and wherein the benzimidazolyl ring of Het-2 may be fused with a ring formed by R3 and A2 together with the nitrogen atom to which they are bonded; in each case as defined in particular as in embodiments 4c and 4d and embodiments 3b-e, 3b-f and 3b-gPreferably, R5 indicates at least one substituent, which is selected from fluorineIn each of the above mentioned embodiments 4, 4a, 4b, 4c and 4d and 5 the remaining substituents R , R2, Z, R3, A1 and A2 may have the meaning as defined for formula (I) and as defined in context with any one of the embodiments described herein, in particular as defined in context with embodiments 2a, 2a-a, 2a-b, 2a-c and 2a-d, as well as 2b, 2b-a, 2b-b, 2b-c and 2b-d, as well as 2c, 2c-a and 2c-b, as well as 2d, 2d-a and 2d-b, as well as 2e and 2f above, and 3, 3a, 3b, 3b-a, 3b-b, 3b-c, 3b-d, 3b-e, 3b-f and 3b-g above.It is further very particularly preferred that in the compounds according to the present invention, such as in particular in the compounds as defined in formula (I) and in embodiments 2a, 2a-a, 2a-b, 2a-c and 2a-d, as well as 2b, 2b-a, 2b-b, 2b-c and 2b-d, as well as 2c, 2c-a and 2c-b, as well as 2d, 2d-a and 2d-b, as well as 2e and 2f and 3, 3a, 3b, 3b-a, 3b-b, 3b-c, 3b-d, 3b-e, 3b-f and, 3b-g, as well as 4, 4a, 4b, 4c and 4d above, as well as 5, A1 and A2 each are optionally substituted alkanediyl, as defined above, and are the same or different and are independently selected from optionally substituted- methylene and- ethane-1 ,2-diyl, or- A1 and R3 together with the nitrogen atom to which they are bonded form an optionally substituted 4- to 6-membered mono- or bicyclic ring, preferably a 4- or 6-membered mono- or bicyclic ring, more preferably a 4-membered ring, as defined above. Therein, more preferably- A1 and A2 are identical and are methylene,- A1 and A2 are identical and are ethane-1 ,2-diyl,- A1 is methylene and A2 is ethane-1 ,2-diyl,- A1 is ethane-1 ,2-diyl and A2 is methylene,- A1 and R3 together with the nitrogen atom to which they are bonded form an optionally substituted 4- to 6-membered mono- or bicyclic ring, preferably a 4-membered ring, and A2 is methylene, or- A1 and R3 together with the nitrogen atom to which they are bonded form an optionally substituted 4- to 6-membered mono- or bicyclic ring, preferably a 4-membered ring, and A2 is ethane-1 ,2-diyl; more preferably- A1 and A2 are identical and are ethane-1 ,2-diyl,- A1 is ethane-1 ,2-diyl and A2 is methylene or- A1 and R3 together with the nitrogen atom to which they are bonded form an optionally substituted 4-membered monocyclic ring, and A2 is ethane-1 , 2-diyl; even more preferably- A1 and A2 are identical and are ethane-1 , 2-diyl, or- A1 is ethane-1 , 2-diyl and A2 is methylene. In further preferred embodiments of compounds according to the general formulae (I), (II), (II I), (IV)and the substructures thereof as defined above, as well as according to the formulae (Va-1 ), (Vb-1 ), (Vc-1 ), (Va-2), (Vb-2) and (Vc-2), the individual substituents have the following definitions in each case:1 . One of R and R2 is designated as R and is hydrogen and one of R or R2 is designated as R2 and is selected from hydrogen, and optionally substituted alkyi, as defined above, preferably aryl- substituted alkyi and heteroaryl-substituted alkyi, wherein the aryl and heteroaryl substituent each may carry 1 to 3 substituents, as defined above, preferably selected from halogen and hydroxy. Particularly preferred is that the at least one of R or R2 which is designated as R2 is optionally substituted aryl-methyl or heteroaryl-methyl, most preferred is optionally substituted heteroaryl-methyl.2. Z is a cyclic group, selected from- optionally substituted 5-or 6-membered heteroaryl, preferably 5-membered heteroaryl,- optionally substituted aryl, preferably phenyl, and- optionally substituted 5- or 6-membered heterocyclyl. Particularly preferred is the meaning of thiazolyl, oxazolyl, triazolyl, oxadiazolyl and pyrazolyl, as defined above.3. A1 and A2 are optionally substituted alkanediyl and are the same or different and are independently selected from- A1 and A2 are identical and are methylene,- A1 and A2 are identical and are ethane-1 ,2-diyl,- A1 is methylene and A2 is ethane-1 ,2-diyl,- A1 is ethane-1 ,2-diyl and A2 is methylene,- A1 and R3 together with the nitrogen atom to which they are bonded form an optionally substituted 4- membered monocyclic ring , and A2 is methylene, or- A1 and R3 together with the nitrogen atom to which they are bonded form an optionally substituted 4-membered monocyclic ring , and A2 is ethane-1 , 2-diyl.Particularly preferred is that A1 is methylene or ethane-1 , 2-diyl and A2 is ethane-1 , 2-diyl, or that A1 and R3 together with the nitrogen atom to which they are bonded form an optionally substituted 4- membered monocyclic ring and A2 is ethane-1 , 2-diyl.4. R3 is hydrogen or optionally substituted alkyi, as defined above, or A1 and R3 together with the nitrogen atom to which they are bonded form an optionally substituted 4- to 6-membered mono- or bicycyclic ring, preferably hydrogen.5. Ar is Het-1 as defined above, preferably optionally substituted mono- or bicyclic heteroaryl, as defined above, preferably optionally substituted benzimidazolyl as defined above.In particular with respect to compounds of formula (I) and according to embodiments 2a, 2a-a, 2a- b, 2a-c and 2a-d it is particularly preferred that R and R2 are different, with one being hydrogen and the other one being an optionally substituted alkyi. More preferably, one of R and R2 is hydrogen and the other one is an alkyi residue, which is substituted with- an optionally substituted aryl group as defined above, preferably with an optionally substituted phenyl group as defined above, or- with an optionally substituted heteroaryl group as defined above, preferably with- an optionally substituted pyridinyl group,- an optionally substituted pyridazinyl group,- an optionally substituted pyrimidinyl group,- an optionally substituted pyrazolyl group,- an optionally substituted imidazolyl group.Even more preferably, one of R and R2 is hydrogen and the other one is an alkyi residue, which is substituted with- an optionally substituted phenyl group,- an optionally substituted pyridinyl group, - an optionally substituted pyridazinyl group,- an optionally substituted pyrimidinyl group,Still more preferably, one of R and R2 is hydrogen and the other one is an alkyl residue, which is substituted with- an optionally substituted phenyl group, or- an optionally substituted pyridinyl group,wherein the optionally substituted pyridinyl group as a substituent of an alkyl residue for one of R and R2 is most preferred. More preferably a halogen substituted pyridinyl group such as in particular a pyridinyl group substituted with one fluorine substituent is selected , such as in particular a group according to formulaIt is further preferred that herein and in particular for compounds of formula (I) and as defined in any one of the above defined embodiments 2a, 2a-a, 2a-b, 2a-c and 2a-d Ar has the meaning of a bicyclic heteroar l, such as in particular benzimidazol, particularly benzimidazol2-yl according to formulaIt is further preferred that herein A1 and A2 each are optionally substituted alkanediyl, as defined above, such as very preferably with A1 and A2 being identical and methylene, or A1 and A2 being identical and ethane-1 ,2-diyl, or A1 being methylene and A2 being ethane-1 ,2-diyl, or A1 being ethane-1 ,2-diyl and A2 being methylene, more preferably with A1 and A2 being identical and ethane-1 ,2-diyl, or with A1 being ethane-1 ,2-diyl and A2 being methylene.In particular with respect to compounds of formula (I) and according to embodiments 2b, 2b-a, 2b- b, 2b-c and 2b-d it is particularly preferred that R and R2 are different, with one being hydrogen and the other one being an optionally substituted alkyl. More preferably, one of R and R2 is hydrogen and the other one is an alkyl residue, which is substituted with an optionally substituted heteroaryl group as defined above, preferably with an optionally substituted pyridinyl group as defined above, more preferably with a halogen substituted pyridinyl group such as in particular a pyridinyl group substituted with one fluorine substituent.It is further preferred that herein and in particular in compounds of formula (I) and as defined in any one of the above defined embodiments 2b, 2b-a, 2b-b, 2b-c and 2b-d Ar has the meaning of a bicyclic heteroaryl, such as in particular benzimidazol, particularly benzimidazol2-yl as defined above.It is further preferred that herein A1 and A2 each are optionally substituted alkanediyl, as defined above, such as very preferably with A1 and A2 being identical and methylene, or A1 and A2 being identical and ethane-1 ,2-diyl, or A1 being methylene and A2 being ethane-1 ,2-diyl, or A1 being ethane-1 ,2-diyl and A2 being methylene, more preferably with A1 and A2 being identical and ethane-1 ,2-diyl, or with A1 being ethane-1 ,2-diyl and A2 being methylene, or wherein A1 and R3 together with the nitrogen atom to which they are bonded form an optionally substituted 4- membered monocyclic ring , and A2 is ethane-1 ,2-diyl.In particular with respect to compounds of formula (I) and according to embodiments 2c, 2c-a and 2c-b it is particularly preferred that R and R2 are different, with one being hydrogen and the other one being an optionally substituted alkyl. More preferably, one of R and R2 is hydrogen and the other one is an alkyl residue, which is substituted with an optionally substituted aryl group as defined above, preferably with an optionally substituted phenyl group as defined above, or with an optionally substituted heteroaryl group as defined above, preferably with an optionally substituted pyridinyl group as defined above, more preferably with a halogen substituted pyridinyl group such as in particular a pyridinyl group substituted with 1 F.It is further preferred that herein and in compounds of formula (I) and according to any one of the above defined embodiments 2c, 2c-a and 2c-b Ar has the meaning of a bicyclic heteroaryl, such as in particular benzimidazol, particularly benzimidazol-2-yl as defined above.It is further preferred that herein A1 and A2 each are optionally substituted alkanediyl, as defined above, such as very preferably with A1 and A2 being identical and methylene, or A1 and A2 being identical and ethane-1 ,2-diyl, or A1 being methylene and A2 being ethane-1 ,2-diyl, or A1 being ethane-1 ,2-diyl and A2 being methylene, more preferably with A1 and A2 being identical and ethane-1 ,2-diyl, or with A1 being ethane-1 ,2-diyl and A2 being methylene.In particular with respect to compounds of formula (I) and according to embodiments 2d, 2d-a and 2d-b it is particularly preferred that R and R2 are different, with one being hydrogen and the other one being an optionally substituted alkyl. More preferably, one of R and R2 is hydrogen and the other one is an alkyl residue, which is substituted with an optionally substituted heteroaryl group as defined above, preferably with an optionally substituted pyridinyl group as defined above, more preferably with a halogen substituted pyridinyl group such as in particular a pyridinyl group substituted with 1 F.It is further preferred that herein and in compounds of formula (I) and according to any one of the above defined embodiments 2d, 2d-a and 2d-b Ar has the meaning of a bicyclic heteroaryl, such as in particular benzimidazol, particularly benzimidazol-2-yl as defined above.It is further preferred that herein A1 and A2 each are optionally substituted alkanediyl, as defined above, such as very preferably with A1 and A2 being identical and methylene, or A1 and A2 being identical and ethane-1 ,2-diyl, or A1 being methylene and A2 being ethane-1 ,2-diyl, or A1 being ethane-1 ,2-diyl and A2 being methylene, more preferably with A1 and A2 being identical and ethane-1 ,2-diyl, or with A1 being ethane-1 ,2-diyl and A2 being methylene.Particularly preferably the compounds according to the present invention are selected from the compounds:4344505153556062or pharmaceutically acceptable salts thereof.More preferred are the compounds according to formula (I), wherein Ar is an optionally substituted, optionally fused bicyclic heteroaryl, such as Examples Nos.:1, 5, 7, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23,24, 25, 26, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 218, 219, 220, 221, 222, 223, 224, 226, 227, 228, 229, 230, 231 , 232, 233, 235, 236, 237, 239, 240, 241 , 242, 243, 244, 245, 246, 247, 248, 249, 250, 251 , 252, 253, 255, 256, 257, 258, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278 and 279.More preferred are the compounds according to formula (I), wherein Ar is an optionally substituted, optionally fused bicyclic heteroaryl and one of R / R2 is heteroaryl or an alkyl substituted with an optionally substituted heteroaryl or a heterocyclyl group, such as Examples Nos.:12, 16, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 54, 55, 56, 57, 58, 59, 60, 61, 64, 76, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213,214, 215, 218, 219, 220, 221, 222, 223, 224, 226, 227, 228, 229, 230, 231, 232, 233, 235, 236, 237, 239, 240, 241 , 242, 243, 244, 245, 246, 247, 248, 249, 250, 251 , 252, 253, 255, 256, 257, 258, 261 , 262, 263, 264, 265, 266, 267, 268, 269, 270, 271 , 272, 273, 274, 275, 276, 277, 278 and 279. More preferred are the compounds according to formula (I), wherein Ar is an optionally substituted, optionally fused bicyclic heteroaryl and one of R / R2 is alkyl substituted with a 6-membered optionally substituted heteroaryl group, such as Examples Nos.:12, 35, 36, 37, 38, 39, 40, 42, 43, 44, 45, 46, 47, 48, 49, 54, 55, 56, 57, 58, 59, 61, 76, 79, 80, 81, 82, 83, 87, 89, 90, 92, 93, 94, 96, 97, 98, 99, 101, 102, 103, 104, 105, 106, 108, 109, 110, 111, 112, 113, 114,115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 218, 219, 220, 221, 222, 223, 224, 226, 227, 228, 229, 230, 231, 232, 233, 235, 236, 237, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251 , 252, 253, 255, 256, 257, 258, 261 , 262, 263, 264, 265, 266, 267, 268, 269, 270, 271 , 272, 273, 274, 275, 276, 277, 278 and 279. More preferred are the compounds according to formula (I), wherein Ar is an optionally substituted, optionally fused bicyclic heteroaryl and one of R / R2 is alkyl substituted with an optionally substituted pyridinyl-group, such as Examples Nos.:12, 35, 36, 37, 38, 39, 40, 42, 43, 45, 47, 48, 49, 54, 55, 56 ,57, 58, 59, 76, 79, 80, 81, 82, 83, 89, 90, 92, 94, 96, 97, 98, 99, 101, 102, 103, 104, 105, 106, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 123, 124, 125, 126, 127, 128, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 156, 157, 158, 159, 160, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 176, 177, 179, 180, 181, 184, 186, 187, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 218, 219, 220, 221, 222, 223, 224, 226, 227, 228, 229, 230, 231, 232, 233, 235, 236, 237, 239, 240, 241, 242, 243, 245, 246, 247, 248, 249, 250, 251 , 252, 253, 255, 256, 257, 258262, 263, 264, 265, 266, 267, 268, 269, 272, 273, 274, 275, 276, 277, 278 and 279.More preferred are the compounds according to formula (I), wherein Ar is an optionally substituted, optionally fused bicyclic heteroaryl and one of R / R2 is alkyl substituted with an optionally substituted pyridinyl-group and Z is an optionally substituted, optionally fused 5-membered heteroaryl group, such as Examples Nos.:12, 35, 36, 37, 38, 39, 40, 42, 43, 45, 47, 48, 49, 54, 55, 56, 57, 58, 59, 76, 79, 80, 81, 82, 83,89, 90, 92, 94, 96, 97, 98, 99, 110, 102, 103, 104, 105, 106, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 123, 124125, 126, 127, 128, 131, 132, 134, 135, 136, 137, 138, 139, 140, 141, 142, 144, 145, 148, 150, 151, 152, 153, 154, 156, 157, 158, 159, 160, 162, 163, 164, 165, 166, 167, 169, 170, 171, 173, 176, 177, 179, 180, 181, 184, 186, 187, 189, 191, 192, 193, 194, 195, 196, 198, 199, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 218, 219, 220, 223, 226, 227, 228, 230,231, 233, 236, 239, 242, 243, 247, 249, 250, 251 , 252, 253, 255, 256, 257, 258, 262, 263264, 265, 266, 267, 268, 269, 272, 273, 274, 275, 276, 277, 278 and 279.More preferred are the compounds according to formula (I), wherein Ar is an optionally substtuted, optionally fused bicyclic heteroaryl and one of R / R2 is alkyl substituted with an optionally substituted pyridinyl-group and Z is an optionally substituted, optionally fused 5-membered heteroaryl group,selected from an oxazolyl-group such as Examples Nos.:126, 127, 128, 137, 141, 171, 173, 206, 207, 208, 223, 226, 227, 228, 230, 233, 239, 247, 249, 250, 251, 252, 253, 255, 256, 257, 258, 262, 263, 264, 265, 266, 267, 268, 269, 272, 273;and / or selected from a thiazolyl-group such as Examples Nos.: 12, 35, 36, 37, 38, 39, 40, 42, 43, 45, 47, 54, 55, 56, 57, 58, 59, 76, 79, 80, 81 , 82, 83, 89, 90, 94, 96, 97, 98, 99, 101 , 102, 103, 104, 105, 106, 108, 1 10, 1 12, 1 13, 1 14, 1 15, 1 16, 1 18, 1 19, 120, 121 , 123, 124, 125, 134, 135, 139, 140, 148, 151 , 152, 154, 157, 158, 159, 160, 163, 164, 165, 166, 176, 177, 179, 180, 184, 186, 189, 193, 194, 195, 196, 199, 209, 21 1 , 212, 213, 214, 215, 218, 231 , 236, 242, 243, 274, 275, 276;and / or selected from a triazolyl-group such as Examples Nos.:169, 170, 181 , 277.Further, compounds with one of R / R2 being a fluorine-substituted pyridinyl-group are preferred , such as as Examples Nos.:40, 77, 94, 1 12, 1 13, 1 14, 1 15, 1 18, 1 19, 120, 121 , 125, 126, 127, 128, 134, 135, 139, 140, 148, 151 , 152, 154, 157, 163, 164, 165, 166, 169, 176, 177, 179, 180, 181 , 186, 193, 196, 199, 206, 208, 209, 21 1 , 212, 213, 214, 218, 223, 226, 227, 228, 230, 231 , 233, 239, 242, 243, 247, 249, 250, 251 , 253, 255, 256, 257, 262, 263, 264, 265, 266, 267, 268, 269, 272, 273, 274, 275, 276, 277 and 279.Pharmaceutically acceptable salts of the compounds according to the invention include, for example, salts with suitable anions, such as carboxylates, sulfonates, sulfates, chlorides, bromides, iodides, phosphates, tartrates, methane sulfonates, hydroxyethane sulfonates, glycinates, maleates, propionates, fumarates, toluene sulfonates, benzene sulfonates, trifluoroacetates,naphthalenedisulfonates-1 ,5, salicylates, benzoates, lactates, salts of malic acid, salts of 3-hydroxy-2- naphthoic acid-2, citrates and acetates.Pharmaceutically acceptable salts of the compounds according to the invention further include, for example, salts with suitable pharmaceutically acceptable bases, such as, for example, salts with alkaline or alkaline-earth hydroxides, such as NaOH, KOH, Ca(OH)2, Mg(OH)2 etc. , amine compounds such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, ethanolamine, diethanolamine, triethanolamine, methylglucamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylarrine, N- methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidin, 2-amino-2-methyl-propanol-(1 ), 2- amino-2-methyl-propandiol-(1 ,3), 2-amino-2-hydroxyl-methyl-propandiol-(1 ,3) (TRIS) etc..Depending on their structure, the compounds according to the invention may exist in stereoisomeric forms (enantiomers, diastereomers) in the presence of asymmetric carbon atoms. The invention therefore includes the use of the enantiomers or diastereomers and the respective mixtures thereof. The pure-enantiomer forms may optionally be obtained by conventional processes of optical resolution, such as by fractional crystallisation of diastereomers thereof by reaction with optically active compounds. Since the compounds according to the invention may occur in tautomeric forms, the present invention covers the use of all tautomeric forms.The compounds provided according to the invention may be present as mixtures of various possible isomeric forms, in particular of stereoisomers such as, for example, E- and Z-, syn and anti, as well as optical isomers. The E-isomers and also the Z-isomers as well as the optical isomers and any mixtures of these isomers are claimed.The novel compounds of the present invention can be present in an amorphous, crystalline or partially crystalline form or they may also be present exist as hydrates.The compounds according to formula (I) and its further embodiments, as defined above, have surprisingly been found to act as ferroportin inhibitors and are thus suitable for the use as ferroportin inhibitors. As already explained above, ferroportin is the iron transport protein, which is responsible for the uptake of the released iron via the intestine and its transfer into the blood circulation, thereby conveying the iron to the appropriate tissues and organs. Inactivation or inhibition of the ferroportin disables the export of the iron, thereby reducing the absorption of iron in the intestine. Ferroportin inhibition in the sense of the present invention therefore includes the inhibition of iron transport from the cells into the blood circulation and the inhibition of iron absorption in the intestine. Therein, the inhibition of iron transport and / or iron reflux may be effected by different ways of mechanism, comprising for example inhibition of iron transport activity of ferroportin and thus inhibition of iron reflux, triggering internalization, degradation and / or reduction of ferroportin, administering hepcidin agonists, i.e. compounds which compete with hepcidin or by compounds, which inhibit the binding of hepcidin to ferroportin. Ferroportin inhibition may be determined by measuring the inhibition of ferroportin mediated iron transport activity in an iron response assay (BLAzer-Assay), as described in more detail in the Examples below. Further, ferroportin inhibition may be determined by measuring ferroportin internalization and / or degradation in the Ferroportin Internalization and Degradation Assay (FACS) or by examining the Ferroportin Ubiquitination and Degradation, each as described in more detail in the Examples below. Further, ferroportin inhibition may be determined by measuring the activity as an hepcidin agonist, for example by determining the Hepcidin binding capacity to ferroportin in the Hepcidin Internalization Assay (J774), as described in more detail in the Examples below. Further, ferroportin inhibition may be determined by confirming the inhibition of hepcidin binding to ferroportin, for example in the Biophysical Ferroportin-Hepcidin Binding Assay (Hep Bind FP), as described in more detail in the Examples below.Further, ferroportin inhibition may be determined by determining the activity of a compound regarding its ability to block iron export via ferroportin, for example with a test for measuring inhibition of iron efflux, as described in more detail in the Examples below.Ferroportin inhibition in the sense of the present invention can thus in particular be defined by exhibiting a ferroportin inhibiting activity in at least one of the aforementioned test methods, shown in particular by:Inhibition of ferroportin mediated iron transport activity in an iron response assay ( Blazer Assay): IC50 value [μιη] of not more than 100 (≤ 100), preferably not more than 50 (≤ 50), more preferably below 50 (< 50).Ferroportin Internalization and Degradation Assay (FACS): : EC50 value [μιη] of not more than 100 (< 100), preferably not more than 50 (< 50), more preferably below 50 (< 50).Ferroportin Ubiquitination and Degradation: visually inspected effect in Western blots of "+ comparable to hepcidin", "+ / - intermediate effect" and "+ / + / - stronger intermediate effect", preferred is an effect "+" or "+ / + / -", most preferred is an effect "+" .Hepcidin Internalization Assay (J774): IC50 value of not more than 100 (< 100), preferably not more than 50 (< 50), more preferably below 50 (< 50).Biophysical Ferroportin-Hepcidin Binding Assay: : IC50 value of not more than 100 (< 100), preferably not more than 50 (< 50), more preferably below 50 (< 50).Inhibition of Iron Efflux: IC50 value of not more than 100 (< 100), preferably not more than 50 (< 50), more preferably below 50 (< 50).Ferroportin inhibition may further be determined in / ' / ? vivo models, as described in more detail in the Examples below. Suitable in vivo models may comprise, for example, examination of hypoferremia in naive mice via measurement of serum iron reduction; examination of prevention of iron absorption in anemic rats via measurement of serum iron inhibition; examination of correction of hyperferremia in beta2- microglobulin deficient mice via measurement of serum iron reduction; examination of prevention of iron overload in beta2-microglobulin deficient mice via measurement of total iron in spleen or liver; examination of improvement of anemia, ineffective erythropoiesis and iron overload in a mouse model of β-thalassemia intermedia.The activity of the compounds of the present invention as ferroportin inhibitors can in particular be determined by the methods as described in the Examples below.As further already explained above, ferroportin inhibition may for example be effected by hepcidin, which is thus an essential regulating factor of iron absorption, inhibiting ferroportin and thus blocking iron transport from the cells into the blood circulation and iron absorption. It has further surprisingly been found that several of the compounds as defined herein act as hepcidin mimetics or hepcidin agonists, which is also included by ferroportin inhibition in the sense of the present irvention.Accordingly, the compounds as defined in the present invention are also suitable for use in the inhibition of iron transport from the cells into the blood circulation and the inhibition of iron absorption in the intestine, as well as for the use as hepcidin mimetics or hepcidin agonists.Due to the activity of the compounds as defined herein as ferroportin inhibitors, the compounds of the present invention are further particularly suitable for the use in the inhibition of iron transport mediated by ferroportin and thereby for the use in the prophylaxis and / or treatment of iron metabolism disorders leading to increased iron levels, of diseases related to or caused by increased iron levels, increased iron absorption or iron overload, such as in particular of tissue iron overload, of diseases associated with ineffective erythropoiesis, or of diseases caused by reduced levels of hepcidin Further, the compounds of the present invention are suitable for the use in an adjunctive therapy by limiting theamount of iron available to pathogenic microorganisms, such as the bacterium Vibrio vulnificus, thereby preventing or treating infections caused by said pathogenic microorganisms.Therein, diseases being associated with, being related to, being caused byor leading to increased iron levels, increased iron absorption, iron overload (e.g. tissue iron overload) or ineffective erythropoiesis comprise thalassemia, hemoglobinopathy, such as hemoglobin E disease (HbE), hemoglobin H disease (HbH), haemochromatosis, hemolytic anemia, such as sickle cell anemia (sickle cell disease) and congenital dyserythropoietic anemia.Diseases being associated with, being related to, being caused by or leading to increased iron levels, increased iron absorption, iron overload (eg. tissue iron overload) further compriseneurodegenerative diseases, such as for example Alzheimer's disease and Parkinson's disease, wherein the compounds are considered to be effective by limiting the deposition or increase of iron in tissue or cells.The compounds