N-Substituted Ferroportin Inhibitors

Abstract

The present invention relates to novel compounds of general formula (IA) as defined in the present application and pharmaceutical compositions comprising them and their use as medicaments, in particular for use as ferroportin inhibitors, more particularly for use in the prevention and / or treatment of diseases caused by a deficiency of hepcidin or disorders of iron metabolism leading to elevated iron levels or increased iron absorption and / or iron overload. JPEG2024534538000238.jpg2778

Description

[Technical field]

[0001] The present invention relates to a compound represented by the general formula (IA)

[0002] [ka] The present invention relates to novel compounds of the formula (IA) and their pharma- ceutically acceptable salts. The compounds of the formula (IA) of the present invention are characterized in that they act as ferroportin inhibitors and contain an N-substituted cyclic group B. The novel compounds are particularly suitable for use as medicines in the prevention and / or treatment of diseases caused by a lack of hepcidin or disorders of iron metabolism leading to elevated iron levels or increased iron absorption. The compounds of the formula (IA) of the present invention are further particularly suitable for use in the prevention and / or treatment of iron overload, including thalassemia, sickle cell disease and hemochromatosis, and for use in the prevention and / or treatment of diseases associated with or caused by elevated iron levels, increased iron absorption or iron overload. [Background technology]

[0003] Iron is an essential trace element for almost all living organisms, and is particularly relevant for growth and blood formation. In this case, the balance of iron metabolism is mainly regulated by the level of iron recovery from the hemoglobin of senescent erythrocytes and the duodenal absorption of dietary iron. The released iron is taken up via the intestine, especially via specific transport systems (DMT-1, ferroportin), transferred to the blood circulation, and thereby delivered to the appropriate tissues and organs (transferrin, transferrin receptor).

[0004] Mammalian organisms cannot actively excrete iron. Iron metabolism is substantially controlled by hepcidin, a peptide hormone produced in the liver, via the cellular release of iron from macrophages, hepatocytes and enterocytes. Hepcidin acts on the absorption of iron through the intestine and placenta, as well as the release of iron from the reticuloendothelial system. In the body, hepcidin is synthesized in the liver from what is known as prohepcidin, which is encoded by a gene known as the HAMP gene. The formation of hepcidin is regulated in direct correlation with the organism's iron level, i.e., when the organism is supplied with sufficient iron and oxygen, more hepcidin is formed, and when iron and oxygen levels are low or erythropoiesis is increased, less hepcidin is formed. In small intestinal mucosal cells and macrophages, hepcidin binds to the transport protein ferroportin, which transports iron that has been recycled phagocytotically from the inside of the cells to the blood.

[0005] The transport protein ferroportin is a 571 amino acid transmembrane protein formed in the liver, spleen, kidney, heart, intestine and placenta. In particular, ferroportin is localized to the basolateral membrane of intestinal epithelial cells. Thus, bound ferroportin acts to export iron into the blood. In this case, ferroportin transports Fe 2+Hepcidin most likely transports iron as a ferroportin complex. When hepcidin binds to ferroportin, ferroportin is transported to the interior of the cell, where its degradation takes place so that the release of phagocytically recycled iron from the cell is almost completely blocked. If ferroportin is inactivated, for example by hepcidin, and is unable to export the iron stored in mucosal cells, the stored iron is lost by the natural shedding of cells through the stool. Thus, when ferroportin is inactivated or inhibited, for example by hepcidin, the absorption of iron in the intestine is reduced. In addition, ferroportin is significantly localized in the reticuloendothelial system (RES), to which macrophages also belong. On the other hand, when serum iron levels decrease, hepcidin production in hepatocytes in the liver decreases, less hepcidin is released, and therefore less ferroportin is inactivated, allowing a greater amount of stored iron to be transported into the serum.

[0006] It becomes clear from this that the hepcidin-ferroportin system directly regulates iron metabolism, and therefore any disturbance in the hepcidin regulatory mechanism directly affects iron metabolism in the organism. In principle, the hepcidin-ferroportin regulatory mechanism acts via two opposing principles:

[0007] On the one hand, an increase in hepcidin leads to the inactivation of ferroportin, thus blocking the release of stored iron from cells into the serum, thus reducing serum iron levels. In pathological cases, a decrease in serum iron levels leads to a decrease in hemoglobin levels, a decrease in erythrocyte production, and thus iron deficiency anemia.

[0008] On the other hand, a decrease in hepcidin leads to an increase in active ferroportin, thus allowing for the promotion of the release of stored iron and the promotion of iron uptake, for example from food, thus increasing serum iron levels, which in pathological cases leads to iron overload.

[0009] Iron overload conditions and diseases are characterized by excess iron levels. Among them, the problem arises from excess serum iron levels leading to non-transferrin-bound iron (NTBI). NTBI is rapidly taken up by organs nonspecifically, leading to the accumulation of iron in tissues and organs. Iron overload causes many diseases and undesirable medical conditions, including cardiac, hepatic and endocrine damage. Furthermore, iron accumulation in the brain has been observed in patients suffering from neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. As a particular harmful aspect of excess free iron, the undesirable formation of radicals must be mentioned. In particular, iron(II) ions catalyze the formation of reactive oxygen species (ROS) (via the Fenton reaction, among others). It is well known and described in the literature that these ROS cause damage to DNA, lipids, proteins and carbohydrates, with far-reaching effects on cells, tissues and organs, leading to the so-called oxidative stress.

[0010] In addition to traditional methods of treating iron overload by removing iron from the body, for example with chelating agents such as deferoxamine (also known as deferrioxamine B, N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide or Desferal®), deferasirox (Exjade®, 4-(3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzoic acid) and deferiprone (Ferriprox®, 3-hydroxy-1,2-dimethylpyridin-4(1H)-one), compounds that act as hepcidin agonists or have inhibitory or suppressive effects on biochemical regulatory pathways in iron metabolism, such as hepcidin mimetic peptides, have been described. Said therapeutic approach is based on directly intervening in the disturbed iron metabolic pathway by providing hepcidin mimetics or hepcidin agonists, by acting directly through the primary regulator hepcidin, i.e., acting as a kind of hepcidin substitute or supplier.This approach is based on the therapeutic rationale of treating iron overload, i.e. excessive serum iron levels, by inhibiting ferroportin through a hepcidin inactivation mechanism, thus blocking excess iron absorption.

[0011] Ferroportin inhibitors and methods for preparing same are described in WO 2017 / 068089, WO 2017 / 068090, WO 2021 / 191202, and unpublished international application PCT / EP2022 / 060546. Additionally, international application WO 2018 / 192973 describes the preparation and crystallization of various specific salts of selected ferroportin inhibitors described therein in WO 2017 / 068089 and WO 2017 / 068090.

[0012] WO 2011 / 029832 relates to thiazole and oxazole compounds that act as hepcidin antagonists that are described as suitable for use to treat iron deficiency diseases.

[0013] WO 2021 / 013771 relates to the use of selected ferroportin inhibitors for treating transfusion-dependent thalassemia.

[0014] WO 2020 / 123850 describes further ferroportin inhibitors having a central heteroaryl bicyclic ring structure. Summary of the Invention [Problem to be solved by the invention]

[0015] The object of the present invention was to provide new therapeutically effective compounds that can be used for effective treatment to prevent and treat iron metabolism disorders associated with elevated iron levels, such as iron overload in particular. In a further object, the new compounds should show high efficacy in the indications of the present invention, show few side effects, have low toxicity and good bioavailability and compatibility. Moreover, in contrast to known iron chelating compounds, these new compounds should be suitable for preventing elevated iron levels and thus the occurrence of related disorders, instead of removing excess iron from the body when iron overload has already occurred. In a further object, the new compounds should have a defined structure (stoichiometry), be preparable by simple synthetic processes, and show low sensitivity and improved long-lasting efficiency compared to known biomolecular compounds, such as antibodies. [Means for solving the problem]

[0016] This goal has been achieved by the development of novel compounds, such as, in particular, according to formulae (IA) and (IB) as defined herein, which have been found to act as ferroportin inhibitors, whereby the novel compounds are suitable for use in inhibiting iron transport and are therefore effective in the prevention and treatment of iron metabolism disorders associated with elevated iron levels, such as, in particular, iron overload, as well as diseases caused by a lack of hepcidin, diseases related to or caused by elevated iron levels or iron overload, and diseases associated with ineffective erythropoiesis. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The inventors have found that certain compounds having the general structural formula (IA) or (IB) as defined herein act as ferroportin inhibitors and thus effectively inhibit iron transport and are therefore particularly suitable for use as medicines, in particular for use in the treatment and / or prevention of diseases caused by a lack of hepcidin, diseases associated with ineffective erythropoiesis or iron metabolism disorders leading to elevated iron levels, such as in particular iron overload conditions, such as in particular thalassemia and hemochromatosis. In particular, the new compounds have been found to be suitable for the treatment of thalassemia and hemochromatosis. The new compounds are also suitable for use in the treatment of diseases caused by pathologically low hepcidin levels and in the inhibition of iron transport. In particular, the new compounds described herein show good metabolic stability and good bioavailability, which makes them particularly suitable as drug compounds.

[0018] Thus, the present invention relates to compounds of the general formula (IA)

[0019] [ka] (In the formula, l is an integer of 1 or 2; L 1 and L2 each represents a linker group containing 1 to 7 carbon atoms; - Straight chain C1-C3 alkyl group -[CH2] m -or- [CH2] n where m and n are independently an integer of 1, 2 or 3, - branched C1-C4-alkyl groups, and - C3-C6-cycloalkyl radicals which may be substituents of linear C1-C3-alkyl radicals or which may form a ring together with the nitrogen atom to which they are attached. are independently selected from; X 1 is N, S or O; X 2 is N, S, O or CR 5 and; X 3 is C or N; However, X 1 and X 2 One of them is N, X 3 If N, then X 2 is CR 5 and; R 5 teeth, -H, - halogen, - linear or branched C1-C3-alkyl, or - Straight or branched C1-C3 haloalkyl represents; A is the (a-1) group.

[0020] [ka] (In the formula, * indicates the bond position; R 1 and R 2 is independent, - halogen, - linear or branched C1-C3-alkyl, - linear or branched C1-C3-haloalkyl, or - Straight or branched C1-C3 alkoxy represents 0, 1 or 2 substituents independently selected from represents; B is the following groups (b-1), (b-2) and (b-3):

[0021] [ka] (In the formula, * indicates the bond position; R 3 teeth, - unsubstituted or substituted 6-membered aryl, - unsubstituted or substituted 5- or 6-membered heteroaryl, - unsubstituted or substituted bicyclic heteroaryl, - unsubstituted or substituted 3- to 6-membered cycloalkyl; - unsubstituted or substituted 5- or 6-membered heterocyclyl, - unsubstituted or substituted 5- or 6-membered heterocyclylalkyl, - unsubstituted or substituted 6-membered arylalkynyl, or - unsubstituted or substituted 5- or 6-membered heteroarylalkynyl represents 0, 1, 2 or 3 substituents independently selected from A substituted aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl, heterocyclyl, heterocyclylalkyl, arylalkynyl, or heteroarylalkynyl group is Halogen C1-C3-alkyl, C1-C3-haloalkyl, and 〇 C1~C3-alkoxy may have 1, 2 or 3 substituents independently selected from: R 4 teeth, - unsubstituted or substituted linear or branched C1-C6-alkyl, - Dialkyl ether group [R 6(CH2) x -O-CH2) y -] (R 6 represents a substituent selected from a C1-C3 alkoxy group; x and y independently represent an integer of 1, 2, or 3; - unsubstituted or substituted 3- to 6-membered cycloalkyl; - unsubstituted or substituted 5- or 6-membered heterocyclyl, or - unsubstituted or substituted 6-membered aryl represents Alkyl, cycloalkyl, heterocyclyl and aryl are Halogen, C1-C3-alkoxy, C6-cycloalkyloxy, Carboxyl, Aminocarbonyl, mono- or di-alkylaminocarbonyl, -NH2, amino groups including mono- and di-alkylamino, unsubstituted or substituted 3- to 6-membered cycloalkyl, unsubstituted or substituted 5- or 6-membered heterocyclyl, unsubstituted or substituted 6-membered aryl, unsubstituted or substituted 5- or 6-membered heteroaryl, and Unsubstituted or substituted bicyclic heteroaryl and optionally substituted with one or two substituents independently selected from Substituted cycloalkyl, heterocyclyl, aryl, heteroaryl and bicyclic heteroaryl groups include Hydroxy, Cyano, Halogen, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, Carboxyl, amino (-NH2) or mono- or di-alkylamino groups, v aminocarbonyl, and Mono- or di-alkylaminocarbonyl and optionally having 1, 2 or 3 substituents independently selected from The monoalkylamino group and the monoalkylaminocarbonyl group are C1-C3-alkoxy, unsubstituted or substituted 6-membered aryl, and Unsubstituted or substituted 5- or 6-membered heteroaryl may have further substituents on the monoalkyl chain selected from Substituted aryl or heteroaryl groups as substituents of a monoalkyl chain may have 1, 2 or 3 substituents independently selected from halogen, C1-C3-alkyl and C1-C3-haloalkyl. represents one of; In formulas (b-2) and (b-3), one of D1, D2 and D3 is present; - a fused 6-membered aryl ring, - a fused 5- or 6-membered heteroaryl ring, a fused 5- or 6-membered cycloalkyl ring, or - a fused 5- or 6-membered heterocyclyl ring represents; The (b-2) and (b-3) groups are - halogen, - linear or branched C1-C3-alkyl, - linear or branched C1-C3-haloalkyl, - Straight or branched C1-C3 alkoxy having 0, 1, 2 or 3 substituents independently selected from The present invention relates to novel compounds of the formula:

[0022] The scope of the present invention excludes the following compounds (X-1), (X-2) and (X-3):

[0023] [ka]

[0024] The present invention also relates to a compound of general formula (IB)

[0025] [ka] in which the substituents have the meanings defined above. The present invention relates to a novel compound. In formula (IB), the substituents may also have the following meanings: l is an integer of 1 or 2; m and n are independently integers of 1, 2, or 3; X 1 is N, S or O; X 2 is N, S, O or CR 5 and; X 3 is C or N; However, X 1 and X 2 One of them is N, X 3 If N, then X 2 is CR 5 and; R 5 teeth, -H, - halogen, - linear or branched C1-C3-alkyl, or - Straight or branched C1-C3 haloalkyl represents; A is the (a-1) group.

[0026] [ka] (In the formula, * indicates the bond position; R 1 and R 2 is independent, - halogen, - linear or branched C1-C3-alkyl, - linear or branched C1-C3-haloalkyl, or - Straight or branched C1-C3 alkoxy represents 0, 1 or 2 substituents independently selected from represents; B is the following groups (b-1), (b-2) and (b-3):

[0027] [ka] (In the formula, * indicates the bond position; R 3 teeth, - unsubstituted or substituted 6-membered aryl, - unsubstituted or substituted 5- or 6-membered heteroaryl, - unsubstituted or substituted bicyclic heteroaryl, - 3 to 6 membered cycloalkyl, - 5- or 6-membered heterocyclyl, - 5- or 6-membered heterocyclylalkyl, or - 6-membered arylalkynyl represents 0, 1, 2 or 3 substituents independently selected from Substituted aryl, heteroaryl and bicyclic heteroaryl groups include Halogen C1-C3-alkyl, C1-C3-haloalkyl, and 〇 C1~C3-alkoxy may have 1, 2 or 3 substituents independently selected from: R 4 teeth, - linear or branched C1-C6-alkyl, - Dialkyl ether group [R 6 (CH2) x -O-CH2) y -] (R 6represents a substituent selected from a C1-C3 alkoxy group; x and y independently represent an integer of 1, 2, or 3; - 3 to 6 membered cycloalkyl, or - 5- or 6-membered heterocyclyl represents Alkyl, cycloalkyl and heterocyclyl are C1-C3-alkoxy, Carboxyl, Aminocarbonyl, mono- or di-alkylaminocarbonyl, 3-6 membered cycloalkyl, and 5- or 6-membered heterocyclyl, unsubstituted or substituted 6-membered aryl, unsubstituted or substituted 5- or 6-membered heteroaryl, and Unsubstituted or substituted bicyclic heteroaryl and optionally substituted with one or two substituents independently selected from Substituted aryl, heteroaryl and bicyclic heteroaryl groups include Hydroxy, Cyano, Halogen, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, Carboxyl, amino (-NH2) or mono- or di-alkylamino groups, Aminocarbonyl, and Mono- or di-alkylaminocarbonyl and optionally having 1, 2 or 3 substituents independently selected from The monoalkylamino group and the monoalkylaminocarbonyl group are C1-C3-alkoxy, unsubstituted or substituted 6-membered aryl, and Unsubstituted or substituted 5- or 6-membered heteroaryl may have further substituents on the monoalkyl chain selected from Substituted aryl or heteroaryl groups as substituents of a monoalkyl chain may have 1, 2 or 3 substituents independently selected from halogen, C1-C3-alkyl and C1-C3-haloalkyl. represents one of; In formulas (b-2) and (b-3), one of D1, D2 and D3 is present; - a fused 6-membered aryl ring, - a fused 5- or 6-membered heteroaryl ring, a fused 5- or 6-membered cycloalkyl ring, or - a fused 5- or 6-membered heterocyclyl ring represents; The (b-2) and (b-3) groups are - halogen, - linear or branched C1-C3-alkyl, - linear or branched C1-C3-haloalkyl, - Straight or branched C1-C3 alkoxy has 0, 1, 2 or 3 substituents independently selected from:

[0028] definition The term "substituted" means that one or more hydrogen atoms on a specified atom or group are replaced with a selection from the indicated group, provided that the normal valence of the specified atom under the existing circumstances is not exceeded.

[0029] The term "optionally substituted", "optional substituent(s)" or "possible substituent(s)" means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, an optionally substituted group can be substituted with as many optional substituents as can be accommodated by replacing hydrogen atoms with non-hydrogen substituents on any available carbon or nitrogen atom. In general, the number of optional substituents, if present, can be 1, 2, 3, 4 or 5, particularly 1, 2 or 3.

[0030] As used herein, the term "one or more" means "one, two, three, four or five, in particular one, two, three or four, more particularly one, two or three, even more particularly one or two", for example in the definition of substituents in the compounds of general formulae (IA) and (IB) of the present invention.

[0031] When used in the claims or specification, the terms "comprise" or "containing" include "consisting of."

[0032] Within this specification, when any item is referred to as "referenced herein" or "defined (anywhere) herein", it means that it may be referenced anywhere in this specification or may have the meaning defined anywhere in this specification.

[0033] Terms used in the claims and specification have the following meanings:

[0034] "Halogen" or "halogen atom" means a fluorine, chlorine, bromine or iodine atom, in particular a fluorine, chlorine or bromine atom, preferred selections being for chlorine or fluorine, further preferred selections being for bromine or fluorine, most preferred being fluorine.

[0035] The term "C1-C6 alkyl" means a linear or branched, saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl radicals. Methyl, ethyl, n-propyl, iso-propyl, n-butyl and iso-butyl radicals are preferred. More preferred are methyl, ethyl, n-propyl and iso-propyl.

[0036] A C1-C6-alkyl group may optionally be substituted with one or two substituents, preferably one substituent. In such a case, the substituted alkyl group is preferably a substituted C1-C3-alkyl group, more preferably a substituted methyl or ethyl group. Such optional substituents are preferably halogen (forming a halogen-substituted C1-C3-alkyl group, as defined below and also denoted herein as "C1-C3-haloalkyl"), such as preferably difluoroalkyl or trifluoroalkyl, C1-C3-alkoxy, such as preferably methoxy, cycloalkyloxy groups, such as preferably C6-cycloalkyloxy groups (cyclohexyloxy), carboxyl groups [-(C=O)OH], aminocarbonyl groups [NH2(C=O)-], monoalkylaminocarbonyl groups, such as preferably methylaminocarbonyl groups [C HNH(C=O)-], -NH2, amino groups including mono- and di-alkylamino, such as preferably mono- or di-methylamino, 3- to 6-membered cycloalkyl (also denoted C3-C6-cycloalkyl) containing 3, 4, 5 or 6 carbon atoms, such as preferably cyclopropyl and cyclohexyl, unsubstituted or substituted 5- or 6-membered heterocyclyl, unsubstituted or substituted 6-membered aryl (phenyl), unsubstituted or substituted 5- or 6-membered heteroaryl, and unsubstituted or substituted bicyclic heteroaryl, such as preferably a benzimidazolyl group.

[0037] Substituted heterocyclyl, aryl, heteroaryl and bicyclic heteroaryl groups as substituents of alkyl may also be selected from 1, 2 or 3 substituents independently selected from hydroxy, cyano, halogen, C1-C3-alkyl as defined herein, such as preferably methyl, C1-C3-haloalkyl as defined herein, such as preferably difluoroethyl or trifluoromethyl (CF3), C1-C3-alkoxy as defined herein, such as preferably methoxy, a carboxyl group, an amino (-NH2) or a mono- or di-alkylamino group, an aminocarbonyl group as defined herein, and a mono- or di-alkylaminocarbonyl group. The mono-alkylaminocarbonyl group may have a further substituent on the monoalkyl chain selected from C1-C3-alkoxy, unsubstituted or substituted 6-membered aryl, and unsubstituted or substituted 5- or 6-membered heteroaryl, and the substituted aryl or heteroaryl group as a substituent on the monoalkyl chain may have 1, 2 or 3 substituents independently selected from halogen, C1-C3-alkyl and C1-C3-haloalkyl, preferably the further substituent on the monoalkyl chain of the mono-alkylaminocarbonyl group is selected from halogen substituted 5- or 6-membered heteroaryl (more preferably fluoro-pyridinyl group).

[0038] As used herein, the term "dialkyl ether" or "dialkyl ether group" refers to a dialkyl ether group in which one CH2- group in the alkyl chain is replaced by -O-, [-(CH2) x -O-CH2) y -] radical (x and y independently represent an integer of 1, 2 or 3). 4 Such dialkyl ether groups as 6 [R 6 (CH2) x -O-CH2) y -] groups. 6 R represents a substituent selected from the group consisting of C1-C3-alkoxy. 6When R represents a hydrogen atom, the dialkyl ether group is unsubstituted and corresponds to an "alkoxy" group as otherwise defined herein. 6 is selected from C1-C3-alkoxy groups, such as in particular methoxy and ethoxy.

[0039] The term "C1-C3-haloalkyl" denotes a linear or branched, saturated, monovalent C1-C3-alkyl group having the meaning defined above, in which one or more of the hydrogen atoms are replaced, identically or differently, by a halogen atom. In particular, said halogen atom is a chlorine or fluorine atom. More particularly, said halogen atom is a fluorine atom, and even more particularly, all said halogen atoms are fluorine atoms ("C1-C3-fluoroalkyl"). Said C1-C3-haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1,3-difluoropropan-2-yl, the trifluoromethyl group (CF3) being particularly preferred.

[0040] The term "C1-C3-alkoxy" means a straight-chain or branched, saturated, monovalent radical of the formula (C1-C3-alkyl)-O-, where the term "C1-C3-alkyl" is as defined above, for example a methoxy, ethoxy, n-propoxy or isopropoxy radical, with the methoxy and isopropoxy radicals being particularly preferred.

[0041] The term cycloalkyloxy refers to a cycloalkyl-O- group, in which a cycloalkyl group as defined below is attached via an oxygen (-O-). Cycloalkyloxy includes "C3-C6-cycloalkyloxy", with C6-cycloalkyloxy (cyclohexyloxy) being preferred.

[0042] A "carboxyl group" refers to a [-(C=O)OH] group.

[0043] The term "mono- or di-alkylamino" denotes an amino group (-NH2) in which one or both hydrogens are replaced by the same or different C1-C3-alkyl groups. Preferred are the mono- and dimethylamino groups, more preferred is the dimethylamino group.

[0044] The term "aminocarbonyl group" refers to the group [NH2-(C=O)-].

[0045] The term "(mono-)alkylaminocarbonyl group" denotes an aminocarbonyl group in which one hydrogen is replaced by a C1-C3-alkyl group [NH2-(C=O)-]. A preferred mono-alkylaminocarbonyl group is the methylaminocarbonyl group [CH3NH(C=O)-].

[0046] In general, the term "aryl" includes aromatic hydrocarbon residues containing 6 to 14 carbon atoms (excluding carbon atoms of possible substituents), which may be monocyclic or bicyclic, including, for example, phenyl, naphthyl, phenanthrenyl and anthracenyl. Preferred are 6-membered aryls, such as phenyl.

[0047] In general, the term "heteroaryl" includes heteroaromatic hydrocarbon residues containing 4 to 9 ring carbon atoms, which further contain 1 to 3 identical or different heteroatoms selected from S, O and N in the ring, thus forming a 5 to 12 membered heteroaromatic residue, which may be monocyclic or bicyclic.

[0048] Monocyclic heteroaryl groups are preferably 5- and 6-membered monocyclic heteroaryl groups, for example 5-membered heteroaryl, for example thiazolyl, for example thiazol-2-yl, 2-thiazol-2-yl, 2-thiazol-4-yl, thienyl (thiophenyl), for example thien-3-yl, pyrazolyl, for example 1-pyrazol-4-yl, 3-pyrazol-5-yl, imidazolyl, for example imidazol-2-yl, 2-imidazol-4-yl, 1-imidazol-5-yl, the groups dazol-4-yl, triazolyl, for example 1-triazol-3-yl, 1-triazol-4-yl, for example 1,2,4-triazol-3-yl or 1,2,3-triazol-4-yl, oxazolyl, for example 2-oxazol-4-yl, 2-oxazol-5-yl, iso-oxazolyl, for example iso-oxazol-4-yl, oxadiazolyl, for example 1,2,4-oxadiazol-3-yl, tetrazolyl and the groups 6-membered Heteroaryl, for example, pyridyl (pyridinyl), for example, 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- The heteroaryl groups include pyridyl (pyridinyl), pyridyl-N-oxide, pyridazinyl, pyrimidyl, pyrazinyl, thienyl (thiophenyl), furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl, including the group 5-yl. Preferred heteroaryl groups are pyridinyl, pyrimidinyl, imidazolyl, oxazolyl, iso-oxazolyl and tetrazolyl.

[0049] Bicyclic heteroaryl groups preferably include indolizinyl, indolyl, benzo[b]thienyl, benzo[b]furyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolinyl, quinoxalinyl, and benzimidazolyl, such as benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl. The benzimidazolyl group is particularly preferred.

[0050] In general, the term "cycloalkyl" includes aliphatic rings containing 3 to 8, more preferably 3 to 6, ring carbon atoms. Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups, with cyclopropyl and cyclohexyl groups being preferred.

[0051] In general, the term "heterocyclyl" refers to any group including, but not limited to, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydrothiophenyl, oxathiolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, thianyl, dithianyl, trithianyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, and the like, such as azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-thiophen-2-yl, tetrahydro- These include saturated or unsaturated monocyclic or bicyclic 4-8 membered heterocyclic residues containing 1-3, preferably 1-2, same or different heteroatoms selected from N, O and S, including thiophene-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. Particularly preferred are 5- or 6-membered heterocyclyl groups, such as pyrrolidinyl, dioxolanyl, dioxanyl, piperidinyl, piperazinyl and morpholinyl residues.

[0052] An aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl or heterocyclyl group can be attached via a direct bond, a C1-C3-alkyl chain, preferably a C1-alkyl or alkynyl chain, such as preferably an ethynyl chain (-C≡C-), or an aryl, heteroaryl, cycloalkyl or heterocyclyl group can be fused with an aromatic ring to form a fused ring system as defined herein.

[0053] The aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl or heterocyclyl groups, including fused aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl and heterocyclyl groups, may bear 1, 2 or 3 identical or different substituents independently selected from halogen as defined above, such as preferably F, Br and Cl, C1-C3-alkyl, such as preferably methyl, C1-C3-haloalkyl as defined above, such as preferably trifluoromethyl, C1-C3-alkoxy as defined above, such as preferably methoxy and C6-cycloalkyloxy.

[0054] An aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl or heterocyclyl group may also carry 1, 2 or 3 substituents which are defined above in the context of the possible substituents for alkyl.

[0055] An aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl or heterocyclyl group as defined herein may form one of the A and / or B groups as defined herein.

[0056] Among them, the A group is the (a-1) group.

[0057] [ka] Represents.

[0058] The (a-1) group is a group having 0 substituents (R 1 / R 2 represents hydrogen) or one or two identical or different substituents R independently selected from halogen as defined above, such as preferably F, Br and Cl, C1-C3-alkyl, such as preferably methyl, C1-C3-haloalkyl as defined above, such as preferably trifluoromethyl, and C1-C3-alkoxy as defined above, such as preferably methoxy. 1 / R 2 is a pyridinyl group having the formula:

[0059] The B group is the following groups (b-1), (b-2) and (b-3).

[0060] [ka] represents one of the following:

[0061] In the above, the (b-1) group is a group having 0 substituents R 3 (i.e., R 3 represents hydrogen) or one or two identical or different substituents R selected from aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl and heterocyclyl groups as defined above, which are attached via a direct bond or via a C1-C3-alkyl chain, preferably a C1-alkyl chain or an alkynyl chain, for example preferably an ethynyl chain. 3 , preferably one substituent R 3 It represents an N-substituted benzimidazolyl group having the formula:

[0062] Preferably, R 3 is selected from unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted bicyclic heteroaryl, unsubstituted or substituted 3- to 6-membered cycloalkyl, unsubstituted or substituted 5- or 6-membered heterocyclyl, unsubstituted or substituted 5- or 6-membered heterocyclylalkyl, unsubstituted or substituted 6-membered arylalkynyl or unsubstituted or substituted 5- or 6-membered heteroarylalkynyl, the substituted aryl, heteroaryl and bicyclic heteroaryl groups optionally carrying 1, 2 or 3 substituents independently selected from halogen, C1-C3-alkyl, C1-C3-haloalkyl and C1-C3-alkoxy.

[0063] An aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl or heterocyclyl ring bonded via a C1-C3-alkyl chain, preferably a C1-alkyl chain, is R 2 which represents an arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocyclylalkyl group. 3 and "alkyl" preferably denotes C1-C3-alkyl. Heterocyclylalkyl groups, such as piperazinylmethyl or morpholinylmethyl groups, are preferred.

[0064] An aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl or heterocyclyl ring attached via an alkynyl chain, e.g. preferably an ethynyl chain, is R which represents an arylalkynyl, heteroarylalkynyl, cycloalkylalkynyl or heterocyclylalkynyl group. 3 and "alkynyl" preferably denotes ethynyl. Arylalkynyl groups, such as phenylethynyl groups, and heteroarylalkynyl groups, such as pyridinylethynyl groups, are preferred. In them, the aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl or heterocyclyl ring may have one, two or three identical or different substituents selected from those defined herein for each group, preferably selected from halogen as defined above, such as preferably F, Br and Cl, C1-C3-alkyl, such as preferably methyl, C1-C3-haloalkyl as defined above, such as preferably trifluoromethyl, and C1-C3-alkoxy as defined above, such as preferably methoxy. Therewith, such groups are also denoted herein as "unsubstituted or substituted arylalkynyl", "unsubstituted or substituted heteroarylalkynyl", "unsubstituted or substituted cycloalkylalkynyl" and "unsubstituted or substituted heterocyclylalkynyl".

[0065] An unsubstituted or substituted aryl ring is directly bonded to R, which represents "unsubstituted or substituted aryl" 3 or R 4With regard to the possible substituents, reference is made to the definitions given above. In particular, for example the substituent R 4 For the aryl group directly bonded to the B group, preferred substituents are selected from halogen, more preferably Cl and C1-C3-alkoxy, more preferably methoxy.

[0066] The (b-2) and (b-3) groups represent fused ring systems, in which in formulae (b-2) and (b-3) the fused aryl, heteroaryl, cycloalkyl or heterocyclyl ring as defined above is present at one of the positions indicated by D1, D2 and D3, preferably forming a fused tricyclic ring system.

[0067] The (b-2) and (b-3) groups may optionally bear 1, 2 or 3 identical or different substituents independently selected from halogen, linear or branched C1-C3-alkyl, linear or branched C1-C3-haloalkyl and linear or branched C1-C3-alkoxy, respectively, as defined above. Such optional substituents are also referred to below as R x It is represented by:

[0068] Among the (a-1) groups, the following groups:

[0069] [ka] is particularly preferred.

[0070] From this, a group (a-1) having the following structure:

[0071] [ka] is more preferred.

[0072] From this, a group (a-1) having the following structure:

[0073] [ka] is most preferred.

[0074] The compounds of formula (IA) and (IB) of the present invention may further comprise a substituent R 4 R 4 In embodiments of the invention where is not a directly bonded substituted or unsubstituted aryl, an "N-substituted" cyclic group B may be referred to as an "N-alkylated" (cyclic) group B, where it is understood that the term "N-alkylated" includes substitution with alkyl groups, dialkyl ether groups as well as cycloalkyl or heterocyclyl groups as defined herein.