of the present invention are further suitable for the use in the prophylaxis and / or treatment of formation of radicals, reactive oxygen species (ROS) and oxidative stresscaused by excess iron or iron overload as well as in the prophylaxis and / or treatment of cardiac, liver and endocrine damage caused by excess iron or iron overload, and further in the prophylaxis and / or treatment of inflammation triggered by excess iron or iron overload.Diseases associated with ineffective erythropoiesis comprise in particular myelodysplastic syndromes (MDS, myelodysplasia) and polycythemia vera as well as congenital dyserythropoietic anemia Further diseases, disorders and / or diseased conditions comprise iron overload caused by mutations in genes involved in sensing the systemic iron stores, such as hepcidin (Hampl ), hemochromatosis protein (HFE), hemojuvelin (HJV) and transferrin receptor 2 (TFR2), such as in particular diseases related to HFE and HJV gene mutations, chronic hemolysis associated diseases, sickle cell diseases, red cell membrane disorders, Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency), erythrpoietic porphyria, Friedrich's Ataxia, as well as subgroups of iron overload such as transfusional iron overload, iron intoxication, pulmonary hemosiderosis, osteopenia, insulin resistense, African iron overload, Hallervordan Spatz disease, hyperferritinemia, ceruloplasmin deficiency, neonatal hemochromatosis and red blood cell disorders comprising thalassemia, including alpha thalassemia, beta thalassemia and delta thalassemia, thalassemia intermedia, sickle cell disease and myelodyplastic syndrome.Further disease and / or disorders and / or diseased conditions associated with elevated iron levels include, but are not limited to, diseases with elevated iron level, comprising ataxia, Friedrich's ataxia, age-related macular degeneration, age-related cataract, age-related retinal diseases and neurodegenrative disease, such as pantothenate kinase-associated neurodegeneration, restless leg syndrom and Huntington's disease.The compounds of the present invention my further be suitable for the use in the prophylaxis and treatment of diseases caused by a lack of hepcidin.In view thereof a further object of the present invention relates to a medicament containing one or more of the compounds as defined above, such as in particular a medicament for the prophylaxis and treatment in any of the indications, states, disorders or diseases as defined above.A further object of the present invention relates to pharmaceutical compositions and medicaments comprising one or more of the compounds according to the invention as defined above as well as optionally one or more pharmacologically acceptable carriers and / or auxiliary substances and / or solvents. A further object of the present invention relates to pharmaceutical compositions and medicaments comprising one or more of the compounds according to the invention as defined above as well as optionally one or more further pharmaceutically effective compounds. The said pharmaceutical compositions contain, for example up to 99 weight-% or up to 90 weight-% or up to 80 weight-% or or up to 70 weight-% of the compounds of the invention, the remainder being each formed by pharmacologically acceptable carriers and / or auxiliaries and / or solvents and / or optionally further pharmaceutically active compounds.Therein, the pharmaceutically acceptable carriers, auxiliary substances or solvents are common pharmaceutical carriers, auxiliary substances or solvents, including various organic or inorganic carrier and / or auxiliary materials as they are customarily used for pharmaceutical purposes, in particular for solid medicament formulations. Examples include excipients, such as saccharose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talcum, calcium phosphate, calcium carbonate; binding agents, such as cellulose, methylcellulose, hydroxypropylcellulose, polypropyl pyrrolidone, gelatine, gum arabic, polyethylene glycol, saccharose, starch; disintegrating agents, such as starch, hydrolyzed starch, carboxymethylcellulose, calcium salt of carboxymethylcellulose, hydroxypropyl starch, sodium glycol starch, sodium bicarbonate, calcium phosphate, calcium citrate; lubricants, such as magnesium stearate, talcum, sodium laurylsulfate; flavorants, such as citric acid, menthol, glycin, orange powder; preserving agents, such as sodium benzoate, sodium bisulfite, paraben (for example methylparaben, ethylparaben, propylparaben, butylparaben); stabilizers, such as citric acid, sodium citrate, acetic acid and multicarboxylic acids from the titriplex series, such as, for example, diethylenetriaminepentaacetic acid (DTPA); suspending agents, such as methycellulose, polyvinyl pyrrolidone, aluminum stearate; dispersing agents; diluting agents, such as water, organic solvents; waxes, fats and oils, such as beeswax, cocoa butter; polyethylene glycol; white petrolatum; etc..Liquid medicament formulations, such as solutions, suspensions and gels usually contain liquid carrier, such as water and / or pharmaceutically acceptable organic solvents. Furthermore, such liquid formulations can also contain pH-adjusting agents, emulsifiers or dispersing agents, buffering agents, preserving agents, wetting agents, gelatinizing agents (for example methylcellulose), dyes and / or flavouring agents, for example as defined above. The compositions may be isotonic, that is, they can have the same osmotic pressure as blood. The isotonicity of the composition can be adjusted by using sodium chloride and other pharmaceutically acceptable agents, such as, for example, dextrose, maltose, boric acid , sodium tartrate, propylene glycol and other inorganic or organic soluble substances. The viscosity of the liquid compositions can be adjusted by means of a pharmaceutically acceptable thickening agent, such as methylcellulose. Other suitable thickening agents include, for example, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, carbomer and the like. The preferred concentration of the thickening agent will depend on the agent selected .Pharmaceutically acceptable preserving agents can be used in order to increase the storage life of the liquid composition. Benzyl alcohol can be suitable, even though a plurality of preserving agents including, for example, paraben, thimerosal, chlorobutanol and benzalkonium chloride can also be used.The above-mentioned pharmaceutical compositions are suitable, for example, for intravenous, intraperitoneal, intramuscular, intravaginal, intrabuccal, percutaneous, subcutaneous, mucocutaneous, oral, rectal, transdermal, topical, intradermal, intragasteral or intracutaneous application and are provided , for example, in the form of pills, tablets, enteric-coated tablets, film tablets, layer tablets, sustained release formulations for oral, subcutaneous or cutaneous administration (in particular as a plaster), depot formulations, dragees, suppositories, gels, salves, syrup, granulates, suppositories, emulsions, dispersions, microcapsules, microformulations, nanoformulations, liposomal formulations, capsules, enteric-coated capsules, powders, inhalation powders, microcrystalline formulations, inhalation sprays, epipastics, drops, nose drops, nose sprays, aerosols, ampoules, solutions, juices, suspensions, infusion solutions or injection solutions etc..A further object of the present invention relates to medicaments or combined preparations containing one or more of the compounds as defined above and at least one further pharmaceutically active compound , such as in particular a compound for the prophylaxis and treatment of iron overload and the associated symptoms, preferably an iron-chelating compound, or a compound for the prophylaxis and treatment of any of the states, disorders or diseases as defined above, such as in particular a pharmaceutically active compound for the prophylaxis and treatment of thalassemia, haemochromatosis, neurodegenerative diseases (such as Alzheimer's disease or Parkinson's disease) and the associated symptoms.A further object of the present invention relates to the use of the compounds as defined above per se, as in particular compounds according to formula (lla-b), (Mb), (l lb-a), (l lb-b), (l lb-c), (l lb-d), (l ie), (l lc-a), (l lc-b), (lid), (l ld-a), (l ld-b), (lie), and (I I f), as well as (Va-1 ), (Va-2), (Vb-1 ), (Vb-2), (Vc-1 ) and (Vc-2), as defined above, in a combination therapy (fixed dose or free dose combinations for sequential use) with one or two other active ingredients (drugs). Such combination therapy comprises co-administration of the compounds of the present invention with the at least one additional pharmaceutically active compound (drug). Combination therapy in a fixed dose combination therapy comprises co-administration of the compounds of the present invention with the at least one additional pharmaceutically active compound in a fixed-dose formulation. Combination therapy in a free dose combination therapy comprises coadministration of the compounds of the present invention and the at least one additional pharmaceutically active compound in free doses of the respective compounds, either by simultaneous administration of the individual compounds or by sequential use of the individual compounds distributed over a time period. The at least one additional pharmaceutically active compound (drug) comprises in particular drugs for reducing iron overload (e.g . Tmprss6-ASO) or iron chelators, in particular curcumin, SSP-004184, Deferitrin, deferasirox, deferoxamine and / or deferiprone, or antioxidants such as n-acetyl cysteine, anti-diabetics such as GLP-1 receptor agonists, antibiotics such as vancomycin (Van) or tobramycin, drugs for the treatment of malaria, anticancer agents, antifungal drugs, drugs for the treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (e.g. dopamine agonists such as Levodopa), anti-viral drugs such as interferon-a or ribavirin, or immunosuppressents (cyclosporine A or cyclosporine A derivatives), iron supplements, vitamin supplements, red cell production stimulators, antiinflammatory biologies, anti-thrombolytics, statins, vasopressors and inotropic compounds.A further object of the present invention relates to the use of the above combinations for the prophylaxis and / or treatment of diseases caused by a lack of hepcidin or iron metabolism disorders, such as particularly iron overload states such as in particular thalassemia and hemochromatosis and other disorders as described in the present application. A further object of the present invention relates to the use of the compounds as defined herein per se, as in particular compounds according to formula (lla-b), (Mb), (llb-a), (llb-b), (llb-c), (llb-d), (lie), (llc-a), (llc-b), (lid), (lld-a), (lld-b), (lie), and (II f), as well as (Va-1 ), (Va-2), (Vb-1 ), (Vb-2), (Vc-1 ) and (Vc-2), as defined above, or the hereinabove described combination therapies, in combination with Blood transfusion.The compounds, medicaments and or combined preparations according to the present invention may be administered orally, parentally, as well as intravenously.For this purpose, the compounds according to the invention are preferably provided in medicaments or pharmaceutical compositions in the form of pills, tablets, such as enteric-coated tablets, film tablets and layer tablets, sustained release formulations for oral administration, depot formulations, dragees, granulates, emulsions, dispersions, microcapsules, microformulations, nanoformulations, liposomal formulations, capsules, such as enteric-coated capsules, powders, microcrystalline formulations, epipastics, drops, ampoules, solutions, suspensions, infusion solutions or injection solutions or in the form of a preparation suitable for inhalation.In a preferred embodiment of the invention the compounds are administered in the form of a tablet or capsule, as defined above. These may be present, for example, as acid resistant forms or with pH dependent coatings.The compounds of the present invention as the active substance can be administered, for example, with a unit dose of 0.001 mg / kg to 500 mg / kg body weight, for example 1 to 4 times a day. However, the dose can be increased or reduced depending on the age, weight, condition of the patient, severity of the disease or type of administration.Accordingly, a further object of the present invention relates to compounds, medicaments, compositions and combined preparations as defined above for the preparation of a medicament, particularly for the prophylaxis and treatment of any indication, state, disorder or disease as defined above, in particular for oral or parenteral administration.A further object of the present invention relates to a method for the prophylaxis and treatment as defined above, such as in particular for the prophylaxis and / or treatment of iron metabolism disorders being associated with or leading to increased iron levels and in particular iron overload, diseases related to or caused by increased iron levels or iron overload, iron storage diseases being associated with or leading to increased iron levels, and diseases being associated with ineffective erythropoiesis, the method comprising administering, to a patient (human or animal) in need thereof, a compound, a medicament, a composition or a combined preparation as defined above.Therein, diseases being associated with, being related to, being caused by or leading to increased iron levels or iron overload are as defined above.A further object of the present invention relates to the use of the compounds as defined above for the preparation of a medicament, particularly for the prophylaxis and treatment and of any indication, state, disorder or disease as defined above.A further object of the present invention relates to the compounds as defined above per se, as well as to the use of the compounds as a medicament (in general), such as in particular compounds according to formula (lla-b), (lib), (llb-a), (llb-b), (llb-c), (llb-d), (lie), (llc-a), (llc-b), (lid), (lld-a), (lld-b), (lie), and (II f), as well as (Va-1 ), (Va-2), (Vb-1 ), (Vb-2), (Vc-1 ) and (Vc-2), as defined above. The invention further very particularly relates to the novel compounds per se, which are selected from the table above, as well as to the use thereof as a medicament (in general), with the exception of Example Compound No. 1.The compounds according to the invention of general structural formula (I) may basically be obtained by the processes described below and as shown in the general procedures (General Schemes). Accordingly, a further object of the invention is a process for the production of the compounds of general formula (I) as described herein, which includes:a) reacting compounds of formula (a)b) further reacting said compounds (c) with compounds of formula (d)(d), with n = 0 to 7, preferably 0 to 5, preferably 0 to 1 or 2, to obtain compounds of formula (I);wherein R , R2, Z, A1 , R3 and Ar have the meaning as defined herein. In principle the order of reaction steps is optional. It is further possible to start with the reaction of compounds (a) with compounds (d), followed by reaction with compound (b) to obtain compounds of formula (I). Further several intermediate steps are possible and several intermediate compounds are obtained as shown in the following Examples in detail. Several of the intermediate compounds are also novel compounds, which shall be covered from the present invention.General Scheme 1NHBocn = 1,2 Rx= H, MeNaBH4, DIPEA MeOHGeneral Procedure 3therein Rx indicates an optional substituent to the thiazolyl-heterocyclen indicates an integer as defined in context with A1R in the RO-(C=0)- indicates...General Scheme 4R = Ar as defined hereinGeneral Scheme 6R3-CI, DIPEA nBuOH, MeOH uW irradiationGeneral Procedure 9General Scheme 83HCIR = Ar as defined hereinGeneral Scheme 12ure 15ii)Fe / AcOHGeneral Scheme 15RyCH 2CI, DIPEA,Ry = Ar as defined hereinDMFGeneral Scheme 16NHR1 R2 HATU, DIPEA DMFRyCHO,Ry = Ar as defined herein DIPEAMgS04,NaBh ,MeOHGeneral Scheme 19Ry = Ar as dHBocGeneral Scheme 20General Scheme 21i) MeCN, DBU ii) Fe / AcOHGeneral Scheme 22General Scheme 26General Scheme 28oYc,General Scheme 29LiOH, THF, waterGeneral Scheme 30LiOH, THF, waterGeneral Scheme 32Y = CH or NNHR1 R2 HATU, DIPEA DMFGeneral Scheme 33General Scheme 34O o NHR1R2H2NCH2CH2NHCBzHATU, DIPEA O OLiOH, THF, water O ODMFEtO v CI ,NHCBzEtO -NHCBzHO ^NA-^N'^NHCBZHGeneral Scheme 35General Scheme 37General Scheme 39General Scheme 41Intermediates:10 Scheme CGeneral Scheme K-lRy = substituent of phenyl as defined hereinEXAMPLESThe invention is illustrated in more detail by the following examples. The examples are merely explanatory, and the person skilled in the art can extend the specific examples to further claimed compounds. Pharmacological Assays1. Hepcidin Internalization Assay (J774)This cellular assay allows quantification of the binding of hepcidin to ferroportin (Fpn) through microscopic detection of internalization of a fluorescently labeled hepcidin into J774 cells. J774 is a mouse macrophage cell line which was shown to express Fpn endogenously upon incubation with iron (Knutson et al, 2005). Binding of hepcidin to Fpn triggers internalization and degradation of both hepcidin and Fpn.However, the TMR (6-carboxytetramethylrhodamine) fluorophore attached to hepcidin remains associated with the cell after degradation of the hepcidin peptide backbone. Therefore, microscopic detection of ceH associated TMR fluorescence is a measure of hepcidin binding to Fpn and internalization of hepcidin and Fpn. If TMR-hepcidin is prevented from binding to Fpn, cellular TMR fluorescence remains low(Durrenberger et al, 2013). The effect of small molecular weight Fpn inhibitor compounds in this assay was evaluated in vitro as described below.J774 cells, harvested from ca. 80% confluent cultures, were plated at 8x10s cells / ml in complete medium (DMEM, 10% FBS, 1 % Penicillin-Streptomycin) containing 200 μΜ Fe(l ll)NTA (ritrilotriacetic acid), 100 μΙ per well of 96 well MicroClear plates (Greiner; Cat. 655090) and grown at 37°C with 5% CQ. After overnight incubation, cells were washed 3 times with pre-warmed DMEM w / o phenol red , 30 μΙ / well ofDMEM w / o phenol red was added after the final wash and 10 μΙ / well of dilution series of test compounds were added in triplicates. J774 cells were pre-incubated with test compounds at 37°C with 5% C for 15 min. before TMR-hepcidin was added at 25 nM final concentration. Cells were intubated in a total volume of 50 μΙ at 37°C with 5% CC¾ for 2 hours, then Hoechst 33342 dye was added to a final concentration of 0.5 μg / ml to stain nuclei and further incubated for 10 min. at 37°C with 5% CQ. Cells were washed 3 times with PBS and fixed in 100 μΙ of 4% paraformaldehyde in PBS for 15 min. at room temperature. After removal of the paraformaldehyde solution, cells were washed 3 times with PBS leaving 100μΙ per well and the plates were sealed with foil plate seal. 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 acquired using a ScanR plate imager (Olympus) with a 20x high NA objective. Four pictures were acquired per well and fluorescence channel covering ca. 1500 cells per well. The acquired image data was analysed with the ScanR image analysis software. Image analysis included detection of nuclei (Hoechst 33342 fluorescence), identification of cell-associated regions, application of a virtual channel and thresholding for rolling-ball-type background reduction, followed by application of the Sum(Mean) algorithm to measure the TMR fluorescence associated with cells as a quantitative measure for internalized TMR- hepcidin. IC50 values were calculated with the Sum(Mean) raw data using"log(inhibitor) vs. response" curve fitting of Prism 5 software (GraphPad Software Inc., version 5.02). For each data set 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 of the preferred model was used . IC50 data of the Fpn inhibitors that were tested in the hepcidin internalization assay are listed in Table! The IC50 of unlabeled hepcidin in this assay is 0.015 ± 0.01 1 μΜ.Table 1 Average (AVE) IC50 data of Fpn inhibitors tested in the hepcidin internalization assay is shown for multiple measurements Table 1Table 1 - continuedTable 1 - continued2. Biophysical Ferroportin-Hepcidin Binding AssayThis biophysical assay was developed to confirm inhibition of hepcidin binding to ferroportin (Fpn) more directly. Incubation of TMR-hepcidin with purified human Fpn isolated from Pichia pastoris yeast cells expressing human Fpn with a C-terminal FLAG affinity tag (Bonaccorsi di Patti, 2014) leads to increased fluorescence polarization (FP) of the TMR-hepcidin ligand. Small molecular weight Fpn inhibitors were tested for inhibition of binding of TMR-hepcidin to Fpn, as detected by dose-dependent decrease of the TMR FP signal, as described in detail below.A mixture of 1 .3 μΜ human Fpn and 30 nM TMR-hepcidin in FP assay buffer containing 50 mM Tris-HCI pH 7.3, 200 mM NaCI, 0.02% DDM, 0.1 % BSA was plated into a 384 well black low volume round bottom plate (Corning , Cat. 3677) at 16 μΙ per well. 8 μΙ of serial dilutions of test compounds were added in duplicates to reach final Fpn and TMR-hepcidin concentrations of 1 μΜ and 20 nM, respectively. Plates were incubated for 90 minutes at room temperature and parallel (S) and perpendicular (P) fluorescence was measured in a Synergy H 1 fluorescence reader (BioTek). FP values were calculated in mP according to the following formula.Fparallel - FperpendicuiarmP = X 1000Fparallel + FperpendicuiarIC50 values were determined with the calculated mP values as described for the hepcidin internalization assay and are listed in Table 2. The ICso of unlabeled hepcidin in this assay is 0.37 ± 0.067 μΜ.Table 2 Average (AVE) IC50 data of Fpn inhibitors tested in the biophysical hepcidin-ferroportin binding assay is shown for multiple measurements. Table 2Table 2 - continued3. Inhibition of Ferroportin mediated Iron Export Activity in an Iron Response AssayIntracellular iron levels are indirectly measured in this assay by monitoring the activity of a beta-lactamase (BLA) reporter gene fused to the human ferritin promoter and the associated iron regulatory element (IRE) contained within the 5' untranslated region of the ferritin mRNA. Expression of ferroportin (Fpn) in such a cell line leads to iron efflux and lower iron levels as reflected by lower activity of the reporter gene. On the other hand, inhibition of Fpn-mediated iron efflux results in elevated cellular iron levels which is detected as increased reporter gene activity. Small molecular weight Fpn inhibitor compounds were tested for dose- dependent effects in this in vitro iron response assay as described below.The HEK-293 cell line #354 was generated by stable integration of (i) a human Fpn-GFP fusion construct inserted in a derivative of the doxycycline-inducible pTRE-Tight-BI plasmid (Clontech, Cat. 631068) and (ii) a human ferritin promoter-BLA reporter gene into a derivative of the HEK-293 Tet-ON Advanced cell line (Clontech). To generate the ferritin-BLA reporter gene construct, a 1.4 kb fragment of the human ferritin H promoter was amplified by PCR from human genomic DNA (forward primer 5'-CAGGTTTGTGAGCATCCTGAA-3'; reverse primer 5'-GGCGGCGACTAAGGAGAGG-3') and inserted in front of the BLA gene present in the pcDNA™6.