[0075] In such cases, especially R 4 The substituents are linear or branched C1-C6-alkyl groups, which may be substituted or unsubstituted, dialkyl ether groups [R 6 (CH2) x -O-CH2) y -], 3- to 6-membered cycloalkyl, or 5- or 6-membered heterocyclyl.

[0076] R 4 When represents a substituted alkyl group, reference is made to the possible alkyl substituents defined above.

[0077] R 4 represents a substituted dialkyl ether group, the term "dialkyl ether" as defined above and its possible substituents R 6 The definition of is referred to.

[0078] R 4 When represents a substituted cycloalkyl or heterocyclyl group, reference is made to a definition of the possible substituents of such a group elsewhere in this specification.

[0079] R 4 When represents a substituted aryl group, reference is made to possible aryl-(phenyl-) substituents as defined above.

[0080] Preferably, R 4 The substituents aryl, alkyl, dialkylether, cycloalkyl and heterocyclyl may be substituted with one or two substituents, in particular as defined above for phenyl, C1-C3-alkyl and dialkylether.

[0081] It is preferred that compounds (IA) and (IB) contain a (b-1) group as defined herein.

[0082] When the (b-2) group is present, the following (b-2) group:

[0083] [ka] (In the formula, R 4 has the meaning defined anywhere in this specification), for example, the (b-2) group:

[0084] [ka] is particularly preferred.

[0085] For example, in formulas (a-1), (b-1), (b-2) and (b-3), as used herein, “ * " indicates the bonding position. In formulae (IA) and (IB), "l" represents an integer of 1 or 2, and preferably l=1.

[0086] In formula (IB), "m" and "n" independently represent an integer of 1, 2 or 3, preferably m=2, and preferably n=1 or 2.

[0087] C3-C6-cycloalkyl groups which may be substituents of linear C1-C3-alkyl groups or which may form a ring together with the nitrogen atom to which they are attached.

[0088] In formula (IA), “L 1" and "L 2 Each of the linker groups or so-called spacers, i.e., "alkyl spacers" containing 1 to 7 carbon atoms. Such alkyl spacer groups or linkers "L 1 " and "L 2 "teeth, - Straight chain C1-C3 alkyl group -[CH2] m -or-[CH2] n - (wherein m and n are independently integers of 1, 2, or 3); or - branched C1-C4-alkyl groups, such as preferably the 2-dimethylethyl group;

[0089] [ka] ;or C3-C6-cycloalkyl groups, which may be substituents of linear C1-C3-alkyl groups, such as

[0090] [ka] or - C3-C6-cycloalkyl groups which form a ring together with the nitrogen atom to which they are attached, e.g. "L 1 Regarding

[0091] [ka] and "L 2 Regarding

[0092] [ka] are independently selected from

[0093] Preferably, the linker "L 1 " is a straight chain C1-C3 alkyl group -[CH2]m - has the meaning.

[0094] Preferably, the linker "L 2 " is defined herein; - Straight chain C1-C3 alkyl group -[CH2] n where n represents an integer of 1, 2 or 3, - branched C1-C4-alkyl groups, and - C3-C6-cycloalkyl radicals which may be substituents of linear C1-C3-alkyl radicals or which may form a ring together with the nitrogen atom to which they are attached. It means a linker group containing 1 to 7 carbon atoms selected from the following:

[0095] In formulas (IA) and (IB), X 1 , X 2 and X 3 teeth, X 1 =N, S or O; X 2 =N, S, O or CR 5 ; X 3 =C or N Selected from; However, X 1 and X 2 One of them is N and the other is X 3 If N, then X 2 is CR 5 and the following group:

[0096] [ka] (In the formula, * indicates the site of attachment to the aminocarbonyl group, ** is -[(CH2)] in formulas (IA) and (IB). m -Amino-[(CH2)] n -group) form one of the

[0097] Among them, R5 X 2 =CR 5 represents an optional substituent, R 5 is preferably selected from halogen, linear or branched C1-C3-alkyl and linear or branched C1-C3-haloalkyl, each as defined above. 5 represents hydrogen.

[0098] Preferred are the oxazole-, isoxazole-, thiazole- and isothiazole-groups:

[0099] [ka] with oxazole- and isoxazole-groups being more preferred. Most preferred are

[0100] [ka] It is based on

[0101] A further aspect is l is an integer of 1 or 2; m and n are independently integers of 1, 2, or 3; X 1 is N, S or O; X 2 is N, S, O or CR 5 and; X 3 is C or N; However, X 1 and X 2 One of them is N, X 3 If N, then X 2 CR 5 and; R 5 represents H; A is a group (a-1)

[0102] [ka] (In the formula, * indicates the bond position; R 1 and R 2 is independent, - halogen, - linear or branched C1-C3-alkyl, - linear or branched C1-C3-haloalkyl, or - Straight or branched C1-C3 alkoxy represents 0, 1 or 2 substituents independently selected from represents; B is the following group (b-1), (b-2) or (b-3):

[0103] [ka] (In the formula, * indicates the bond position; R 3 teeth, - unsubstituted or substituted phenyl, - unsubstituted or substituted 5- or 6-membered heteroaryl, - unsubstituted or substituted bicyclic heteroaryl, - 6-membered heterocyclyl, - 6-membered heterocyclylalkyl, - phenylethynyl, or - Pyridinylethynyl represents 0, 1, 2 or 3 substituents independently selected from Substituted phenyl, heteroaryl and bicyclic heteroaryl groups include Halogen C1-C3-alkyl, C1-C3-haloalkyl, and 〇 C1~C3-alkoxy may have 1, 2 or 3 substituents independently selected from: R 4 teeth, - linear or branched C1-C6-alkyl, - Dialkyl ether group [R 6 (CH2) x -O-CH2) y -] (R 6 represents a C1-C3 alkoxy group; x and y independently represent integers 1, 2, or 3; or - 5- or 6-membered unsubstituted heterocyclyl, or - unsubstituted or substituted phenyl represents The substituents on the phenyl are Halogens, and 〇 C1~C3-alkoxy Selected from; Alkyl is Halogen, C1-C3-alkoxy, C6-cycloalkyloxy, Carboxyl, Aminocarbonyl, mono-alkylaminocarbonyl, Dialkylamino, 3-6 membered cycloalkyl, 5- or 6-membered heterocyclyl, unsubstituted or substituted 6-membered aryl, unsubstituted or substituted 5- or 6-membered heteroaryl, and Unsubstituted or substituted bicyclic heteroaryl and optionally substituted with one or two substituents independently selected from Substituted aryl, heteroaryl and bicyclic heteroaryl groups include Halogen, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, Aminocarbonyl, and Mono-alkylaminocarbonyl and optionally having 1, 2 or 3 substituents independently selected from The mono-alkylaminocarbonyl group may have further substituents on the monoalkyl chain selected from halogen substituted 5- or 6-membered heteroaryl. represents one of; In formulae (b-2) and (b-3), one of D1, D2 and D3 is present; - fused phenyl rings, - a fused 6-membered heteroaryl ring, a fused 6-membered cycloalkyl ring, or - a fused 5- or 6-membered heterocyclyl ring represents; The (b-2) and (b-3) groups are - halogen, - linear or branched C1-C3-alkyl, - linear or branched C1-C3-haloalkyl, and - Straight or branched C1-C3 alkoxy having 0 or 1 substituent selected from It relates to compounds of formula (IA) and (IB) as defined above, and to pharma- ceutically acceptable salts thereof.

[0104] In a further aspect of the invention, compounds of formula (IA) and (IB) as defined anywhere herein are R 3 represents H, C1-C3-alkoxy, pyridinylethynyl, or unsubstituted or substituted phenyl, the substituted phenyl group optionally carrying 1, 2 or 3 substituents independently selected from halogen, C1-C3-alkyl, C1-C3-haloalkyl and C1-C3-alkoxy, more preferably R 3 represents H or unsubstituted or substituted phenyl, where the substituted phenyl group may carry 1, 2 or 3 substituents independently selected from halogen, C1-C3-alkyl, C1-C3-haloalkyl and C1-C3-alkoxy; and / or R 4is a linear or branched C1-C6 alkyl, dialkyl ether group [R 6 (CH2) x -O-CH2) y -](R 6 represents a C1-C3-alkoxy group, and x and y independently represent an integer of 1, 2 or 3), or a 5- or 6-membered unsubstituted heterocyclyl, or a substituted or unsubstituted phenyl, the phenyl substituents being selected from halogen and C1-C3-alkoxy; It is preferable that the present invention is characterized in that

[0105] Among them, alkyl is - halogen, - C1-C3-alkoxy, - cyclohexyloxy, - carboxyl, - aminocarbonyl, - mono-alkylaminocarbonyl, - dialkylamino, cyclopropyl or cyclohexyl, - 6-membered heterocyclyl, unsubstituted or substituted phenyl, - unsubstituted or substituted 5- or 6-membered heteroaryl, and - unsubstituted or substituted bicyclic heteroaryl and optionally substituted with one or two substituents independently selected from Substituted phenyl, heteroaryl and bicyclic heteroaryl groups include Halogen, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, aminocarbonyl, and Mono-alkylaminocarbonyl and the mono-alkylaminocarbonyl group may have a further substituent on the monoalkyl chain selected from halogen substituted 5- or 6-membered heteroaryl.

[0106] More preferably, R 4 is a linear or branched C1-C6 alkyl, dialkyl ether group [R 6 (CH2) x -O-CH2) y -](R 6 represents a C1-C3 alkoxy group, and x and y independently represent an integer of 1, 2 or 3), or a 5- or 6-membered unsubstituted heterocyclyl, wherein alkyl is - C1-C3-alkoxy, - carboxyl, - aminocarbonyl, - mono-alkylaminocarbonyl, - cyclopropyl, - 6-membered heterocyclyl, unsubstituted or substituted phenyl, - unsubstituted or substituted 5- or 6-membered heteroaryl, and - unsubstituted or substituted bicyclic heteroaryl and optionally substituted with one or two substituents independently selected from Substituted phenyl, heteroaryl and bicyclic heteroaryl groups include C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, aminocarbonyl, and Mono-alkylaminocarbonyl and the mono-alkylaminocarbonyl group may have a further substituent on the monoalkyl chain selected from halogen substituted 5- or 6-membered heteroaryl.

[0107] In a further aspect of the invention, compounds of formula (IA) and (IB) as defined anywhere herein may be provided in which one or more of the substituents defined therein are in particular - the halogen substituents are selected from F, Cl and Br, more preferably F and Cl; and / or - the linear or branched C1-C6-alkyl substituents are selected from methyl, ethyl, propyl, iso-propyl, n-butyl and iso-butyl; and / or - the C1-C3-alkoxy substituents are selected from methoxy and ethoxy; and / or - the C1-C3-haloalkyl substituents are selected from difluoroethyl (-CH2-CHF2) and trifluoromethyl (CF3); and / or - R 4 the substituted alkyl group at position represents a substituted C1-C3-alkyl group; and / or the bicyclic heteroaryl group is selected from the benzimidazolyl group; It is preferable that the present invention is characterized in that is selected as follows.

[0108] In a particularly preferred embodiment, the compounds according to formula (IA) and (IB) as defined anywhere herein are selected from the group consisting of the following compounds:

[0109] [Table 1] JPEG2024534538000027.jpg209124 JPEG2024534538000028.jpg206124 JPEG2024534538000029.jpg201124 JPEG2024534538000030.jpg216124 JPEG2024534538000031.jpg217124 JPEG2024534538000032.jpg210124 JPEG2024534538000033.jpg187124JPEG2024534538000034.jpg220124 JPEG2024534538000035.jpg193124 JPEG2024534538000036.jpg205124 JPEG2024534538000037.jpg209124 JPEG2024534538000038.jpg211124 JPEG2024534538000039.jpg190124 JPEG2024534538000040.jpg225124 JPEG2024534538000041.jpg216124 JPEG2024534538000042.jpg217124 JPEG2024534538000043.jpg177124 is selected from.

[0110] 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, methanesulfonates, hydroxyethanesulfonates, glycinates, maleates, propionates, fumarates, toluenesulfonates, benzenesulfonates, trifluoroacetates, naphthalenedisulfonates-1,5, salicylates, benzoates, lactates, salts of malic acid, salts of 3-hydroxy-2-naphthoic acid-2, citrates and acetates. HCl salts are preferred.

[0111] Pharmaceutically acceptable salts of the compounds according to the invention further include, for example, salts with suitable pharma- ceutically acceptable bases, such as, for example, salts with alkali or alkaline earth hydroxides, such as NaOH, KOH, Ca(OH)2, Mg(OH)2, and the like, amine compounds, such as, for example, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, ethanolamine, diethanolamine, triethanolamine, methylglucamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine, 2-amino-2-methyl-propanol-(1), 2-amino-2-methyl-propanediol-(1,3), 2-amino-2-hydroxy-methyl-propanediol-(1,3) (TRIS), and the like.

[0112] The novel compounds of the present invention may exist in amorphous, crystalline or partially crystalline form, or may also exist as hydrates.

[0113] The novel compounds according to formula (IA) and (IB) defined elsewhere herein have been found to act as ferroportin inhibitors and are therefore suitable for pharmaceutical use, such as, in particular, for use as ferroportin inhibitors.

[0114] As already explained above, ferroportin is an iron transport protein responsible for the uptake of released iron through the intestine and its transport into the blood circulation, thereby delivering iron to the appropriate tissues and organs. Inactivation or inhibition of ferroportin results in the inability to export iron, thereby reducing intestinal iron absorption. Thus, ferroportin inhibition in the sense of the present invention includes the inhibition of iron transport from cells to the blood circulation and the inhibition of iron absorption in the intestine. Therein, the inhibition of iron transport and / or iron reflux can be carried out by various mechanisms, including, for example, the inhibition of the iron transport activity of ferroportin and thus the inhibition of iron reflux, the induction of the internalization, degradation and / or reduction of ferroportin, the administration of hepcidin agonists, i.e. compounds that compete with hepcidin or inhibit the binding of hepcidin to ferroportin.

[0115] Ferroportin inhibition can 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 following examples. Furthermore, ferroportin inhibition can be determined by measuring ferroportin internalization and / or degradation in a ferroportin internalization and degradation assay (FACS), or by investigating ferroportin ubiquitination and degradation, each as described in more detail in the following examples. Furthermore, ferroportin inhibition can be determined by measuring the activity as a hepcitidine agonist, for example by determining the hepcitidine binding ability to ferroportin in a hepcitidine internalization assay (J774), as described in more detail in the following examples. Furthermore, ferroportin inhibition can be determined by confirming the inhibition of hepcidin binding to ferroportin, for example in a biophysical ferroportin-hepcidin binding assay (Hep Bind FP), as described in more detail in the following examples. Additionally, ferroportin inhibition can be determined by determining the activity of the compound with respect to its ability to block iron export via ferroportin, for example, using an assay to measure inhibition of iron efflux, as described in more detail in the Examples below.

[0116] Thus, ferroportin inhibition within the meaning of the present invention can be particularly defined by exhibiting ferroportin inhibitory activity in at least one of the aforementioned test methods, in particular as demonstrated by: Inhibition of ferroportin-mediated iron transport activity in the Blazer Assay: IC of less than or equal to 100 (≦100), preferably less than or equal to 50 (≦50), and more preferably less than 50 (<50). 50 Value [μM]. Ferroportin internalization and degradation assay (FACS): EC of 100 or less (≦100), preferably 50 or less (≦50), more preferably less than 50 (<50) 50 Value [μM]. Ferroportin ubiquitination and degradation: visually inspected effects in Western blots of "+ comparable to hepcidin", "+ / - intermediate effect" and "+ / + / - intermediate effect stronger than"; preferred is an effect "+" or "+ / + / -", most preferred is an effect "+". Hepcidin internalization assay (J774): IC of 100 or less (≦100), preferably 50 or less (≦50), more preferably less than 50 (<50) 50 Value [μM]. Biophysical ferroportin-hepcidin binding assay: IC of 100 or less (≦100), preferably 50 or less (≦50), more preferably less than 50 (<50) 50 Value [μM]. Inhibition of iron efflux: IC of 100 or less (≦100), preferably 50 or less (≦50), more preferably less than 50 (<50) 50 value.

[0117] Ferroportin inhibition can be further determined in in vivo models, as described in more detail in the Examples below. Suitable in vivo models can include, for example, testing for hypoferremia in naive mice via measurement of serum iron reduction; testing for inhibition of iron absorption in anemic rats via measurement of serum iron inhibition; testing for correction of hyperferremia in beta2-microglobulin deficient mice via measurement of serum iron reduction; testing for inhibition of iron overload in beta2-microglobulin deficient mice via measurement of total iron in the spleen or liver; testing for amelioration of anemia, ineffective erythropoiesis and iron overload in a mouse model of beta-thalassemia intermedia.

[0118] The activity of the compounds of the present invention as ferroportin inhibitors can be determined, inter alia, by the methods described in the Examples below.

[0119] Furthermore, as already explained above, ferroportin inhibition can be brought about, for example, by hepcidin, which is thus an essential regulator of iron absorption, inhibiting ferroportin and thus blocking iron transport from cells to blood circulation and iron absorption.It has further been found that some of the compounds defined herein act as hepcidin mimetics or hepcidin agonists, and are also included in ferroportin inhibition in the sense of the present invention.

[0120] The compounds defined in the present invention are therefore also suitable for use in inhibiting iron transport from cells into the blood circulation and in inhibiting iron absorption in the intestine, as well as for use as hepcidin mimetics or hepcidin agonists.

[0121] Due to the activity of the compounds defined herein as ferroportin inhibitors, the compounds of the invention are further particularly suitable for use in the inhibition of iron transport mediated by ferroportin, thereby in the prevention and / or treatment of disorders of iron metabolism leading to elevated iron levels, diseases associated with or caused by elevated iron levels, increased iron absorption or iron overload, such as in particular tissue iron overload, diseases associated with ineffective erythropoiesis or diseases caused by reduced hepcidin levels. Furthermore, the compounds of the invention are suitable for use in adjunctive therapy by limiting the amount of iron available to pathogenic microorganisms, such as the bacterium Vibrio vulnificus, thereby preventing or treating infections caused by said pathogenic microorganisms.

[0122] Among them, diseases associated with, related to, caused by, or leading to elevated iron levels, increased iron absorption, iron overload (e.g., tissue iron overload) or ineffective erythropoiesis include thalassemia, hemoglobinopathies such as hemoglobin E disease (HbE), hemoglobin H disease (HbH), hemochromatosis, hemolytic anemias such as sickle cell anemia (sickle cell disease) and congenital dyserythropoietic anemias.

[0123] Diseases associated with, related to, caused by, or leading to elevated iron levels, increased iron absorption, iron overload (e.g., tissue iron overload) further include neurodegenerative diseases, e.g., Alzheimer's disease and Parkinson's disease, and it is believed that the compounds are effective by limiting the deposition or increase of iron in tissues or cells.

[0124] The compounds of the present invention are further suitable for use in the prevention and / or treatment of the formation of radicals, reactive oxygen species (ROS) and oxidative stress caused by excess iron or iron overload, as well as in the prevention and / or treatment of cardiac, hepatic and endocrine damage caused by excess iron or iron overload, and further in the prevention and / or treatment of inflammation induced by excess iron or iron overload.

[0125] Diseases associated with ineffective erythropoiesis include, inter alia, myelodysplastic syndromes (MDS, myelodysplasia) and polycythemia vera, as well as congenital dyserythroplastic anemia.

[0126] Further diseases, disorders and / or disease states include iron overload caused by mutations in genes involved in sensing whole body iron stores, such as hepcidin (Hamp1), hemochromatosis protein (HFE), hemojuvelin (HJV) and transferrin receptor 2 (TFR2), such as diseases associated with HFE and HJV gene mutations in particular, chronic hemolysis-related disease, sickle cell disease, red blood cell membrane disorders, glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency), erythroblastic nephropathy, and the like. Includes porphyrias, Friedreich's ataxia, and subgroups of iron overload diseases such as transfusional iron overload, iron poisoning, pulmonary hemosiderosis, osteoporosis, insulin resistance, African iron overload, Hallervorden-Spatz disease, hyperferritinemia, ceruloplasmin deficiency, neonatal hemochromatosis, and thalassemias including alpha thalassemia, beta thalassemia and delta thalassemia, thalassemia intermedia, red blood cell disorders including sickle cell disease, and myelodysplastic syndromes.

[0127] Further diseases and / or disorders and / or disease states associated with elevated iron levels include diseases involving elevated iron levels, including, but not limited to, ataxia, Friedreich's ataxia, age-related macular degeneration, age-related cataracts, age-related retinal diseases and neurodegenerative diseases, such as pantothenate kinase-associated neurodegeneration, restless legs syndrome and Huntington's disease.

[0128] The compounds of the invention may further be suitable for use in the prevention and treatment of diseases caused by a deficiency of hepcidin.

[0129] In view of that, a further object of the invention relates to medicaments containing one or more of the compounds defined above, such as medicaments for the prevention and treatment of any of the indications, conditions, disorders or diseases defined above.

[0130] Further objects of the present invention relate to pharmaceutical compositions and medicaments comprising one or more of the compounds according to the invention as defined above and optionally one or more pharmacologically acceptable carriers and / or auxiliary substances and / or solvents. Further objects of the present invention relate to pharmaceutical compositions and medicaments comprising one or more of the compounds according to the invention as defined above and optionally one or more further pharma- ceutical active compounds. Said pharmaceutical compositions contain, for example, up to 99% by weight or up to 90% by weight or up to 80% by weight or up to 70% by weight of the compounds of the invention, the remainder being formed by pharmacologically acceptable carriers and / or auxiliary substances and / or solvents and / or optionally further pharma- ceutical active compounds, respectively.

[0131] Among them, pharma- ceutically acceptable carriers, auxiliary substances or solvents are common pharmaceutical carriers, auxiliary substances or solvents, including various organic or inorganic carriers and / or auxiliary materials, as they are customarily used for pharmaceutical purposes, especially for solid pharmaceutical formulations. Examples include excipients, such as saccharose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate; binders, such as cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethylene glycol, saccharose, starch; disintegrants, 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, talc, calcium carbonate ... flavorings such as citric acid, menthol, glycine, orange powder; preservatives such as sodium benzoate, sodium bisulfite, parabens (e.g., methylparaben, ethylparaben, propylparaben, butylparaben); stabilizers such as citric acid, sodium citrate, acetic acid and the titriplex series of multicarboxylic acids, e.g., diethylenetriaminepentaacetic acid (DTPA); suspending agents such as methylcellulose, polyvinylpyrrolidone, aluminum stearate; dispersing agents; diluents such as water, organic solvents; waxes, fats and oils such as beeswax, cocoa butter; polyethylene glycol; white petrolatum, and the like.

[0132] Liquid pharmaceutical formulations, such as solutions, suspensions and gels, usually contain a liquid carrier, such as water and / or a pharma- ceutically acceptable organic solvent. In addition, such liquid formulations may also contain pH adjusting agents, emulsifying or dispersing agents, buffers, preservatives, wetting agents, gelatinizing agents (e.g., methylcellulose), dyes and / or flavoring agents, e.g., as defined above. The composition may be isotonic, i.e., have the same osmotic pressure as blood. The isotonicity of the composition may be adjusted by using sodium chloride and other pharma- ceutically acceptable agents, e.g., dextrose, maltose, boric acid, sodium tartrate, propylene glycol and other inorganic or organic soluble substances. The viscosity of the liquid composition may be adjusted by a pharma-ceutically acceptable thickening agent, e.g., methylcellulose. Other suitable thickening agents include, e.g., xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, carbomer, and the like. The preferred concentration of the thickening agent depends on the drug selected.

[0133] To extend the shelf life of the liquid composition, a pharma- ceutically acceptable preservative can be used. For example, benzyl alcohol can be preferred, although a number of preservatives can be used, including parabens, thimerosal, chlorobutanol, and benzalkonium chloride.

[0134] The pharmaceutical compositions are, for example, suitable for intravenous, intraperitoneal, intramuscular, intravaginal, buccal, percutaneous, subcutaneous, mucocutaneous, oral, rectal, transdermal, topical, intradermal, intragastric or intradermal application and are provided, for example, in the form of pills, tablets, enteric coated tablets, film tablets, layer tablets, sustained release preparations for oral, subcutaneous or dermal administration (in particular as plasters), depot preparations, dragees, suppositories, gels, ointments, syrups, granules, suppositories, emulsions, suspensions, microcapsules, micropreparations, nanopreparations, liposomal preparations, capsules, enteric coated capsules, powders, inhalation powders, microcrystalline preparations, inhalation sprays, dustings, drops, nasal drops, nasal sprays, aerosols, ampoules, liquids, juices, suspensions, infusions or injection solutions, etc.

[0135] A further object of the present invention relates to a medicament or combined preparation containing one or more of the compounds defined above and at least one further pharma- ceutical active compound, such as a compound, in particular for the prevention and treatment of iron overload and related conditions, preferably an iron chelating compound, or a compound for the prevention and treatment of any of the conditions, disorders or diseases defined above, such as a pharma- ceutical active compound, in particular for the prevention and treatment of thalassemia, hemochromatosis, neurodegenerative diseases (e.g. Alzheimer's disease or Parkinson's disease) and related conditions.

[0136] A further object of the present invention relates to the use of the compound as defined above in combination therapy (fixed dose or free dose combination for sequential use) with one or two other active ingredients (drugs). Such combination therapy includes the co-administration of the compound of the present invention and at least one additional pharma- ceutical active compound (drug). Combination therapy in fixed dose combination therapy includes the co-administration of the compound of the present invention and at least one additional pharma- ceutical active compound in a fixed dose formulation. Combination therapy in free dose combination therapy includes the co-administration of the compound of the present invention and at least one additional pharma- ceutical active compound in a free dose of each compound, either by simultaneous administration of the individual compounds or by sequential use of the individual compounds distributed over a period of time. The at least one additional pharma- ceutically active compound (drug) may in particular be a drug for reducing iron overload (e.g., Tmprss6-ASO) or an iron chelator, in particular curcumin, SSP-004184, deferithrine, deferasirox, deferoxamine and / or deferiprone, or an antioxidant, for example n-acetylcysteine, an antidiabetic drug, for example a GLP-1 receptor agonist, an antibiotic, for example vancomycin (VAN) or tobramycin, a malaria parasite, for example serotonin, or a steroid ... These include drugs for treating rheumatoid arthritis, anti-cancer drugs, anti-fungal drugs, drugs for treating neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (e.g., dopamine agonists such as levodopa), anti-viral drugs such as interferon-alpha or ribavirin, or immunosuppressants (cyclosporine A or cyclosporine A derivatives), iron supplements, vitamin supplements, erythropoiesis stimulators, anti-inflammatory biological agents, anti-thrombolytic drugs, statins, hypertensive drugs, and inotropic compounds.

[0137] A further object of the invention relates to the use of said combination for preventing and / or treating diseases caused by a deficiency of hepcidin or by disorders of iron metabolism, such as in particular iron overload conditions, such as in particular thalassemia and hemochromatosis, as well as other disorders described in the present application.

[0138] A further object of the invention relates to the use of the compounds as defined herein, either as such or in combination therapy as described above, in combination with blood transfusion.

[0139] The compounds, medicaments and / or combined preparations according to the invention may be administered orally, parenterally and intravenously.

[0140] For this purpose, the compounds according to the invention are preferably provided in medicaments or pharmaceutical compositions in the form of pills, tablets, e.g. enteric coated tablets, film tablets and layer tablets, sustained release preparations for oral administration, depot preparations, dragees, granules, emulsions, suspensions, microcapsules, microformulations, nanoformulations, liposomal preparations, capsules, e.g. enteric coated capsules, powders, microcrystalline preparations, dusting powders, drops, ampoules, solutions, suspensions, infusion or injection solutions, or in the form of preparations suitable for inhalation.

[0141] In a preferred embodiment of the invention, the compounds are administered in the form of tablets or capsules, as defined above, which may be, for example, in an acid-resistant form or with a pH-dependent coating.

[0142] The compound of the present invention as an active substance can be administered, for example, 1 to 4 times a day, at a unit dose of, for example, 0.001 mg / kg to 500 mg / kg body weight. However, the dose can be increased or decreased depending on the age, weight, condition, severity of the disease, or type of administration of the patient.

[0143] A further object of the present invention therefore relates to compounds, medicaments, compositions and combined preparations as defined above for preparing medicaments, in particular for oral or parenteral administration, for the prevention and treatment of any indication, condition, disorder or disease as defined above.

[0144] A further object of the present invention relates to a method for the prevention and treatment as defined above, such as for the prevention and / or treatment of iron metabolism disorders, diseases associated with or caused by elevated iron levels or iron overload, iron storage diseases associated with or led to elevated iron levels, and diseases associated with ineffective erythropoiesis, which comprises the administration of a compound, medicament, composition or combined preparation as defined above to a patient (human or animal) in need thereof.

[0145] Among these are diseases associated with, related to, caused by or leading to elevated iron levels or iron overload as defined above.

[0146] A further object of the present invention relates to the use of the compounds as defined above for preparing a medicament, in particular for the prevention and treatment of any of the indications, conditions, disorders or diseases as defined above.

[0147] The compounds according to the present invention of general structural formulas (IA) and (IB) can essentially be prepared by the processes described in international application WO 2021 / 191202, which is incorporated herein by reference.

[0148] In particular, the following general procedure describes a suitable preparation process:

[0149] Step 1: Scheme a)

[0150] [ka] or scheme b)

[0151] [ka] or scheme c)

[0152] [ka] Subsequent ester cleavage:

[0153] [ka]

[0154] Step 2:

[0155] [ka]

[0156] Step 3: Step 3a - Formula (IA):

[0157] [ka] Step 3a illustrates a general scheme for preparing compounds of formula (IA). 1 , X 2 , X 3 and the A and B groups, and l, L 1 and L 2 has the meaning defined elsewhere in this specification.

[0158] Step 3b - Formula (IB): To prepare a compound of formula (IB), 1 " and "L 2 " are independently -[CH2] m - and -[CH2] n -representing a CH-, CH2-CH- or CH2-CH2-CH- group depending on the desired resulting alkylene chain length), a general scheme for step 3 is illustrated as follows: Step 3b:

[0159] [ka] X 1 , X 2 , X 3 and the A and B groups, and l, L 1 , m and n have the meanings defined elsewhere herein, 1 " group is -[CH2] m represents a CH-, a CH2-CH- or a CH2-CH2-CH- group, depending on the desired resulting alkylene chain length defined by -.

[0160] In a further aspect, the present invention covers intermediate compounds obtainable by the processes described herein, such as intermediate compounds obtained in particular from the individual steps of the general reaction schemes described above and in further detail herein. Details of the preparation conditions are provided in the following examples. EXAMPLES

[0161] The present invention is illustrated in more detail by the following examples, which are merely illustrative and one skilled in the art can extend the specific examples further to the claimed compounds.

[0162] Pharmacological assays 1. Hepcidin internalization assay (J774) This cellular assay allows for quantification of hepcidin binding to ferroportin (Fpn) through microscopic detection of internalization of fluorescently labeled hepcidin into J774 cells. J774 is a mouse macrophage cell line that has been shown to endogenously express Fpn 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 cells even after degradation of the hepcidin peptide backbone. Thus, microscopic detection of cell-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 low molecular weight Fpn inhibitor compounds in this assay was evaluated in vitro as described below.

[0163] J774 cells harvested from approximately 80% confluent cultures were plated at 8 × 10 in complete medium (DMEM, 10% FBS, 1% penicillin-streptomycin) containing 200 μM Fe(III)NTA (nitrilotriacetic acid) in 100 μl per well of a 96-well MicroClear plate (Greiner; catalog 655090). 5Cells / ml were plated and grown at 37°C in 5% CO2. After overnight incubation, cells were washed three times with pre-warmed DMEM w / o phenol red, 30 μl / well of DMEM w / o phenol red was added after the final wash, and 10 μl / well of a dilution series of test compounds was added in triplicate. J774 cells were pre-incubated with test compounds for 15 min at 37°C in 5% CO2, followed by addition of TMR-hepcidin at a final concentration of 25 nM. Cells were incubated for 2 h in a total volume of 50 μl at 37°C in 5% CO2, then Hoechst 33342 dye was added to a final concentration of 0.5 μg / ml to stain the nuclei and further incubated for 10 min at 37°C in 5% CO2. Cells were washed three times with PBS and fixed in 100 μl of 4% paraformaldehyde in PBS for 15 min at room temperature. After removing the paraformaldehyde solution, the cells were washed three times with PBS to leave 100 μl per well, and the plate was sealed with a foil plate seal. Fluorescence images of 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) were acquired using a ScanR plate imager (Olympus) equipped with a 20x high NA objective. Four pictures were acquired per well, with the fluorescence channels covering approximately 1500 cells per well. The acquired image data were analyzed with ScanR image analysis software. Image analysis included detection of nuclei (Hoechst 33342 fluorescence), identification of cell-associated regions, application of virtual channels, and thresholding for rolling-ball background reduction, followed by application of the Sum(Mean) algorithm to measure cell-associated TMR fluorescence as a quantitative measure of internalized TMR-hepcidin. 50IC values ​​were calculated on the Sum(Mean) raw data using the "Log(inhibitor) vs. response" curve fitting in Prism5 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 IC of the preferred model was calculated. 50 Data were used. IC of Fpn inhibitors tested in the hepcidin internalization assay 50 The data are listed in Table 1. IC of unlabeled hepcidin in this assay 50 is 0.015±0.011 μM.