-½GeneBLAzer™-DEST plasmid (Invitrogen, Cat. 12578- 043) thereby replacing the original CMV promoter and placing the IRE that regulates translation of the ferritin gene ca. 170 bp upstream of the start codon of the reporter gene. #354 cells were havested from ca. 80% confluent cultures, seeded at 1.8x10s cells / ml in DMEM / F12 GlutaMAX™ medium (Invitrogen, Cat. 31331-028) containing 10% FBS (Clontech, Cat. 631 106), 1 % Penicillin-Streptomycin, 200 ig / m\ Hygromycin B (Invitrogen, Cat. 10687-010), Blasticidin 5 μg / ml, (Invitrogen, Cat. R210-01 ), 4 μg / ml doxycycline (Clontech, Cat. 63131 1 ), 50 μΙ per well of 384 well PDL-coated plates and grown at 37°C with 5% C02. After overnight incubation, 10 μΙ / well of dilution series of the test compounds were addedin quadruplicates and plates were further incubated overnight at 37°C with 5% CQ. Cells were washed 3 times with HBSS leaving 25 μΙ per well. BLA activity was detected by adding 5 μΙ / well of the GeneBlazer reagent CCF4-AM (Invitrogen, Cat. K1085) to the cells. After incubation of the plates in the dark at 18°C for 60 min., blue and green fluorescence signals were measured in a Safre2 fluorescence plate reader (Tecan) with excitation at 410 nm and emissions at 458 nm (blue) and 522 nm (green). The ratio of blue / green fluorescence as a measure for BLA activity was calculated and EQ0 values were determined with the calculated blue / green fluorescence ratios as described for the hepcidin internalization assay. The EC50 data of the tested Fpn inhibitors is listed in Table 3. The EQo Of hepcidin in this assay is 0.096 ± 0.063 μΜ (n=37).Table 3 Average (AVE) EC50 data of Fpn inhibitors tested in the iron response assay is shown for multiple measurements. Table 3Exp. BLAzer Exp. BLAzer Exp. BLAzer Exp. BLAzer Comp. EC50 Comp. EC50 Comp. EC50 Comp. EC50 No. (uM) No. (uM) No. (uM) No. (uM)2 1.64 97 1.81 160 1.91 229 4.0612 8.27 99 22.80 161 17.18 230 6.3813 27.02 100 6.56 162 4.37 232 12.0515 2.22 101 2.92 164 2.1 1 236 12.7224 12.84 102 1.85 165 2.59 237 2.4629 2.53 105 2.63 167 2.84 239 0.8832 1.87 107 20.98 169 8.23 243 1.4037 7.92 108 4.12 170 3.96 244 3.8638 2.98 109 2.62 171 1.23 245 6.1439 2.90 1 1 1 0.62 173 0.10 246 12.9140 1.45 1 12 13.47 174 7.73 247 3.1542 36.26 1 14 4.45 179 25.94 248 6.3443 30.95 1 16 2.79 181 3.72 249 1.5544 18.31 1 18 2.69 182 6.84 250 0.4646 38.67 120 1.60 183 3.58 251 2.2751 4.47 122 4.33 184 1.60 253 3.17652 2.08 123 3.04 186 4.94 256 0.628>39.0755 1.23 126 1.26 188 257 0.636< 5056 10.38 127 0.42 189 3.10 258 2.52557 2.1 1 128 0.097 190 27.30 265 1.99858 1.72 129 10.56 191 8.38 273 3.60459 1.38 131 0.75 193 3.64 274 1.122>3.2261 37.46 132 13.94 194 277 0.17< 50>20.064 4.53 133 195 3.55< 5065 32.33 134 4.09 196 12.72>20.0067 33.46 135 197 18.10< 50>20.0068 10.40 136 199 5.70<5071 1.79 137 5.75 200 45.1475 6.00 138 1.72 201 39.40>20.0079 0.84 139 205 3.83< 50>20.0082 0.76 140 206 3.26< 5084 13.15 141 1.1 1 207 2.7685 18.69 144 0.47 208 0.5086 22.34 145 4.7 209 3.3887 16.56 151 0.72 21 1 6.188 13.08 152 0.17 220 17.089 5.05 154 0.74 221 16.990 4.03 155 8.17 224 8.292 17.78 156 16.13 226 2.3493 20.55 158 0.62 227 24.9094 0.53 159 1.16 228 2.12 4. Ferroportin Internalization and Degradation AssayHEK-293 cell line #354 (described in example 3) was used to measure the capacity of the compounds to induce internalization and degradation of ferroportin (Fpn) by fluorescence activated cell sorting (FACS). Growing HEK-293 #354 cells in doxycycline containing media induced expression of human Fpn-GFP fusion protein on the cell surface. Data from 10 independent experiments showed that cultivation of HEK#354 cells for 48h in the presence of 4 μg / ml doxycycline induced in average 42.6% ± 6.4 % Fpn GFP-positive cells. Small molecular weight Fpn inhibitor compounds were tested for dosedependent effects on the Fpn-GFP mean fluorescence intensity (MFI) on HEK-293 cell line #354, as described below. HEK#354 cells were harvested from ca. 80% confluent cultures, seeded at 0.6x1 $ cells / ml in DMEM / F12 GlutaMAX™ medium (Invitrogen, Cat. 31331 -028) containing 10% FBS (Clontech, Cat. 631 106), 1 % Penicillin-Streptomycin (Invitrogen, Cat. 15140-122), 200 μg / ml Hygromycin B (Invitrogen, Cat.10687-010), Blasticidin 5 pg / ml, (Invitrogen, Cat. R210-01 ), 4 g / ml doxycycline (Clontech, Cat. 63131 1 ), 50 μΙ per well of 384 well plates (Greiner; Cat. 781091 ) and grown at 37°C with 5% CQ. After overnight incubation, 10 μΙ / well of dilution series of the test compounds were added in quadruplicates and plates were further incubated overnight at 37°C with 5% C02. Cells were washed once with FACS buffer (PBS containing 1 % FBS, 2 mM EDTA and 0.05% Na ^), harvested in FACS buffer with 0.5 μg / ml propidium iodide (Sigma, Cat. P4864) and analyzed in a flow cytometer (CANT0m I I, BD Biosciences) equipped with high throughput sampler. Live HEK#354 cells were gated as propidium iodide negative population and analyzed for expression of Fpn-GFP. MFI of Fpn-GFP of > 2000 live cells for each compound dilution was calculated using FlowJo (Tree Star's, Oregon) and the potencyof the Fpn-inhibitors to induceinternalization and degradation of Fpn-GFP was calculated as described for the hepcidin internalization assay. EC50 data of the Fpn inhibitors that were tested in the ferroportin internalization and degradation assay by FACS are listed in Table 4. The average Ε(¾0 value of hepcidin in this assay is 0.004 ± 0.002 μΜ.Table 4 Average (AVE) EC50 data of Fpn inhibitors tested in the ferroportin internalization and degradation assay is shown for multiple measurements.Table 4Table 4 - continued5. Ferroportin ubiquitination and degradationExposure of cells expressing ferroportin (Fpn) to hepcidin is known to trigger ubiquitination and subsequent internalization and degradation of Fpn (Qiao, 2012). The potential of Fpn inhibitors to induce Fpn ubiquitination and degradation was investigated with an immunoprecipitation assay using the J774 mouse macrophage cell line which expresses Fpn upon treatment with iron.J774 cells (DSMZ, Cat. ACC 170) were seeded at 0.8x106 cells / ml in 15 ml of medium (DMEM Gibco Cat. 1 1971-025, 10% heat inactivated FBS Gibco Cat. 10500-064, 1 % Penicillin-Streptomycin Gibco Cat. 15140-122) containing 200μΜ Fe(ll l)-NTA into 10 cm tissue culture dishes (Greiner Cat. 664160) and grown overnight at 37°C with 5% C<¾. Cells were incubated with synthetic human hepcidin (Bachem, Cat. H-5926) or Fpn inhibitor compounds for 10 min or 120 min. Cells were washed and lysed win ice-cold lysis buffer (Pierce, Life Technoligies, Cat. 87787) including 1 X HALT protease inhibitor cocktail (Life technologies, Cat. 78429) and 10 mM iodoacetamide (Sigma, Cat. 16125) to stabilize ubiquitinated proteins. Immunoprecipitation was done using the Pierce Classic IP Kit (Life Technologies, Cat. 26146) following the manufacturer's protocol. Briefly, 2 mg protein in 1 .25 ml IP lysis buffer was incubated by mixing for 1 h at 4°C with control agarose beads to pre-clear the lysate and reduce nonspecific signal. Unbound lysate was then incubated overnight with 12 μg per reaction of the affinity purified anti-Fpn antibody F308 that was raised against a GST fusion protein of mouse Fpn amino acids 224308. Immune complexes were captured by pipetting 14μΙ settled Pierce Protein A / G Plus Agarose beads (LifeTechnologies, Cat. 20423) per reaction and the slurry was incubated for 1.5 h at 4°C with gentle endover- end mixing. The beads were washed and immune complexes were eluted directly with 75 μΙ SDS NuPAGE LDS sample buffer (Life Technologies, Cat. NP0007) containing DTT (Life Technologies, Cat. NP0009). After immunoprecipitation samples were analyzed by Western blotting using a rabbit ant+mouse MTP1 antiserum (Alpha Diagnostic International, Cat. MTP1 1-A) and a mouse anti-mono- andpolyubiquitinylated conjugates monoclonal antibody (Enzo Lifesciences, Cat. BML-PW8810) for detection of ferroportin and ubiquitin, respectively. Mouse monoclonal antkabbit IgG light chain (Abeam, Cat.ab99697) and anti-mouse IgG H&L (Abeam, Cat. ab6789) HRP conjugates were used as secondary antibodies.A selection of eleven Fpn inhibitors were tested in this assay and compared to hepcidin. As shown in Fig. 1 and Table 5, treatment of cells with Fpn inhibitors lead to rapid ubiquitination within 10 minutes (Fig. 1 upper panel) and degradation after 2 hours of Fpn (Fig. 1 lower panel). The degree of Fpn degradation by the Fpn inhibitors was comparable to the effect of hepcidin. However, hepcidin treatment resulted in ubiquitinated Fpn with higher molecular weight compared to Fpn inhibitor treatment, suggesting poly ubiquitination versus mono-ubiquitination by hepcidin versus Fpn inhibitors, respectively. Table 5 Summary of Fpn inhibitors tested in the Fpn ubiquitination and degradation assay. The effects of treatment with Fpn inhibitors on Fpn degradation and Fpn ubiquitination were scored by visual inspection of Western blots (+ comparable to hepcidin; - no effect; + / - intermediate effect).Table 5Figure 1 Fpn inhibitor trigger ubiquitination and degradation of Fpn expressed in a mouse macrophage cell line. J774 cells were incubated overnight with Fe(lll)-NTA to induce expression of Fpn. Cells were then treated with ca. 10-fold IC50 concentrations, as determined in the hepcidin irternalization assay (see Table 1 ), of hepcidin (Hepcidin, 150 nM) or Fpn inhibitors Example Compound No. 208 (210 nM), Example Compound No. 167 (1 .5 μΜ), Example Compound No. 127 (120 nM), Example Compound No. 152 (40 nM) for 10 or 120 min before harvesting and immunoprecipitation with the anti-Fpn antibody F308. Mock treated cells were harvested after 120 min (Control).Immunoblotting of immunoprecipitates with the anti-Fpn antibody MTP1 revealed disappearance of ferroportin 120 min after treatment with the Fpn inhibitors, to a similar extent as in the sample treated with hepcidin (upper panel). Rapid ubiquitination of Fpn was observed 10 min after treatment of cells with Fpn inhibitors and hepcidin. Protein molecular weight standards are indicated on tie left in kD. 6. Inhibition of Iron Efflux by Ferroportin InhibitorsThe activity of hepcidin and ferroportin inhibitor compounds regarding their ability to block iron export via ferroportin was tested on T47D cells (ECACC, Cat. 85102201 ) as described belowCells were plated in 24-well plates (Greiner, Cat. 662160) containing 350Ό00 cells / well and incubated overnight with 100 μΜ 58Fe (58Fe(ll)-Sulfate, Vifor Pharma Batch No. ROR 3085) in 500 μΜ L-Ascorbic Acid (Sigma Aldrich, Cat. 795437) containing growth medium . Cells were washed once with 500 μΙ iron uptake buffer (IUB; PIPES 40mM, Cat. P1851 , Glucose Monohydrate 10 mM, Cat. 49158, Sodium Chloride 260 mM, Cat. 71379, Potassium Chloride 20 mM, Cat. P9541 , Magnesium Sulfate 2 mM, Cat. 63138, Sigma Aldrich), then once with removal buffer (2 min incubation, BPDS 100 μΜ, Cat. 1 1890 and Na2S204 500 μΜ, Cat. 157953, Sigma Aldrich, in IUB) and again twice with IUB. A serial dilution of hepdicin (Bachem) or ferroportin inhibitors (4 μΜ-0.0064 μΜ, 5 fold dilution) was added in a total volume of 0.6 ml per well. Cells were incubated at 37°C with 5% C02 for 20 h. Supernatants were collected and 58Fe was measured using inductively coupled plasma mass spectrometry (ICP-MS, Thermo Scientific, Element 2). Pellets were harvested for protein concentration measurements. Results are plotted as ng58Fe in supernatant per mg protein in cell lysates. Example Compound No. 127 inhibited iron efflux with similar potency as the endogenous Fpn ligand hepcidin (Fig. 2).Figure 2 Representative iron efflux inhibition of Hepcidin (Κ¾0: 0.086 μΜ) and Example Compound No. 127 (IC50: 0.080 μΜ). 7. Hypoferremia in naive miceInjection of synthetic hepcidin in wild-type (WT) naive mice resulted in a reduction of serum iron levels (40- 50% from the vehicle control) with a maximal effect at 3-4 hours post treatment (Rivera, 2005; Fig. 3A). This data suggested that the injected hepcidin binds to and triggers the internalization of ferroportin (Fpn) on duodenal enterocytes and splenocytes, causing a rapid drop in serum iron. Similarly, orallyadministered small molecular weight Fpn inhibitors decreased the levels of serum iron of WT C57BL / 6 mice in a dose-dependent manner (Fig . 3B) with an efficacy comparable to hepcidin. This data validated the use of WT mice as a simple and reliable model for testing theacute efficacy of Fpn inhibitors in vivo. Female C57BL / 6 mice (Janvier, France) at age of 9 weeks were fed a standard diet (Harlan Provimi Kliba 3436) and treated per os (p.o.) with compounds or the corresponding amount of vehicle at a volume of 10 ml / kg body weight. Fpn inhibitors were formulated in 0.5% methylcellulose / water or 20% cremophor EL / water and dosed p.o. in mice at 10, 30 or 100 mg / kg body weight. Three hours later, mice were pre terminally anesthetized in isoflurane chambers and blood was collected by retro-orbital bleeding. Mice were sacrificed by cervical dislocation and spleens, livers and duodena were harvested and used for biomarker analysis. All experiments have been conducted in compliance with the license approved by the responsible veterinarian authorities. Serum was isolated by centrifugation of blood into gelcontaining microtainers and serum iron was determined by the MULTIGENT Iron assay (Abbott Diagnostics, 6K95). Eight mice per group were used and one-way ANOVA with Bonferroni's multiple comparison test was performed to analyze the statistical differences between the experimental groups. The efficacy of selected Fpn inhibitors in WT C57BL / 6 mice is shown in Table 6.Figure 3 Serum iron reduction induced by hepcidin and ferroportin inhibitor according to Example Compound 94 (Example Compound No. 94).A Kinetic of serum iron in naive C57BL / 6 mice injected with synthetic hepcidin (5 mg / kg) intraperitoneally (i.p.) for the indicated time. * - ***- indicate statistically significant serum iron reduction compared to PBS- treated mice.B Serum iron levels in naive C57BL / 6 mice treated with the indicated amounts of either hepcidin (i.p.) or Example Compound 94 (Example Compound No. 94). (p.o.) for 3h.Table 6 Efficacy of Fpn inhibitors tested in the naive mouse hypoferremia model.Serum iron reduction induced by selected ferroportin inhibitors dosed p.o. in naive WT C57BL / 6 mice at 10, 30 and 100 mg / kg. Relative serum iron reduction at 3h after dosing was calculated by subtractingthe average of serum iron values of animals dosed with the Fpn inhibitor from that of vehicletreated animals. The difference in average serum iron values between vehicle and compound treated groups was then divided by the average of serum iron of the vehble control group and listed as percentage.Table 68. Prevention of iron absorption in anemic ratsTo assess the in vivo efficacy of ferroportin (Fpn) inhibitors to block iron absorption, a series of Fpn inhibitors were tested in an anemic rat model for iron absorption. Wistar rats (3-4 weeks old, n=5, Janvier Labs) were fed a low iron diet (Provimi-Kliba, Cat. 2039) until their hemoglobin (Hb) values reached 7 - 8 g / dl one day before dosing of the Fpn inhibitor compounds. One hour before oral application of 0.5 mg / kg of ferrous sulfate, test compounds formulated in methyl cellulose or Cremophor were dosed orally. Blood samples were taken by tail vein puncture one hour before administration of iron fl h), immediately after dosing of the Fpn inhibitors (Oh) and one hour (1 h), three hours (3h) and occasionally up to 6 hours (6h) after dosing of the test compounds. Serum iron levels were measured (Abbott Diagnostics, Cat. 6K95) and inhibition of the rise of serum iron three hours after dosing of the test compound was calculated as a measure for efficacy of the Fpn inhibitors in blocking iron absorption (Table 7). As shownin Fig. 4, oral administration of the Fpn inhibitor Example Compound No. 55 at 3 mg / kg, 10 mg / kg or 30 mg / kg reduced serum iron levels by 54%, 72% and 89%, respectively, three hours after iron dosing when compared to serum iron levels of vehicle-control animals before iron dosing and corrected for the baseline serum iron levels in vehicle-treated animals that did not receive a dose of iron.Table 7 Fpn inhibitors tested in the anemic rat model for inhibition of iron absorption. Relative inhibition values (%) of serum iron levels are shown, corrected for average baseline serum iron levels of the control group which did not receive a dose of oral iron, compared to control groups treated with vehicle before iron dosing. Average values of groups (n=5) treated with the indicated doses of Fpn inhibitor are shown.Statistically significant (2-way ANOVA with Bonferroni post test) differences observed between compound- treated and vehicle-treated groups are indicated (*** p<0.001 ; ** p<0.01 , * p<0.05).Figure 4 Dose-dependent block of iron absorption in anemic rats by Fpn inhibitorExample Compound No. 55. One hour before oral administration of a dose of ferrous sulfate (0.5 mg / kg), Example Compound No. 55 was orally administered either at 3 mg / kg (light blue line), 10 mg / kg (green line) or 30 mg / kg (dark blue line). Dosing of Example Compound No. 55 led to statistically significant (p<0.001 ) and dose-dependent inhibition of the increase in serum iron observed 3 hours after iron dosing in animals treated with vehicle (red line). Baseline serum iron levels in the vehicle-treated group that did not receive a dose of iron are also shown (black line). Averages with standard deviations are plotted for each treatment group and time point.Table 79. Correction of hyperferremia in beta2-microglobulin deficient miceMutations in genes involved in sensing the systemic iron stores, such as hepcidin (Hampl ),hemochromatosis protein (HFE), hemojuvelin (HJV) and transferrin receptor 2 (TFR2) cause iron overload in mice and men. HFE, HJV and TFR2 molecules on hepatocytes are necessary for signaling of appropriate hepcidin production and their deficiency results in pathophysiologically low hepcidin levels and excessive iron absorption. HFE mutations is the most frequent cause of hereditary hemochromatosis (HH) in Caucasian adults. HFE is a MHC class Hike membrane molecule that associates with bela 2- microglobulin and participates in hepcidin transcriptional regulation through the bone morphogenetic protein receptor (BMPR) pathway. HFE- / - mice have decreased hepcidin levels, develop hyperferremia and high hepatic iron levels, which makes them a sutable animal model for studying iron overload in humans (Zhou, 1998). Mice deficient in beta 2-microglobulin (b2m- / -) develop hyperferremia and hemochromatosis similarly to HFE- / - animals, as beta 2-microglobulin is necessary for the cell-surface expression and function of HFE (Rothenberg and Voland, 1996). Due to the unavailability of HFE- / - mice, b2m- / - mice were used as a model of iron overload. A pilot study confirmed that HFE- / - and b2m- / - mice have similar iron metabolism-related parameters.Female and male homozygous b2m- / - mice were supplied from Jackson Laboratories (B6.129P2- B2mtm 1 Unc / J, Stock Number: 002087) at age of 6 to 7 weeks and fed standard diet (Harlan Provimi Kliba 3436) ad libitum. Age and gender matched WT C57BL / 6 mice were supplied byCharles River. To study the acute effects of ferroportin (Fpn) inhibitors in iron overload b2rr> / - mice were treated with compounds or the corresponding amount of vehicle at a volume of 10 ml / kg body weight. Fpn inhibitor compounds were formulated in 0.5% methylcellulose / water or 20% cremophor EL / water and dosed p.o. in mice at 50 mg / kg body weight. WT controls received only vehicle. Three hours later, mice were preterminally anesthetized in isoflurane chambers and blood was collected by retro-orbital bleeding. Mice were sacrificed by cervical dislocation and spleens, livers and duodena were harvested and used for biomarker analysis. All experiments have been performed in compliance with license approved by the responsible veterinarian authorities. Serum was isolated by centrifugation of blood into gel-containing microtainers (BD Biosciences) and serum iron was determined by the MULTIGENT Iron assay (Abbott Diagnostics, Cat. 6K95). Four to nine mice per group were used and one-way ANOVA with Bonferroni's multiple comparison test was applied to analyze the statistical differences between the experimental groups.To investigate the effects of Fpn inhibitors Example Compound No. 40 and Example Compound No. 94 in conditions of iron overload b2m- / - mice or WT controls were dosed with Fpn inhibitors or vehicle for 3h. Due to their genetic deficiency, b2m- / - mice treated with vehicle showed significantly higher serum iron levels compared to WT mice (Fig. 5, group average of 60 μΜ in A and 56 μΜ in B). Treatment of b2m- / - mice with Example Compound No. 40 or Example Compound No. 94at 50 mg / kg for 3h corrected the elevated serum iron to the levels observed in WT controls (Fig. 4). These data demonstrated the acute efficacy of small molecular weight ferroportin inhibitors in a disease relevant model. Serum iron correction was observed in further studies as summarized in Table 8.Fig. 5 Complete correction of the elevated serum iron levels in b2m- / - mice by treatment with the ferroportin inhibitors Example Compound No. 40 / methylcellulose (A.) and Example Compound No. 94 / cremophor EL (B.) for 3h.Table 8 Fpn inhibitors tested in the beta2-microglobulin deficient mouse model for lowering elevated serum iron levelsBlood was collected 1 (#) or 3 (##) hours after oral administration of the indicated doses of Fpn inhibitors to beta2-microglobulin deficient mice and serum iron concentrations were measured. Relative reduction (%) of serum iron levels are shown, which were calculated by subtracting the average of serum iron values of animals dosed with the Fpn inhibitor from that of vehicle-treated animals. The difference in average serum iron values between vehicle and compound treated groups was then divided by the average of serumiron of the vehicle control group and listed as percentage. Values are listed separately for female (?) and male (c?) animals, because a marked sex-dependent difference in efficacy was noted. Statistically significant (2- way ANOVA with Bonferroni post test) differences observed between compound-treated and vehicle- treated groups are indicated (*** p<0.001 ; ** p<0.01 , * p<0.05).Table 810. Prevention of iron overload in beta2-microglobulin deficient miceAs a result of decreased hepcidin levels and increased iron absorption in the gut beta2-microglobulin deficient (b2m- / -) mice on a standard diet accumulate excessive amounts of iron in liver, heart and pancreas. A pilot study showed that liver iron loading in b2m- / - starts at age of 3-4 weeks and that liver iron levels reached up to 4 fold the liver iron content of wild-type (WT) mice at age of 6 weeks. In addition, feeding 3 week old b2m- / - mice a diet with low iron content (LID) immediately after weaning prevented liver iron loading by age of 6-7 weeks. The efficacy of the Fpn inhibitors to prevent I er iron accumulation in b2m- / - mice was investigated . Three weeks old b2- / - mice fed LID were dosed with either Fpn inhibitor or vehicle (methylcellulose; 10 ml / kg). Mice had access to drinking water supplemented with 1 mM58Fe(ll)- sulfate and 10 mM ascorbic acid. Dosing of Fpn inhibitor or vehicle followed by exposure to iron-containing water was repeated for 14 days. Mice were euthanized and the liver and spleen iron contents were analyzed by ICP-OES (all iron isotopes) and liver tissue was also analyzedfor 58Fe concentration (ICP- MS). The data summarized in Table 9 illustrates that oral dosing of Fpn inhibitors for two weeks prevented liver iron loading in b2m- / - mice and increased spleen iron concentrations, indicating inhibition of ferroportin both in the intestine and in the spleen.These data demonstrated the efficacy of a small molecular weight ferroportin inhibitor to prevent liver iron loading in b2- / - mice, which provides a proof of concept in a disease-relevant model. Table 9 Fpn inhibitors tested in the beta2-microglobulin deficient mouse model for inhibition of liver iron overload.Livers and spleens were collected after 14 day treatment (p.o. ; b.i.d) of beta2-microglobulin deficient mice with the indicated doses of Fpn inhibitors. Total liverand spleen tissue iron concentrations were measured using ICP-OES and 58Fe liver concentrations were determined with ICP-MS. Relative changes (%) of tissue iron levels are shown, which were calculated by normalizing the difference between the averages of tissue iron values of animals dosed with the Fpn inhibitors and those of vehicletreated animals with the average of vehicle controls. Values are listed separately for female ($) and male (c?) animals, because a marked sex-dependent difference in efficacy was noted. Statistically significant (2-way ANOVA with Bonferroni post test) differences observed between compound-treated and vehicle-treated groups are indicated (*** p<0.001 ; ** p<0.01 , * p<0.05). nd, not determined; na, not available.Table 911. Improvement of anemia, ineffective erythropoiesis and iron overload in a mouse model of B- thalassemia intermediaβ-thalassemia is inherited anemia caused by mutations in the β -globin gene of hemoglobin resulting in abnormal red blood cells with decreased life span. The most severe form, thalassemia major, requires blood transfusions which result in secondary iron overload. Patients with thalassemia intermedia have a moderate transfusion-independent anemia but still develop iron overload due to inefficient erythropoiesis and chronic repression of hepcidin production.As shown in the previous examples, oral ferroportin (Fpn) inhibitors similarly to hepcidin blocked ferroportin mediated export of iron from cells in vitro and upon dosing in wild- type mice transiently reduced serum iron. Based on these findings and published studies (Schmidt PJ, et al , Blood 2013, Guo S, et al, JCI, 2013 and Casu C. et al, Blood, 2016) Fpn inhibitors were examined with respect to its capacity to prevent iron loading and improve erythropoiesis in thalassemia intermedia by restricting iron absorption and reutilization from senescent erythrocytes. The efficacy of Fpn inhibitors was investigated using a mouse model of transfusion-independent β -thalassemia. Mice with heterozygous deletion of β 1 and β 2 globin genes (called Hbb th3 / + mice) develop transfusion-independent anemia, ineffective erythropoiesis, splenomegaly and secondary iron overload in spleen, liver and kidneys. Heterozygous Hbb th3 / + mice were supplied from Jackson Laboratories (B6;129P-Hbb-b1tm1 Unc Hbb-b2tm1 Unc / J, Stock Number: 002683) at age of 8-18 weeks and during experiments fed a low iron diet (Harlan Provimi Kliba 2039, 13.4 ppm Fe) ad libitum. Hbb th3 / + mice were dosed twice daily with either compound at 20 or 60 mg / kg or with methylcellulose (10 ml / kg, Sigma, Cat. 274429) as a vehicle. Between both doses mice had access to drinking water supplemented with 1 mM 58Fe(ll)-sulfate (Vifor Pharma, Batch No. ROR 3096) and 10 mM ascorbic acid (Sigma, Cat. 795437) for 6h. The concentration of58Fe(ll)-Sulfate supplied in the drinking water has been adjusted to substitute for intake of standard rodent diet with iron content of 250 ppm. Water without 58Fe(ll)-Sulfate and ascorbic acid was provided during the remaining 18h. Dosing of Fpn inhibitors or vehicle followed by exposure to iron-containing water was repeated for 20 to 46 days in individual experiments.As previously shown in wild-type and b2m- / - mice, Fpn inhibitors dosed for 3h in Hbb th3 / + mice reduced efficiently serum iron levels also in this mouse strain (Table 10), demonstrating the ability of these small molecules to cause iron restriction.Hbb th3 / + mice are anemic with hemoglobin levels in the range of 70-80 g / L. Oral administration of Fpn inhibitors in Hbb th3 / + mice for two weeks increased significantly hemoglobin levels compared to vehicle treated mice (Table 10). The change of hemoglobin levels in compound-dosed compared to vehicle-treated group reached 19-22 g / L by the study end. Additional hematologic parameters were measured in terminal blood using automated blood cell analyzer. Treating Hbb th3 / + mice with Fpn inhibitors increased red blood cell counts, hematocrit and decreased reticulocyte concentration and red cell distributionwidth (RDW), indicating improved erythropoiesis. In addition, Hbb th3 / + mice receiving Fpn inhibitors had significantly lower leucocyte counts in blood compared to the vehicle group, further demonstrating the beneficial effect of Fpn inhibitors in correcting pathologically altered parameters in the disease model. Therefore, Fpn inhibitors improved significantly anemia and corrected blood composition in the mouse model of thalassemia intermedia.The inefficient erythropoiesis of Hbb th3 / + mice causes excessive proliferation of erythroid precursors in spleen, leading to splenomegaly. Treatment of Hbb th3 / + mice with Fpn inhibitors resulted in significant reduction in spleen weight, therefore highlighting the potential of Fpn inhibitors to revert splenomegaly (Table 10).The effect of Fpn inhibitors on erythropoiesis was studied by analyzing the percentage of differentiating erythroid precursors in bone marrow and spleen using flow cytometry and Ter1 19 (eBioscience, Cat. 1 5921 ) and CD44 (BioLegend , Cat. 103028) markers. Bone marrow or spleen cells isolated from Hbb th3 / + mice treated with Fpn inhibitors contained significantly reduced percentage of the early erythroid precursors proerythroblasts, basophilic, and polychromatic erythroblast and increased percertage of mature erythrocytes compared to vehicle-treated Hbb th3 / + mice (Table 10). These data demonstrated that Fpn inhibitors ameliorated the inefficient erythropoiesis in Hbb th3 / + mice and are in agreement with the improved hematological parameters in blood.Serum erythropoietin levels in Hbb th3 / + mice and patients with thalassemia are upregulated due to a feedback response to anemia, hypoxia and inefficient erythropoiesis (Guo et al. JCI, 2013). Hbb th3 / + mice treated with Fpn inhibitors produced significantly less serum erythropoietin (DuoSet ELISA R&D Systems, Cat. DY959) compared to the vehicle group, most likely as a consequence of partially corrected anemia and improved erythropoiesis (Table 10).Elevated erythropoietin levels in Hbb th3 / + mice hduced overexpression of erythroferrone, an erythroid regulator hormone known to suppress hepcidin (Kautz L. et al , Nat. Genet. , 2014). In agreement with reduced serum erythropoietin, erythroferrone mRNA expression was significantly reduced in spleens of Fpn inhibitor-treated Hbb th3 / +mice compared to those administered with vehicle alone (Table 10).Erythroferrone is produced by erythrocyte precursors proliferating massively in spleens of Hbb th3 / + mice as a consequence of extramedullar erythropoiesis. Therefore, the effect of Fpn inhibitors on erythroferrone expression in spleen is mediated by the improved erythropoiesis.Increased iron demand due to inefficient erythropoiesis and chronically low hepcidin levels in patients with thalassemia causes organ iron loading and associated morbidities, such as hepatocellular carcinoma and heart failure (Rivella S. Haematologica, 2015). Hbb th3 / + mice absorb excessive amounts of iron as a consequence of inadequately low hepcidin levels relative to the high iron cortent in liver, spleen and kidney and increased ferroportin expression in duodenum (Gardenghi S. , Blood, 2007). Total liver iron and 58Fe content in organs of Hbb th3 / + mice treated with either vehicle or Fpn inhibitors were analyzed by inductively coupled plasma optical emission spectrometry (ICP-OES) and inductively coupled plasma mass spectrometry (ICP-MS), respectively. Fe concentrations in livers and spleens of Hbb th3 / + mice dosed with Fpn inhibitors were significantly lower compared to those of vehble treated mice, indicating that Fpn inhibitors prevent organ iron accumulation (Table 10).As Fpn inhibitors are systemically available, they are able to block iron export in all ferroportin expressing tissues, including duodenum, spleen and liver. Accordingly, Fpn inhibitors are expected to prevent iron absorption from duodenum, however, they could not remove pre-existing iron in liver and spleen. Indeed, total liver iron in mice treated with Fpn inhibitor or vehicle remained unchanged (not shown). Impatantly, Fpn inhibitors reduced significantly 58Fe concentration in spleens and livers of Hbb th3 / + mice, demonstrating the ability of these small molecules to prevent iron loading.Additionally, reactive oxygen species (ROS) were detected in bone marrow cells using a fluorescent indicator, CM-H2DCFDA (Thermo Fisher Scientific, Cat. C6827). Flow cytometric analysis showed that Fpn inhibitors decreased significantly ROS in mature erythroid cells compared to vehicle treated Hbb th3 / + mice (Table 10).These data demonstrated the disease-modifying capacity of orally administered small molecular weight ferroportin inhibitors in improving anemia and ineffective erythropoiesis, as well in reducing splenomegaly and preventing further liver and spleen iron loading in a disease model of β -thalassemia intermedia.Exp. Comp. Exp. Comp.ParameterNo. 