[0164] [Table 2]

[0165] 2. Biophysical Ferroportin-hepcidin Binding Assay This biophysical assay was developed to more directly confirm the inhibition of hepcidin binding to ferroportin (Fpn). 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 an increase in the fluorescence polarization (FP) of the TMR-hepcidin ligand. Low molecular weight Fpn inhibitors are tested for inhibition of TMR-hepcidin binding to Fpn, detected by a dose-dependent decrease in the TMR FP signal, as described in detail below.

[0166] A mixture of 1.3 μM human Fpn and 30 nM TMR-hepcidin in FP assay buffer containing 50 mM Tris-HCl pH 7.3, 200 mM NaCl, 0.02% DDM, 0.1% BSA is plated in 384-well black low volume round bottom plates (Corning, catalog 3677) at 16 μl per well. 8 μl of serial dilutions of test compound are added in duplicate to reach final Fpn and TMR-hepcidin concentrations of 1 μM and 20 nM, respectively. Plates are incubated at room temperature for 90 minutes and parallel (S) and perpendicular (P) fluorescence is measured in a Synergy H1 fluorescence reader (BioTek). FP values ​​are calculated in mP according to the following formula:

[0167]

number

[0168] I C 50 The IC value is determined with the calculated mP value as described for the hepcidin internalization assay. 50 is approximately 0.37±0.067 μM.

[0169] 3. Inhibition of ferroportin-mediated iron export activity in iron response assays This assay indirectly measures intracellular iron levels by monitoring the activity of a beta-lactamase (BLA) reporter gene fused to the human ferritin promoter and associated iron regulatory element (IRE) contained within the 5' untranslated region of ferritin mRNA. Expression of ferroportin (Fpn) in such cell lines leads to iron efflux and low iron levels, as reflected by low activity of the reporter gene. On the other hand, inhibition of Fpn-mediated iron efflux leads to elevated cellular iron levels, detected as increased reporter gene activity. Low molecular weight Fpn inhibitor compounds are tested for dose-dependent effects in this in vitro iron response assay, as described below.

[0170] The HEK-293 cell line #354 is generated by stably integrating (i) a human Fpn-GFP fusion construct inserted into a derivative of the doxycycline-inducible pTRE-Tight-BI plasmid (Clontech, catalog 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™6.2 / cGeneBLAzer™-DEST plasmid (Invitrogen, catalog 12578-043), thereby replacing the original CMV promoter and placing an IRE regulating the translation of the ferritin gene approximately 170 bp upstream of the start codon of the reporter gene. #354 cells were harvested from approximately 80% confluent cultures and cultured at 1.8 × 10 cells in 50 μl per well of a 384-well PDL-coated plate in DMEM / F12 GlutaMAX™ medium (Invitrogen, catalog 31331-028) containing 10% FBS (Clontech, catalog 631106), 1% penicillin-streptomycin, 200 μg / ml hygromycin B (Invitrogen, catalog 10687-010), 5 μg / ml blasticidin (Invitrogen, catalog R210-01), 4 μg / ml doxycycline (Clontech, catalog 631311). 5Cells / ml are seeded and grown at 37°C in 5% CO2. After overnight incubation, 10 μl / well of serially diluted test compounds are added in quadruplicate and the plates are further incubated overnight at 37°C in 5% CO2. Cells are washed three times with HBSS, leaving 25 μl per well. BLA activity is detected by adding 5 μl / well of GeneBlazer reagent CCF4-AM (Invitrogen, Cat K1085) to the cells. After incubating the plates for 60 min in the dark at 18°C, blue and green fluorescent signals are measured in a Safire2 fluorescent plate reader (Tecan) with excitation at 410 nm and emission at 458 nm (blue) and 522 nm (green). The ratio of blue / green fluorescence as a measure of BLA activity is calculated and the EC was calculated using the blue / green fluorescence ratio calculated as described for the hepcidin internalization assay. 50 Determine the EC value for hepcidin in this assay. 50 is approximately 0.096 ± 0.063 μM (n = 37).

[0171] 4. Ferroportin Internalization and Degradation Assay The HEK-293 cell line #354 (described in Example 3) is used to measure the ability of compounds to induce ferroportin (Fpn) internalization and degradation by fluorescence-activated cell sorting (FACS). HEK-293#354 cells were grown in doxycycline-containing medium to induce the expression of human Fpn-GFP fusion protein on the cell surface. Data from 10 independent experiments show that 48 hours of culture of HEK#354 cells in the presence of 4 μg / ml doxycycline induces an average of 42.6%±6.4% Fpn-GFP positive cells. Small molecular weight Fpn inhibitor compounds are tested for dose-dependent effects on Fpn-GFP mean fluorescence intensity (MFI) in HEK-293 cell line #354 as described below.

[0172] HEK#354 cells were harvested from approximately 80% confluent cultures and cultured at 0.6 × 10 in 50 μl per well of a 384-well plate (Greiner; Cat. 781091) in DMEM / F12 GlutaMAX™ medium (Invitrogen, Cat. 31331-028) containing 10% FBS (Clontech, Cat. 631106), 1% penicillin-streptomycin (Invitrogen, Cat. 15140-122), 200 μg / ml hygromycin B (Invitrogen, Cat. 10687-010), 5 μg / ml blasticidin (Invitrogen, Cat. R210-01), 4 μg / ml doxycycline (Clontech, Cat. 631311). 6 Cells / ml are seeded and grown at 37°C in 5% CO2. After overnight incubation, 10 μl / well of serially diluted test compounds are added in quadruplicate, and the plate is further incubated overnight at 37°C in 5% CO2. Cells are washed once with FACS buffer (PBS containing 1% FBS, 2 mM EDTA and 0.05% NaN3), harvested in FACS buffer containing 0.5 μg / ml propidium iodide (Sigma, Cat P4864), and analyzed on a flow cytometer (CANTO™ II, BD Biosciences) equipped with a high-throughput sampler. Live HEK#354 cells are gated as the propidium iodide negative population and analyzed for the expression of Fpn-GFP. The MFI of Fpn-GFP over 2000 live cells for each compound dilution is calculated using FlowJo (Tree Star's, OR), and the ability of Fpn inhibitors to induce internalization and degradation of Fpn-GFP is calculated as described for the hepcidin internalization assay. The mean EC 50 The value is approximately 0.004±0.002 μM.

[0173] 5. Ferroportin Ubiquitination and Degradation Exposure of cells expressing ferroportin (Fpn) to hepcidin is known to trigger ubiquitination and subsequent internalization and degradation of Fpn (Qiao, 2012). The ability of Fpn inhibitors to induce Fpn ubiquitination and degradation is investigated by immunoprecipitation assays using the J774 mouse macrophage cell line, which expresses Fpn upon treatment with iron.

[0174] J774 cells (DSMZ, Catalog ACC170) are seeded at 0.8×106 cells / ml in 15 ml of medium (DMEM Gibco Catalog 11971-025, 10% heat-inactivated FBS Gibco Catalog 10500-064, 1% penicillin-streptomycin Gibco Catalog 15140-122) containing 200 μM Fe(III)-NTA in 10 cm tissue culture dishes (Greiner Catalog 664160) and grown overnight at 37° C. in 5% CO2. Cells are incubated with synthetic human hepcidin (Bachem, Catalog H-5926) or Fpn inhibitor compounds for 10 or 120 minutes. Cells are washed and lysed with ice-cold lysis buffer (Pierce, Life Technologies, catalog 87787) containing 1x HALT protease inhibitor cocktail (Life technologies, catalog 78429) and 10 mM iodoacetamide (Sigma, catalog I6125) to stabilize ubiquitinated proteins. Immunoprecipitation is performed using the Pierce Classic IP kit (Life Technologies, catalog 26146) according to the manufacturer's protocol. Briefly, 2 mg of protein in 1.25 ml of IP lysis buffer is incubated by mixing with control agarose beads for 1 h at 4 °C to pre-clear the lysate and reduce non-specific signals. The unbound lysate is then incubated overnight with 12 μg per reaction of affinity-purified anti-Fpn antibody F308, which is made against a GST fusion protein of mouse Fpn amino acids 224-308. Immune complexes are captured by pipetting 14 μl of precipitating Pierce Protein A / G Plus agarose beads (Life Technologies, catalog 20423) per reaction, and the slurry is incubated with gentle tilt mixing for 1.5 h at 4° C. The beads are washed and immune complexes are eluted directly with 75 μl of SDS NuPAGE LDS sample buffer (Life Technologies, catalog NP0007) containing DTT (Life Technologies, catalog NP0009).

[0175] After immunoprecipitation, samples are analyzed by Western blotting using rabbit anti-mouse MTP1 antiserum (Alpha Diagnostic International, Cat. MTP11-A) and mouse anti-mono- and polyubiquitin conjugated monoclonal antibodies (Enzo Lifesciences, Cat. BML-PW8810) to detect ferroportin and ubiquitin, respectively. Mouse monoclonal anti-rabbit IgG light chain (Abcam, Cat. ab99697) and anti-mouse IgG H&L (Abcam, Cat. ab6789) HRP conjugate are used as secondary antibodies.

[0176] 6. Inhibition of iron efflux by ferroportin inhibitors The activity of hepcidin and ferroportin inhibitor compounds for their ability to block ferroportin-mediated iron export is tested in T47D cells (ECACC, catalog 85102201) as described below.

[0177] Cells were plated in 24-well plates (Greiner, Cat. 662160) containing 350000 cells / well and incubated at 100 μM in growth medium containing 500 μM L-ascorbic acid (Sigma Aldrich, Cat. 795437). 58 Fe(sulfate 58Incubate overnight with 500 μl of iron uptake buffer (IUB; PIPES 40 mM, 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). Wash once with removal buffer (2 min incubation, BPDS 100 μM, Cat. 11890 and Na2S2O4 500 μM, Cat. 157953, Sigma Aldrich, in IUB) and twice again with IUB. Add serial dilutions of hepcidin (Bachem) or ferroportin inhibitors (4 μM to 0.0064 μM, 5-fold dilutions) in a total volume of 0.6 ml per well. Cells are incubated at 37° C. in 5% CO2 for 20 hours. Supernatants are collected and analyzed using inductively coupled plasma mass spectrometry (ICP-MS, Thermo Scientific, Element2). 58 Measure Fe. Harvest the pellet for protein concentration measurement. Results are expressed as Fe in the supernatant per mg of protein in the cell lysate. 58 Plot as ng of Fe.

[0178] Preparation of Example Compounds General Experimental Details Commercially 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 400 MHz spectrometer in deuterated solvents. Chemical shifts (δ) are in parts per million.

[0179] Compounds were purified by flash column chromatography on normal phase silica on a Biotage Isolera system using the appropriate SNAP cartridge and gradient. Alternatively, compounds were purified in reverse phase using a Biotage Isolera system with the appropriate C18 SNAP cartridge and reverse phase eluents, or by preparative HPLC (if otherwise stated).

[0180] Abbreviation EtOAc Ethyl acetate CH2Cl2Dichloromethane Et2O Diethyl ether MeOH Methanol EtOH Ethanol Brine Saturated sodium chloride solution Chloroform-d Deuterated chloroform DMSO-d6 Deuterated dimethyl sulfoxide s singlet br s bright singlet d doublet dd Double doublet dt Triplet Doublet td Doublet Triplet hept. septet m multiplet q quartet δ Chemical shift ppm parts per million M Molar concentration mm millimolar concentration umol micromolar concentration g grams mg milligram l Liter mL Milliliters h time min %-w / w mass percentage TLC Thin Layer Chromatography UHPLC Ultra High Performance Liquid Chromatography MS mass spectrometry ESI Electrospray Ionization m / z mass-to-charge ratio H + proton MHz Megahertz sm starting material Jones Reagent CrO3 in H2SO4 CrO3 Chromium Trioxide HCl Hydrochloric acid H2SO4 Sulfuric acid NH4Cl Ammonium chloride Na2SO4 Sodium Sulfate NaOH Sodium hydroxide Bn Benzyl MS Mass Spectrum ESI Electrospray Ionization SNAP Biotage column trade name for flash column chromatography R f retention factor TLC Thin Layer Chromatography

[0181] chemical nomenclature Chemical names of intermediates and final example compounds were generated by using Chem Draw Professional 17.0.

[0182] All R f Values ​​are based on the following TLC plates: Merck, TLC silica gel 60 F 254 was determined using

[0183] Preparation details Example No. 1 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0184] [ka] 2-(1-(2-Methoxyethyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine (Chemspace) (100 mg, 0.46 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (113 mg, 0.46 mmol) were added to a solution of NaOH (9 mg, 0.23 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 1 (89 mg, 0.19 mmol, 41%) as an off-white solid. JPEG2024534538000054.jpg20164

[0185] Example No. 2 2-(2-((2-(1-butyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0186] [ka] 2-(1-Butyl-1H-benzo[d]imidazol-2-yl)ethan-1-amine (Chemspace) (100 mg, 0.46 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (114 mg, 0.46 mmol) were added to a solution of NaOH (9 mg, 0.23 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 2 (118 mg, 0.25 mmol, 55%) as an off-white solid. JPEG2024534538000056.jpg20166

[0187] Example No. 3 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0188] [ka] 2-(1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine (Chemspace) (100 mg, 0.4 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (98 mg, 0.4 mmol) were added to a solution of NaOH (8 mg, 0.2 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 3 (63 mg, 0.13 mmol, 32%) as an off-white solid. JPEG2024534538000058.jpg12165

[0189] Example No. 4 2-(2-((2-(1-butyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide dihydrochloride

[0190] [ka] 0.1 ml of HCl solution (4M in dioxane) was added to a solution of 2-(2-((2-(1-butyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide 2 (100 mg, 0.2 mmol) in 5 ml of dichloromethane. The resulting mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. The isolated material was dried under HV to give the title compound 4 (112 mg, 0.21 mmol, 97%) as an off-white solid. JPEG2024534538000060.jpg20165

[0191] Example No. 5 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0192] [ka] 2-(1-Methyl-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.40 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (100 mg, 0.40 mmol) were added to a solution of NaOH (40 mg, 1.00 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 5 (33.4 mg, 0.08 mmol, 20%) as an off-white solid. JPEG2024534538000062.jpg12166

[0193] Example No. 6 2-(2-((2-(1-ethyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0194] [ka] 2-(1-Ethyl-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.38 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (94 mg, 0.38 mmol) were added to a solution of NaOH (38 mg, 0.95 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 6 (22.2 mg, 0.05 mmol, 13%) as an off-white solid. JPEG2024534538000064.jpg12166

[0195] Example No. 9 2-(2-((2-(1-butyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-chloropyridin-2-yl)methyl)oxazole-4-carboxamide (VIT-101131nda112)

[0196] [ka] 2-(1-Butyl-1H-benzo[d]imidazol-2-yl)ethan-1-amine (Chemspace) (75 mg, 0.35 mmol) and N-((3-chloropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (91 mg, 0.35 mmol) were added to a solution of NaOH (7 mg, 0.5 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 6 (101 mg, 0.21 mmol, 60%) as an off-white solid. JPEG2024534538000066.jpg20166

[0197] Example No. 10 2-(2-((2-(1-butyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((4-methylpyridin-2-yl)methyl)oxazole-4-carboxamide (VIT-101124nda110)

[0198] [ka] 2-(1-Butyl-1H-benzo[d]imidazol-2-yl)ethan-1-amine (Chemspace) (100 mg, 0.46 mmol) and N-((3-methylpyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (112 mg, 0.46 mmol) were added to a solution of NaOH (10 mg, 0.23 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 2 (70 mg, 0.15 mmol, 32%) as an off-white solid. JPEG2024534538000068.jpg20163

[0199] Example No. 11 2-(2-((2-(1-butyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-(pyridin-2-ylmethyl)oxazole-4-carboxamide

[0200] [ka] 2-(1-Butyl-1H-benzo[d]imidazol-2-yl)ethan-1-amine (Chemspace) (100 mg, 0.46 mmol) and N-(pyridin-2-ylmethyl)-2-vinyloxazole-4-carboxamide (106 mg, 0.46 mmol) were added to a solution of NaOH (10 mg, 0.23 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 2 (67 mg, 0.15 mmol, 33%) as an off-white solid. JPEG2024534538000070.jpg20167

[0201] Example No. 23 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-phenethyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide (VIT-101133rxu463)

[0202] [ka] 2-(1-phenethyl-1H-benzo[d]imidazol-2-yl)ethan-1-amine hydrochloride (Chemspace) (100 mg, 0.33 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (82 mg, 0.33 mmol) were added to a solution of NaOH (20 mg, 0.5 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 6 (90.8 mg, 0.18 mmol, 54%) as an off-white solid. JPEG2024534538000072.jpg20164

[0203] Example No. 37 2-(2-((2-(1-butyl-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide (VIT-101136nda117)

[0204] [ka] 2-(1-Butyl-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.29 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (71 mg, 0.29 mmol) were added to a solution of NaOH (29 mg, 0.72 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 6 (77 mg, 0.15 mmol, 51%) as an off-white solid. JPEG2024534538000074.jpg20166

[0205] Example No. 44 2-(2-((2-(1-(2-(1H-benzo[d]imidazol-2-yl)ethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0206] [ka] Example compound no. 43 is prepared similarly as described for example no. 2. JPEG2024534538000076.jpg12164

[0207] Example No. 45 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(3-methoxyphenethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0208] [ka] 2-(1-(3-Methoxyphenethyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine (Chemspace) (100 mg, 0.34 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (84 mg, 0.34 mmol) were added to a solution of NaOH (7 mg, 0.17 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 6 (161.4 mg, 0.3 mmol, 87%) as an off-white solid. JPEG2024534538000078.jpg20166

[0209] Example No. 46 2-(2-((2-(1-butyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-methoxypyridin-2-yl)methyl)oxazole-4-carboxamide

[0210] [ka] 2-(1-Butyl-1H-benzo[d]imidazol-2-yl)ethan-1-amine (Chemspace) (75 mg, 0.35 mmol) and N-((3-methoxypyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (90 mg, 0.35 mmol) were added to a solution of NaOH (7 mg, 0.5 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 6 (63 mg, 0.13 mmol, 38%) as an off-white solid. JPEG2024534538000080.jpg20165

[0211] Example No. 47 2-(2-((2-(1-butyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-(trifluoromethyl)pyridin-2-yl)methyl)oxazole-4-carboxamide

[0212] [ka] 2-(1-Butyl-1H-benzo[d]imidazol-2-yl)ethan-1-amine (Chemspace) (75 mg, 0.35 mmol) and N-((3-(trifluoromethyl)pyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (103 mg, 0.35 mmol) were added to a solution of NaOH (7 mg, 0.5 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 6 (110 mg, 0.21 mmol, 61%) as an off-white solid. JPEG2024534538000082.jpg20167

[0213] Example No. 8 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-isobutyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0214] [ka] 2-(1-Isobutyl-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.35 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (85 mg, 0.35 mmol) were added to a solution of NaOH (34 mg, 0.86 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound (32 mg, 0.07 mmol, 20%) as an off-white solid. JPEG2024534538000084.jpg20164

[0215] Example No. 14 2-(2-(2-((2-(4-(((3-fluoropyridin-2-yl)methyl)carbamoyl)oxazol-2-yl)ethyl)amino)ethyl)-1H-benzo[d]imidazol-1-yl)acetic acid

[0216] [ka] 2-(2-(2-aminoethyl)-1H-benzo[d]imidazol-1-yl)acetic acid dihydrochloride (Chemspace) (100 mg, 0.34 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (85 mg, 0.34 mmol) were added to a solution of NaOH (48 mg, 1.2 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 14 (47 mg, 0.1 mmol, 30%) as an off-white solid. JPEG2024534538000086.jpg20162

[0217] Example No. 15 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(2-(methylamino)-2-oxoethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0218] [ka] 2-(2-(2-aminoethyl)-1H-benzo[d]imidazol-1-yl)-N-methylacetamide dihydrochloride (Chemspace) (100 mg, 0.33 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (81 mg, 0.33 mmol) were added to a solution of NaOH (33 mg, 0.82 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 15 (31 mg, 0.06 mmol, 20%) as an off-white solid. JPEG2024534538000088.jpg12160

[0219] Example No. 16 2-(2-((2-(1-(2-amino-2-oxoethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0220] [ka] 2-(2-(2-aminoethyl)-1H-benzo[d]imidazol-1-yl)acetamide dihydrochloride (Chemspace) (100 mg, 0.34 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (85 mg, 0.34 mmol) were added to a solution of NaOH (35 mg, 0.86 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 16 (22.9 mg, 0.05 mmol, 15%) as an off-white solid. JPEG2024534538000090.jpg20166

[0221] Example No. 17 2-(2-((2-(1-benzyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0222] [ka] 2-(1-benzyl-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.31 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (76 mg, 0.31 mmol) were added to a solution of NaOH (31 mg, 0.77 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 17 (89 mg, 0.19 mmol, 41%) as an off-white solid. JPEG2024534538000092.jpg12166

[0223] Example No. 21 2-(2-((2-(1-(2-cyclopropylethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0224] [ka] 2-(1-(2-cyclopropylethyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.33 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (82 mg, 0.33 mmol) were added to a solution of NaOH (33 mg, 0.83 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 21 (89 mg, 0.19 mmol, 41%) as an off-white solid. JPEG2024534538000094.jpg20162

[0225] Example No. 25 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(3-(methylamino)-3-oxopropyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0226] [ka] 3-(2-(2-aminoethyl)-1H-benzo[d]imidazol-1-yl)-N-methylpropanamide dihydrochloride (Chemspace) (100 mg, 0.31 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (78 mg, 0.31 mmol) were added to a solution of NaOH (32 mg, 0.78 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 25 (89 mg, 0.19 mmol, 41%) as an off-white solid. JPEG2024534538000096.jpg20161

[0227] Example No. 30 2-(2-((2-(1-(2-(3,5-dimethylisoxazol-4-yl)ethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0228] [ka] 2-(1-(2-(3,5-dimethylisoxazol-4-yl)ethyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.28 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (70 mg, 0.28 mmol) were added to a solution of NaOH (28 mg, 0.7 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 30 (89 mg, 0.19 mmol, 41%) as an off-white solid. JPEG2024534538000098.jpg20166

[0229] Example No. 31 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(2-(oxazol-2-yl)ethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0230] [ka] 2-(1-(2-(oxazol-2-yl)ethyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.3 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (75 mg, 0.33 mmol) were added to a solution of NaOH (30 mg, 0.76 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 31 (14 mg, 0.003 mmol, 9%) as an off-white solid. JPEG2024534538000100.jpg12164

[0231] Example No. 34 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(2-(1-methyl-1H-imidazol-2-yl)ethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0232] [ka] 2-(1-(2-(1-methyl-1H-imidazol-2-yl)ethyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.29 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (73 mg, 0.29 mmol) were added to a solution of NaOH (29 mg, 0.73 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 34 (88 mg, 0.17 mmol, 59%) as an off-white solid. JPEG2024534538000102.jpg12164

[0233] Example No. 35 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(2-(pyridin-2-yl)ethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0234] [ka] 2-(1-(2-(pyridin-2-yl)ethyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine (Chemspace) (100 mg, 0.38 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (93 mg, 0.38 mmol) were added to a solution of NaOH (8 mg, 0.2 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 35 (89 mg, 0.19 mmol, 41%) as an off-white solid. JPEG2024534538000104.jpg20165

[0235] Example No. 39 2-(2-((2-(1-butyl-5-(2-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0236] [ka] 2-(1-Butyl-5-(2-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.25 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (63 mg, 0.25 mmol) were added to a solution of NaOH (25 mg, 0.63 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 39 (88 mg, 0.15 mmol, 62%) as an off-white solid. JPEG2024534538000106.jpg20165

[0237] Example No. 40 2-(2-((2-(1-butyl-6-(2-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0238] [ka] 2-(1-Butyl-6-(2-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.25 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (62 mg, 0.25 mmol) were added to a solution of NaOH (25 mg, 0.63 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 40 (96 mg, 0.17 mmol, 67%) as an off-white solid. JPEG2024534538000108.jpg12167

[0239] Example No. 41 2-(2-((2-(1-butyl-6-phenyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0240] [ka] 2-(1-Butyl-6-phenyl-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.27 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (68 mg, 0.27 mmol) were added to a solution of NaOH (28 mg, 0.68 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 41 (89 mg, 0.19 mmol, 41%) as an off-white solid. JPEG2024534538000110.jpg20164

[0241] Example No. 42 2-(2-((2-(1-butyl-5-phenyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0242] [ka] 2-(1-Butyl-5-phenyl-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.27 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (68 mg, 0.27 mmol) were added to a solution of NaOH (28 mg, 0.68 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 42 (89 mg, 0.19 mmol, 41%) as an off-white solid. JPEG2024534538000112.jpg20164

[0243] Example No. 48 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(2-(2-methoxyethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0244] [ka] 2-(1-(2-(2-Methoxyethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.30 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (74 mg, 0.30 mmol) were added to a solution of NaOH (30 mg, 0.74 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 48 (89 mg, 0.19 mmol, 41%) as a pale oil. JPEG2024534538000114.jpg20167

[0245] Example No. 49 2-(2-(4-(1-butyl-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0246] [ka] 1-Butyl-2-(piperidin-4-yl)-1H-benzo[d]imidazole dihydrochloride (Chemspace) (100 mg, 0.3 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (75 mg, 0.3 mmol) were added to a solution of NaOH (30 mg, 0.76 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 49 (89 mg, 0.19 mmol, 41%) as an off-white solid. JPEG2024534538000116.jpg20163

[0247] Example No. 50 2-(2-((2-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0248] [ka] 2-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.35 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (86 mg, 0.35 mmol) were added to a solution of NaOH (35 mg, 0.87 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 50 (89 mg, 0.19 mmol, 41%) as an off-white solid. JPEG2024534538000118.jpg20161

[0249] Example No. 51 2-(2-((2-(1-(cyclohexylmethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0250] [ka] 2-(1-(cyclohexylmethyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.3 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (75 mg, 0.3 mmol) were added to a solution of NaOH (30 mg, 0.76 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 51 (89 mg, 0.19 mmol, 41%) as an off-white solid. JPEG2024534538000120.jpg20161

[0251] Example No. 52 2-(2-((1-(1-butyl-1H-benzo[d]imidazol-2-yl)-2-methylpropan-2-yl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0252] [ka] 1-(1-Butyl-1H-benzo[d]imidazol-2-yl)-2-methylpropan-2-amine dihydrochloride (Chemspace) (100 mg, 0.33 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (82 mg, 0.33 mmol) were added to a solution of NaOH (33 mg, 0.82 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 52 (89 mg, 0.19 mmol, 41%) as an off-white solid. JPEG2024534538000122.jpg20167

[0253] Example No. 53 2-(2-((2-(1-(2,2-difluoroethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0254] [ka] 2-(1-(2,2-difluoroethyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.34 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (83 mg, 0.34 mmol) were added to a solution of NaOH (34 mg, 0.84 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 53 (89 mg, 0.19 mmol, 41%) as an off-white solid. JPEG2024534538000124.jpg20162

[0255] Example No. 54 2-(2-((2-(1-(2-chlorobenzyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0256] [ka] 2-(1-(2-chlorobenzyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.28 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (69 mg, 0.28 mmol) were added to a solution of NaOH (28 mg, 0.70 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 54 (89 mg, 0.19 mmol, 41%) as an off-white solid. JPEG2024534538000126.jpg20167

[0257] Example No. 55 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0258] [ka] 2-(1-Phenyl-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.32 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (80 mg, 0.32 mmol) were added to a solution of NaOH (32 mg, 0.81 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 55 (89 mg, 0.19 mmol, 41%) as an off-white solid. JPEG2024534538000128.jpg12164

[0259] Example No. 56 2-(2-((2-(1-(2-(dimethylamino)ethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0260] [ka] 2-(2-(2-aminoethyl)-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethan-1-amine trihydrochloride (Chemspace) (100 mg, 0.29 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (72 mg, 0.29 mmol) were added to a solution of NaOH (41 mg, 1 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 56 (89 mg, 0.19 mmol, 41%) as an off-white solid. JPEG2024534538000130.jpg20163

[0261] Example No. 57 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(2-isopropoxyethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0262] [ka] 2-(1-(2-isopropoxyethyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.31 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (77 mg, 0.31 mmol) were added to a solution of NaOH (31 mg, 0.78 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 57 (89 mg, 0.19 mmol, 41%) as an off-white solid. JPEG2024534538000132.jpg20166

[0263] Example No. 58 2-(2-((2-(1-(4-chlorobenzyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0264] [ka] 2-(1-(4-chlorobenzyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.28 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (69 mg, 0.28 mmol) were added to a solution of NaOH (28 mg, 0.7 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 58 (89 mg, 0.19 mmol, 41%) as an off-white solid. JPEG2024534538000134.jpg20166

[0265] Example No. 60 2-(2-((2-(1-butyl-1H-benzo[d]imidazol-2-yl)-2-methylpropyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0266] [ka] 2-(1-Butyl-1H-benzo[d]imidazol-2-yl)-2-methylpropan-1-amine dihydrochloride (Chemspace) (100 mg, 0.3 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (78 mg, 0.3 mmol) were added to a solution of NaOH (31 mg, 0.79 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 60 (84 mg, 0.17 mmol, 57%) as an off-white solid. JPEG2024534538000136.jpg20165

[0267] Example No. 61 2-(2-(((1-(1-butyl-1H-benzo[d]imidazol-2-yl)cyclohexyl)methyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0268] [ka] (1-(1-Butyl-1H-benzo[d]imidazol-2-yl)cyclohexyl)methanamine dihydrochloride (Chemspace) (100 mg, 0.28 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (69 mg, 0.28 mmol) were added to a solution of NaOH (28 mg, 0.7 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 61 (63 mg, 0.12 mmol, 42%) as an off-white solid. JPEG2024534538000138.jpg20165

[0269] Example No. 62 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(pyrimidin-4-ylmethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0270] [ka] 2-(1-(pyrimidin-4-ylmethyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.31 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (76 mg, 0.31 mmol) were added to a solution of NaOH (31 mg, 0.77 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 62 (64 mg, 0.13 mmol, 41%) as an off-white solid. JPEG2024534538000140.jpg12166

[0271] Example No. 63 N-((3-fluoropyridin-2-yl)methyl-2-(2-((2-(1-(3-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0272] [ka] 2-(1-(3-Methoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.3 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (76 mg, 0.3 mmol) were added to a solution of NaOH (30 mg, 0.73 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 63 (68 mg, 0.13 mmol, 44%) as an off-white solid. JPEG2024534538000142.jpg12165

[0273] Example No. 64 2-(2-((2-(1-(3-chlorophenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0274] [ka] 2-(1-(3-chlorophenyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (103 mg, 0.27 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (67 mg, 0.27 mmol) were added to a solution of NaOH (38 mg, 0.94 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 h. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the title compound 64 (67 mg, 0.13 mmol, 48%) as an off-white solid. JPEG2024534538000144.jpg12164

[0275] Example No. 65 2-(2-((2-(1-(2-(2-methoxyethoxy)ethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-methoxypyridin-2-yl)methyl)oxazole-4-carboxamide (VIT-101207nda152)

[0276] [ka] 2-(1-(2-(2-Methoxyethoxy)ethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.29 mmol) and N-((3-methoxypyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (72 mg, 0.29 mmol) were added to a solution of NaOH (29 mg, 0.72 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 65 (56 mg, 0.11 mmol, 37%) as a pale oil. JPEG2024534538000146.jpg20164

[0277] Example No. 66 2-(2-((2-(1-(2-(2-methoxyethoxy)ethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-methoxypyridin-2-yl)methyl)oxazole-4-carboxamide

[0278] [ka] 2-(1-(2-(2-Methoxyethoxy)ethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.25 mmol) and N-((3-Methoxypyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (66 mg, 0.25 mmol) were added to a solution of NaOH (25 mg, 0.64 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 66 (38 mg, 0.07 mmol, 26%) as a pale oil. JPEG2024534538000148.jpg20163

[0279] Example No. 67 2-(2-((2-(1-(2-methoxyethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-methoxypyridin-2-yl)methyl)oxazole-4-carboxamide