40 No. 127Decrease in serum iron by28 / 58% 68 / 81 %20 / 60 mg / kg compoundCorrection of anemia at day6 / 13 g / L 12 / 20 g / L20-48 by 20 / 60 mg / kgIncrease in blooderythrocyte counts by 20 / 2 / 22% 0 / 36%60 mg / kg compoundDecrease in bloodreticulocyte counts by 20 / 19 / 43% 16 / 61 %60 mg / kg compoundIncrease in hematocrit by 200 / 1 % 3 / 20% / 60 mg / kg compoundDecrease in RDW by 20 / NA / NA 19 / 25%60 mg / kg compoundDecrease in leukocytecounts by 20 / 60 mg / kg 0 / 36% 46 / 66%compoundDecreased in ROS in boneNA NA NA 75%marrow erythrocytesDecrease in relative spleen23 / 48% 40 / 61 %weight by 20 / 60 mg / kgDecrease in 58Fe spleeniron content by 20 / 60 19 / 51 % 43 / 68%mg / kg compound Prevention of liver Fe20 / 48% 39 / 59%loading by 20 / 60 mg / kgDecrease in serumerythropoietin by 20 / 60 6 / 37% 32 / 33%mg / kg compoundDecrease in spleen1012 / erythroferrone mRNA by 20 NA NA3031 % / 60 mg / kg compoundTable 10. Efficacy of Ferroportin inhibitors in a mouse model of thalassemia intermedia (Hbb th3 / + mice). The indicated Fpn inhibitors were dosed twice daily for 27 days (Example Compound 127) or 46 days (Example Compound 40). Data are expressed as difference to the vehicle control group for hemoglobin and as % change to the vehicle control group for all other parameter shownPreparation of Example Compounds General Experimental DetailsCommercially available reagents and solvents (HPLC grade) were used without further purification. 1 H NMR spectra were recorded on a Bruker DRX 500 MHz spectrometer, a Bruker DPX 250 MHz spectrometer or a Bruker Avance spectrometer 400 MHz indeuterated solvents. Chemical shifts (δ) are in parts per million.Compounds were purified by flash column chromatography on normal phase silica on Biotage Isolera systems using the appropriate SNAP cartridge and gradient. Alternatively compounds were purified on reverse phase using Biotage Isolera systems with the appropriate C18 SNAP cartridge and reverse-phase eluent or by preparative HPLC (if stated otherwise). Analytical HPLC-MSMethod A (MET / CR / 1673)Method B (MET / CR / 1600)Method C (MET / CR / 1416)Waters Atlantis dC18 (Part No. 186001295)Column2.1 x 100 mm, 3 μιηColumn Temp 40°CA, Water + 0.1 % Formic acidMobile PhaseB, Acetonitrile + 0.1 % Formic acidGradient Time (mins) % organic0.00 55.00 1005.40 1005.42 5Flow rate 0.6 ml / minInjection Vol 3 μΙDetectionSignal UV 215PDA Spectrum Range: 210-420 nm step: 1 nmMSD Signal Scan Pos: 100-1000settingsMethod D - (MET / UPLC / AB101)Phenomenex Kinetix-XB C18 (Part No.OOD-4498-AN)Column2.1 x 100 mm, 1.7 μιηColumn Temp 40°CA, Water + 0.1 % Formic acidMobile PhaseB, Acetonitrile + 0.1 % Formic acidGradient Time (mins) % organic 0.00 55.30 1005.80 1005.82 5Flow rate 0.6 ml / minInjection Vol 1 μΙDetectionSignal UV 215PDA Spectrum Range: 200-400 nm step: 1 nmMSD Signal Scan Pos: 150-850settingsMethod E - (MET / CR / 1278)Waters Atlantis dC18 (Part No. 186001291 )Column2.1 x 50 mm, 3 μιηColumn Temp 40°CA, Water + 0.1 % Formic acidMobile PhaseB, Acetonitrile + 0.1 % Formic acidGradient Time (mins) % organic0.00 52.50 1002.70 1002.71 53.50 5Flow rate 1 ml / minInjection Vol 3 μΙDetectionSignal UV 215PDA Spectrum Range: 210-420 nm step: 1 nmMSD Signal Scan Pos (Shimadzu): 100-1000settings Scan Pos (MS14): 130-850Method F - MET / CR / 0990Phenomenex Gemini-NX C18 (00B-4453-B0)Column2.0 x 50mm, 3umColumn Temp 40°CA, 2 mM Ammonium bicarbonate, buffered to pH 10Mobile PhaseB, AcetonitrileGradient Time (mins) % organic0.00 11.80 1002.10 1002.30 13.50 1Flow rate 1 ml / minInjection Vol 3 μΙ DetectionSignal UV 215PDA Spectrum Range: 210-420 nm step: 1 nmMSD Signal Scan Pos: 150-850settingsMethod G - MET / CR / 2044Thermofisher Hypercarb™ Porous Graphitic CarbonColumn2.1 mm x 50 mm, 3μπηColumn Temp 40°CA, 25 mM Ammonium acetate in HPLC grade water pH~5Mobile PhaseB, 25 mM Ammonium acetate in HPLC grade acetonitrileGradient Time (mins) % organic0.00 24 1005 1006 26.5 2Flow rate 0.5 ml / minInjection Vol 3 μΙDetectionSignal UV 215PDA Spectrum Range: 210-420nm step: 1 nmMSD Signal Scan Pos: 150-850settingsMethod H - METUPLCMS-A-004Acquity UPLC BEH C18Column2.1 mm X 50 mm, 1.7 μΜColumn Temp AmbientA, Water / acetonitrile, 9: 1 + 0.1 % formic acidMobile PhaseB, Acetonitrile / water, 9: 1 + 0.1 % formic acidGradient Time (mins) % organic0.00 51.5 1001.7 1001.8 52.0 5Flow rate 0.7 ml / minInjection Vol 4 μΙDetectionSignal UV 215PDA Spectrum Range: 210-420nmMSD Signal Scan Pos: 150-800settings Method I - METUPLCMS-A-006Acquity UPLC HSS T3Column2.1 mm X 100 mm , 1.8 MmColumn Temp 40°CA, Water / acetonitrile, 9:1 + 0.1 % formic acidMobile PhaseB, Acetonitrile / water, 9: 1 + 0.1 % formic acidGradient Time (mins) % organic0.00 55.30 1005.80 1005.82 56.00 5Flow rate 0.7 ml / minInjection Vol 4 μΙDetectionSignal UV 215PDA Spectrum Range: 210-420 nmMSD Signal Scan Pos: 150-800settingsMethod J - METUPLCMS-A-007Acquity UPLC BEH C18Column2.1 X 100 mm , 1 .7 μιτιColumn Temp 40°CA, 2 mM Ammonium BicarbonateMobile PhaseB, Acetonitrile : 2 mM Ammonium Bicarbonate ( 95 : 5)Gradient Time (mins) % organic0.00 55.30 1005.80 1005.82 56.00 5Flow rate 0.6 ml / minInjection Vol 4 μΙDetectionSignal UV 215PDA Spectrum Range: 210-420 nmMSD Signal Scan Pos: 150-800settingsMethod K - MET / UPLCMS-A / 013Acquity UPLC HSS T3Column2.1 X 100 mm , 1 .8 μιηColumn Temp 40°C A, Water + 0.1 % formic acid, acetonitrile + 0.1 % formic acid (90: 10)Mobile PhaseB, Acetonitrile + 0.1 % formic acid, water + 0.1 % formic acid (90: 10)Gradient Time (mins) % organic0.00 305.30 1005.80 1005.82 306.00 30Flow rate 0.6 ml / minDetectionSignal UV 215PDA Spectrum Range: 210-420nmMSD Signal Scan Pos: 150-800settingsMethod L - MET-THERMOMS-B-015X-bridge C-18Column250 X .6 mm , 5 μιτιColumn Temp NAInjection Vol. 10 μΙA, 2mM Ammonium Bicarbonate ( pH-10) / pH 10 adjustedMobile Phase using liq. NH3B, AcetonitrileGradient Time (mins) % organic0.0 510.0 10010.5 1001 1.0 512.0 5DetectionSignal UV 215MSD Signal Scan Pos: 50-1000settingsMethod M - MET / CR / 14101.20 1001.30 1001.31 5Flow rate 1.2 ml / minInjection Vol 3 μΙPreparative HPLC - neutral pH methodPreparative HPLC - high pH prep method (basic)Column Waters Xbridge C18 (Part no.186003930) 30 x 100mm, 10μιηColumn Temp Room temperatureA, Water+ 0.2%Ammonium hydroxideMobile PhaseB, Acetonitrile + 0.2% Ammonium hydroxideGradient Time (mins) % organic0 52.5 516.05 9518.2 9519.1 520 5Flow rate 40ml / minInjection Vol 1500μΙDetectionSignal UV 215AbbreviationsAcOH Acetic acidAIBN 2,2'-Azobis(2-methylpropionitrile)BH3 BoraneBoc20 Di-ferf-butyl dicarbonateCaC03 Calcium carbonateCBz Benzyloxy carbamateCDI 1 , 1 '-CarbonyldiimidazoleCHC Chloroformd Day(s)DAST N-ethyl-N-(trifluoro-lambda-4-sulfanyl)ethanamineDBU 1 ,8-Diazabicycloundec-7-eneDCC N,N'-dicyclohexylcarbodiimideDCE 1 ,2-DichloroethaneDCM DichloromethaneDIAD Diisopropyl azodicarboxylateDIPEA A / ,A / -diisoproylethylamineDMAP A / ,A / -dimethylpyridin-4-amineDMF A / ,A / -dimethylformamideEt20 Diethyl etherEtOAc Ethyl acetateEtOH Ethanolh Hour(s)HATU 1-[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridiiOxide HexafluorophosphateHCI Hydrochloric acidHPLC High Performance Liquid ChromatographyIPA Isopropyl alcoholK2C03 Potassium carbonateKO'Bu Potassium fert-butoxideKHMDS Potassium 1 , 1 , 1 ,3,3,3-hexamethyldisilazan-2-ide KHS04 Potassium bisulfateUAIH4 Lithium Aluminium HydrideLiCI Lithium chlorideLiOH Lithium hydroxideMeCN AcetonitrileMel Methyl iodideMeOH Methanolmin Minute(s)MW Molecular weightNaBH4 Sodium borohydrideNaHCOs Sodium hydrogen carbonateNaH Sodium Hydride (60% in mineral oil)NaOH Sodium hydroxideNBS / V-bromosuccinimideNCS / V-chlorosuccinimideNH4CI Ammonium chloridePd / C Palladium on carbonPdCI2(dppf) Dichloro[1 , 1 '-bis(diphenylphosphino)ferrocene]palladium(l l)Pd2dba3 Tris(dibenzylideneacetone)dipalladium(0)PP 3 TriphenylphosphinePTSA p-Toluenesulfonic acidTBME ferf-butyl methyl etherTBSCI tert-Butyldimethylsilyl chlorideTEA TriethylamineTFA Trifluoroacetic acidTMOF Trimethyl orthoformateXantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene Example Compound No 1Example compound No. 1 can be prepared as described in WO 201 1 / 029832. IntermediatesScheme A above:Tert-butyl N-[(3-fluoropyridin-2-yl)methyl]carbamate (A1 )A suspension of 3-fluoropyridine-2-carbonitrile (8.0 g, 6.55 mmol), dhtert-butyl dicarbonate (15.7 g, 72.07 mmol), TEA (10.05 ml, 72.07 mmol) in EtOH (300 ml) was purged with N>. Pd / C (10% wt. , 0.7g , 6.55 mmol) was added and the reaction mixture was stirred under an atmosphere of hydrogen for 16 h. The reaction mixture was filtered through celite, rinsed with MeOH (100 ml) and the filtrates were re moved under vacuum to afford the crude product. Purification by flash column chromatography (gradient elution 0-70% EtOAc / heptane) afforded the title compound (1 1 .3 g , 72%) as an off-white solid .1 H-NMR (DMSO-d6, 250 MHz): d[ppm]= 8.41 - 8.31 (m, 1 H), 7.65 (ddd, J = 10.1 , 8.3, 1 .3 Hz, 1 H), 7.38 (dt, J = 8.5, 4.4 Hz, 1 H), 7.18 (s, 1 H), 4.30 (d, J = 5.4 Hz, 2H), 1 .37 (s, 9H)HPLCMS (Method A): [m / z]: 226.9 [M+H]+ (3-Fluoropyridin-2-yl)methanamine dihydrochloride (A2)In a similar fashion to general procedure 2, tert-butyl N-[(3-fluoropyridin-2-yl)methyl]carbamate (A1 ) (1 1 .3 g, 47.45 mmol) and 12M HCI (59.3 ml, 71 1 .72 mmol) in MeOH (150 ml) at 40°C for 2 h, gave the title compound (9.7 g , 100%) as an off-white solid.1 H-NMR (Methanol-d4, 500 MHz): d[ppm]= 8.48 (dt, J = 4.7, 1 .3 Hz, 1 H), 7.69 (ddd, J = 9.7, 8.5, 1 .2Hz, 1 H), 7.50 (dt, J = 8.8, 4.5 Hz, 1 H), 4.37 (s, 2H)HPLCMS (Method A): [m / z]: 126.9 [M+H]+Scheme B above:(4, 6-Dimethylpyridin-3-yl)methanamine hydrochloride (B1 )2HCI4,6-dimethylpyridine-3-carbonitrile (0.15 g , 1 .135 mmol) in MeOH (150 ml) was subjected to the H-Cube with 10% palladium on carbon at a flow rate of 1 ml / min using at 50 bar and room temperature into a solution of 1 M HCI (1 ml). The solvent was evaporated in vacuo to give the title compound (190 mg, 64%) as a white solid. Used without purification.1 H-NMR (DMSO-d6, 500 MHz): d[ppm]= 8.74 - 8.66 (m, 1 H), 8.62 - 8.42 (m, 3H), 7.76 - 7.64 (m, 1 H), 4.23 - 4.13 (m, 2H), 2.66 - 2.63 (m, 3H), 2.58 - 2.54 (m, 3H)HPLCMS (Method E): [m / z]: 136.9 [M+H]+ Scheme C above:2-(Hydroxymethyl)benzonitrile (C1 ) 1 M BH3 in THF (1 .51 ml) was added to an ice-cooled (0°C) solution of 3-formylpyridine-2-carbonitrile (200 mg, 1.51 mmol) in THF (5 ml). The reaction was allowed to warm to room temperature and stirred for 15 h. The reaction was poured onto ice / water (25 ml). The aqueous layer extracted with EtOAc (3 x 20ml). The combined organic layers were dried (Ν¾804), filtered and the solvent evaporated to give a brown oil. Purification by flash column chromatography (eluting with a gradient 20-100% EtOAc / heptane) gave the titled compound (45.5 mg, 22.4%) as a yellow solid.1 H-NMR (CDCI3, 500 MHz): d[ppm]= 8.55 (dd, J = 4.7, 1.4 Hz, 1 H), 8.01 - 7.95 (m, 1 H), 7.49 (dd, J = 8.0,4.7 Hz, 1 H), 4.89 (s, 2H)HPLCMS (Method A): [m / z]: 134.85 [M+H]+ tyldimethylsilyl)oxy]methyl}benzonitrile (C2)1 M TBSCI in DCM (0.369 ml, 0.369 mmol) was added dropwise to a solution of 3-(hydroxymethyl)pyridine- 2-carbonitrile (C1) (45 mg, 0.335 mmol) and imidazole (46 mg, 0.671 mmol) in DMF (2 ml). The reaction was stirred at room temperature for 15 h. The solvent was evaporated and the crude product purified by flash column chromatography (eluting with a gradient of 0-50% EtOAc-heptane) to give the titled compound (44 mg, 52.8%) as a yellow oil.1 H-NMR (CDCb, 500 MHz): d[ppm]= 8.60 - 8.58 (m, 1 H), 8.10 - 7.96 (m, 1 H), 7.53 (dd, J = 8.0, 4.7 Hz, 1 H), 4.94 (s, 2H), 0.95 (s, 9H), 0.15 (s, 6H)HPLCMS (Method A): [m / z]: 249.00 [M+H]+( yldimethylsilyl)oxy]methyl}pyridir>2-yl)methanamine (C3)2M UAIH4 in THF (0.09 ml) was added dropwise to an ice-cooled solution (0°C) of 3-{[(tert- butyldimethylsilyl)oxy]methyl}pyridine-2-carbonitrile (C2) (44 mg, 0.18 mmol) in THF (3 ml). The reaction was allowed to warm to room temperature and stirred for 2 h. Diethyl ether (5 ml) was added followed by H20 (1 ml), then 20% w / w NaOH (1 ml) and water (3 ml). The layers separated. The aqueous layer was extracted with EtOAc (3 x 10 ml). The combined organic layers were dried (N¾S04), filtered and the solvent evaporated. The crude product was purified by flash column chromatography (eluting with a gradient of 0-100% EtOAc / heptane) to give the title compound (10 mg, 22.4%) as a yellow oil.HPLCMS (Method A): [m / z]: 252.95 [M+H]+N-(2-Nitrophenyl)prop-2-enamide (D) To a stirring suspension of 2-nitroaniline (5.0 g, 36.2 mmol) and K2C03 (15.01 g, 108.6 mmol) in acetone (100 ml) at room temperature was added acryloyl chloride (1 1.8 ml, 145 mmol) and the mixture stirred for 16 h. The reaction mixture was filtered and concentrated in vacuo to give the crude product. Purification by flash column chromatography (gradient elution 10-15% EtOAc / heptane) afforded the title compound (6.95 g, 78%) as a yellow solid.1 H-NMR (CDCI3, 250 MHz): d[ppm]= 10.59 (s, 1 H), 8.90 (dd, J = 8.6, 1.3 Hz, 1 H), 8.25 (dd, J = 8.5, 1.6 Hz, 1 H), 7.68 (ddd, J = 8.5, 7.3, 1.4 Hz, 1 H), 7.21 (ddd, J = 8.6, 7.3, 1 .4 Hz, 1 H), 6.54- 6.28 (m, 2H), 5.89 (dd, J = 9.9, 1.3 Hz, 1 H)HPLCMS (Method A): [m / z]: 192.9 [M+H]+2-(Chloromethyl)-5-(trifluoromethyl)-1 H-1,3-benzodiazole (E)12 M HCI (1 ml, 12 mmol) was added to a mixture of 4-(trifluoromethyl)benzene-1 ,2-diamine (1 g, 5.68 mmol) and chloroacetic acid (0.590 g, 6.25 mmol) in water (20 ml) and the mixture was heated at 100°C for 2 h. Further 12 M HCI (4 ml, 48 mmol) was added and the reaction mixture heated at 120°C for 3 h. The mixture was then cooled to room temperature and quenched by addition of 7 M ammonia in MeOH until basic, extracted with EtOAc (3 x 20 ml) and the combined organic layers were washed with brine (20 ml), dried (MgSC¼), filtered and evaporated in vacuo. Flash column chromatography (eluting with a gradient 5- 50% EtOAc / heptane) afforded the crude title compound as a purple solid (0.571 g, 24%, 56% purity) which was used without further purification.HPLCMS (Method E): [m / z]: 234.85 [M+H]+Tert-Butyl 2-(chloromethyl) methyl-1 H-1 ,3-benzodiazole-1-carboxylate (F)To the solution 2-(chloromethyl)-6-methyl-1 H-1 ,3-benzodiazole (1g, 6 mmol) in DMF (20 ml) was added DIPEA (1 .4 g, 1 1 mmol) followed by addition of Boc anhydride (1.8 g, 8 mmol). The reaction was stirred for 18 h. Water was added to the reaction and extracted with ethyl acetate. The organic phase was dried, Na2S04, concentrated in vacuo to the crude product which was purified by flash column chromatography using n-hexane to ethyl acetate / n-hexane (5 : 95) to hexane to give the required product as a yellow oil (0.7 g, 22 %). The required product was obtained as a mixture which wasnot separable and used in the next step.1 H-NMR (CDCI3, 400 MHz): d[ppm]= 7.84 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 8.2 Hz, 1 H), 7.53 (s, 1 H), 7.20 (dd, J = 13.0, 4.6 Hz, 2H), 5.05 (s, 2H), 5.04 (s, 2H), 2.50 (s, 3H), 2.47 (s, 3H), 1 .74 (s, 9H), 1.73 (s, 9H)N-(3-fluoro-2-nitrophenyl)prop-2-enamide (G) To an N2 purged suspension of 3-fluoro-2-nitroaniline (500 mg, 3.20 mmol) and K2C03 (1.33 g, 9.61 mmol) in acetone (10 ml) was added prop-2-enoyl chloride dropwise (1 .0 ml, 12.8 mmol). The reaction mixture was left stirring at room temperature for 16 h. The reaction was filtered, concentrated / n vacuo and purified by flash column chromatography (eluting with a gradient of 0-70% EtOAc / heptane) to afford the title compound (604 mg, 87%) as a yellow solid.1 H-NMR (DMSO-d6, 250 MHz): d[ppm]= 10.58 (s, 1 H), 7.69 (m, 1 H), 7.46- 7.33 (m, 2H), 6.43 (dd, J = 17.0, 9.8 Hz, 1 H), 6.27 (dd, J = 17.0, 2.1 Hz, 1 H), 5.85 (dd, J = 9.8, 2.1 Hz, 1 H)HPLCMS (Method A): [m / z]: 210.95 [M+H]+ itrophenyl)prop-2-enamide (H)Acryloyl chloride (1.03 ml, 12.67 mmol) was slowly added to a suspension of 3-chloro-2-nitroaniline (0.729 g, 4.22 mmol) and K2C03 (2.34 g, 16.9 mmol) in acetone (20 ml). The recation mixture was stirred at room temperature for 4 h, filtered and the residue was rinsed with acetone. The combined filtrates were evaporated in vacuo. Purification by flash column chromatography (eluting with a gradient of 0-60% EtOAc / heptane) afforded the title compound (0.52 g, 47%) as a yellow solid.1 H-NMR (CDCI3, 500 MHz): d[ppm]= 8.36 (dd, J = 8.3, 1 .1 Hz, 1 H), 8.28 (s, 1 H), 7.49 (dd, J = 8.3, 8.3 Hz, 1 H), 7.32 (dd, J = 8.3, 1 .1 Hz, 1 H), 6.47 (dd, J = 16.9, 0.8 Hz, 1 H), 6.25 (dd, J = 16.9, 10.3 Hz, 1 H), 5.90 (dd, J = 10.3, 0.8 Hz, 1 H)HPLCMS (Method M): [m / z]: 227.00 [M+H]+N-(2-methoxy-6-nitrophenyl)prop-2-enamide (I)To an N2 purged stirring suspension of 2-methoxy-6-nitroaniline (0.52 g, 3.09 mmol) and l¾C03 (1.71 g, 12.4 mmol) in acetone (30 ml) was added acryloyl chloride (0.754 ml, 9.28 mmol) dropwise.The reaction mixture was left stirring at room temperature for 16 h. The mixture was filtered, concentrated, diluted with EtOAc, washed with water, dried (MgS04), filtered and concentrated to give the crude product. Purification by flash column chromatography (eluting with a gradient of 0-100% EtOAc / heptane followed by 0-2% MeOH / EtOAc) afforded the title compound (0.674 g, 96%) as an orange solid.1 H-NMR (CDCI3, 250 MHz): d[ppm]= 7.82 (s, 1 H), 7.57 (dd, J = 8.2, 1 .3 Hz, 1 H), 7.31 (t, J = 8.3 Hz, 1 H), 7.19 (dd, J = 8.3, 1.3 Hz, 1 H), 6.47 (dd, J = 17.0, 1.7 Hz, 1 H), 6.33 (dd, J = 17.0, 9.8 Hz, 1 H), 5.85 (dd, J = 9.8, 1 .7 Hz, 1 H), 3.97 (s, 3H)HPLCMS (Method M): [m / z]: 223.05 [M+H]+N-(5-fluoro-2-nitrophenyl)prop-2-enamide (J) Acryloyl chloride (3.8 ml, 46.5 mmol) was added slowly to a suspension of 5fluoro-2-nitroaniline (2.4 g, 15.5 mmol) and K2C03 (8.57 g, 62 mmol) in acetone (100 ml) and the mixture was stirred at room temperature for 3 d and at reflux for 6 h. Further acryloyl chloride (3.8 ml, 46.5 mmol) and DMAP (0.95 g, 7.75 mmol) were added and the mixture heated at reflux for a further 2 h. The reaction mixture was cooled to room temperature and filtered. The residue was rinsed with acetone and the combined fltrates evaporated under vacuum. The resultant residue was re-dissolved in Et20 (350 ml) and saturated NaHC03 (aq) (200 ml). The mixture was stirred vigourously for 15 min.The phases were separated and the organic phase washed with a further portion of saturated NaHC03 (aq) (100 ml) and brine (100 ml), dried (sodium sulphate) and evaporated under vacuum. Purification by flushing through a plug of silica (eluting with a gradient of 0-4% Et20 / heptane) afforded the title compound (1 .04 g, 32%) as a pale ye!low solid.1 H-NMR (CDCI3, 250MHz): d[ppm]= 10.83 (s, 1 H), 8.79 (dd, J = 1 1.2, 2.5 Hz, 1 H), 8.34 (dd, J = 9.2, 5.7 Hz, 1 H), 6.99 - 6.82 (m, 1 H), 6.53 (d, J = 16.9 Hz, 1 H), 6.35 (dd, J = 17.1 , 9.9 Hz, 1 H), 5.95 (d, J = 10.1 Hz, 1 H)HPLCMS (Method M): [m / z]: 21 1.15 [M+H]+General Scheme K-l above:N-(2-chloro-5-fluorophenyl)prop-2-enamide (K1)To an N2 purged suspension of 2-chloro-5-fluoroaniline (3.0 g, 20.6 mmol) and K2C03 (1 1 .4 g, 82.4 mmol) in acetone (80 ml) at room temperature was added dropwise prcp-2-enoyl chloride (5.0 ml, 61 .8 mmol) and stirred for 16 h. The reaction mixture was filtered, concentrated in vacuo and purified by flash column chromatography (eluting with a gradient of 0-35% EtOAc / heptane) to afford the title compound (3.99 g, 84%) as a white solid.1 H-NMR (CDCI3, 250 MHz): d[ppm]= 8.40 (dd, J = 10.9, 3.0 Hz, 1 H), 7.79 (s, 1 H), 7.35 (dd, J = 8.9, 5.6 Hz, 1 H), 6.81 (ddd, J = 8.9, 7.6, 3.0 Hz, 1 H), 6.50 (dd, J = 16.9, 1.2 Hz, 1 H), 6.32 (dd, J = 16.9, 10.0 Hz, 1 H), 5.88 (dd, J = 10.0, 1.2 Hz, 1 H)HPLCMS (Method A): [m / z]: 200.10 [M+H]+N-(6-chloro-3-fluoro-2-nitrophenyl)prop-2-enamide (K2)To an N2 purged solution of N-(2-chloro-5-fluorophenyl)prop-2-enamide (K1 ) (3.99 g, 17.4 mmol), concentrated H2S04 (15 ml) and AcOH (6 ml) at 0°C was added red fuming HN03 (1.8 ml, 38.3 mmol) dropwise and the reaction was left stirring for 2 h. The reaction mixture was poured onto ice water and extracted using DCM (4 x 40 ml). The combined organic extracts were dried (MgSQ), filtered, concentrated in vacuo and purified by flash column chromatography (eluting with a gradient of 0-70% EtOAc / heptane) to give the title compound (1.08 g, 20%) as a white solid.1 H-NMR (CDCI3, 250 MHz): d[ppm]= 7.64 (dd, J = 9.1 , 5.0 Hz, 1 H), 7.51 (s, 1 H), 7.19 (m, 1 H), 652 (dd, J = 16.9, 1.1 Hz, 1 H), 6.32 (dd, J = 16.9, 10.2 Hz, 1 H), 5.94 (dd, J = 10.1 , 1.1 Hz, 1 H)HPLCMS (Method A): [m / z]: 244.95 [M+H]+ N-(2,4-difluorophenyl)prop-2-enamide (K3)To an N2 purged suspension of 2,4-difluoroaniline (2 g, 1.49 mmol) and 2CO3 (8.56 g, 61.7 mmol) in acetone (60 ml) at room temperature was added prop-2-enoyl chloride (3.7 ml, 46.5 mmol) dropwise. The reaction mixture was left stirring for 16 h. The reaction was filtered, concentrated, purified by flash column chromatography (eluting with a gradient of 0-30% EtOAc / heptane) and triturated with heptane to give the title compound (2.9 g, 100%) as a white solid.1 H-NMR (CDCI3, 250 MHz): d[ppm]= 8.49 - 8.29 (m, 1 H), 7.33 (s, 1 H), 6.99 - 6.84 (m, 2H), 6.48 (dd, J = 16.9, 1.4 Hz, 1 H), 6.29 (dd, J = 16.8, 10.1 Hz, 1 H), 5.85 (dd, J = 10.1 , 1.4 Hz, 1 H)HPLCMS (Method A): [m / z]: 183.95 [M+H]+N-(2,4-difluoro-6-nitrophenyl)prop-2-enamide (K4)To an N2 purged solution of N-(2,4-difluorophenyl)prop-2-enamide (K3) (2.9 g, 15.4 mmol), AcOH (5 ml) and concentrated H2S04 (13 ml) at 0°C was added red fuming nitric acid (1.6 ml) dropwise. The reaction mixture was left stirring for 2 h. The reaction was poured onto ice water and the resulting solution extracted using DCM (4 x 40 ml). The combined organic extracts were washed with brine, dried (MgS04), filtered, concentrated in vacuo and triturated with heptane to give the crude product as a beige solid (3.23 g). Purification by flash column chromatography (eluting with a gradient of 0-40% EtOAc / heptane) gave the title compound (1.25 g, 35.5%) as a white solid.1 H-NMR (CDCI3, 250 MHz): d[ppm]= 8.17 (s, 1 H), 7.67 (dt, J = 7.9, 2.4 Hz, 1 H), 7.34- 7.28 (m, 1 H), 6.51 (dd, J = 17.0, 1.4 Hz, 1 H), 6.35 (dd, J = 17.0, 9.9 Hz, 1 H), 5.92 (dd, J = 9.9, 1 .3Hz, 1 H)HPLCMS (Method A): [m / z]: 229.05 [M+H]+ N-(2,5-difluorophenyl)prop-2-enamide (K5)To an N2 purged stirring solution of 2,5-difluoroaniline (1.5 ml, 15.5 mmol) and (¾C03 (6.42 g, 46.5 mmol) in acetone (60 ml) at room temperature was added prop-2-enoyl chloride (5.0 ml, 61.96 mmol) dropwise. The reaction mixture was left stirring at room temperature for 2 h. The reaction was filtered and the filtrate concentrated to give a white solid, which was triturated with heptane to give the title compound 2.91 g, quantitative) as a white solid.1 H-NMR (CDCI3, 250 MHz): d[ppm]= 8.30 (m, 1 H), 7.50 (s, 1 H), 7.07 (m, 1 H), 6.85- 6.70 (m, 1 H), 6.50 (dd, J = 16.8, 1.2 Hz, 1 H), 6.30 (dd, J = 16.9, 10.1 Hz, 1 H), 5.87 (dd, J = 10.1 , 1.2 Hz, 1 H)HPLCMS (Method A): [m / z]: 183.95 [M+H]+ N-(3,6-difluoro-2-nitrophenyl)prop-2-enamide (K6)To an N2 purged stirring solution of N-(2,5-difluorophenyl)prop-2-enamide (K5) (2.91 g, 15.9 mmol), AcOH (5 ml) and conconcentrated H2S04 (13 ml) at 0°C was added red fuming HN<¾ (1.6 ml, 34.0 mmol) dropwise. The reaction mixture was left stirring for 2 h. The reaction was poured onto ice water and the resulting solution was extracted using DCM (4 x 40 ml). The combined organic extracts were washed with brine, dried (MgS04), filtered and concentrated in vacuo. Purification by flash column chromatography (eluting with a gradient of 0-60% EtOAc / heptane), followed by flash column chromatography (eluting with a gradient of 20% EtOAc / heptane) gave the title compound (0.316 g, 8%) as a whte solid.1 H-NMR (CDCI3, 500 MHz): d[ppm]= 7.64 (s, 1 H), 7.39 (m, 1 H), 7.19 (m, 1 H), 6.51 (dd, J = 17.0, 0.7 Hz, 1 H), 6.32 (dd, J = 17.0, 10.4 Hz, 1 H), 5.93 (dd, J = 10.4, 0.7 Hz, 1 H)HPLCMS (Method A): [m / z]: 228.95 [M+H]+N-[2-(trifluoromethyl)phenyl]prop-2-enamide (K7)To an N2 purged suspension solution of 2-(trifluoromethyl)aniline (3.1 ml, 24.83 mmol) and H½C03 (10.3 g, 74.48 mmol) in acetone (90 ml) was added prop-2-enoyl chloride (8.0 ml, 99.30 mmol) dropwise. The reaction mixture was left stirring at room temperature for 3 h. The reaction was filtered, concentrated in vacuo and triturated with heptane to afford the title compound (4.74 g, 86%) as a white solid.1 H-NMR (CDCI3, 250 MHz): d[ppm]= 8.34 (d, J = 8.2 Hz, 1 H), 7.70 - 7.45 (m, 3H), 7.28 - 7.22 (m, 1 H), 6.46 (dd, J = 16.9, 1.3 Hz, 1 H), 6.29 (dd, J = 16.9, 10.0 Hz, 1 H), 5.86 (dd, J = 10.0, 1.3 Hz, 1 H)HPLCMS (Method A): [m / z]: 215.90 [M+H]+N-[2-nitro-6-(trifluoromethyl)phenyl]prop-2-enamide (K8)To an N2 purged solution of N-[2-(trifluoromethyl)phenyl]prop-2-enamide (K7) (4.64 g, 20.91 mmol), AcOH (5 ml) and concentrated H2S04 (13 ml) at 0°C was added red fuming HNO3 (1.6 ml, 34.05 mmol) dropwise. The reaction mixture was left stirring at room temperature for 16 h. The reaction was pouredonto ice water and then extracted using DCM (4 x 40 ml). The combined organic extracts were dried (MgSQ), filtered and concentrated in vacuo. Purification by flash column chromatography (eluting with a gradient of 0-20% EtOAc / heptane) gave the title compound (0.829 g, 12%) as a beige solid.HPLCMS (Method A): [m / z]: 260.95 [M+H]+N-(2,3-Difluorophenyl)prop-2-enamide (K9)To an N2 purged solution of 2,3-difluoroaniline (3 ml, 31 mmol) and 2CO3 (12.9 g, 92.9 mmol) in acetone (120 ml) at room temperature was added dropwise prop-2-enoyl chloride (10 ml, 124 mmol). The reaction mixture was left stirring for 16 h. The reaction was filtered and the filtrate concentrated to give a white solid which was triturated from heptane to give the title compound (4.97g, 87%) as a white solid.1 H-NMR (CDCI3, 250 MHz): d[ppm]= 8.29 - 8.12 (m, 1 H), 7.46 (s, 1 H), 7.18 - 7.04 (m, 1 H), 7.02 - 6.85 (m, 1 H), 6.50 (dd, J = 16.8, 1.3 Hz, 1 H), 6.31 (dd, J = 16.9, 10.1 Hz, 1 H), 5.87 (dd, J = 10.1 , 1 .3 Hz, 1 H) HPLCMS (Method A): [m / z]: 184.2 [M+H]+N-(2,3-Difluoro-6-nitrophenyl)prop-2-enamide (K10)To an N2 purged solution of N-(2,3-difluorophenyl)prop-2-enamide (K9) (4.9 g, 26.8 mmol), AcOH (5 ml) and concentrated H2S04 (13 ml) at 0°C was added nitric acid (1.6 ml) dropwise. The reaction mixture was left stirring for 2 h. The reaction was poured onto ice / water and the solution extracted using DCM (5 x 30 ml). The combined organic extracts were washed with brine (50 ml), dried over MgSQ, filtered and concentrated to give the crude product. This was triturated with heptane (100 ml). The suspension was filtered and the residue collected to give a mixture of both para / ortho nitrated regioisomers as a beige solid (6 g). Purification by acidic prep-HPLC gave the title compound (42 g) as a white solid.HPLCMS (Method A): [m / z]: 228.95 [M+H]+General Scheme K-ll above:N-(4-Cyanophenyl)prop-2-enamide (K11)Acryloyl chloride (0.69 ml, 8.46 mmol) was added to an ice-cold suspension of 4-aminobenzonitrile (250 mg, 2.12 mmol) and K2C03 (880 mg, 6.35 mmol) in acetone (5 ml). The mixture was stirred for 18h whilst warming to room temperature. The reaction mixture was filtered and the residue rinsed with acetone (5 ml). The combined filtrates were evaporated in vacuo and the crude purification by flash column chromatography using an elution gradient 0-80% EtOAc / heptane to afford the title compound (353 mg, 96%) as a white solid.1 H-NMR (CDCI3, 250 MHz): d[ppm]= 7.73 (d, J = 8.8 Hz, 2H), 7.68 - 7.58 (m, 2H), 7.37 (s, 1 H), 6.49 (dd, J = 16.8, 1.0 Hz, 1 H), 6.25 (dd, J = 16.8, 10.2 Hz, 1 H), 5.86 (dd, J = 10.2, 1 .0 Hz, 1 H)HPLCMS (Method M): [m / z]: 173.45 [M+H]+N-(4-Cyano-2-nitrophenyl)prop-2-enamide (K12)Nitric acid (0.6 ml) was added dropwise to an ice-cold solution of N-(4-cyanophenyl)prop-2-enamide (K11 ) (1.03 g, 5.75 mmol) in acetic acid (2 ml) and sulfuric acid (4.75 ml). The reaction mixture was stirred for 3h, then poured into ice-cold water and the mixture extracted with DCM (4 x 20 ml). The combined organic extracts were dried (MgS04) and evaporated in vacuo. Purification by flash column chromatography using an elution gradient 0-90% EtOAc / heptane afforded the title compound (1.2 g, 93%) as a yellow solid.1 H-NMR (CDCI3, 250 MHz): d[ppm]= 10.77 (s, 1 H), 9.14 (d, J = 8.9 Hz, 1 H), 8.58 (d, J = 2.0 Hz, 1 H), 7.90 (dd, J = 8.9, 1.7 Hz, 1 H), 6.54 (dd, J = 17.0, 0.9 Hz, 1 H), 6.35 (dd, J = 17.0, 10.1 Hz, 1 H), 5.98 (dd, J = 10.1 , 0.9 Hz, 1 H)Tert-butyl 2-(chloromethyl)-1H-1,3-benzodiazole-1-carboxylate (L)A mixture of 2-(chloromethyl)-1 H-1 ,3-benzodiazole (10 g, 0.06 mol), BOQO (18 ml, 0.06 mol) and TEA (6.07 g, 0.06 mol) in DCM (304 ml) was cooled to 0°C. A catalytic amount of DMAP (0.73 g, 0.006 mol) was added and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (150 ml), washed with saturated NaHCQ (150 ml), brine (150 ml), dried (N¾S04), filtered and concentrated to give the crude product. Purification by flash column chromatography(eluting with a gradient of 5-10% EtOAc / heptane) gave the title compound (7 g, 44%) as an off white oil.HPLCMS (Method H): [m / z]: 167.2 [M-Boc+H]+General Scheme 1 above:General procedure 1 : ethyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate (1)To a suspension of ethyl 3-bromo-2-oxopropanoate (12.35 ml, 107.69 mmol) and tert-butyl (3-amino-3- thioxopropyl) carbamate (20 g, 97.9 mmol) in EtOH (200 ml) was added CaCQ (5.3 g, 52.87 mmol) portion wise and the reaction mixture stirred at room temperature for 12 h. The mixture was concentrated in vacuo and the residue partitioned between EtOAc (200 ml) and sat. NaHCQ (100 ml). The organic layer was separated and washed with water (100 ml), brine (100 ml), dried (MgSQ), filtered and concentrated in vacuo to give the required product. Purification by flash column chromatography (isocratic elution 20% EtOAc / heptane) afforded the title compound (22 g, 69.6%) as a yellow solid.1 H-NMR (Methanol-d4, 250 MHz): d[ppm]= 8.29 (s, 1 H), 4.39 (q, J = 7.1 Hz, 2H), 3.47 (t, J = 6.5 Hz, 2H), 3.22 (t, J = 6.5 Hz, 2H), 1.41 (d, J = 6.2 Hz, 14H)HPLCMS (Method A): [m / z]: 301.0 [M+HfMethyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate (2)In a similar fashion to general procedure 1 , tert-Butyl (3-amino-3-thioxopropyl)carbamate (10 g, 48.95 mmol), methyl 3-bromo-2-oxopropanoate (5.73 ml, 53.85 mmol) and CaC(¾ (0.9 ml, 26.43 mmol) in EtOH (120 ml) afforded the title compound (10.2 g, 60%, 83% purity) as a yellow solid after purifcation by flash chromatography (eluting with a gradient of 20-80% EtOAc / heptane).HPLCMS (Method A): [m / z]: 286.9 [M+H]+Methyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1 ,3-thiazole-4-carboxylate (3)In a similar fashion to general procedure 1 , tert-butyl N-(2-carbamothioylethyl)carbamate (0.89 g, 4.35 mmol), methyl 3-bromo-2-oxobutanoate (0.93 g, 4.78 mmol) and CaCCb (0.23 g, 2 mmol) in EtOH (15 ml) afforded the title compound (0.769 g, 58%) as a yellow oil after purification by flash columnchromatography (eluting with a gradient of 10-60% EtOAc / heptane).1 H-NMR (CDCI3, 250 MHz): d[ppm]= 4.88 (s, 1 H), 3.95 (s, 3H), 3.55 (q, J = 6.5 Hz, 2H), 3.17 (t, J = 6.5 Hz, 2H), 2.76 (s, 3H), 1.46 (s, 9H)HPLCMS (Method A): [m / z]: 301.05 [M+H]+Ethyl 2-(3-{[(tert-butoxy)carbonyl]amino}propyl)-1,3-thiazole-4-carboxylate (4)NHBocIn a similar fashion to general procedure 1 , tert-butyl N-(3-carbamothioylpropyl)carbamate (535 mg, 2.45 mmol), ethyl 3-bromo-2-oxopropanoate (0.31 ml, 2.7 mmd) and CaC03 (132 mg, 1 .32 mmol) in EtOH (10 ml) afforded the title compound (726 mg, 93%) as a yellow oil after purification by flash column chromatography (eluting with a gradient of 0-50% EtOAc / heptane).1 H-NMR (DMSO-d6, 500MHz): d[ppm]= 8.38 (s, 1 H), 6.90 (s, 1 H), 4.29 (q, J = 7.1 Hz, 2H), 3.15 - 2.90 (m, 4H), 1.83 (m, 2H), 1 .38 (s, 9H), 1.30 (t, J = 7.1 Hz, 3H)HPLCMS (Method A): [m / z]: 315 [M+H]+General procedure 2: Methyl 2-(2-aminoethyl)-1,3-thiazole-4-carboxylate (5)4M HCI in dioxane (44 ml, 176 mmol) was added to a solution of methyl 2-(2-{[(tert- butoxy)carbonyl]amino}ethyl)-1 ,3-thiazole-4-carboxylate (2) (10.2 g, 35.62 mmol) in dioxane and the mixture was stirred at room temperature for 12 h, then at 40°C for 24 h. The mixture was cooled b room temperature and evaporated in vacuo. The residue was dissolved in DCM (20 ml) and washed with saturated NaHC03 (3 x 10 ml). The combined aqueous phases were re-extracted with diethyl ether (3 x 100 ml) and the combined organic phases were dried (MgS04), filtered and evaporated in vacuo to afford the title compound (1 .96 g, 30%) as a brown solid.HPLCMS (Method A): [m / z]: 186.9 [M+H]+ General procedure 3: Methyl 2-{2-[(1 H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-1,3-thiazole-4- carboxylate (6)A suspension of methyl 2-(2-aminoethyl)-1 ,3-thiazole-4-carboxylate (5) (1.96 g, 10.52 mmol), 1 H- benzimidazole-2-carbaldehyde (2.31 g, 15.79 mmol) and DIPEA (1.83 ml, 10.52 mmol) in MeOH (100 ml) was stirred at room temperature for 12 h. The reaction mixture was cooled to 0°C, NaBH4 (0.597 g, 15.79 mmol) was added and the mixture stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the residue dissolved in EtOAc (100 ml) and washed with saturated N¾C03 (2 x 50 ml). The combined aqueous layers were extracted with EtOAc (3 x 50 ml) and the combined organic layers dried (MgS04), filtered and evaporated in vacuo. Purification by flash column chromatography (KP- NH, eluting with a gradient of 0-10% MeOH / DCM) afforded the title compound (1.4 g, 38%, 90% purity) as a tan solid.1 H-NMR (Methanol-d4, 250 MHz): d[ppm]= 8.27 (s, 1 H), 7.60 - 7.49 (m, 2H), 7.29 - 7.17 (m, 2H), 4.09 (s, 2H), 3.92 (s, 3H), 3.26 (t, J = 6.3 Hz, 2H), 3.10 (t, J = 6.8 Hz, 2H)HPLCMS (Method A): [m / z]: 317 [M+H]+General procedure 4:Tert-butyl 2-({[(tert-butoxy)carbonyl]({2-[4-(methoxycarbonyl)-1,3-thiazol-2-yl]ethyl})amino} methyl)- 1 H-1 ,3-benzodiazole-1 -carboxylate (7)To a solution of methyl 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)amino]ethyl}-1 ,3-thiazole-4-carboxylate (6) (74%, 2.94 g, 6.88 mmol), Boc¾0 (3.75 g, 17.19 mmol) and TEA (2.38 ml, 17.19 mmol) in THF (60 ml) was added DMAP (168 mg, 1.38 mmol) and the reaction was stirred at room temperature for 16 h. The reaction was evaporated to dryness, diluted with EtOAc (100 ml) and washed with water (3x 50 ml). The organic was dried over MgS04, filtered and evaporated to dryness. The crude residue was purified by FCC eluting with 0-100% EtOAc in heptane to give 3.8 g of desired product.General procedure 5: 2-(2-{[(Tert-butoxy)carbonyl]({1-[(tert-butoxy)carbonyl]-1 H-1,3-benzodiazol-2- yl}methyl)amino}ethyl)-1,3-thiazole-4-carboxylic acid (8)Lithium hydroxide (0.48 mg, 20.08 mmol) was added to a solution of tert-butyl 2-({[(tert- butoxy)carbonyl]({2-[4-(methoxycarbonyl)-1 ,3-thiazol-2-yl]ethyl})amino}methyl)-1 H-1 ,3-benzodiazole-1- carboxylate (7) (3.8 g, 6.69 mmol) in THF / water (40 ml / 10 ml) at 0°C. The reaction mixture was stirred at room temperature for 48 h. The mixture was concentrated in vacuo and acidified to pH -3-4 using AcOH. The reaction mixture was extracted with THF / EtOAc (3:1, 3 x 50 ml). The combined organic extracts were washed with brine (100 ml), dried (MgS04), filtered, reduced in vacuo and azeotroped with heptane (3 x 50 ml) to give the title compound (2.4 g, 84.6%) as a yellow foam.1H-NMR (Methanol-d4, 250 MHz): d[ppm]= 8.15 (d, J = 17.0 Hz, 1H), 7.69 (s, 2H), 7.27 (dd, J = 6.1, 3.2 Hz, 2H), 4.79 (s, 2H), 3.87 -3.74 (m, 2H), 3.40 -3.33 (m, 3H), 1.38- 1.01 (m, 10H)HPLCMS (Method A): [m / z]: 403 [M+H]+General procedure 6: Tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyridin-2- ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (9)To a stirring solution of 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3- thiazole-4-carboxylic acid (8) (3 g, 7.08 mmol), 1-(pyridin-2-yl)methanamine (1.1 ml, 10.62 mmol), DIPEA (3.7 ml, 21.24 mmol) and DMF (50 ml) at room temperature was added HATU (5.39 g, 14.16 mmol). The reaction mixture was allowed to stir at room temperature for 16 h.The reaction was diluted with EtOAc (100 ml) and washed with sat. NaHCQ (3 x 50 ml) and brine (3 x 50 ml). The organic layer was separated, dried (MgS04), filtered and evaporated to dryness. The crude residue was purified by flash column chromatography (kp-NH, eluting with a gradient of 20-100% EtOAc in heptane) and then azeotroped with heptane to give the title compound (2.2 g, 62%) as a yellow foam. 1H-NMR (MeOD, 500 MHz): d[ppm]= 8.49 (d, J = 4.4 Hz, 1H), 8.10 (s, 1H), 7.80 (td, J = 7.8, 1.7 Hz, 1H), 7.54 (s, 2H), 7.42 (d, J = 7.9 Hz, 1H), 7.31 (dd, J = 7.1, 5.2 Hz, 1H), 7.26- 7.20 (m, 2H), 4.75 (d, J = 12.3 Hz, 2H), 4.70 (s, 2H), 3.92-3.79 (m, 2H), 3.36 (d, J = 8.1 Hz, 1H), 1.43- 1.25 (m, 10H)HPLCMS (Method D): [m / z]: 493.1 [M+H]+Tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(cyclohexylmethyl)carbamoyl>1,3-thiazol-2- yl}ethyl)carbamate (10)In a similar fashion to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (99.8 mg, 0.248 mmol),cyclohexylmethanamine (33.69 mg, 0.298 mmol), DIPEA (96.16 mg, 0.744 mmol) and HATU (113.16 mg, 0.298 mmol) in DMF (4 ml) at room temperature for 1 h afforded the title compound (116 mg, 47% purity) as an off white oil after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH / DCM). The title compound was used in the next step without further purification.HPLCMS (Method H): [m / z]: 498.7 [M+H]+ Tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1,3- thiazol-2-yl]ethyl}carbamate (11)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (99.8 mg , 0.248 mmol), 1 ,2,3,4- tetrahydroisoquinoline (39.64 mg, 0.298 mmol), DIPEA (96.16 mg, 0.744 mmol) and HATU (1 13.16 mg, 0.298 mmol) in DMF (4 ml) at room temperature for 1 h afforded the title compound (124 mg , 59% purity) as an off white oil after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH / DCM). The title compound was used in the next step without further purification.HPLCMS (Method H): [m / z]: 518.7 [M+H]+ Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(thiophen-2-ylmethyl)carbamoyl]-1 ,3-th yl}ethyl)carbamate (12)To a solution of 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4- carboxylic acid (8) (150 mg, 0.373 mmol) in DMF (10 ml) was added 1 H-1 ,2,3-benzotriazol-1 -ol (50 mg , 0.373 mmol) and EDC:HCI (71 mg , 0.373 mmol) at CfC. The reaction mixture was allowed to stir for 15 min before TEA (38 mg, 0.373 mmol) was added followed bythiophen-2-ylmethanamine (42 mg, 0.373 mmol). The reaction mixture was allowed to warm up to room temperature and stir overnight. The title compound (185 mg, 16% purity) was obtained after work up following general procedure 6. This was used in the next step without purification.HPLCMS (Method H): [m / z]: 498.6 [M+H]+Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-(2-{4-[benzyl(methyl)carbamoyl]-1 ,3-thiazol-2- yl}ethyl)carbamate (13)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (99.8 mg , 0.248 mmol),benzyl(methyl)amine (36.06 mg, 0.298 mmol), DIPEA (96.16 mg , 0.744 mmol) and HATU (1 13.16 mg, 0.298 mmol) in DMF (4 ml) at room temperature for 1 h afforded the title compound (1 18 mg , 55% purity) as an off white oil after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH / DCM). The title compound was used in the next step without further purification.HPLCMS (Method H): [m / z]: 506.7 [M+H]+Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-{2-[4-(morpholine-4-carbonyl)-1 ,3-thiazol-2- yl]ethyl}carbamate (14)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (99.8 mg, 0.248 mmol), morpholine (25.93 mg, 0.298 mmol), DIPEA (96.16 mg, 0.744 mmol) and HATU (1 13.16 mg, 0.298 mmol) in DMF (4 ml) at room temperature for 1 h afforded the title compound (1 10 mg) as an off white oil after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH / DCM). The title compound was used in the next step without further purification.Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[methyl(phenyl)carbamoyl]-1,3-thiazol-2- yl}ethyl)carbamate (15)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (99.8 mg, 0.248 mmol), N-methylaniline (31 .89 mg, 0.298 mmol), DIPEA (96.16 mg, 0.744 mmol) and HATU (1 13.16 mg, 0.298 mmol) in DMF (4 ml) at room temperature for 1 h afforded the title compound (1 18 mg, 59% purity) as an off white oil after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH / DCM). The title compound was used in the next step without further purification.HPLCMS (Method H): [m / z]: 492.7 [M+H]+ Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(pyrrolidin-1-yl)phenyl]methyl}carbamoyl)- 1 ,3-thiazol-2-yl]ethyl}carbamate (16)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (200 mg, 0.497 mmol), [3-(pyrrolidin-1- yl)phenyl]methanamine (105 mg, 0.596 mmol), DIPEA (193 mg, 1.491 mmol) and HATU (227 mg, 0.596 mmol) in DMF (5 ml) at room temperature for 1 h afforded the title compound (100 mg, 30%, 84% purity) as an off white oil after purification by flash column chromatography (eluting with a gradient of 010% MeOH / DCM).HPLCMS (Method H): [m / z]: 561.7 [M+H]+Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-(dimethylcarbamoyl)-1,3-thiazol-2- yl]ethyl}carbamate (17)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.248 mmol), dimethylamine (2 M solution in THF) (13 mg, 0.298 mmol), DIPEA (96 mg, 0.745 mmol) and HATU (1 13 mg, 0.298 mmol) in DMF (10 ml) at room temperature for 1 h afforded the title compound (90 mg, 67%, 80% purity) as a white solid after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH / DCM). HPLCMS (Method H): [m / z]: 430.6 [M+H]+Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-(2-{4-[cyclohexyl(propan-2-yl)carbamoyl]-1 ,3-thiazol- 2-yl}ethyl)carbamate (18)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (99.8 mg, 0.248 mmol), N-(propan-2- yl)cyclohexanamine (42.04 mg , 0.298 mmol), DIPEA (96.16 mg , 0.744 mmol) and HATU (113.16 mg , 0.298 mmol) in DMF (4 ml) at room temperature for 1 h afforded the title compound (124 mg , 17% purity) as an off white oil after purification by flash column chromatography (eluting with a gradient of 010% MeOH / DCM). The title compound was used in the next step without further purification.HPLCMS (Method H): [m / z]: 526.8 [M+H]+ Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(2-phenylpropan-2-yl)carbamoyl]-1 ,3-thiazol-2- yl}ethyl)carbamate (19)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (99.8 mg, 0.248 mmol), 2-phenylpropan-2- amine (40.24 mg, 0.298 mmol), DIPEA (96.16 mg, 0.744 mmol) and HATU (1 13.16 mg, 0.298 mmol) in DMF (4 ml) at room temperature for 1 h afforded the title compound (120 mg, 51 % purity) as an off white oil after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH / DCM). The title compound was used in the next step without further purification.HPLCMS (Method H): [m / z]: 520.7 [M+H]+Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-{2-[4-(benzylcarbamoyl)-1 ,3-thiazol-2- yl]ethyl}carbamate (20)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (350 mg, 0.87 mmol), phenylmethanamine (103 mg, 0.957 mmol), DIPEA (337 mg, 2.61 mmol) and HATU (397 mg, 1.04 mmol) in DMF (10 ml) afforded the title compound (390 mg, 89% purity) as a white sdid after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH / DCM).HPLCMS (Method H): [m / z]: 492.6 [M+H]+Tert-butyl N-{2-[4-(benzylcarbamoyl)-1,3-thiazol-2-yl]ethyl}-N-[(1 -methyl-1 H-1,3-benzodiazol-2- yl)methyl]carbamate (21)To a stirred solution of tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-{2-[4-(benzylcarbamoyl)-1 ,3-thiazol- 2-yl] ethyl} carbamate (20) (380 mg, 0.773 mmol) and TEA (78 mg, 0.773 mmol) in DCM (15 ml) was added Mel (165 mg, 1.159 mmol) under argon atmosphere. The reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated under vacuum to dryness to afford the title compound (280 mg, 72% purity) as an off white solid. The crude product was used in the next step without purification.HPLCMS (Method H): [m / z]: 506.6 [M+H]+ Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(^yl}ethyl)carbamate (22)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (199.6 mg, 0.496 mmol), pyridin-3- yimethanamine (59 mg, 0.546 mmol), DIPEA (192.3 mg, 1.488 mmol) and HATU (226 mg, 0.595 mmol) in DMF (8 ml) afforded the title compound (184 mg, 75%) as a white solid after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH / DCM).1 H-NMR (CDCI3, 400 MHz): d[ppm]= 8.61 (d, J = 1.6 Hz, 1 H), 8.52 (d, J = 3.6 Hz, 1 H), 7.96 (s, 1 H), 7.81 (s, 1 H), 7.73 - 7.67 (m, 1 H), 7.55 (dd, J = 6.0, 3.2 Hz, 2H), 7.28 (s, 1 H), 7.25 (dd, J = 6.1 , 3.2 Hz, 2H), 4.63 (d, J= 6.6 Hz, 4H), 3.77 (t, J = 6.5 Hz, 2H), 3.22 (t, J = 6.3 Hz, 2H), 1 .37 (s, 9H)HPLCMS (Method H): [m / z]: 493.4 [M+H]+Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyridin-4-ylmethyl)carbamoyl]-1 ,3-thiazol-2- yl}ethyl)carbamate (23)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (199.6 mg, 0.496 mmol), pyridin-4- ylmethanamine (59 mg , 0.546 mmol), DIPEA (192.3 mg, 1 .488 mmol) and HATU (226 mg, 0.595 mmol) in DMF (8 ml) afforded the title compound (140 mg, 57%) as a white solid after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH / DCM).1 H-NMR (CDCI3, 400 MHz): d[ppm]= 8.56 (d, J = 5.9 Hz, 2H), 7.98 (s, 1 H), 7.82 (s, 1 H), 7.59- 7.48 (m, 2H), 7.24 (dd , J = 6.0, 3.2 Hz, 4H), 4.62 (d, J = 6.6 Hz, 4H), 3.78 (t, J = 6.5 Hz, 2H), 3.25 (t, J = 6.4 Hz, 2H), 1 .41 (d , J = 13.9 Hz, 9H)HPLCMS (Method H): [m / z]: 493.4 [M+H]+Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[3-(trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1 ,3-thiazol-2-yl]ethyl}carbamate (24)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (80.09 mg, 0.199 mmol), [3- (trifluoromethyl)pyridin-2-yl]methanamine hydrochloride (46.54 mg , 0.219 mmol), DIPEA (102.9mg, 0.796 mmol) and HATU (90.8 mg, 0.239 mmol) in DNF (2.5 ml) afforded the title compound (85 mg, 76%, 98% purity) as a white solid after purification by flash column chromatography (eluting with a gradient of 010% MeOH / DCM).HPLCMS (Method H): [m / z]: 561 .5 [M+H]+Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl]- 1 ,3-thiazol-2-yl}ethyl)carbamate (25)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (80.09 mg, 0.199 mmol), N-methyl-5, 6,7,8- tetrahydroquinolin-8-amine dihydrochloride (48.4 mg, 0.219 mmol), DIPEA (102.9 mg , 0.796 mmol) and HATU (90.8 mg, 0.239 mmol) in DMF (2.5 ml) afforded the title compound (92 mg, 87%) as a white solid after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH / DCM).HPLCMS (Method H): [m / z]: 533.5 [M+H]+Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-{2-[4-({5H,6H,7H-cyclopenta[b]pyridin-7- yl}carbamoyl)-1 ,3-thiazol-2-yl]ethyl}carbamate (26)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (80.9 mg, 0.199 mmol), N-methyl- 5H,6H,7H-cyclopenta[b]pyridin-7-amine hydrochloride (37.35 mg, 0.219 mmol), DIPEA (102.9 mg, 0.796 mmol) and HATU (90.8 mg, 0.239 mmol) in DMF (2.5 ml) afforded the title compound (90 mg, 87%) as a white solid after purification by flash column chromatography (eluting with a gradient of 010% MeOH / DCM).HPLCMS (Method H): [m / z]: 519.5 [M+H]+ Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(4-methylmorpholin-2-yl)methyl]c^1,3-thiazol-2-yl)ethyl]carbamate (27)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (3 g, 7.545 mmol), (3-fluoropyridin-2- yl)methanamine dihydrochloride (A2) (2.26 g, 1 1 .18 mmol), DIPEA (12.98 ml, 74.54 mmol) and HATU (4.251 g, 1 1 .18 mmol) in DMF (60 ml) afforded the title compound (4.13 mg, 89%) as a yellow oil after purification by flash column chromatography (kp-NH, eluting with a gradient of 20-100% EtOAc / heptane followed by 0-20% MeOH / EtOAc).1 H-NMR (DMSO-d6, 500 MHz): d[ppm]= 12.29 (s, 1 H), 8.69 (s, 1 H), 8.36 (s, 1 H), 8.17(s, 1 H), 7.70 (t, J = 9.5 Hz, 1 H), 7.48 (s, 2H), 7.40 (dt, J = 8.6, 4.4 Hz, 1 H), 7.14 (s, 2H), 4.66 (d, J = 8.8 Hz, 4H), 3.73 (s, 2H), 2.52 (s, 2H), 1 .99 (s, 4H), 1.26 (d, J = 44.9 Hz, 9H)HPLCMS (Method A): [m / z]: 51 1.15 [M+H]+Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(4-methylmo1,3-thiazol-2-yl)ethyl]carbamate (28)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (99.8 mg, 0.248 mmol), (4- methylmorpholin-3-yl)methanamine (35.5 mg, 0.273 mmol), DIPEA (96.16 mg, 0.744 mmol) and T3P (189.4 mg, 0.298 mmol) in DMF (4 ml) afforded the title compound (90 mg, 70%) as a white solid after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH / DCM).1 H-NMR (CDCI3, 400 MHz): d[ppm]= 7.90 (s, 1 H), 7.59 (s, 3H), 7.28 (t, J = 3.6 Hz, 1 H), 4.64 (s, 2H), 3.79 (td, J = 12.0, 4.7 Hz, 5H), 3.70 - 3.59 (m, 2H), 3.47 (ddd, J = 14.7, 10.3, 6.6 Hz, 4H), 3.22 (t, J = 6.4 Hz, 2H), 2.74 (d, J = 1 1.4 Hz, 1 H), 2.49 - 2.32 (m, 6H), 1 .40 (s, 9H) Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-methylpyridin-2-yl)methyl]carbamoy^ thiazol-2-yl)ethyl]carbamate (29)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid 6 (99.8 mg, 0.248 mmol), (6-methylpyridin-2- yl)methanamine (33.33 mg, 0.273 mmol), DIPEA (96.16 mg, 0.744 mmol) and T3P (189.4 mg, 0.298 mmol) in DMF (4 ml) afforded the title compound (95 mg, 75%) as a white solid after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH / DCM).1 H-NMR (CDCI3, 400 MHz): d[ppm]= 8.14 (s, 1 H), 7.90 (s, 1 H), 7.55 (dd,J = 14.1 , 6.6 Hz, 3H), 7.23 (dd, J = 6.0, 3.2 Hz, 2H), 7.14 (d, J = 7.7 Hz, 1 H), 7.06 (d, J = 7.7 Hz, 1 H), 4.71 (d, J = 5.5 Hz, 2H), 4.66 (s, 2H), 3.80(t, J = 6.3 Hz, 2H), 3.22 (t, J = 6.4 Hz, 2H), 2.55 (s, 3H), 1.34 (s, 9H)Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(5-fluoropyridin-2-yl)methyl]carbamoyl}-1,3- thiazol-2-yl)ethyl]carbamate (30)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (99.8 mg, 0.248 mmol), (5-fluoropyridin-2- yl)methanamine (34.41 mg, 0.273 mmol), DIPEA (96.16 mg, 0.744 mmol) and T3P (189.4 mg, 0.298 mmol) in DMF (4 ml) afforded the title compound (89 mg, 70%) as a white solid after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH / DCM).1 H-NMR (CDCI3, 400 MHz): d[ppm]= 8.44 (s, 1 H), 8.12 (s, 1 H), 7.92 (s, 1 H), 7.56 (s, 2H), 7.44- 7.30 (m, 2H), 7.25 (dd, J = 6.1 , 3.2 Hz, 2H), 4.73 (d, J = 5.6 Hz, 2H), 4.66 (s, 2H), 3.79 (t, J = 6.3 Hz, 2H), 3.23 (t, J = 6.3Hz, 2H), 3.04 (s, 1 H), 1.34 (s, 9H) Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyrim^2-yl}ethyl)carbamate (31)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (150 mg, 0.373mmo), pyrimidin-4- ylmethanamine (48.8 mg , 0.447 mmol), DIPEA (48.1 mg, 0.373 mmol)and HATU (141.7 mg, 0.373 mmol) in DMF (2 ml) at room temperature overnight gave the title compound (80 mg, 60% purity) as an yellow oil after purification by flash column chromatography (eluting with a gradient of 10% MeOH in DCM). HPLCMS (Method H): [m / z]: 494.6 [M+H]+ Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(5-methoxypyridin-2-yl)methyl]carbamoyl}- 1 ,3-thiazol-2-yl)ethyl]carbamate (32)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (150 mg, 0.373mmo), (5-methoxypyridin-2- yl)methanamine (48.17 mg , 0.447 mmol), DIPEA (48.1 mg, 0.373 mmol)and HATU (141.7 mg, 0.373 mmol) in DMF (2 ml) at room temperature overnight gave the title compound (80 mg, 41 %) as brown solid after purification by flash column chromatography (eluting with a gradient of 10% MeOH in DCM).HPLCMS (Method H): [m / z]: 523.6 [M+H]+Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyrazin-2-ylmethyl)carbamoyl]-1 ,3-thiazol-2- yl}ethyl)carbamate (33)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (150 mg, 0.373 mmol), pyrazin-2- ylmethanamine (48.8 mg , 0.447 mmol), DIPEA (192.68 mg, 1.491 mmol) and HATU (141.7 mg, 0.373 mmol) in DMF (2 ml) at room temperature overnight gave the title compound (95 mg , 52%) as yellow solid after purification by flash column chromatography (eluting with a gradient of 10% MeOH in DCM).HPLCMS (Method H): [m / z]: 394.5 [M+H-Boc]+Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-oxo-1,6-dihydropyridin-2- yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (34)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (150 mg, 0.373 mmol), 6-(aminomethyl)- 1 ,2-dihydropyridin-2-one (55.52 mg , 0.447 mmol), DIPEA (48.17 mg, 0.373 mmol) and HATU (141.7 mg, 0.373 mmol) in DMF (2 ml) at room temperature overnight gave the title compound (90 mg , 47%) as yellow solid after purification by flash column chromatography (eluting with a gradient of 10% MeOH / DCM).HPLCMS (Method H ): [m / z]: 509.6 [M+H]+Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-carbamoylpyridin-3-yl)methyl]carbamoyl}- 1,3-thiazol-2-yl)ethyl]carbamate (35) andTert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-cyanopyridin-3-yl)methyl]carbamoyl}-1,3- thiazol-2-yl)ethyl]carbamate (36)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.248 mmol), 5- (aminomethyl)pyridine-2-carbonitrile (33 mg, 0.248 mmol), HATU (189 mg, 0.497 mmol) and DIPEA (96 mg, 0.745 mmol) in DMF (1 ml) at room temperature for 18 h, gave a 2: 1 Btio of boc amide and boc nitrile (80 mg) after purification by flash column chromatography (DCM : MeOH, 9: 1 ). The mixture was used in the next step without separation.HPLCMS (Method H): [m / z]: 418.5 [M+H-boc]+ and 436.3 [M+H-boc]+ Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4^1 ,3-thiazol-2-yl)ethyl]carbamate (37)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (0.3 g, 0.708 mmol), (3,5-dimethylpyridin-2- yl)methanamine hydrochloride (0.183 g, 1.062 mmol), DIPEA (0.555 ml, 3.187 mmol) and