[0280] [ka] 2-(1-(2-Methoxyethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.3 mmol) and N-((3-Methoxypyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (74 mg, 0.3 mmol) were added to a solution of NaOH (29 mg, 0.7 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 67 (58 mg, 0.11 mmol, 36%) as a pale oil. JPEG2024534538000150.jpg20166

[0281] Example No. 68 2-(2-((2-(1-(2,2-difluoroethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-methoxypyridin-2-yl)methyl)oxazole-4-carboxamide

[0282] [ka] 2-(1-(2,2-difluoroethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.28 mmol) and N-((3-methoxypyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (73 mg, 0.28 mmol) were added to a solution of NaOH (28 mg, 0.7 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 68 (20 mg, 0.04 mmol, 14%) as an off-white solid. JPEG2024534538000152.jpg20164

[0283] Example No. 69 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(5-(2-methoxyethyl)-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0284] [ka] 2-(5-(2-Methoxyethyl)-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.3 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (74 mg, 0.3 mmol) were added to a solution of NaOH (30 mg, 0.75 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 69 (84 mg, 0.17 mmol, 55%) as an off-white solid. JPEG2024534538000154.jpg20164

[0285] Example No. 70 2-(2-((2-(5-(2-methoxyethyl)-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)ethyl)amino)ethyl)-N-((3-methoxypyridin-2-yl)methyl)oxazole-4-carboxamide

[0286] [ka] 2-(5-(2-Methoxyethyl)-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.3 mmol) and N-((3-methoxypyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (77 mg, 0.3 mmol) were added to a solution of NaOH (30 mg, 0.75 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 70 (87 mg, 0.17 mmol, 55%) as an off-white solid. JPEG2024534538000156.jpg20166

[0287] Example No. 71 2-(2-((2-(1-(2,2-difluoroethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0288] [ka] 2-(1-(2,2-difluoroethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.28 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (70 mg, 0.28 mmol) were added to a solution of NaOH (28 mg, 0.7 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 71 (56 mg, 0.11 mmol, 38%) as an off-white solid. JPEG2024534538000158.jpg12165

[0289] Example No. 72 2-(2-((2-(5,6-dimethoxy-1-(3-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0290] [ka] 2-(5,6-Dimethoxy-1-(3-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.25 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (62 mg, 0.25 mmol) were added to a solution of NaOH (25 mg, 0.63 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 72 (59 mg, 0.1 mmol, 41%) as an off-white solid. JPEG2024534538000160.jpg20163

[0291] Example No. 73 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(2-isopropoxyethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0292] [ka] 2-(1-(2-isopropoxyethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.26 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (65 mg, 0.26 mmol) were added to a solution of NaOH (26 mg, 0.66 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 73 (32 mg, 0.06 mmol, 23%) as a pale oil. JPEG2024534538000162.jpg20163

[0293] Example No. 74 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(2-(piperidin-1-yl)ethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0294] [ka] 2-(1-(2-(piperidin-1-yl)ethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethan-1-amine trihydrochloride (Chemspace) (100 mg, 0.23 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (56 mg, 0.23 mmol) were added to a solution of NaOH (32 mg, 0.8 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 74 (49 mg, 0.09 mmol, 37%) as a pale oil. JPEG2024534538000164.jpg20165

[0295] Example No. 75 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(5-(3-methoxyphenyl)-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0296] [ka] 2-(5-(3-Methoxyphenyl)-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.26 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (64 mg, 0.26 mmol) were added to a solution of NaOH (26 mg, 0.65 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 75 (53 mg, 0.1 mmol, 37%) as an off-white solid. JPEG2024534538000166.jpg12166

[0297] Example No. 76 2-(2-((2-(1-(2-(dimethylamino)ethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-methoxypyridin-2-yl)methyl)oxazole-4-carboxamide

[0298] [ka] 2-(2-(2-aminoethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-1-yl)-N,N-dimethylethan-1-amine trihydrochloride (Chemspace) (100 mg, 0.25 mmol) and N-((3-methoxypyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (65 mg, 0.25 mmol) were added to a solution of NaOH (35 mg, 0.88 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 76 (42 mg, 0.08 mmol, 31%) as a pale oil. JPEG2024534538000168.jpg20164

[0299] Example No. 77 2-(2-((2-(1-(2-(dimethylamino)ethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0300] [ka] 2-(2-(2-aminoethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-1-yl)-N,N-dimethylethan-1-amine trihydrochloride (Chemspace) (100 mg, 0.25 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (62 mg, 0.25 mmol) were added to a solution of NaOH (35 mg, 0.88 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 77 (53 mg, 0.1 mmol, 39%) as a pale oil. JPEG2024534538000170.jpg12162

[0301] Example No. 81 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(2-morpholinoethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0302] [ka] 2-(1-(2-morpholinoethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethan-1-amine trihydrochloride (Chemspace) (100 mg, 0.23 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (56 mg, 0.23 mmol) were added to a solution of NaOH (32 mg, 0.79 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 81 (61 mg, 0.11 mmol, 46%) as a pale oil. JPEG2024534538000172.jpg20164

[0303] Example No. 82 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(5-phenyl-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0304] [ka] 2-(5-phenyl-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.28 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (70 mg, 0.28 mmol) were added to a solution of NaOH (28 mg, 0.71 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 82 (40 mg, 0.08 mmol, 27%) as an off-white solid. JPEG2024534538000174.jpg12165

[0305] Example No. 83 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-phenyl-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0306] [ka] 2-(1-phenyl-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.27 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (67 mg, 0.27 mmol) were added to a solution of NaOH (27 mg, 0.68 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 83 (43 mg, 0.08 mmol, 29%) as an off-white solid. JPEG2024534538000176.jpg12165

[0307] Example No. 84 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(2-(4-methylpiperazin-1-yl)ethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0308] [ka] 2-(1-(2-(4-methylpiperazin-1-yl)ethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethan-1-amine trihydrochloride (Chemspace) (100 mg, 0.22 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (59 mg, 0.24 mmol) were added to a solution of NaOH (24 mg, 0.6 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 84 (31 mg, 0.052 mmol, 24%) as a pale oil. JPEG2024534538000178.jpg20163

[0309] Example No. 85 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-phenyl-5-(pyridin-2-ylethynyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0310] [ka] 2-(1-Phenyl-5-(pyridin-2-ylethynyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine trihydrochloride (Chemspace) (100 mg, 0.22 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (55 mg, 0.22 mmol) were added to a solution of NaOH (31 mg, 0.78 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 85 (42 mg, 0.07 mmol, 31%) as an off-white solid. JPEG2024534538000180.jpg12162

[0311] Example No. 86 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(2-methoxyethyl)-5-(pyridin-2-ylethynyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0312] [ka] 2-(1-(2-Methoxyethyl)-5-(pyridin-2-ylethynyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine trihydrochloride (Chemspace) (100 mg, 0.23 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (58 mg, 0.23 mmol) were added to a solution of NaOH (33 mg, 0.82 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 86 (33 mg, 0.06 mmol, 25%) as an off-white solid. JPEG2024534538000182.jpg12167

[0313] Example No. 87 2-(2-((2-(1-butyl-5,6-dimethoxy-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0314] [ka] 2-(1-Butyl-5,6-dimethoxy-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.29 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (71 mg, 0.29 mmol) were added to a solution of NaOH (29 mg, 0.71 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 87 (29 mg, 0.006 mmol, 19%) as an off-white solid. JPEG2024534538000184.jpg20166

[0315] Example No. 88 2-(2-((2-(1-(2-(cyclohexyloxy)ethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0316] [ka] 2-(1-(2-(cyclohexyloxy)ethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.24 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (59 mg, 0.24 mmol) were added to a solution of NaOH (24 mg, 0.6 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 88 (38 mg, 0.064 mmol, 27%) as an off-white solid. JPEG2024534538000186.jpg20163

[0317] Example No. 89 2-(2-((2-(1-(cyclopropylmethyl)-5-(pyridin-2-ylethynyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0318] [ka] 2-(1-(cyclopropylmethyl)-5-(pyridin-2-ylethynyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine trihydrochloride (Chemspace) (100 mg, 0.24 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (58 mg, 0.24 mmol) were added to a solution of NaOH (33 mg, 0.82 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 89 (45 mg, 0.08 mmol, 33%) as an off-white solid. JPEG2024534538000188.jpg12167

[0319] Example No. 90 2-(2-((2-(1-(3,4-dimethoxyphenyl)-5,6-dimethoxy-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0320] [ka] 2-(1-(3,4-dimethoxyphenyl)-5,6-dimethoxy-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (200 mg, 0.47 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (115 mg, 0.47 mmol) were added to a solution of NaOH (46 mg, 1.16 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 90 (81 mg, 0.13 mmol, 29%) as an off-white solid. JPEG2024534538000190.jpg20162

[0321] Example No. 91 2-(2-((2-(1-(2-(cyclohexyloxy)ethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-methoxypyridin-2-yl)methyl)oxazole-4-carboxamide

[0322] [ka] 22-(1-(2-(cyclohexyloxy)ethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.24 mmol) and N-((3-methoxypyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (62 mg, 0.24 mmol) were added to a solution of NaOH (24 mg, 0.6 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 91 (41 mg, 0.068 mmol, 28%) as an off-white solid. JPEG2024534538000192.jpg20166

[0323] Example No. 92 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(3-methoxyphenyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0324] [ka] 2-(1-(3-Methoxyphenyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.25 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (62 mg, 0.25 mmol) were added to a solution of NaOH (25 mg, 0.63 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 92 (38 mg, 0.066 mmol, 27%) as an off-white solid. JPEG2024534538000194.jpg20162

[0325] Example No. 93 2-(2-((2-(1-(3-methoxyphenyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-methoxypyridin-2-yl)methyl)oxazole-4-carboxamide

[0326] [ka] 2-(1-(3-Methoxyphenyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.25 mmol) and N-((3-methoxypyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (65 mg, 0.25 mmol) were added to a solution of NaOH (25 mg, 0.63 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 93 (23 mg, 0.04 mmol, 16%) as an off-white solid. JPEG2024534538000196.jpg20166

[0327] Example No. 94 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(2-(oxazol-2-yl)ethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0328] [ka] 2-(1-(2-(oxazol-2-yl)ethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.26 mmol) and N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (58 mg, 0.24 mmol) were added to a solution of NaOH (33 mg, 0.83 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 94 (42 mg, 0.075 mmol, 29%) as an off-white solid. JPEG2024534538000198.jpg20166

[0329] Example No. 95 N-((3-methoxypyridin-2-yl)methyl)-2-(2-((2-(1-(2-(oxazol-2-yl)ethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethyl)amino)ethyl)oxazole-4-carboxamide

[0330] [ka] 2-(1-(2-(oxazol-2-yl)ethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethan-1-amine dihydrochloride (Chemspace) (100 mg, 0.26 mmol) and N-((3-methoxypyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (67 mg, 0.26 mmol) were added to a solution of NaOH (36 mg, 0.9 mmol) in 10 ml of water. The resulting mixture was heated at 80° C. under stirring for 72 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 6 by using 2N HCl and extracted with dichloromethane (3×10 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the title compound 95 (36 mg, 0.063 mmol, 24%) as an off-white solid. JPEG2024534538000200.jpg20165

[0331] Intermediate compounds for preparing examples Nos. 96 and 97 2-(2-(3-(1H-benzo[d]imidazol-2-yl)azetidin-1-yl)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0332] [ka] 2-(azetidin-3-yl)-1H-benzo[d]imidazole (210 mg, 1.21 mmol, 1 equiv) was suspended in HO (12 mL) and treated with NaOH (30% Wt, 0.18 g, 1.33 mmol, 1.1 equiv). After the material was completely dissolved, N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazole-4-carboxamide (300 mg, 1.21 mmol, 1 equiv) was added. The reaction mixture was heated to 80° C. until LC / MS showed complete conversion of the starting material. The reaction mixture was acidified to pH=5-6 with 1M HCl and then concentrated under reduced pressure. The crude material was redissolved in methanol, concentrated under reduced pressure onto RP-silica, and purified by RP18 flash column chromatography to give the desired 2-(2-(3-(1H-benzo[d]imidazol-2-yl)azetidin-1-yl)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide (160 mg, 379 μmol, 31%) as a white solid. LCMS (ESI) m / z=421.6. JPEG2024534538000202.jpg28163

[0333] Example No. 96 N-((3-fluoropyridin-2-yl)methyl)-2-(2-(3-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)ethyl)oxazole-4-carboxamide

[0334] [ka] Under an inert atmosphere, 2-(2-(3-(1H-benzo[d]imidazol-2-yl)azetidin-1-yl)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide (115 mg, 274 μmol, 1 equiv.) was dissolved in N,N-dimethylformamide (3 mL) and cooled to 0° C. NaH (60% Wt, 14 mg, 342 μmol, 1.25 equiv.) was added. The reaction mixture was stirred at 0° C. for 30 min, then 1-bromo-2-methoxyethane (28.3 μL, 301 μmol, 1.1 equiv.) was added. The ice bath was removed and the reaction mixture was allowed to warm overnight. The reaction was quenched by the addition of saturated aqueous ammonium chloride. The mixture was concentrated under reduced pressure. The concentrate was redissolved in a mixture of dichloromethane and water. The phases were separated and the aqueous phase was re-extracted with dichloromethane (3x). The combined organic phases were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH, 0->20% MeOH) to give the desired N-((3-fluoropyridin-2-yl)methyl)-2-(2-(3-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)ethyl)oxazole-4-carboxamide (25 mg, 52 μmol, 19%) as a yellowish oil. LCMS (ESI) m / z=479.6. JPEG2024534538000204.jpg28162

[0335] Example No. 97 2-(2-(3-(1-(2-(dimethylamino)ethyl)-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide

[0336] [ka] Under an inert atmosphere, 2-(2-(3-(1H-benzo[d]imidazol-2-yl)azetidin-1-yl)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide (260 mg, 618 μmol, 1 equiv.) was dissolved in DMF (3 mL). Potassium carbonate (256 mg, 1.86 mmol, 3 equiv.) was added. The reaction mixture was stirred at 23° C. for 10 min, followed by the addition of 2-bromo-N,N-dimethylethan-1-amine hydrobromide (187 mg, 1.3 equiv., 804 μmol). The reaction mixture was stirred at 23° C. for 16 h. The reaction was concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH, 0→20% MeOH) to give the desired 2-(2-(3-(1-(2-(dimethylamino)ethyl)-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-4-carboxamide (21 mg, 43 μmol, 7%) as a brownish solid. LCMS (ESI) m / z=492.5. JPEG2024534538000206.jpg28167