HATU (0.404 g, 1.062 mmol) in DMF (6 ml) at room temperature for 4 h, gave the title compound (0.198 g, 51 %) as a yellow oil after purification by flash column chromatography (kp-NH, eluting with a gradient of EtOAc (30%) / heptane (70%) followed by 100% EtOAc).1 H-NMR (DMSO-d6, 500 MHz): d[ppm]= 12.29 (s, 1 H), 8.75 (s, 1 H), 8.19 (s, 2H), 7.56 (d, J = 7.6 Hz, 1 H), 7.48 - 7.40 (m, 2H), 7.14 (p, J = 7.0 Hz, 2H), 4.66 (s, 2H), 4.53 (d, J = 4.8 Hz, 2H), 3.73 (s, 2H), 2.27 (s, 3H), 2.23 (s, 3H), 1.31 (s, 9H)HPLCMS (Method A): [m / z]: 521.15 [M+HfTert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyrimidin-2-ylmethyl)carbamoyl]-1 ,3-thi 2-yl}ethyl)carbamate (38)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.20 mmol), 1-(pyrimidin-2- yl)methanamine (22 mg, 0.20 mmol), DIPEA (0.1 ml, 0.60 mmol) and HATU (1 13 mg, 0.30 mmol) in DCM (5 ml) afforded the title compound (86 mg, 73%) as a brown residue after purification by flash column chromatography (eluting with a gradient of 0-20% MeOH / EtOAc).HPLCMS (Method A): [m / z]: 494.1 [M+H]+Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(4-methylpiperazin-1-yl)phenyl] methyl} carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (39)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (130mg, 0.24mmol, 75% purity), 1-[2-(4- methylpiperazin-1-yl)phenyl]methanamine (75 mg, 0.36 mmol), DIPEA (127 μΙ, 0.73 mmol) and HATU (138 mg, 0.36 mmol) in DMF (2 ml) afforded the title compound (13 mg, 9%) as a white solid following purification by basic prep-HPLC.HPLCMS (Method D): [m / z]: 590.3 [M+H]+Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(2,6-difluorophenyl)methyl]carbamoyl}-1 ,3- thiazol-2-yl)ethyl]carbamate (40)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (1 10 mg, 0.25 mmol, 90% purity), 1-(2,6- difluorophenyl)methanamine (53 mg, 0.37 mmol), DIPEA (0.13 ml, 0.74 mmol) and HATU (140 mg, 0.37 mmol) in DMF (2 ml) afforded the title compound (90 mg, 68%) as a yellow oil after purification by flash column chromatography (kp-NH, eluting with a gradient of 2-100% EtOAc / heptane).HPLCMS (Method E): [m / z]: 528.3 [M+H]+Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(dimethylamino)phenyl]methyl}carbamoyl>- 1,3-thiazol-2-yl]ethyl}carbamate (41)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (109 mg, 0.22 mmol, 80% purity), 2- (aminomethyl)-N,N-dimethylaniline (66 mg, 0.44 mmol), DIPEA (226 μΙ, 1 .30 mmol) and HATU (240 mg, 0.64 mmol) in DMF (2 ml) at 50°C afforded the title compound (73 mg, 61 %) as an orange oil after purification by flash column chromatography (kp-NH, eluting with a gradient of 5-100% EtOAc / heptane). HPLCMS (Method D): [m / z]: 535.2 [M+H]+Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(2-cyanophenyl)methyl]carbamoyl}-1,3- thiazol-2-yl)ethyl]carbamate (42)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (109 mg, 0.22 mmol, 80% purity), 2- (aminomethyl)benzonitrile hydrochloride (74 mg, 0.44 mmol), DIPEA (226 μΙ, 1 .30 mmol) and HATU (240 mg, 0.64 mmol) in DMF (2 ml) at 50°C afforded the crude title compound (54 mg, 30%, 63% purity) as an orange oil after purification by flash column chromatography (kp-NH, eluting with a gradient of 5-100% EtOAc / heptane).HPLCMS (Method D): [m / z]: 517.2 [M+H]+ Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(trifluoromethoxy)phenyl]methyl}carbamoyl)-1 ,3-thiazol-2-yl]ethyl}carbamate (43)In a similar fashion to general procedure 6, 2 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (109 mg, 0.22 mmol, 80% purity), 1-[2- (trifluoromethoxy)phenyl]methanamine (103 mg, 0.54 mmol), DIPEA (283 μΙ, 1 .63 mmol) and HATU (248 mg, 0.65 mmol) in DMF (2 ml) at 50°C afforded the crude title compound (1 10 mg , 78%, 88% purity) as a yellow oil after purification by flash column chromatography (kp-NH, eluting with a gradient of 8-100% EtOAc / heptane).HPLCMS (Method E): [m / z]: 576.2 [M+H]+Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(1 -phenylethyl)carbamoyl]-1 ,3-thiazol-2- yl}ethyl)carbamate (44)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (0.1 1 g , 0.22 mmol, 80% purity), 1- phenylethanamine (0.07 ml, 0.54 mmol), DIPEA (0.303 ml, 1 .63 mmol) and HATU (0.25 g , 0.64 mmol) in DMF (2 ml) afforded the crude title compound (1 10 mg, 77%, 77% purity) as a yellow oil after purification by flash column chromatography (KP-NH, eluting with a gradient of 8-100% EtOAc / heptane).HPLCMS (Method E): [m / z]: 506.2 [M+H]+Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(difluoromethoxy)phenyl]methyl}carbamoyl)-1 ,3-thiazol-2-yl]ethyl}carbamate (45)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (109 mg, 0.22 mmol, 80% purity), 1-[2- (difluoromethoxy)phenyl]methanamine (83 mg, 0.48 mmol), DIPEA (0.23 ml, 1.3 mmol) and HATU (250 mg, 0.65 mmol) in DMF (2 ml) afforded the crude title compound (470 mg) as an orange oil which was used in the next step without purification.HPLCMS (Method A): [m / z]: 558.25 [M+H]+Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(morpholine-4- sulfonyl)phenyl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (46)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (109 mg, 0.217 mmol, 80% purity), 1-[2- (morpholin-4-ylsulfonyl)phenyl]methanamine hydrochloride (140 mg, 0.48 mmol), DIPEA (0.23 ml, 1.3 mmol) and HATU (247 mg, 0.65 mmol) in DMF (2 ml) afforded the crude title compound (440 mg) as an orange oil after direct evaporation of the reaction mixture / n vacuo. The material was used without purification.HPLCMS (Method A): [m / z]: 641.35 [M+H]+ Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[2-(pyridin-2-yl)ethyl]carbamoyl}-1,3-thiazol^ yl)ethyl]carbamate (47)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.2 mmol, 80% purity), 2-(pyridin- 2-yl)ethanamine (49 mg, 0.4 mmol), DIPEA (104 μΙ, 0.6 mmol) and HATU (151 mg, 0.4 mmol) in DMF (2 ml) afforded the title compound (52 mg, 52%) as a cream solid after purification by flash column chromatography KP-NH, eluting with a gradient of 5-100% EtOAc / heptane).HPLCMS (Method A): [m / z]: 507.15 [M+H]+ Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(3-fluoropyridin-2-yl)carbamoyl]-1,3-thiazol-2- yl}ethyl)carbamate (48)In a similar fashion to general procedure 6, a solution of 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (80%, 150 mg, 0.3 mmol), 3-fluoropyridin-2- amine (100 mg, 0.89 mmol), DIPEA (312 μΙ, 1.78 mmol) and HATU (340 mg, 0.87 mmol) in DMF(2 ml) was heated at 100°C for 16 h. The reaction mixture was concentrated in vacuo to give the crude title compound (705 mg) as a brown oil which was used in the next step without purification.HPLCMS (Method A): [m / z]: 497.10 [M+H]+Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(2-phenylethyl)carbamoyl]-1 ,3-thiazol-2- yl}ethyl)carbamate (49)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (0.1 g, 0.25 mmol), 2-phenylethanamine (0.03 ml, 0.25 mmol), DIPEA (0.13 ml, 0.75 mmol) and HATU (0.14 g, 0.37 mmol) in DMF (2 ml) afforded the title compound (71 mg, 56%) as a yellow oil after purification by flash column chromatography (eluting with a gradient of 2-100% EtOAc / heptane).HPLCMS (Method A): [m / z]: 506.2 [M+H]+Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-fluoro-6-methylpyridin-2- yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (50)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (150 mg, 0.298 mmol, 80% purity), (3- fluoro-6-methylpyridin-2-yl)methanamine hydrochloride (79 mg, 0.447 mmol), DIPEA (156 μΙ, 0.894 mmol) and HATU (230 mg, 0.596 mmol) in DMF (3 ml) afforded the title compound (76 mg, 48%) as a pale yellow oil after purification by flash column chromatography (kp-NH, eluting with a gradient of 0-100% EtOAc / heptane).HPLCMS (Method A): [m / z]: 525.40 [M+H]+ Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[1-(pyridin-2-yl)ethyl]carbamoyl}-1,3-thiazol-^ yl)ethyl]carbamate (51 )In a similar manner to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (150 mg, 0.298 mmol, 80% purity), 1- (pyridin-2-yl)ethanamine (55 mg, 0.447 mmol), DIPEA (156 μΙ, 0.894 mmol) and HATU (227 mg, 0.596 mmol) in DMF (3 ml) afforded the title compound (78 mg, 50%) as a colourless oil after purificationby flash column chromatography (kp-NH, eluting with a gradient of 0-100% EtOAc / heptane).HPLCMS (Method A): [m / z]: 507.20 [M+H]+ Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[6-(trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (52)In a similar manner to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (150 mg, 0.298 mmol, 80% purity), 1-[6- (trifluoromethyl)pyridin-3-yl]methanamine (79 mg, 0.447 mmol), DIPEA (156 μΙ, 0.894 mmol) and HATU (227 mg, 0.596 mmol) in DMF (3 ml) afforded the title compound (92 mg, 46%) as a colourless oil after purification by flash column chromatography (kp-NH, eluting with a gradient of 0-100% EtOAc / heptane). HPLCMS (Method A): [m / z]: 561.35 [M+H]+ Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-chloropyridin-2-yl)methyl]carbamoyl}-1,3- thiazol-2-yl)ethyl]carbamate (53)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (150 mg, 0.34 mmol, 92% purity), 1-(3- chloropyridin-2-yl)methanamine dihydrochloride (1 1 1 mg, 0.51 mmol), DIPEA (299 μΙ, 1.71 mmol) and HATU (196 mg, 0.51 mmol) in DMF (2 ml) afforded the title compound (161 mg, 73% purity, 63%) as a yellow oil after purification by flash column chromatography (kp-NH, eluting with a gradient of 20-100% EtOAc / heptane).1 H-NMR (CDCI3, 500 MHz): d[ppm]= 10.47 (s, 1 H), 8.59 (s, 1 H), 8.52 - 8.42 (m, 1 H), 7.92 (s, 1 H), 7.71 (d, J = 8.2 Hz, 2H), 7.32 (s, 1 H), 7.25 - 7.16 (m, 3H), 4.85 (d, J = 4.8 Hz, 2H), 4.69 (s, 2H), 3.81 (s, 2H), 3.23 (t, J = 6.5 Hz, 2H), 1.35 (s, 9H)HPLCMS (Method A): [m / z]: 527.35 [M+H]+Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(tert-butoxy)pyridin-3- yl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (54)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (150 mg, 0.34 mmol, 92% purity), 1-(2-tert- butoxypyridin-3-yl)methanamine (93 mg, 0.514 mmol), DIPEA (179 μΙ, 1.03 mmol) and HATU (196 mg, 0.51 mmol) in DMF (2 ml) afforded the title compound (205 mg, 61 %, 58% purity) as a yellow oil after purification by flash column chromatography (kp-NH, eluting with a gradient of 20-100% EtOAc / heptane). 1 H-NMR (CDCI3, 500 MHz): d[ppm]= 10.09 (s, 1 H), 7.89 (d, J = 15.7 Hz, 2H), 7.71 (s, 1 H), 7.54- 7.45 (m, 2H), 7.40 (d, J = 4.9 Hz, 1 H), 7.24 (s, 1 H), 6.77 (td, J = 7.3, 5.0 Hz, 2H), 4.60 (s, 2H), 4.49 (d, J = 6.5 Hz, 2H), 3.77 (t, J = 6.5 Hz, 2H), 3.22 (s, 2H), 1 .63 (s, 9H), 1.33 (s, 9H)HPLCMS (Method A): [m / z]: 565.15 [M+H]+Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(1-methyl-1 H-imidazol-5- yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (55)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (150 mg, 0.37 mmol), (1-methyl-1 H- imidazol-5-yl)methanamine (62 mg, 0.56 mmol), DIPEA (185 μΙ, 1 .12 mmol) and HATU (213 mg, 0.56 mmol) in DMF (2 ml) afforded the title compound (175 mg, 95%) as a yellow oil after purification by flash column chromatography (eluting with a gradient of 0-3% MeOH / DCM).1 H-NMR (Methanol-d4, 500 MHz): d[ppm]= 8.08 (s, 1 H), 7.58 - 7.52 (m, 3H), 7.26 - 7.20 (m, 2H), 6.96 (s, 1 H), 4.69 (d, J = 12.4 Hz, 2H), 4.60 (s, 2H), 3.95- 3.75 (m, 2H), 3.70 (s, 3H), 3.39 - 3.24 (m, 2H), 1.44 - 1.26 (m, 9H)HPLCMS (Method A): [m / z]: 496.05 [M+H]+ Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(1 ,3-oxazol-2-ylmethyl)carbamoyl]-1,3-thiazol- 2-yl}ethyl)carbamate (56)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (150 mg, 0.298 mmol, 80% purity), 1 ,3- oxazol-2-ylmethanamine dihydrochloride (102 mg, 0.596 mmol), DIPEA (312 μΙ, 1 .79 mmol) and HATU (227 mg, 0.596 mmol) in DMF (3 ml) afforded the title compound (94 mg, 63%) as a tan oil after pirification by flash column chromatography (kp-NH, eluting with a gradient of 0-100% EtOAc / heptane).HPLCMS (Method A): [m / z]: 483.05 [M+H]+Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(1-methyl-1 H-pyrazol-3-yl)methyl]carbamoyl}- 1,3-thiazol-2-yl)ethyl]carbamate (57)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (150 mg, 0.298 mmol, 80% purity), 1-(1- methyl-1 H-pyrazol-3-yl)methanamine (50 mg, 0.45 mmol), DIPEA (156 μΙ, 0.894 mmol) and HATU (227 mg, 0.596 mmol) in DMF (3 ml) afforded the title compound (53 mg, 34%) as a tan oil after purification by flash column chromatography (kp-NH, eluting with a gradient of 0-100% EtOAc / heptane).HPLCMS (Method A): [m / z]: 496.45 [M+H]+Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyridazin-3-ylmethyl)carbamoyl]-1 ,3-thiazol-2- yl}ethyl)carbamate (58)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.23 mmol, 92% purity), 1- (pyridazin-3-yl)methanamine (37 mg, 0.34 mmol), DIPEA (1 19 μΙ, 0.69 mmol) and HATU (130 mg, 0.34 mmol) in DMF (2 ml) afforded the title compound (101 mg, 88%) as a pale yellow oil after purification by flash column chromatography (kp-NH, eluting with a gradient of 50-100% EtOAc / heptane followed by 0- 15% MeOH / EtOAc).HPLCMS (Method A): [m / z]: 494.1 [M+H]+ Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(1-methyl-1 H-pyrazol-5-yl)methyl]carbamoyl}- 1,3-thiazol-2-yl)ethyl]carbamate (59)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.23 mmol, 92% purity), 1-(1 - methyl-1 H-pyrazol-5-yl)methanamine (38 mg, 0.34 mmol), DIPEA (1 19 μΙ, 0.69 mmol) and HATU (130 mg, 0.34 mmol) in DMF (2 ml) afforded the title compound (51 mg, 45%) as a pale yellow oil after purification by flash column chromatography (kp-NH, eluting with a gradient of 50-100% EtOAc / heptane followed by 0-20% MeOH / EtOAc).HPLCMS (Method A): [m / z]: 496.3 [M+H]+Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-fluoropyridin-4-yl)methyl]carbamoyl}-1,3- thiazol-2-yl)ethyl]carbamate (60)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.23 mmol, 92% purity), 1-(3- fluoropyridin-4-yl)methanamine (43 mg, 0.34 mmol), DIPEA (1 19 μΙ, 0.69 mmol) and HATU (130 mg, 0.34 mmol) in DMF (3 ml) afforded the title compound (137 mg, 83%, 71 % purity) as a yellow oil after flash column chromatography (kp-NH, eluting with a gradient of 50-100% EtOAc / heptane).1 H-NMR (CDCI3, 500 MHz): d[ppm]= 10.10 (s, 1 H), 8.43 (d, J = 6.0 Hz, 1 H), 8.37 (dd, J = 9.8, 4.9 Hz, 2H), 7.96 (s, 1 H), 7.81 - 7.68 (m, 2H), 7.40 (d, J = 8.6 Hz, 1 H), 7.35 - 7.27 (m, 1 H), 7.25 - 7.22 (m, 1 H), 4.68 (d, J = 6.0 Hz, 2H), 4.62 (s, 2H), 3.78 (t, J = 6.5 Hz, 2H), 3.27- 3.23 (m, 2H), 1.37 (s, 9H)HPLCMS (Method A): [m / z]: 51 1.15 [M+H]+Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-methylpyridin-4-yl)methyl]carbam thiazol-2-yl)ethyl]carbamate (61)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (700 mg, 1 .65 mmol, 95% purity), (3- methylpyridin-4-yl)methanamine dihydrochloride (387 mg, 1.98 mmol), DIPEA (863 μΙ, 4.9 mmol) and HATU (1260 mg, 3.3 mmd) in DMF (10 ml) afforded the title compound (363 mg, 43%) as a yellow oil after purification by flash chromatography (kp-NH, using an elution gradient 20-100% EtOAc / heptane).HPLCMS (Method A): [m / z]: 507.1 [M+H]+Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(1-methyl-1 H-pyrazol-4-yl)methyl]carbamoyl}- 1,3-thiazol-2-yl)ethyl]carbamate (62)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.25 mmol), (1-methyl-1 H-pyrazol- 4-yl)methanamine (41 mg, 0.37 mmol), DIPEA (130 μΙ, 0.75 mmol) and HATU (142 mg, 0.37 mmol) in DMF (2 ml) afforded the title compound (125 mg, quant.) as a yellow oil after purification by flash column chromatography (eluting with a gradient of 0-20% MeOH / EtOAc).HPLCMS (Method A): [m / z]: 496.1 [M+H]+Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-methylpyridazin-3-yl)methyl]carbamoyl}- 1,3-thiazol-2-yl)ethyl]carbamate (63)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.23 mmol, 92% purity), (6- methylpyridazin-3-yl)methanamine (42 mg, 0.34 mmol), DIPEA (1 19 μΙ, 0.69 mmol) and HATU (130 mg, 0.34 mmol) in DMF (3 ml) afforded the crude title compound (99 mg, 67%, 79% purity) after flash column chromatography (kp-NH, eluting with a gradient of 70-100% EtOAc / heptane).1 H-NMR (CDCI3, 500 MHz): d[ppm]= 10.50 (s, 1 H), 8.28 (s, 1 H), 7.92 (s, 1 H 7.72 (s, 1 H), 7.40 - 7.29 (m, 3H), 7.23 (dd, J = 6.4, 2.8 Hz, 2H), 4.68 (s, 2H), 3.82 (s, 2H), 3.24 (s, 2H), 2.73 (s, 2H), 2.71 (s, 3H), 1.36 (s, 9H)HPLCMS (Method A): [m / z]: 508.10 [M+H]+Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(1 H-imidazol-2-ylmethyl)carbamoyl]-1,3- thiazol-2-yl}ethyl)carbamate (64)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.25 mmol), 1-(1 H-imidazol-2- yl)methanamine (42 mg, 0.25 mmol), DIPEA (164 μΙ, 0.99 mmol) and HATU (188 mg, 0.50 mmol) in DMF (2 ml) afforded the title compound (65 mg, 54%) as a yellow oil after purification by flash column chromatography (kp-NH, eluting with a gradient 0-5% MeOH / DCM).HPLCMS (Method A): [m / z]: 482.25 [M+H]+Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(morpholin-4-yl)pyridin-4- yl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (65)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.25 mmol), [3-(morpholin-4- yl)pyridin-4-yl]methanamine (48 mg, 0.25 mmol), DIPEA (164 μΙ, 0.99 mmol) and HATU (189 mg, 0.50 mmol) in DMF (2 ml) afforded the title compound (1 12 mg, 78%) as a yellow solid after purification by flash column chromatography (kp-NH, eluting with a gradient of 50-100% EtOAc / heptane).HPLCMS (Method A): [m / z]: 578.10 [M+H]+Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(5-methylpyridin-2-yl)methyl]carbamoyl}-1,3- thiazol-2-yl)ethyl]carbamate (66)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.20 mmol, 80% purity), 1-(5- methylpyridin-2-yl)methanamine (29 mg, 0.24 mmol), DIPEA (104 μΙ, 0.60 mmol) and HATU (15 1 mg, 0.40 mmol) in DMF (2 ml) afforded the title compound (48 mg, 47%) as a colourless oil after purification by flash column chromatography (kp-NH, eluting with a gradient of 0-100% EtOAc / heptane).HPLCMS (Method A): [m / z]: 507.1 [M+H]+Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[6-(dimethylamino)pyridin-3- yl]methyl}carbamoyl)-1 ,3-thiazol-2-yl]ethyl}carbamate (67)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.20 mmol, 80% purity), 5- (aminomethyl)-N,N-dimethylpyridin-2-amine (30 mg, 0.20 mmol), DIPEA (104 μΙ, 0.60 mmol) and HATU (151 mg, 0.40 mmol) in DMF (2 ml) afforded the title compound (36 mg, 34%) as a colourless oil after purification by flash column chromatography (kp-NH, eluting with a gradient of 0-100% EtOAc / heptane). HPLCMS (Method A): [m / z]: 536.35 [M+H]+ Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(2-methylpyridin-4-yl)methyl]carbam thiazol-2-yl)ethyl]carbamate (68)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.20 mmol, 80% purity), 1-(2- methylpyridin-4-yl)methanamine (36 mg, 0.30 mmol), DIPEA (104 μΙ, 0.60 mmol) and HATU (151 mg, 0.40 mmol) in DMF (2 ml) afforded the title compound (36 mg, 36%) as a colourless oil after purfication by flash column chromatography (kp-NH, eluting with a gradient of 0-100% EtOAc / heptane).HPLCMS (Method A): [m / z]: 507.3 [M+H]+ Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(1,5-dimethyl-1 H-pyrazol-4- yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (69)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.20 mmol, 80% purity), 1-(1 ,5- dimethyl-1 H-pyrazol-4-yl)methanamine (37 mg, 0.30 mmol), DIPEA (104 μΙ, 0.60 mmol) and HATU (151 mg, 0.40 mmol) in DMF (2 ml) afforded the title compound (74 mg, 73%) as a colourless oil after purification by flash column chromatography (kp-NH , eluting with a gradient of 0-100% EtOAc / heptane). HPLCMS (Method A): [m / z]: 510.15 [M+H]+Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[3-chloro-5-(trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1 ,3-thiazol-2-yl]ethyl}carbamate (70)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.236 mmol), 1-[3-chloro-5- (trifluoromethyl)pyridin-2-yl]methanamine hydrochloride (87 mg, 0.354 mmol), DIPEA (0.21 ml, 1 .18 mmol), and HATU (135 mg, 0.354 mmol) in DMF (3 ml) afforded the title compound (216 mg, 69%, 45% purity) as a yellow oil after flash column chromatography (KP-NH, eluting with a gradient of 20-100% EtOAc / heptane). The title compound was used in the next step without further purification.HPLCMS (Method A): [m / z]: 595.1 [M+H]+Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-chloro-5-fluoropyridin-2- yl)methyl]carbamoyl}-1 ,3-thiazol-2-yl)ethyl]carbamate (71 )In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.236 mmol), (3-chloro-5- fluoropyridin-2-yl)methanamine hydrochloride (70 mg, 0.354 mmol), DIPEA (0.21 ml, 1 .18 mmol), and HATU (135 mg, 0.354 mmol) in DMF (3 ml) afforded the title compound (157 mg , 76%, 62% purity) as a yellow oil after flash column chromatography (KP-NH, eluting with a gradient of 20-100% EtOAc / heptane). The title compound was used in the next step without further purification.HPLCMS (Method A): [m / z]: 545.15 [M+H]+ Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(2-fluoropyridin-3-yl)methyl]carbamoyl}-1 ,3- thiazol-2-yl)ethyl]carbamate (72)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.236 mmol, 95% purity), 1-(2- fluoropyridin-3-yl)methanamine (47.01 mg, 0.373 mmol), DIPEA (0.13 ml, 0.745 mmol) and HATU (141 .7 mg, 0.373 mmol) in DMF (2 ml) afforded the title compound (0.359 g, quant.) as a brown solid after evaporation of the solvent. The title compound was used in the next step without further purification.HPLCMS (Method A): [m / z]: 51 1 .10 [M+H]+ Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(2-methoxypyridin-4-yl)methyl]carbamoyl}- 1 ,3-thiazol-2-yl)ethyl]carbamate (73)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.236 mmol, 95% purity), 1-(2- methoxypyridin-4-yl)methanamine (49 mg , 0.354 mmol), DIPEA (0.12 ml, 0.708 mmol) and HATU (135 mg, 0.354 mmol) in DMF (3 ml) afforded the title compound (104 mg, 81 %, 96% purity) as a white solid after purification by flash column chromatography (eluting with a gradient of 30-100% EtOAc / heptane).1 H-NMR (CDCI3, 500 MHz): d[ppm]= 10.07 (s, 1 H), 8.10 (d , J = 5.3 Hz, 1 H), 7.96 (s, 1 H), 7.73 - 7.66 (m, 2H), 7.41 - 7.37 (m, 1 H), 7.25 - 7.22 (m, 2H), 6.85 - 6.82 (m, 1 H), 6.69 (s, 1 H), 4.62 (s, 2H), 4.56 (d, J = 6.3 Hz, 2H), 3.91 (s, 3H), 3.78 (t, J = 6.6 Hz, 2H), 3.24 (t, J = 6.2 Hz, 2H), 1 .39 (s, 9H)HPLCMS (Method A): [m / z]: 523.3 [M+H]+Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(4,6-dimet^1 ,3-thiazol-2-yl)ethyl]carbamate (74)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.236 mmol, 95% purity), (4,6- dimethylpyridin-3-yl)methanamine dihydrochloride (B1 ) (93 mg, 0.354 mmol, 80% purity), DIPEA (0.206 ml, 1 .18 mmol) and HATU (135 mg, 0.354 mmol) in DMF (3 ml) afforded the title compound (77 mg, 63 %) as a yellow oil after purification by flash column chromatography (eluting with a gradient ofO-15% MeOH / EtOAc).HPLCMS (Method A): [m / z]: 521 .05 [M+H]+Tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(4-methylpyridin-2-yl)methyl]carbamoyl}1 ,3- thiazol-2-yl)ethyl]carbamate (75)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.236 mmol, 95% purity), (4,6- dimethylpyridin-3-yl)methanamine dihydrochloride (93 mg, 0.354 mmol), DIPEA (0.123 ml, 0.708 mmol) and HATU (135 mg , 0.354 mmol) in DMF (2 ml) afforded the title compound (90 mg, 72%) as a yellow oil after purification by flash column chromatography (KP-NH, eluting with a gradient of 20-100% EtOAc / heptane followed by 0-20% MeOH / EtOAc).HPLCMS (Method A): [m / z]: 507.10 [M+H]+Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-(5,6,7,8-tetrahydro-1,6-naphthyridine-6- carbonyl)-1 ,3-thiazol-2-yl]ethyl}carbamate (76)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.236 mmol, 95% purity), 5,6,7,8- tetrahydro-1 ,6-naphthyridine dihydrochloride (62 mg, 0.298 mmol), DIPEA (0.173 ml, 0.994 mmol) and HATU (151 mg, 0.398 mmol) in DMF (2 ml) afforded the title compound (90mg, 72%) as a colourless oil after purification by flash column chromatography (kp-NH, eluting with a gradient of 0-100% EtOAc / heptane).HPLCMS (Method A): [m / z]: 519.15 [M+H]+Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3,5-difluoropyridin-2-yl)methyl] carbamoyl} - 1,3-thiazol-2-yl)ethyl]carbamate (77)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.236 mmol, 95% purity), (3,5- difluoropyridin-2-yl)methanamine dihydrochloride (65 mg, 0.298 mmol), DIPEA (0.173 ml, 0.994 mmol) and HATU (151 mg, 0.398 mmol) in DMF (3 ml) afforded the title compound (1 12 mg, quant.) as a colourless oil after purification by flash column chromatography (kp-NH, eluting with a gradient of 0-100% EtOAc / heptane).HPLCMS (Method A): [m / z]: 529.10 [M+H]+Tert-butyl N-(1 H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-{[(tert-butyldimethylsilyl)oxy]methyl} pyridin-2-yl) methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (78)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (15.94 mg, 0.04 mmol), (3-{[(tert- butyldimethylsilyl)oxy]methyl}pyridin-2-yl)methanamine (C3) (10 mg, 0.04 mmol), DIPEA (0.03 ml, 0.16 mmol) and HATU (30.13 mg, 0.08 mmol) in DMF (2 ml) afforded the title compound (17.5 mg, 34%, 30% purity) as an orange oil after purification by flash column chromatography (eluting with a gradient of 0 100% EtOAc / heptane).HPLCMS (Method A): [m / z]: 637.15 [M+H]+Tert-butyl 2-{[(2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 ,3-thiazol- 4-yl)formamido]methyl}piperidine-1-carboxylate (79)In a similar fashion to general procedure 6, 2-{2-[(1 H-1 ,3-benzodiazol-2-ylmethyl)[(tert- butoxy)carbonyl]amino]ethyl}-1 ,3-thiazole-4-carboxylic acid (8) (200 mg, 0.5 mmol), tert-butyl 2-(aminomethyl)piperidine-l-carboxylate (149 mg, 0.7 mmol), TEA (66.16 μΙ, 0.5 mmol) and HATU (280 mg, 0.75 mmol) in DMF (5 ml) at room temperature for 2 h, afforded the title compound (50 mg, 17%) as an orange oil after purification by flash column chromatography (eluting with a gradient of 0-100% EtOAc / heptane) followed by basic prep-HPLC.HPLCMS (Method A): [m / z]: 599.4 [M+H]+2-{2-[(1 H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(pyridin-2-ylmethyl)-1,3-thiazole-4- carboxamide trihydrochloride (Example Compound No. 12)In a similar fashion to general procedure 2, 4M HCI in dioxane (1 1 ml) aid tert-butyl N-(1 H-1 ,3- benzodiazol-2-ylmethyl)-N-(2-{4-[(pyridin-2-ylmethyl)carbamoyl]-1 ,3-thiazol-2-yl}ethyl)carbamate (9) (2.2 g, 4.47 mmol) in dioxane (30ml) at room temperature for 16 h, gave the title compound (HCI salt) (1.7 g, 76%) as a yellow solid after trituration from Et20 (2 x 30 ml) followed by DCM (2 x 20 ml) and EfcO (2 x 30 ml). 1 H-NMR (DMSO-d6, 500 MHz): d[ppm]= 10.39 (s, 1 H), 9.68 (t, J = 6.0 Hz, 1 H), 8.86 - 8.75 (m, 1 H), 8.44 (td, J = 7.9, 1.5 Hz, 1 H), 8.30 (s, 1 H), 7.96 - 7.84 (m, 2H), 7.76 (dt, J = 6.5, 3.3 Hz, 2H), 7.44 (dq, J = 6.5, 3.4 Hz, 2H), 4.86 (d, J = 6.0 Hz, 2H), 4.76 (s, 2H), 3.66 (dt, J = 38.8, 7.1 Hz, 4H)HPLCMS (Method C): [m / z]: 493.4 [M+H]+2-{2-[(1 H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(cyclohexylmethyl)-1,3-thiazole-4-carboxamide (Example Compound No. 13)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-(2-{4- [(cyclohexylmethyl)carbamoyl]-1 ,3-thiazol-2-yl}ethyl)carbamate (10) (1 1 1.5 mg, 0.224 mmol) and 50% TFA in DCM (10 ml) at room temperature overnight gave the title compound (30 mg, 34%, 98% purity) as a white oil after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH in DCM).1 H-NMR (CDCI3, 400 MHz): d[ppm]= 7.96 (s, 1 H), 7.56 - 7.53 (m, 2H), 7.41 (s, 1 H), 7.25 - 7.17 (m, 2H), 4.16 (s, 2H), 3.25 (t, J = 6.9 Hz, 2H), 3.17 - 3.13 (m, 4H), 1.79 - 1.60 (m, 5H), 1.60 - 1.46 (m, 1 H), 1.29 - 1.06 (m, 4H), 0.95 (m, 2H)HPLCMS (Method J): [m / z]: 498.5 [M+H]+(1 H-1 ,3-Benzodiazol-2-ylmethyl)({2-[4-(1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 ,3-thiazo^ yl]ethyl})amine (Example Compound No. 15)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-{2-[4-(1 , 2,3,4- tetrahydroisoquinoline-2-carbonyl)-1 ,3-thiazol-2-yl]ethyl}carbamate (11) (1 15.95 mg, 0.224 mmol) and 50% TFA in DCM (10 ml) at room temperature overnight gave the title compound (25 mg, 27%, 99% purity) as a white oil after purification by flash column chromatography (eluting with a gradient of 010% MeOH in DCM).1 H-NMR (CDCI3, 400 MHz): d[ppm]= 7.70 (s, 1 H), 7.55 (m, 2H), 7.14 - 6.94 (m, 6H), 4.89 (s, 2H), 4.14 (s, 2H), 3.95 (m, 2H), 3.22 (m, 2H), 3.13 (m, 2H), 2.96- 2.85 (m, 2H)HPLCMS (Method J): [m / z]: 416.5 [M+H]+2-{2-[(1 H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(thiophen-2-ylmethyl)-1,3-thiazole-4- carboxamide (Example Compound No. 16)In a similar fashion to general procedure 7, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(thiophen- 2-ylmethyl)carbamoyl]-1 ,3-thiazol-2-yl}ethyl)carbamate (12) (180 mg, 0.362 mmol) and 50% TFA in DCM (10 ml) at room temperature overnight gave the title compound (51 mg, 34%, 98% purity) as a white oil after purification by prep-HPLC.1 H-NMR (CDCb, 400 MHz): d[ppm]= 8.05 (s, 1 H), 7.59 (m, 3H), 7.24 (m, 2H), 7.21 - 7.19 (dd, J = 5.1 , 1 .2 Hz, 1 H), 7.01 (m, 1 H), 6.94 (m, 1 H), 4.78 (d, J = 6.0, 2H), 4.15 (s, 2H), 3.27 - 3.07 (m, 4H)HPLCMS (Method J): [m / z]: 398.5 [M+H]+2-{2-[(1 H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-benzyl-N-methyl-1,3-thiazole-4-carboxamide (Example Compound No. 17)In a similar fashion using general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-(2-{4- [benzyl(methyl)carbamoyl]-1 ,3-thiazol-2-yl}ethyl)carbamate (13) (1 13.26 mg, 0.224 mmol) and 50% TFA ' DCM (10 ml) at room temperature overnight gave the title compound (40 mg, 44%, 99% purity) as a white oil after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH in DCM). 1 H-NMR (CDCI3, 400 MHz): d[ppm]= 7.64 (bs, 1 H), 7.56 (bs, 2H), 7.39 - 7.27 (m, 4H), 7.19 (m, 3H), 4.78 (bs, 2H), 4.25 - 3.93 (m, 2H), 3.17 - 3.12 (m, 4H), 3.06 (bs, 3H)HPLCMS (Method J): [m / z]: 406.5 [M+H]+(1 H-1,3-Benzodiazol-2-ylmethyl)({2-[4-(morpholine-4-carbonyl)-1,3-thiazol-2-yl]ethyl})ami(Example Compound No. 18)In a similar fashion using general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-{2-[4- (morpholine-4-carbonyl)-1 ,3-thiazol-2-yl]ethyl}carbamate (14) (105.6 mg, 0.224 mmol) and 50% TFA in DCM (10 ml) at room temperature overnight gave the title compound (20 mg, 24%, 95% purity) as a white oil after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH in DCM). 1 H-NMR (CDCb, 400 MHz): d[ppm]= 7.68 (s, 1 H), 7.58 -7.56 (m, 2H), 7.23 (m, 2H), 4.17 (s, 2H), 3.79 - 3.78 (m, 4H), 3.69 (bs, 4H), 3.22 (m, 2H), 3.14 (s, 2H)HPLCMS (Method J): [m / z]: 372.5 [M+H]+2-{2-[(1 H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-methyl-N-phenyl-1,3-thiazole-4-carboxamide (Example Compound No. 19)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-(2-{4- [methyl(phenyl)carbamoyl]-1 ,3-thiazol-2-yl}ethyl)carbamate (15) (1 10.12 mg, 0.224 mmol) and 50% TFA in DCM (10 ml) at room temperature overnight gave the title compound (40 mg, 45%, 85% purty) as a white oil after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH in DCM). 1 H-NMR (CDCb, 400 MHz): d[ppm]= 7.69 (bs, 2H), 7.29 - 7.21 (m, 5H), 7.10 (s, 2H), 4.28 (s, 2H), 3.60 - 3.43 (m, 3H), 3.18 (bs, 2H), 3.05 (bs, 2H)HPLCMS (Method J): [m / z]: 392.5 [M+H]+2-{2-[(1 H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-{[2-(pyrrolidin-1-yl)phenyl]methyl}-1,3-thiazole- 4-carboxamide (Example Compound No. 21)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2- (pyrrolidin-1-yl)phenyl]methyl}carbamoyl)-1 ,3-thiazol-2-yl]ethyl}carbamate (16) (100 mg, 0.178 mmol) and 50% TFA in DCM (8 ml) at room temperature overnight gave the title compound (70 mg, 69%, 82% purity) as a white oil after purification by flash column chromatography (eluting with a gradient of 5-7% MeOH in DCM).1 H-NMR (CDCI3, 400 MHz): d[ppm]= 7.94 (s, 1 H), 7.85 (t, J = 5.6 Hz, 1 H), 7.53 - 7.47 (m, 2H), 7.24 - 7.16 (m, 2H), 7.12 (t, J =7.8 Hz, 1 H), 6.59 (d, J = 7.5 Hz, 1 H), 6.48 (s, 1 H), 6.43 (d, J = 8.1 Hz, 1 H), 4.53 (d, J = 5.9 Hz, 2H), 4.14 (s, 2H), 3.21 (m, 4H), 3.12 - 3.05 (m, 4H), 2.00 - 1.90 (m, 4H)HPLCMS (Method J): [m / z]: 461.6 [M+H]+2-{2-[(1 H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N,N-dimethyl-1,3-thiazole-4-carboxami(Example Compound No. 22)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-{2-[4- (dimethylcarbamoyl)-1 ,3-thiazol-2-yl]ethyl}carbamate (17) (90 mg, 0.209 mmol) and 50% TFA in DCM (5 ml) at room temperature overnight gave the title compound (18 mg, 25%) as a white oil after purification by flash column chromatography (eluting with a gradient of 5-7% MeOH in DCM).1 H-NMR (CDCb, 400 MHz): d[ppm]= 7.63 (s, 1 H), 7.56 (dd, J = 5.8, 3.1 Hz, 2H), 7.26- 7.14 (m, 2H), 4.73 (s, 2H), 3.29 - 3.01 (m, 10H)HPLCMS (Method I): [m / z]: 330.4 [M+H]+2-{2-[(1 H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-cyclohexyl-N-(propan-2-yl)-1,3-thiazole-4- carboxamide (Example Compound No. 25)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-(2-{4- [cyclohexyl(propan-2-yl)carbamoyl]-1 ,3-thiazol-2-yl}ethyl)carbamate (18) (275 mg, 0.523 mmol) and 4M HCI in dioxane (20 ml) at room temperature overnight gave the title compound (70 mg, 29%) as an off white oil after purification by flash column chromatography (eluting with a gradient of 1 15% MeOH in DCM).1 H-NMR (CDCb, 400 MHz): d[ppm]= 7.56 (dt, J = 6.5, 3.3 Hz, 2H), 7.37 (s, 1 H), 7.20- 7.15 (m, 2H), 4.09 (s, 2H), 3.60 (br s, 1 H), 3.43 (dd, J = 12.4, 5.9 Hz, 1 H), 3.18 (t, J = 6.2 Hz, 2H), 3.06 (m, 3H), 2.16- 2.08 (m,1 H), 1 .80 (m, 4H), 1 .64 - 1.54 (m, 3H), 1 .40 (d, J = 6.5 Hz, 3H), 1 .21 (m, 4H)HPLCMS (Method K): [m / z]: 426.2 [M+H]+2-{2-[(1 H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(2-phenylpropan-2-yl)-1,3-thiazole-4- carboxamide (Example Compound No. 26)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(2- phenylpropan-2-yl)carbamoyl]-1 ,3-thiazol-2-yl}ethyl)carbamate (19) (305 mg, 0.587 mmol) and 4M HCI in dioxane (20 ml) at room temperature overnight gave the title compound (80 mg, 32%) as an off white oil after purification by flash column chromatography (eluting with a gradient of 10-15% MeOH in DCM).1 H-NMR (CDCI3, 400 MHz): d[ppm]= 7.82 (s, 1 H), 7.75 (s,1 H), 7.49 (dd, J = 5.9, 3.1 Hz, 2H), 7.47- 7.39 (m, 2H), 7.26 (t, J = 7.7 Hz, 2H), 7.20 - 7.14 (m, 2H), 4.05 (s, 2H), 3.09 (d, J = 5.6 Hz, 2H), 3.05 (d, J = 5.7 Hz, 2H), 1.78 (s, 6H)HPLCMS (Method J): [m / z]: 420.4 [M+H]+N-Benzyl-2-(2-{[(1-methyl-1 H-1 ,3-benzodiazol-2-yl)m(Example Compound No. 28)In a similar fashion to general procedure 2, tert-butyl N-{2-[4-(benzylcarbamoyl)-1 ,3-thiazol-2-yl]ethyl}-N- [(1-methyl-1 H-1 ,3-benzodiazol-2-yl)methyl]carbamate (21) (280 mg, 0.554 mmol) and 20% TFA in DCM (20 ml) at room temperature overnight gave the title compound (50 mg, 21 %) as a white solid after purification by flash column chromatography (eluting with a gradient of 10-15% MeOH in DCM).1 H-NMR (CDCI3, 400 MHz): d[ppm]= 8.22 (s, 1 H), 7.58 (dd, J = 12.6, 8.1 Hz, 2H), 7.38 (d, J = 1 .0 Hz, 1 H), 7.33 - 7.18 (m, 6H), 4.69 (s, 2H), 4.58 (s, 2H), 3.85 (s, 3H), 3.73 (t, J = 6.4 Hz, 2H), 3.57 (t, J = 6.4 Hz, 2H) HPLCMS (Method J): [m / z]: 406.07 [M+H]+2-{2-[(1 H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(pyridin-3-ylmethyl)-1,3-thiazole-4- carboxamide trihydrochloride (Example Compound No. 35)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyridin-3- ylmethyl)carbamoyl]-1 ,3-thiazol-2-yl}ethyl)carbamate (22) (184 mg, 0.374 mmol) and 4M HCI in dioxane (15 ml) at room temperature for 18 h gave the title compound (80 mg, 53%) as the tri HCI salt as a white solid after precipitation with Et20.1 H-NMR (DMSO-d6, 400 MHz): d[ppm]= 10.28 (bs, 3H), 9.64 (t, J = 6.2 Hz, 1 H), 8.90 (s, 1 H), 8.81 (d, J = 5.4 Hz, 1 H), 8.55 (d, J = 8.1 Hz, 1 H), 8.25 (s, 1 H), 8.00 (dd, J = 8.0, 5.7 Hz, 1 H), 7.73 (m, 2H), 7.48- 7.34 (m, 2H), 4.71 (s, 2H), 4.65 (d, J = 6.2 Hz, 2H), 3.66 (t, J = 6.6 Hz, 2H), 3.57 (t, J = 6.3 Hz, 2H)HPLCMS (Method J): [m / z]: 493.3 [M+H]+2-{2-[(1 H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(pyridin-4-ylmethyl)-1,3-thiazole-4- carboxamide trihydrochloride (Example Compound No. 36)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyridin-4- ylmethyl)carbamoyl]-1 ,3-thiazol-2-yl}ethyl)carbamate (23) (145.8 mg, 0.296 mmol) and 4M HCI in dioxane (15 ml) at room temperature for 18 h gave the title compound (70 mg, 47%) as the tri HCI salt as a white solid after precipitation with Et20.1 H-NMR (DMSO, 400 MHz): d[ppm]= 10.40 (bs, 3H), 9.69 (t, J = 6.2 Hz, 1 H), 8.83 (d, J = 6.7 Hz, 2H), 8.28 (s, 1 H), 7.98 (d, J = 6.6 Hz, 2H), 7.81 - 7.69 (m, 2H), 7.49 - 7.37 (m, 2H), 4.73 (d, J = 5.1 Hz, 4H), 3.68 (t, J = 6.5 Hz, 2H), 3.60 (t, J = 6.4 Hz, 2H)HPLCMS (Method J): [m / z]: 493.3 [M+H]+2-{2-[(1 H-1,3-Benzodiazol-2-ylmethyl)amino]et^thiazole-4-carboxamide (Example Compound No. 37)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[3- (trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1 ,3-thiazol-2-yl]ethyl}carbamate (24) (86.33 mg, 0.154 mmol) and 4M HCI in dioxane (10 ml) at room temperature for 18 h gave the title compound (25 mg, 35%) as a yellow oil after purification by flash column chromatography (eluting with a gradient of 1 15% MeOH in DCM).1 H-NMR (MeOD, 400 MHz): d[ppm]= 8.62 (d, J = 4.8 Hz, 1 H), 8.13 - 8.09 (m, 1 H), 8.08 (s, 1 H), 7.52 - 7.47 (m, 2H), 7.47 - 7.41 (m, 1 H), 7.22 - 7.14 (m, 2H), 4.86 (s, 2H), 4.09 (s, 2H), 3.27 (t, J = 6.6 Hz, 2H), 3.13 (t, J = 6.6 Hz, 2H)HPLCMS (Method J): [m / z]: 461.6 [M+H]+2-{2-[(1 H-1 ,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(5,6J,8-tetrahydroquinolin-8-ylmetthiazole-4-carboxamide (Example Compound No. 38)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(5, 6,7,8- tetrahydroquinolin-8-ylmethyl)carbamoyl]-1 ,3-thiazol-2-yl}ethyl)carbamate (25) (82.03 mg, 0.154 mmol) and 4M HCI in dioxane (10 ml) at room temperature for 18 h gave the title compound (35 mg, 52%) as a yellow oil after purification by flash column chromatography (eluting with a gradient of 10-15% MeOH in DCM).1 H-NMR (MeOD, 400 MHz): d[ppm]= 8.27 (d, J = 3.6 Hz, 1 H), 8.08 (s, 1 H), 7.58 (d, J = 7.6 Hz, 1 H), 7.49 (m, 2H), 7.27 - 7.15 (m, 3H), 5.22 - 5.12 (m, 1 H), 4.05 (s, 2H), 3.21 (t, J = 6.7 Hz, 2H), 3.05 (t, J = 6.4 Hz, 2H), 2.96 - 2.77 (m, 2H), 2.34 - 2.20 (m, 1 H), 2.05 - 1.79 (m, 3H)HPLCMS (Method J): [m / z]: 433.6 [M+H]+2-{2-[(1 H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1,3- thiazole-4-carboxamide trihydrochloride (Example Compound No. 39)In a similar fashion to general procedure 2, 4M HCI in dioxane (6.36 ml) was added to tertbutyl N-(1H-1,3- benzodiazol-2-ylmethyl)-N-{2-[4-({5H,6HJH-cyclopenta[b]pyridin-7-yl}carbamoyl)-1,3-thiazol 2- yl]ethyl}carbamate (26) (1.32 g, 2.55 mmol) in dioxane (30 ml) and stirred atroom temperature for 48 h to give the title compound (1.03 g, 76%) after crystalisation from DCM / MeOH.1H-NMR (MeOD, 500 MHz): d[ppm]= 8.56 (d, J = 5.8 Hz, 1H), 8.52-8.48 (m, 1H), 8.31 (s, 1H), 7.92 (dd, J = 7.7, 6.0 Hz, 1H), 7.86 (dt, J = 6.7, 3.3 Hz,2H), 7.66 (dt, J = 6.3, 3.3 Hz, 2H), 5.95 (t, J = 8.8 Hz, 1H), 5.01 (s, 2H), 3.87 (t, J = 6.2 Hz, 2H), 3.71 -3.63 (m, 2H), 3.42-3.35 (m, 1H), 3.21 (dt, J = 17.1, 8.7 Hz, 1H), 2.86 - 2.77 (m, 1H), 2.51 (dq, J = 12.9, 9.2 Hz, 1H)HPLCMS (Method C): [m / z]: 419.05 [M+H]+2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,^carboxamide trihydrochloride (Example Compound No.40)In a similar fashion to general procedure 2,4M HCI in dioxane (16.57 ml, 66.26 mmd) was added to tertbutyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1 ,3-thiazol-2- yl)ethyl]carbamate (27) (4.13 g, 6.63 mmol) in dioxane (40 ml) and stirred at room temperature for 16 h to give the title compound (3.04 g, 88%) as a white solid after precipitation from E¾0 (100 ml).1H-NMR (MeOD, 500 MHz): d[ppm]= 8.47 (d, J = 5.1 Hz, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.84 (dd, J = 6.1, 3.1 Hz, 2H), 7.76 (s, 1H), 7.62 (dd, J = 6.1, 3.0 Hz, 2H), 4.99 (s, 2H), 4.95 (s, 2H), 3.84 (t, J = 6.2 Hz, 2H), 3.65 (t, J = 6.2 Hz, 2H)HPLCMS (Method D): [m / z]: 411.1 [M+H]+ 2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(4-methylmorpholin-2-yl)methyl]-1,3-thiazole- 4-carboxamide (Example Compound No.41)In a similar fashion to general procedure 2, tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(4- methylmorpholin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(28) (80.8 mg, 0.157 mmol) and 4M HCI in dioxane (15 ml) at room temperature overnight gave the tile compound (31 mg, 47%) as a pale yellow oil after purification by flash column chromatography (eluting with a gradient of 10-15% MeOH in DCM).1H-NMR (MeOD, 400 MHz):d[ppm]= 8.05 (s, 1H), 7.53 (m, 2H), 7.26-7.17 (m, 2H), 4.08 (s, 2H), 3.82- 3.69 (m, 2H), 3.65 - 3.49 (m, 2H), 3.40 - 3.33 (m, 2H), 3.25 (t, J = 6.6 Hz, 2H), 3.10 (t, J = 6.6 Hz, 2H), 2.69 (m, 1H), 2.37 (s, 3H), 2.36-2.28 (m, 2H)HPLCMS (Method J): [m / z]: 415.6 [M+H]+ 2-{2-[(1 H-1 ,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(6-methylpyridin-2-yl)methycarboxamide (Example Compound No. 42)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6- methylpyridin-2-yl)methyl]carbamoyl}-1 ,3-thiazol-2-yl)ethyl]carbamate (29) (79.5 mg, 0.157 mmol) and 4M HCI in dioxane (15 ml) at room temperature overnight gave the title compound (25.5 mg, 36%) as a pale yellow oil after purification by flash column chromatography (eluting with a gradient of 10-15% MeOH in DCM).1 H-NMR (MeOD, 400 MHz): d[ppm]= 8.09 (s, 1 H), 7.63 (t, J = 7.7 Hz, 1 H), 7.50 (m, 2H), 7.23 - 7.17 (m, 3H), 7.15 (m, 2H), 4.63 (s, 2H), 4.08 (s, 2H), 3.26 (t, J = 6.7 Hz, 2H), 3.1 1 (t, J = 6.6 Hz, 2H), 2.50 (s, 3H) HPLCMS (Method J): [m / z]: 405.5 [M+H]+2-{2-[(1 H-1 ,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(5-fluoropyridin-2-yl)methyl]-1 ,3-thi carboxamide (Example Compound No. 43)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(5- fluoropyridin-2-yl)methyl]carbamoyl}-1 ,3-thiazol-2-yl)ethyl]carbamate (30) (80.2 mg, 0.157 mmol) and 4M HCI in dioxane (15 ml) at room temperature overnight gave the title compound (12.5 mg, 17%) as a pale yellow oil after purification by flash column chromatography (eluting with a gradient of 10-15% MeOH in DCM).1 H-NMR (MeOD, 400 MHz): d[ppm]= 8.36 (d, J = 2.6 Hz, 1 H), 8.08 (s, 1 H), 7.59 - 7.46 (m, 3H), 7.42 (m, 1 H), 7.20 (m, 2H), 4.66 (s, 2H), 4.08 (s, 2H), 3.26 (t, J = 6.5 Hz, 2H), 3.1 1 (t, J = 6.5 Hz, 2H)HPLCMS (Method J): [m / z]: 41 1.5 [M+H]+2-{2-[(1 H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(pyrimidin-4-ylmethyl)-1,3-thiazole-4- carboxamide (Example Compound No. 44)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-(2-{4- [(pyrimidin-4-ylmethyl)carbamoyl]-1 ,3-thiazol-2-yl}ethyl)carbamate (31) (75 mg, 0.152 mmol) and 4M HCI in dioxane (2 ml) at room temperature for 4 h gave the title compound (22 mg, 37%) as a yellow solidafter purification by flash column chromatography (eluting with a gradient of 8% MeOH in DCM). 1 H-NMR (MeOD, 400 MHz): d[ppm]= 9.05 (d, J = 1.1 Hz, 1 H), 8.67 (d, J = 5.3 Hz, 1 H), 8.12 (s, 1 H), 7.51 (dd, J = 6.0, 3.2 Hz, 2H), 7.46 (d, J = 5.3 Hz, 1 H), 7.26- 7.18 (m, 2H), 4.68 (s, 2H), 4.10 (s, 2H), 3.28 (t,J = 6.5 Hz, 2H), 3.14 (t, J = 6.6 Hz, 2H)HPLCMS (Method J): [m / z]: 394.4 [M+H]+2-{2-[(1 H-1 ,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(5-methoxypyridin-2-yl)methcarboxamide (Example Compound No. 45)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(5- methoxypyridin-2-yl)methyl]carbamoyl}-1 ,3-thiazol-2-yl)ethyl]carbamate (32) (80 mg, 0.153 mmol) and 4M HCI in dioxane (2 ml) at room temperature for 4 h gave the title compound (53 mg, 82%) as a yellow solid after purification by flash column chromatography (eluting with a gradient of 8% MeOH in DCM).1 H-NMR (MeOD, 400 MHz): d[ppm]= 8.17 - 8.13 (m, 1 H), 8.08 (s, 1 H), 7.54 - 7.47 (m, 2H), 7.35 - 7.31 (m, 2H), 7.25 - 7.18 (m, 2H), 4.61 (s, 2H), 4.07 (d, J = 8.0 Hz, 2H), 3.84 (s, 3H), 3.26 (t, J = 6.6 Hz, 2H), 3.1 1 (t, J = 6.6 Hz, 2H)HPLCMS (Method J): [m / z]: 423.4 [M+H]+2-{2-[(1 H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(pyrazin-2-ylmethyl)-1,3-thiazole-4- carboxamide (Example Compound No. 46)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyrazin- 2-ylmethyl)carbamoyl]-1 ,3-thiazol-2-yl}ethyl)carbamate (33) (70 mg, 0.142 mmol) and 4M HCI in dioxane (2 ml) at room temperature for 4 h gave the title compound (30 mg, 53.7%) as a brown solid after purification by flash column chromatography (eluting with a gradient of 8% MeOH in DCM).1 H-NMR (MeOD, 400 MHz): d[ppm]= 8.63 (s, 1 H), 8.56- 8.51 (m, 1 H), 8.48 (d, J = 2.6 Hz, 1 H), 8.12 (s, 1 H), 7.52 (dd, J = 6.0, 3.2 Hz, 2H), 7.22 (dd, J = 6.1 , 3.1 Hz, 2H), 4.74 (s, 2H), 4.13 (s, 2H), 3.28 (t, J = 6.5Hz, 2H), 3.17 (t, J = 6.5 Hz, 2H)HPLCMS (Method I): [m / z]: 394.4 [M+H]+ 2-{2-[(1 H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(6-oxo-1,6-dihydropyridin-2-yl)methyl]-1,3- thiazole-4-carboxamide (Example Compound No. 47)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-oxo- 1 ,6-dihydropyridin-2-yl)methyl]carbamoyl}-1 ,3-thiazol-2-yl)ethyl]carbamate (34) (70 mg, 0.138 mmol) and 4M HCI in dioxane HCI (2 ml) at room temperature for 4 h gave the title compound (30 mg, 53%) as a yellow solid after purification by flash column chromatography (eluting with a gradient of 8% MeOH in DCM).1 H-NMR (MeOD, 400 MHz): d[ppm]= 8.12 (s, 1 H), 7.51 (m, 3H), 7.22 (dd, J = 6.0, 3.2 Hz, 2H), 6.42 (d, J = 9.1 Hz, 1 H), 6.30 (d, J = 6.9 Hz, 1 H), 4.44 (s, 2H), 4.09 (s, 2H), 3.27 (t, J = 6.7 Hz, 2H), 3.12 (t, J = 6.7 Hz, 2H)HPLCMS (Method J): [m / z]: 409.4 [M+H]+2-{2-[(1 H-1 ,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(6-cyanopboxamide (Example Compound No. 56) and5-{[(2-{2-[(1 H-1 ,3-Benzodiazol-2-ylmethyl)amino]ethyl}-1 ,3-thiazol-4-yl)formamido]methyl}pyridine-2- carboxamide (Example Compound No. 54)In a similar fashion to general procedure 2, a mixture of tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-[2- (4-{[(6-carbamoylpyridin-3-yl)methyl]carbamoyl}-1 ,3-thiazol-2-yl)ethyl]carbamate (35) and tert-butyl N-(1 H- 1 ,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-cyanopyridin-3-yl)methyl]carbamoyl}-1 ,3-thiazol-2- yl)ethyl]carbamate (36) (80 mg, 0.155 mmol) and 4 M HCI in dioxane (3 ml) at room temperature for 18 h gave two products. Formamide (Example Compound No. 54) (16 mg, 23%) was isolated following flash column chromatography (eluting with a gradient of DCM / MeOH, 9: 1 ). Crude nitrile(Example Compound No. 56) was also isolated and was further purified by basic prep-HPLC to give the required product as a brown solid (24 mg, 37%).Formamide: 1 H-NMR (Methanol-d4, 400 MHz): d[ppm]= 8.49 (t, J = 10.2 Hz, 1 H), 7.99 (s, 1 H), 7.94 (t, J = 10.0 Hz, 1 H), 7.78 (dt, J = 8.1 , 4.0 Hz, 1 H), 7.46 -7.34 (m, 2H), 7.1 1 (dd , J = 6.0, 3.1 Hz, 2H), 4.56 (d, J = 14.2 Hz, 2H), 4.02 (d , J = 8.0 Hz, 2H), 3.19 (m, 4H), 3.06 (t, J = 6.5 Hz, 2H)HPLCMS (Method I): [m / z]: 436.5 [M+H]+Nitrile: 1 H-NMR (DMSO-d6, 500 MHz): d[ppm]= 12.18 (s, 1 H), 9.08 (t, J = 6.2 Hz, 1 H), 8.70 (s, 1 H), 8.14 (s, 1 H), 7.97 (d , J = 8.0 Hz, 1 H), 7.92 (dd, J = 8.1 , 2.0 Hz, 1 H), 7.48 (d , J = 294 Hz, 2H), 7.12 (d, J = 4.7 Hz, 2H), 4.54 (d, J = 6.2 Hz, 2H), 4.10 (d , J = 5.2 Hz, 1 H), 3.96 (s, 2H), 3.18- 3.15 (m, 2H), 2.98 (d, J = 6.6 Hz, 2H)HPLCMS (Method I): [m / z]: 418.2 [M+H]+2-{2-[(1 H-1 ,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3,5-dimethylpyridin-2-yl)methyl]-1 ,3-thiazole- 4-carboxamide (Example Compound No. 57)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3,5- dimethylpyridin-2-yl)methyl]carbamoyl}-1 ,3-thiazol-2-yl)ethyl]carbamate (37) (198 mg, 0.36 mmol) and 12 M HCI (0.307 ml, 8.42 mmol) in MeOH (10 ml) at 40°C for 21 h gave the title compound (90 mg , 59%) as a yellow solid after purification by neutral prep-HPLC. 1 H-NMR (DMSO-d6, 500 MHz): d[ppm]= 12.17 (s, 1 H), 8.71 (t, J = 4.8 Hz, 1 H), 8.16 (s, 1 H), 8.14 (s, 1 7.51 (s, 1 H), 7.42 (s, 2H), 7.12 (d, J = 4.9 Hz, 2H), 4.52 (d, J = 4.9 Hz, 2H), 3.97 (s, 2H), 3.17 (d, J = 4. Hz, 2H), 2.98 (t, J = 6.8 Hz, 2H), 2.27 (s, 3H), 2.24 (s, 3H)HPLCMS (Method B): [m / z]: 421.2 [M+Hf2-{2-[(1 H-1 ,3-Benzodiazol-2-ylmethyl)amino]eth^carboxamide (Example Compound No. 61)In a similar fashion to general procedure 2, tert-butyl 2-({[(tert-butoxy)carbonyl](2-{4-[(pyrimidin-2- ylmethyl)carbamoyl]-1 ,3-thiazol-2-yl}ethyl)amino}methyl)-1 H-1 ,3-benzodiazole-1-carboxylate (38) (86 mg, 0.145 mmol) and 12 M HCI (0.282 ml, 3.378 mmol) in MeOH (2 ml) at 4(?C for 24 h gave the title compound (24 mg, 42%) as a brown solid after purification by flash column chromatography(eluting with a gradient 100% DCM, 90% DCM: 10% MeOH and 90% DCM : 10% methanolic ammonia) followed by basic prep-HPLC.1 H-NMR (DMSO-d6, 500 MHz): d[ppm]= 12.18 (s, 1 H), 8.75 (dd, J = 10.2, 5.4 Hz, 3H), 8.13 (s, 1 H), 7.48 (d, J = 36.0 Hz, 2H), 7.39 (t, J = 4.9 Hz, 1 H), 7.19 - 7.03 (m, 2H), 4.66 (d, J = 5.8 Hz, 2H), 3.97 (s, 2H), 3.20 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 6.8 Hz, 2H), 2.66 (s, 1 H)HPLCMS (Method B): [m / z]: 394.2 [M+H]+ 2-{2-[(1 H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-{[2-(4-^thiazole-4-carboxamide Exam le ompound No. 68)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(4- methylpiperazin-1-yl)phenyl]methyl}carbamoyl)-1 ,3-thiazol-2-yl]ethyl}carbamate (39) (13.4 mg, 0.02 mmol) in dioxane (0.5 ml) and 4M HCI in dioxane (55.1 μΙ) at 5C C for 16 h gave the title compound (1 1 .5 mg, 85%) as a white solid after trituration with DCM.1 H-NMR (Methanol-d4, 500 MHz): d[ppm]= 8.28 (s, 1 H), 7.88 (dt, J = 6.6, 3.3 Hz, 2H), 7.69 (dt, J = 6.3, 3.3 Hz, 2H), 7.45 (t, J = 7.6 Hz, 1 H), 7.33 (d, J = 6.7 Hz, 2H), 7.20- 7.14 (m, 1 H), 5.06 (s, 2H), 4.78 (s, 2H), 3.87 (t, J = 6.2 Hz, 2H), 3.72 - 3.59 (m, 4H), 3.49 (t, J = 10.5 Hz, 2H), 3.37 (s, 2H), 3.27 (d, J = 1 1.0 Hz, 2H), 3.02 (s, 3H)HPLCMS (Method D): [m / z]: 490.3 [M+H]+2-{2-[(1 H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(2,6-difluorophenyl)methyl]-1,3-thiazole-4- carboxamide (Example Compound No. 69)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(2,6- difluorophenyl)methyl]carbamoyl}-1 ,3-thiazol-2-yl)ethyl]carbamate (40) (90 mg , 0.17 mmol) in dioxane (2 ml) and 4M HCI in dioxane (427 μΙ) at room temperature for 16 h gave the title compound (15 mg, 20.6%) as a off white solid after purification by prep-HPLC.1 H-NMR (Methanol-d4, 500 MHz): d[ppm]= 8.06 (s, 1 H), 7.53 (dd, J = 5.8, 3.2 Hz, 2H), 7.34 (tt, J = 8.4, 6.5 Hz, 1 H), 7.29 - 7.16 (m, 2H), 7.03 - 6.88 (m, 2H), 4.68 (s, 2H), 4.07 (s, 2H), 3.23 (t, J = 6.6 Hz, 2H), 3.09 (t, J = 6.6 Hz, 2H)HPLCMS (Method A): [m / z]: 428.1 [M+H]+2-{2-[(1 H-1 ,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-{[2-(dimethylamino)phenyl]meththiazole-4-carboxamide (Example Compound No. 70)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2- (dimethylamino)phenyl]methyl}carbamoyl)-1 ,3-thiazol-2-yl]ethyl}carbamate (41 ) (73 mg , 0.14 mmol) in dioxane (2 ml) and 4M HCI in dioxane (341 μΙ) at 50°C for 16 h gave title compound (8.7 mg, 14%) following purification by prep-HPLC.1 H-NMR (Methanol-d4, 500 MHz): d[ppm]= 8.08 (s, 1 H), 7.53 (dd, J = 5.9, 3.2 Hz, 2H), 7.29 - 7.14 (m, 5H), 7.02 (td, J = 7.4, 1 .1 Hz, 1 H), 4.68 (s, 2H), 4.08 (s, 2H), 3.25 (t, J = 6.7 Hz, 2H), 3.1 1 (t, J = 6.8 Hz, 2H), 2.67 (s, 6H)HPLCMS (Method D): [m / z]: 435.3 [M+H]+2-{2-[(1 H-1 ,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(2-cyanophenyl)methyl]-1 ,3-thiazole-4- carboxamide (Example Compound No. 71)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(2- cyanophenyl)methyl]carbamoyl}-1 ,3-thiazol-2-yl)ethyl]carbamate (42) (54 mg , 0.1 mmol) in dioxane (2 ml) and 4M HCI in dioxane (261 μΙ) at 50°C for 12 h gave the title compound (8 mg, 18%) as a yellow solid after purification by prep-HPLC.1 H-NMR (Methanol-d4, 500 MHz): d[ppm]= 8.1 1 (s, 1 H), 7.74 - 7.69 (m, 1 H), 7.60 (td , J = 7.8, 1 .2 Hz, 1 H), 7.56 - 7.50 (m, 3H), 7.43 (t, J = 7.6 Hz, 1 H), 7.25 - 7.19 (m, 2H), 4.78 (s, 2H), 4.09 (s, 2H), 3.27 (t, J = 6.6 Hz, 2H), 3.13 (t, J = 6.6 Hz, 2H) 2-{2-[(1 H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-{[2-(trifluoromethoxy)phenyl]methyl}- thiazole-4-carboxamide (Example Compound No. 72)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2- (trifluoromethoxy)phenyl]methyl}carbamoyl)-1 ,3-thiazol-2-yl]ethyl}carbamate (43) (1 10 mg, 0.191 mmol), 12M HCI (0.317 ml, 4.458 mmol) in MeOH (2 ml) at room temperature for 16 h, gave the title compound (41 mg, 45%) as a white solid after purification by basic prep-HPLC.1 H-NMR (DMSO-d6, 500 MHz): d[ppm]= 12.19 (s, 1 H), 8.88 (t, J = 6.2 Hz, 1 H), 8.15 (s, 1 H), 7.48 (d, J = 31 .2 Hz, 2H), 7.42 - 7.30 (m, 4H), 7.13 (d, J = 4.9 Hz, 2H), 4.53 (d, J = 6.3 Hz, 2H), 3.97 (s, 2H), 3.19 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 6.8 Hz, 2H)HPLCMS (Method A): [m / z]: 476.2 [M+H]+2-{2-[(1 H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(1-phenylethyl)-1,3-thiazole-4-carboxamide (Example Compound No. 73)In a similar fashion to general procedure 2, tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(1 - phenylethyl)carbamoyl]-1 ,3-thiazol-2-yl}ethyl)carbamate (44) (1 10 mg, 0.218 mmol), 12M HCI (0.423 ml, 5.07 mmol) in MeOH (2 ml) at room temperature for 16 h, afforded the title compound (13 mg, 15%) as a white solid after purification by basic prep-HPLC.1 H-NMR (DMSO-d6, 500 MHz): d[ppm]= 12.17 (s, 1 H), 8.51 (d, J = 8.5 Hz, 1 H), 8.09 (s, 1 H), 7.46 (s, 2H), 7.39 (d, J = 7.4 Hz, 2H), 7.30 (t, J = 7.6 Hz, 2H), 7.22 (t, J = 7.3 Hz, 1 H), 7.13 (s, 2H), 5.20- 5.02 (m, 1 H), 3.96 (s, 2H), 3.17 (d, J = 6.7 Hz, 2H), 2.97 (t, J = 6.9 Hz, 2H), 1.49 (d, J = 7.1 Hz, 3H)HPLCMS (Method B): [m / z]: 406.2 [M+H]+2-{2-[(1 H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-{[2-(difluoromethoxy)phenyl]methyl}-1,3- thiazole-4-carboxamide (Example Compound No. 74)In a similar fashion to general procedure 2, crude tert-butyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2- (difluoromethoxy)phenyl]methyl}carbamoyl)-1 ,3-thiazol-2-yl]ethyl}carbamate (45) (470 mg), 12 M HCI (5ml) in MeOH (5ml) at 50°C for 2 h, afforded the title compound (56 mg, 35%) as a pale yellow solid after purification by flash column chromatography (KP-NH, eluting with a gradient of 0-15% MeOH / DCM) followed by prep-HPLC.1 H-NMR (DMSO-d6, 500MHz): d[ppm]= 12.18 (s, 1 H), 8.79 (t, J = 6.2 Hz, 1 H), 8.13 (s, 1 H), 7.47 (s, 2H), 7.35 - 7.28 (m, 2H), 7.25 - 7.06 (m, 5H), 4.48 (d, J = 6.2 Hz, 2H), 3.96 (s, 2H), 3.22- 3.17 (m, 2H), 2.98 (t, J = 6.8 Hz, 2H) HPLCMS (Method D): [m / z]: 458.2 [M+H]2-{2-[(1 H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-{[2-(morpholine-4-sulfonyl)phenyl] methyl}-"! ,3- thiazole-4-carboxamide Exam le ompound No. 75)In a similar fashion to general procedure 2, crude tertbutyl N-(1 H-1 ,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2- (morpholine-4-sulfonyl)phenyl]methyl}carbamoyl)-1 ,3-thiazol-2-yl]ethyl}carbamate (46) (440 mg), 12M HCI (5 ml) in MeOH (5 ml) at 50°C for 2 h, afforded the title compound (67 mg, 42%) as a pale yellow solid after purification by flash column chromatography (KP-NH, eluting with a gradient of 0-15% MeOH / DCM) followed by prep-HPLC.1 H-NMR (DMSO-d6, 500 MHz): d[ppm]= 12.19 (s, 1 H), 8.88 (t, J = 6.3 Hz, 1 H), 8.17 (s, 1 H), 7.84 (d, J = 7.9 Hz, 1 H), 7.66 (t, J = 7.6 Hz, 1 H), 7.50 (dd, J = 1 1 .8, 7.7 Hz, 4H), 7.17- 7.06 (m, 2H), 4.81 (d, J = 6.2 Hz, 2H), 3.97 (s, 2H), 3.70 - 3.61 (m, 4H), 3.20 (t, J = 6.8 Hz, 2H...