Claims

1. Formula (IA) 【Chemical 1】 (In the formula, l is an integer of 1 or 2; L １ and L ２ each represents a linker group containing 1 to 7 carbon atoms; - linear C １ ~C ３ -Alkyl group -[CH ２ ] ｍ - or - [CH ２ ] ｎ wherein m and n are independently an integer of 1, 2, or 3; - Branch C １ ~C ４ alkyl groups, and - Linear C １ ~C ３ - a C which may be a substituent of an alkyl group or which may form a ring together with the nitrogen atom to which it is attached ３ ~C ６ -cycloalkyl group are independently selected from X １ is N, S or O; X ２ is N, S, O or CR ５ and X ３ is C or N; However, X １ and X ２ One of the is N, X ３ If N, then X ２ is CR ５ and R ５ teeth, -H, - halogens, - Linear or branched C １ ~C ３ - alkyl, or - Linear or branched C １ ~C ３ -haloalkyl represents; A is a group (a-1) 【Chemistry 2】 (In the formula, ＊ indicates the bond position; R １ and R ２ is independent, - halogens, - Linear or branched C １ ~C ３ - alkyl, - Linear or branched C １ ~C ３ -haloalkyl, or - Linear or branched C １ ~C ３ -alkoxy represents 0, 1 or 2 substituents independently selected from represents; B is the following groups (b-1), (b-2) and (b-3): 【Chemistry 3】 (In the formula, ＊ indicates the bond position; R ３ teeth, unsubstituted or substituted 6-membered aryl, unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted bicyclic heteroaryl, unsubstituted or substituted 3- to 6-membered cycloalkyl, unsubstituted or substituted 5- or 6-membered heterocyclyl, unsubstituted or substituted 5- or 6-membered heterocyclylalkyl, unsubstituted or substituted 6-membered arylalkynyl, or unsubstituted or substituted 5- or 6-membered heteroarylalkynyl represents 0, 1, 2 or 3 substituents independently selected from A substituted aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl, heterocyclyl, heterocyclylalkyl, arylalkynyl, or heteroarylalkynyl group is Halogen ○ C １ ~C ３ - alkyl, ○ C １ ~C ３ -haloalkyl, and ○ C １ ~C ３ -alkoxy may have 1, 2 or 3 substituents independently selected from R ４ teeth, - unsubstituted or substituted linear or branched C １ ~C ６ - alkyl, - a dialkyl ether group [R ６ (CH ２ ) ｘ -O-CH ２ ) ｙ -] (R ６ is C １ ~C ３ represents an alkoxy group, x and y independently represent an integer of 1, 2, or 3; unsubstituted or substituted 3- to 6-membered cycloalkyl, unsubstituted or substituted 5- or 6-membered heterocyclyl, or unsubstituted or substituted 6-membered aryl represents Alkyl, cycloalkyl, heterocyclyl and aryl are Halogen, ○ C １ ~C ３ -alkoxy, ○ C ６ -cycloalkyloxy, Carboxyl, 〇 Aminocarbonyl, mono- or di-alkylaminocarbonyl, ○-NH ２ , an amino group selected from mono-alkylamino and di-alkylamino; unsubstituted or substituted 3- to 6-membered cycloalkyl, unsubstituted or substituted 5- or 6-membered heterocyclyl, unsubstituted or substituted 6-membered aryl, unsubstituted or substituted 5- or 6-membered heteroaryl, and Unsubstituted or substituted bicyclic heteroaryl and optionally substituted with one or two substituents independently selected from Substituted cycloalkyl, heterocyclyl, aryl, heteroaryl and bicyclic heteroaryl groups include Hydroxy, ・ Cyano, - halogens, ・C １ ~C ３ - alkyl, ・C １ ~C ３ -haloalkyl, ・C １ ~C ３ -alkoxy, ・Carboxyl, Amino (-NH ２ ) or a mono- or di-alkylamino group, aminocarbonyl, and Mono- or di-alkylaminocarbonyl and optionally have 1, 2, or 3 substituents independently selected from The monoalkylamino group and the monoalkylaminocarbonyl group are ・C １ ~C ３ -alkoxy, unsubstituted or substituted 6-membered aryl, and unsubstituted or substituted 5- or 6-membered heteroaryl may have further substituents on the monoalkyl chain selected from The substituted aryl or heteroaryl group as a substituent of the monoalkyl chain may be selected from halogen, C １ ~C ３ -Alkyl and C １ ~C ３ -haloalkyl) represents one of: In formulas (b-2) and (b-3), one of D1, D2, and D3 is present; a fused 6-membered aryl ring, a fused 5- or 6-membered heteroaryl ring, a fused 5- or 6-membered cycloalkyl ring, or - fused 5- or 6-membered heterocyclyl ring represents; The (b-2) and (b-3) groups are - halogens, - linear or branched C １ ~C ３ - alkyl, - linear or branched C １ ~C ３ -haloalkyl, - linear or branched C １ ~C ３ -alkoxy having 0, 1, 2 or 3 substituents independently selected from: The following compounds (X-1), (X-2) and (X-3) are excluded: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof.

2. The compound according to formula (IA) is represented by formula (IB) 【Chemistry 5】 (In the formula, l is an integer of 1 or 2; m and n are independently integers of 1, 2, or 3; X １ is N, S or O; X ２ is N, S, O or CR ５ and X ３ is C or N; However, X １ and X ２ One of the is N, X ３ If N, then X ２ is CR ５ and R ５ teeth, -H, - halogens, - Linear or branched C １ ~C ３ - alkyl, or - Linear or branched C １ ~C ３ -haloalkyl represents; A is a group (a-1) 【Chemistry 6】 (In the formula, ＊ indicates the bond position; R １ and R ２ is independent, - halogens, - Linear or branched C １ ~C ３ - alkyl, - Linear or branched C １ ~C ３ -haloalkyl, or - Linear or branched C １ ~C ３ -alkoxy represents 0, 1 or 2 substituents independently selected from represents; B is the following groups (b-1), (b-2) and (b-3): 【Chemistry 7】 (In the formula, ＊ indicates the bond position; R ３ teeth, unsubstituted or substituted 6-membered aryl, unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted bicyclic heteroaryl, 3- to 6-membered cycloalkyl, - 5- or 6-membered heterocyclyl, a 5- or 6-membered heterocyclylalkyl, or - 6-membered arylalkynyl represents 0, 1, 2 or 3 substituents independently selected from Substituted aryl, heteroaryl and bicyclic heteroaryl groups include Halogen, ○ C １ ~C ３ - alkyl, ○ C １ ~C ３ -haloalkyl, and ○ C １ ~C ３ -alkoxy may have 1, 2 or 3 substituents independently selected from R ４ teeth, - Linear or branched C １ ~C ６ - alkyl, - a dialkyl ether group [R ６ (CH ２ ) ｘ -O-CH ２ ) ｙ -] (R ６ is C １ ~C ３ represents an alkoxy group, x and y independently represent an integer of 1, 2, or 3; 3- to 6-membered cycloalkyl, or - 5- or 6-membered heterocyclyl represents Alkyl, cycloalkyl and heterocyclyl are ○ C １ ~C ３ -alkoxy, Carboxyl, 〇 Aminocarbonyl, mono- or di-alkylaminocarbonyl, 3- to 6-membered cycloalkyl, and 5- or 6-membered heterocyclyl, unsubstituted or substituted 6-membered aryl, unsubstituted or substituted 5- or 6-membered heteroaryl, and Unsubstituted or substituted bicyclic heteroaryl and optionally substituted with one or two substituents independently selected from Substituted aryl, heteroaryl and bicyclic heteroaryl groups include Hydroxy, ・ Cyano, - halogens, ・C １ ~C ３ - alkyl, ・C １ ~C ３ -haloalkyl, ・C １ ~C ３ -alkoxy, ・Carboxyl, Amino (-NH ２ ) or a mono- or di-alkylamino group, aminocarbonyl, and Mono- or di-alkylaminocarbonyl and optionally have 1, 2, or 3 substituents independently selected from The monoalkylamino group and the monoalkylaminocarbonyl group are ・C １ ~C ３ -alkoxy, unsubstituted or substituted 6-membered aryl, and unsubstituted or substituted 5- or 6-membered heteroaryl may have further substituents on the monoalkyl chain selected from The substituted aryl or heteroaryl group as a substituent of the monoalkyl chain may be selected from halogen, C １ ~C ３ -Alkyl and C １ ~C ３ -haloalkyl) represents one of: In formulas (b-2) and (b-3), one of D1, D2, and D3 is present; a fused 6-membered aryl ring, a fused 5- or 6-membered heteroaryl ring, a fused 5- or 6-membered cycloalkyl ring, or - fused 5- or 6-membered heterocyclyl ring represents; The (b-2) and (b-3) groups are - halogens, - linear or branched C １ ~C ３ - alkyl, - linear or branched C １ ~C ３ -haloalkyl, - linear or branched C １ ~C ３ -alkoxy having 0, 1, 2 or 3 substituents independently selected from: The compounds (X-1), (X-2) and (X-3) are excluded.

2. The compound of claim 1, selected from the compounds according to the formula:

3. l is an integer of 1 or 2; m and n are independently integers of 1, 2, or 3; X １ is N, S or O; X ２ is N, S, O or CR ５ and X ３ is C or N; However, X １ and X ２ is N, X ３ If N, then X ２ is CR ５ and R ５ represents H; A is group (a-1) 【Chemistry 8】 (In the formula, ＊ indicates the bond position; R １ and R ２ is independent, - halogens, - Linear or branched C １ ~C ３ - alkyl, - Linear or branched C １ ~C ３ -haloalkyl, or - Linear or branched C １ ~C ３ -alkoxy represents 0, 1 or 2 substituents independently selected from represents; B is the following groups (b-1), (b-2) and (b-3): 【Chemistry 9】 (In the formula, ＊ indicates the bond position; R ３ teeth, unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted bicyclic heteroaryl, - 6-membered heterocyclyl, 6-membered heterocyclylalkyl, - phenylethynyl, or - Pyridinylethynyl represents 0, 1, 2 or 3 substituents independently selected from Substituted phenyl, heteroaryl and bicyclic heteroaryl groups include: Halogen, ○ C １ ~C ３ - alkyl, ○ C １ ~C ３ -haloalkyl, and ○ C １ ~C ３ -alkoxy may have 1, 2 or 3 substituents independently selected from R ４ teeth, - Linear or branched C １ ~C ６ - alkyl, - a dialkyl ether group [R ６ (CH ２ ) ｘ -O-CH ２ ) ｙ -] (R ６ is C １ ~C ３ represents an alkoxy group, x and y independently represent an integer of 1, 2, or 3; or - 5- or 6-membered unsubstituted heterocyclyl, or - substituted or unsubstituted phenyl represents The substituents on the phenyl are: Halogens, and ○ C １ ~C ３ -alkoxy Selected from: Alkyl is Halogen, ○ C １ ~C ３ -alkoxy, ○ C ６ -cycloalkyloxy, Carboxyl, 〇 Aminocarbonyl, mono-alkylaminocarbonyl, Dialkylamino, 3- to 6-membered cycloalkyl, unsubstituted or substituted 5- or 6-membered heterocyclyl, unsubstituted or substituted 6-membered aryl, unsubstituted or substituted 5- or 6-membered heteroaryl, and Unsubstituted or substituted bicyclic heteroaryl and optionally substituted with one or two substituents independently selected from Substituted heterocyclyl, aryl, heteroaryl and bicyclic heteroaryl groups include - halogens, ・C １ ~C ３ - alkyl, ・C １ ~C ３ -haloalkyl, ・C １ ~C ３ -alkoxy, aminocarbonyl, and Mono-alkylaminocarbonyl and optionally have 1, 2, or 3 substituents independently selected from The mono-alkylaminocarbonyl group may have further substituents on the monoalkyl chain selected from halogen-substituted 5- or 6-membered heteroaryl. represents one of: In formulas (b-2) and (b-3), one of D1, D2, and D3 is present; - fused phenyl rings, a fused 6-membered heteroaryl ring, a fused 6-membered cycloalkyl ring, or - fused 5- or 6-membered heterocyclyl ring represents; The (b-2) and (b-3) groups are - halogens, - linear or branched C １ ~C ３ - alkyl, - linear or branched C １ ~C ３ -haloalkyl, and - linear or branched C １ ~C ３ -alkoxy and having 0 or 1 substituent selected from The compounds (X-1), (X-2) and (X-3) are excluded.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

4. The B group is a (b-1) or (b-2) group; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

5. X １ , X ２ and X ３ is the following group: 【Chemistry 10】 (In the formula, ＊ indicates the binding site to the aminocarbonyl group, ＊＊ Ha-[(CH ２ )] ｍ -amino-[(CH ２ )] ｎ - indicates the site of attachment to the group; R ５ teeth, -H, - halogens, - Linear or branched C １ ~C ３ - alkyl, or - Linear or branched C １ ~C ３ -haloalkyl (represents is selected to form one of 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

6. The A group has the following structure: 【Chemistry 11】 2. The compound of claim 1, wherein:

7. R ３ but, -H, - C １ ~C ３ -alkoxy, - pyridinylethynyl, - unsubstituted or substituted phenyl represents The substituted phenyl group is Halogen, ○ C １ ~C ３ - alkyl, ○ C １ ~C ３ -haloalkyl, and ○ C １ ~C ３ -alkoxy may have 1, 2 or 3 substituents independently selected from and / or R ４ but, - Linear or branched C １ ~C ６ - alkyl, - a dialkyl ether group [R ６ (CH ２ ) ｘ -O-CH ２ ) ｙ -] (R ６ is C １ ~C ３ represents an alkoxy group, x and y independently represent an integer of 1, 2, or 3; or - 5- or 6-membered unsubstituted heterocyclyl, - substituted or unsubstituted phenyl (The substituents on the phenyl are: Halogens, and ○ C １ ~C ３ -alkoxy ), and unsubstituted or substituted 5- or 6-membered heterocyclyl represents The alkyl is Halogen, ○ C １ ~C ３ -alkoxy, o cyclohexyloxy, Carboxyl, 〇 Aminocarbonyl, mono-alkylaminocarbonyl, Dialkylamino, o cyclopropyl or cyclohexyl, 6-membered heterocyclyl, unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, and Unsubstituted or substituted bicyclic heteroaryl and optionally substituted with one or two substituents independently selected from Substituted phenyl, heteroaryl and bicyclic heteroaryl groups include - halogens, ・C １ ~C ３ - alkyl, ・C １ ~C ３ -haloalkyl, ・C １ ~C ３ -alkoxy, aminocarbonyl, and Mono-alkylaminocarbonyl and optionally have 1, 2, or 3 substituents independently selected from The mono-alkylaminocarbonyl group may have further substituents on the monoalkyl chain selected from halogen-substituted 5- or 6-membered heteroaryls; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

8. the halogen substituents are selected from F, Cl and Br; and / or - linear or branched C １ ~C ６ the alkyl substituents are selected from methyl, ethyl, propyl, iso-propyl, n-butyl and iso-butyl; and / or - C １ ~C ３ the alkoxy substituents are selected from methoxy and ethoxy; and / or - C １ ~C ３ -haloalkyl substituent is difluoroethyl (-CH ２ -CHF ２ ) and trifluoromethyl (CF ３ and / or -R ４ The substituted alkyl group at position C １ ~C ３ represents an alkyl group; and / or the bicyclic heteroaryl group is selected from benzimidazolyl groups, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

9. X 1 , X 2 and X 3 are the following groups: 【Chemistry 12】 is selected to form The A group has the following structure: 【Chemistry 13】 2. The compound of claim 1, wherein:

10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 represents a C 1 -C 3 -alkyl group substituted with an amino group selected from —NH 2 , mono-alkylamino and di-alkylamino.

11. The compound according to formula (IA), 【Table 1】 2. The compound of claim 1, selected from: or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1, wherein the compound according to formula (IA) is represented by the following formula: or a pharmaceutically acceptable salt thereof. 【Chemistry 14】

13. A pharmaceutical comprising a compound or a salt thereof according to any one of claims 1 to 12.

14. An agent for use as a ferroportin inhibitor or for use in inhibiting iron transport mediated by ferroportin, comprising a compound according to any one of claims 1 to 12 or a salt thereof.

15. A pharmaceutical composition containing one or more compounds or salts thereof described in any one of claims 1 to 12.

16. 16. A pharmaceutical composition according to claim 15 for use in the prevention and / or treatment of disorders of iron metabolism leading to elevated iron levels or increased iron absorption and / or iron overload.

17. 16. The pharmaceutical composition according to claim 15, for use in the prevention and / or treatment of a disease associated with or caused by elevated iron levels, increased iron absorption or iron overload selected from thalassemia selected from alpha-thalassemia, beta-thalassemia and delta-thalassemia, hemoglobinopathies, hemoglobin E disease, hemoglobin H disease, hemochromatosis and hemolytic anemia.

18. The pharmaceutical composition described in claim 16, wherein the disease associated with or caused by elevated iron levels, increased iron absorption or iron overload is selected from beta-thalassemia, hemochromatosis, sickle cell disease, polycythemia vera and myelodysplastic syndrome.

19. - diseases associated with ineffective erythropoiesis; and / or - a disease caused by a decrease in hepcidin levels; and / or - infections caused by pathogenic microorganisms in adjuvant therapy by limiting the amount of iron available to said pathogenic microorganisms; and / or - neurodegenerative diseases by limiting iron deposition or accumulation in tissues or cells; and / or - formation of radicals, reactive oxygen species (ROS) and oxidative stress; and / or cardiac, hepatic and endocrine damage caused by iron overload; and / or - Inflammation caused by excess iron 16. The pharmaceutical composition according to claim 15 for use in the prevention and / or treatment of 20. The pharmaceutical composition of claim 15, further comprising one or more compounds selected from pharmaceutical carriers, adjuvants, and solvents.

21. The pharmaceutical composition of claim 15, further comprising at least one additional pharmaceutically active compound.

22. 16. The pharmaceutical composition of claim 15, in the form of a formulation for oral or parenteral administration.

23. The pharmaceutical composition of claim 21 for use in combination therapy comprising co-administration of a compound according to any one of claims 1 to 12, or a salt thereof, with at least one additional pharmaceutically active compound, said co-administration of said combination therapy can be in fixed dose combination therapy by co-administration of said compound or salt thereof with at least one additional pharmaceutically active compound in a fixed dose formulation; or The pharmaceutical composition, wherein said co-administration of said combination therapy may be carried out in free dose combination therapy by co-administration of said compound or salt thereof and said at least one additional pharmaceutically active compound at a free dose of each compound, either by simultaneous administration of the individual compounds or by sequential use of the individual compounds spread over a period of time.

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