Claims

CLAIMS:

1. Compounds according to formula (I)or pharmaceutically acceptable salts thereof, for the use as ferroportin inhibitorsfor the prophylaxis and / or treatment of iron metabolism disorders leading to increased iron levels, increased iron absorption, iron overload and / or diseases related to or caused by increased iron levels, increased iron absorption or iron overload, whereinR and R2 are the same or different and are independently selected from the group consisting of- hydrogen,- optionally substituted alkyl,- optionally substituted aryl,- optionally substituted heteroaryl, or- R and R2 together with the nitrogen atom to which they are bonded form an optionally substituted 3- to 6- membered ring, which may optionally contain further heteroatoms, or- one of R and R2 is an alkanoyl-group, which together with Z being an amino group (-NH-) forms a 5- or 6-membered heterocyclic diketone containing two nitrogen atoms;Z is a cyclic group or a linear group and is selected from- optionally substituted 5-or 6-membered heteroaryl- optionally substituted aryl,- optionally substituted 5- or 6-membered heterocyclyl,- amino (-NH-),- an alkylaminocarbonyl group [-(CH2)-NH-(C=0)-], or- an alkylcarbonylamino group [-(CH2)-(C=0)-NH-];A1 is optionally substituted alkanediyi;A2 is- optionally substituted alkanediyi,- a direct bond, or- a sulfonyl group;R3 is- hydrogen, or- optionally substituted alkyl; orA1 and R3 together with the nitrogen atom to which they are bonded form an optionally substituted 4- to 6- membered mono- or bicyclic ring; orR3 and A2 together with the nitrogen atom to which they are bonded form an optionally substituted 4- to 7- membered ring; and Ar is- optionally substituted aryl,- optionally substituted monocyclic heteroaryl, or- optionally substituted bicyclic heteroaryl, which may be fused with a ring formed byR3 and A2 together with the nitrogen atom to which they are bonded.

2. Compounds for the use according to claim 1 , whereinR and R2 are the same or different and are independently selected from the group consisting of- hydrogen,- optionally substituted alkyl, or- R and R2 together with the nitrogen atom to which they are bonded form an optionally substituted 3- to 6- membered ring, which may optionally contain further heteroatoms;Z is a cyclic group or a linear group and is selected from- optionally substituted 5-or 6-membered heteroaryl- optionally substituted aryl,- optionally substituted 5- or 6-membered heterocyclyl,- amino (-NH-),- an alkylaminocarbonyl group [-(CH2)-NH-(C=0)-], or- an alkylcarbonylamino group [-(CH2)-(C=0)-NH-];A1 is optionally substituted alkanediyi;A2 is- optionally substituted alkanediyi, or- a direct bond; R3 is- hydrogen, or- C-|-C3-alkyl; orA1 and R3 together with the nitrogen atom to which they are bonded form an optionally substituted 4- membered monocyclic ring ; orR3 and A2 together with the nitrogen atom to which they are bonded form an optionally substituted 4- to 7- membered aliphatic ring; and Ar is optionally substituted bicyclic heteroaryl.

3. Compounds for the use according to any one of the preceding claims, whereinAr is an optionally substituted mono- or bicyclic heteroaryl, forming compounds according to formula (IV)with Het-2 being- an optionally substituted, 5- or 6-membered monocyclic heteroaryl, or- an optionally substituted bicyclic heteroaryl, which may be fused with a ring formed by R3 and A2 together with the nitrogen atom to which they are bonded; andwherein R , R2, Z, R3, A1 and A2 have the meaning as defined in the preceding claims.

4. Compounds for the use according to any one of the preceding claims, wherein Ar is an optionally substituted bicyclic heteroaryl, forming compounds according to formula (IVc) with- both Y2 being C or- one Y2 being N and one Y2 being C,wherein the bicyclic heteroaryl ring may carry 1 to 3 substituents, preferably 1 or 2 substituents; and wherein the bicyclic heteroaryl ring may be fused with a ring formed by R3 and A2 together with the nitrogen atom to which they are bonded, andwherein R , R2, Z, R3, A1 and A2 have the meaning as defined in the preceding claims.

5. Compounds for the use according to any one of the preceding claims, wherein Ar is an optionally substituted bicyclic heteroaryl, forming compounds according to formula (IVd)wherein the bicyclic heteroaryl ring may carry 1 to 3 substituents, preferably 1 or 2 substituents; and wherein the bicyclic heteroaryl ring may be fused with a ring formed by R3 and A2 together with the nitrogen atom to which they are bonded, andwherein R , R2, Z, R3, A1 and A2 have the meaning as defined in the preceding claims.

6. Compounds for the use according to any one of the preceding claims, whereinZ is an optionally substituted cyclic group Z-Cycl, forming compounds according to formula (II),with Z-Cycl being selected from- an optionally substituted 5-or 6-membered heteroaryl,- an optionally substituted aryl, and- an optionally substituted 5- or 6-membered heterocyclyl; and wherein R , R2, R3, A1 , A2 and Ar have the meaning as defined in any one of the preceding cla'7. Compounds for the use according to any one of the preceding claims, whereinZ is an optionally substituted cyclic group Z-Cycl, selected from an optionally substituted aromatic group, comprising- an optionally substituted heteroaryl and- an optionally substituted aryl.

8. Compounds for the use according to any one of the preceding claims, whereinZ is an optionally substituted cyclic group Z-Cycl, selected from an optionally substituted 5-membered heteroaryl, forming a compound of the formula (Ila)wherein 1 to 3 heteroatoms X are present,wherein X1 to X4 may be the same or different and are independently selected from the group consisting of C, N, S and O,preferably in formula (Ila) 1 to 3 heteroatoms X are present, whereinX is C, N, S or O;X2 is C or N;X3 is C, N, S or O; andX4 is C, N, S or O,and wherein X1, X3 and X4 with the meaning of C or N may carry a further substituent; and wherein R , R2, R3, A1 , A2 and Ar have the meaning as defined in the preceding claims.

9. Compounds for the use according to any one of the preceding claims, whereinZ is an optionally substituted cyclic group Z-Cycl, selected from an optionally substituted 5-membered heteroaryl, forming a compound of the formula (lla-a)wherein one or two further heteroatoms X (X2, X3, X4) are present, and whereinX2 is C or N;X3 is C, N, S or O; andX4 is C or N;with the proviso that in case of two further heteroatoms both are selected to be N or one is N and one (except X2) is O; andwherein X3 and X4 with the meaning of C or N may carry a further substituent;and wherein R , R2, R3, A1 , A2 and Ar have the meaning as defined in the preceding claims.

10. Compounds for the use according to any one of the preceding claims, wherein the compounds are defined by formula (lla-d)with X4 being C, which may carry a further substituent; andwherein R , R2, R3, A1 , A2 and Ar have the meaning as defined in the preceding claims.1 1. Compounds for the use according to any one of the preceding claims, wherein the compounds are defined by formula (lla-c)with X4 being C, which may carry a further substituent, andwherein R , R2, R3, A1 , A2 and Ar have the meaning as defined in the preceding claims.

12. Compounds for the use according to any one of the preceding claims, wherein the compounds are defined by formula (lla-b)with X1 and X4 being C and wherein X1 and / or X4 may carry a further substituent; andwherein R , R2, R3, A1 , A2 and Ar have the meaning as defined in the preceding claims.

13. Compounds for the use according to any one of the preceding claims, wherein the com ounds are defined b formula (lla-e)with X1 being C, which may carry a further substituent; andwherein R , R2, R3, A1 , A2 and Ar have the meaning as defined in the preceding claims.

14. Compounds for the use according to any one of the preceding claims, whereinZ is an optionally substituted cyclic group Z-Cycl, selected from an optionally substituted 6-membered heteroaryl, forming a compound of the formula (lib) wherein Y is N or C, with at least one Y being N, preferably with one Y being N;and wherein any Y with the meaning of C may carry a further substituent;and wherein R , R2, R3, A1 , A2 and Ar have the meaning as defined in the preceding claims.

15. Compounds for the use according to claim 14, wherein in the formula (Mb) one Y is N and the remaining Y are C, which may carry a further substituent.

16. Compounds for the use according to any one of the preceding claims, wherein the compounds are defined by- formula (llb-a)- formula (Ib-b)- formula (Ib-c)- formula (Ib-d)wherein in in each case R , R2, R3, A1 , A2 and Ar have the meaning as defined in the preceding claims, and wherein in each case the pyridinyking may optionally carry one or more further substituents.

17. Compounds for the use according to any one of the preceding claims, whereinZ is an optionally substituted cyclic group Z-Cycl, selected from an optionally substituted 6-membered forming a compound of the formula (lie)wherein R , R2, R3, A1 , A2 and Ar have the meaning as defined in the preceding claims and wherein the phenyl-ring may be substituted with 1 to 3 substituents.

18. Compounds for the use according to any one of the preceding claims, whereinwherein Z is an optionally substituted 5- or 6-membered heterocyclic group N-Cycl of the formula (lid))wherein N-Cycl is a nitrogen containing 5- or 6-membered heterocyclyl group andwherein R , R2, R3, A1 , A2 and Ar have the meaning as defined in the preceding claims, forming compounds according to formula (lld-a) or (lld-b)wherein the heterocyclyking may be substituted with 1 to 3 substituents.

19. Compounds for the use according to any one of the preceding claims, whereinat least one of R and R2 is a linear or branched alkyl group -[CQ]n- with Q = H or Ci-C4-alkyl and n = 1 , 2 or 3, which is substituted with a cyclic group "Cycl", designated as R2*, whereinCycl is selected from- optionally substituted aryl, and- optionally substituted heteroaryl,and wherein n is an integer of 1 to 3;the remaining of R or R2, designated as R , is selected from- hydrogen, and- optionally substituted alkyl; andZ, R3, A1 , A2 and Ar have the meaning as defined in the preceding claims.Compounds for the use according to claim 19 according to formula (A-lll)21. Compounds for the use according to any one of the preceding claims, according to formula (Allla) wherein Q, n, R , Z, R3, A1 , A2 and Ar have the meaning as defined in any one of the preceding claims.Compounds for the use according to any one of the preceding claims, according to formula (Alllb)with Het-1 being- an optionally substituted, optionally fused 5- to 6-membered heteroaryl, or- an optionally substituted 5- or 6-membered heterocyclyl, such as preferably a 6-membered heterocyclyl, which contain 1 or 2 identical or different heteroatoms selected from the group consisting of N, O and S, preferably N;and wherein Q, n, R , Z, R3, A1 , A2 and Ar have the meaning as defined in any one of the preceding claims.Compounds for the use according to any one of the preceding claims, according to formula (lllbe)wherein Q, n, R , Z, R3, A1 , A2 and Ar have the meaning as defined in any one of the preceding claims and wherein the pyridinyl ring of Het-1 may carry 1 to 3, preferably 1 or 2 further substituents.Compounds for the use according to claim 23, wherein the compounds are defined by formula (A- wherein R indicates 1 to 3, preferably 1 or 2 optional substituents, which may be selected from Q-C3-alkyl and halogen.

25. Compounds for the use according to any one of the preceding claims, wherein the compounds are defined by formula (A-lllb-g)wherein R is preferably selected from Ci-C3-alkyl and halogen;and wherein n is an integer of 1 to 3;the remaining of R or R2, designated as R , is selected from- hydrogen, and- optionally substituted alkyl; andQ, Z, R3, A1 , A2 and Ar have the meaning as defined in the preceding claims.Compounds for the use according to claim 24 or 25, wherein R is fluorine.

27. Compounds for the use according to any one of the preceding claims, wherein the compounds are defined by- formula (A-lllb-c), or■formula (A-lllb-d)wherein the pyrimidinyl and pyridazinyl ring each may carry 1 to 3, preferably 1 or 2 further substituents, and wherein in each case n is an integer of 1 to 3;the remaining of R or R2, designated as R , is selected from- hydrogen, and- optionally substituted alkyl; andQ, Z, R3, A1 , A2 and Ar have the meaning as defined in the preceding claims.

28. Compounds for the use according to any one of the preceding claims, wherein the compounds are defined by any one of the formulae (Va-1 ), (Vb-1 ) or (Vc-1 ) or (Va-2), (Vb-2) or (Vc-2)wherein Q, n, R , Z, R3, A1 and A2 as well as R5 and Y2 have the meaning as defined in any one of the preceding claims.

29. Compounds for the use according to claim 28, wherein the pyridinyl ring carries at least one substituent R5, which is selected from fluorine.

30. Compounds for the use according to any one of the preceding claims, whereinA1 and A2 are optionally substituted alkanediyl and are the same or different and are independently selected from optionally substituted- methylene and- ethane-1 ,2-diyl, or wherein- A1 and R3 together with the nitrogen atom to which they are bonded form an optionally substituted 4- membered aliphatic monocyclic ring.

1. Compounds for the use according to any one of the preceding claims, which are selected from388389390391392393394395396397398399400401402403404405406407408or pharmaceutically acceptable salts thereof.

32. Compounds for the use according to any one of the preceding claims for the use in the inhibition of iron transport mediated by ferroportin.

33. Compounds for the use according to any one of the preceding claims, wherein the diseases related to or caused by increased iron levels, increased iron absorption or iron overload are diseases associated with ineffective erythropoiesis.

34. Compounds as defined in any one of the preceding claims for the use as ferroportin inhibitors for the use in the prophylaxis and / or treatment of diseases associated with ineffective erythropoiesis, such as myelodysplastic syndromes (MDS, myelodysplasia), polycythemia vera and congenital dyserythropoietic anemia.

35. Compounds as defined in any one of the preceding claims for the use as ferroportin inhibitors for the use in the prophylaxis and / or treatment of diseases caused by reduced levels of hepcidin.

36. Compounds as defined in any one of the preceding claims for the use as ferroportin inhibitors for the use in an adjunctive therapy by limiting the amount of iron available to pathogenic microorganisms, such as the bacterium Vibrio vulnificus, thereby treating infections caused by said pathogenic microorganisms.

37. Compounds for the use according to any one of the preceding claims, wherein the diseases related to or caused by increased iron levels, increased iron absorption or iron overload are selected from thalassemia, hemoglobinopathy, hemoglobin E disease, hemoglobin H disease, haemochromatosis, hemolytic anemia.

38. Compounds for the use according to claim 37, wherein the thalassemia includes alpha- thalassemia, beta-thalassemia and delta-thalassemia.

39. Compounds for the use according to claim 37, wherein the hemolytic anemia is sickle cell anemia or congenital dyserythropoietic anemia.

40. Compounds for the use according to any one of the preceding claims, wherein the diseases related to or caused by increased iron levels, increased iron absorption or iron overload are selected from neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, therein limiting the deposition or increase of iron in tissue or cells.41 . Compounds for the use according to any one of the preceding claims for the use in the prophylaxis and / or treatment of formation of radicals, reactive oxygen species (ROS) and oxidative stress 42. Compounds for the use according to any one of the preceding claims for the use inthe prophylaxis and / or treatment of cardiac, liver and endocrine damage caused by iron overload .

43. Compounds for the use according to any one of the preceding claims, wherein the diseases related to or caused by increased iron levels or tissue iron overload are selected from inflammation triggered by excess iron.

44. A medicament containing one or more of the compounds as defined in any one of the preceding claims for the use according to any one of the preceding claims.

45. The medicament according to claim 44, which further contains one or more pharmaceutical carriers and / or auxiliaries and / or solvents.

46. The medicament according to any one of claims 44 or 45, which further contains at least one additional pharmaceutically active compound.

47. The medicament according to claim 46, wherein the at least one additional pharmaceutically active compound is selected from active compounds for the prophylaxis and treatment of iron overload , thalassemia, or haemochromatosis.

48. The medicament according to claim 46, wherein the at least one additional pharmaceutically active compound is selected from active compounds for the prophylaxis and treatment of neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease, and the associated symptoms.

49. The medicament according to any one of claims 44 to 48, which contains at least one additional pharmaceutically active compound, which is an iron-chelating compound.

50. The medicament according to any one of claims 44 to 49, which is in the form of a formulation for oral or parenteral administration. 51 . Compounds for the use according to any one of the preceding claims in a combination therapy, comprising co-administration of the compounds as defined in any of the preceding claims with at least one additional pharmaceutically active compound.

52. Compounds for the use according to claim 50, wherein the co-administration of the combination therapy is carried out in a fixed dose combination therapy by co-administration of the compounds as defined in any of the preceding claims with at least one additional pharmaceutically active compound in a fixed-dose formulation.

53. Compounds for the use according to claim 51 , wherein the co-administration of the combination therapy is carried out in a free dose combination therapy by co-administration of the compounds as defined in any of the preceding claims and the at least one additional pharmaceutically active compound in free doses of the respective compounds, either by simultaneous administration of the individual compounds or by sequential use of the individual compounds distributed over a time period.

54. Compounds for the use according to any one of the preceding claims in a combination therapy comprising co-administration of the compounds as defined in any of the preceding claims with one or more other pharmaceutically active compounds for reducing iron overload, which are selected from Tmprss6- ASO, iron chelators, curcumin, SSP-004184, Deferitrin, deferasirox, deferoxamine and / or deferiprone.

55. Compounds for the use according to any one of the preceding claims in a combination therapy comprising co-administration of the compounds as defined in any of the preceding claims with one or more other pharmaceutically active compounds which are selected from antioxidants, such as n-acetyl cysteine; anti-diabetics, such as GLP-1 receptor agonists; antibiotics, such as vancomycin (Van) or tobramycin; drugs for the treatment of malaria; anticancer agents; antifungal drugs; drugs for the treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, comprising dopamine agonists such as Levodopa; anti-viral drugs, such as interferon-a or ribavirin; immunosuppressents, such as cyclosporine A or cyclosporine A derivatives; iron supplements; vitamin supplements; red cell production stimulators; anti-inflammatory biologies; anti-thrombolytics; statins; vasopressors; and inotropic compounds.