Bicyclic 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 lack of hepcidin or disorders of iron metabolism leading to elevated iron levels or increased iron absorption and / or iron overload. JPEG2025535398000130.jpg36129

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 and pharmaceutically acceptable salts thereof. The compounds of general formula (IA) of the present invention act as ferroportin inhibitors. The novel compounds are particularly suitable for use as pharmaceuticals in the prevention and / or treatment of diseases caused by a lack of hepcidin or iron metabolism disorders leading to elevated iron levels or increased iron absorption. The compounds of general formula (IA) of the present invention are further particularly suitable for use in the prevention and / or treatment of iron overload disorders, including thalassemia, sickle cell disease, and hemochromatosis, as well as for 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, particularly in relation to growth and blood formation. The balance of iron metabolism in this context is primarily regulated by the level of iron recovery from hemoglobin in senescent red blood cells and the duodenal absorption of dietary iron. Released iron is taken up via the intestine, particularly via specific transport systems (DMT-1, ferroportin), and transferred to the blood circulation, where it is delivered to the appropriate tissues and organs (transferrin, transferrin receptor).

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

[0005] The transport protein ferroportin is a transmembrane protein consisting of 571 amino acids that is formed in the liver, spleen, kidney, heart, intestine, and placenta. In particular, ferroportin is localized to the basolateral membrane of intestinal epithelial cells. Therefore, this bound ferroportin acts to transport 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, it is transported to the interior of the cell, where it is degraded, almost completely blocking the release of phagocytically recycled iron from the cell. If ferroportin is inactivated, for example, by hepcidin and cannot export iron stored in mucosal cells, the stored iron is lost through natural cell shedding via feces. Therefore, when ferroportin is inactivated or inhibited, for example, by hepcidin, iron absorption 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, leading to less hepcidin release and therefore less ferroportin inactivation, allowing greater amounts of stored iron to be transported into the serum.

[0006] It becomes clear 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 works through two opposing principles:

[0007] On the one hand, increased 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, reduced serum iron levels lead to reduced hemoglobin levels, reduced red blood cell production, and therefore iron deficiency anemia.

[0008] On the other hand, a decrease in hepcidin leads to an increase in active ferroportin, thus promoting the release of stored iron and the uptake of iron, 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 excessive iron levels. The problem arises from excessive serum iron levels, which leads to non-transferrin-bound iron (NTBI). NTBI is rapidly taken up nonspecifically by organs, leading to iron accumulation in tissues and organs. Iron overload causes many diseases and undesirable medical conditions, including cardiac, hepatic, and endocrine damage. Furthermore, brain iron accumulation has been observed in patients with neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. A particular harmful aspect of excess free iron is the unwanted formation of radicals. In particular, iron(II) ions catalyze the formation of reactive oxygen species (ROS) (e.g., via the Fenton reaction). These ROS are well known and documented to cause damage to DNA, lipids, proteins, and carbohydrates, resulting in widespread effects on cells, tissues, and organs, leading to so-called oxidative stress.

[0010] In addition to traditional methods of treating iron overload by removing iron from the body with chelating agents such as deferoxamine (deferioxamine B, also known as 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. The therapeutic approach is based on directly interfering with the disturbed iron metabolic pathway by providing hepcidin mimetics or hepcidin agonists, 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 via a hepcidin inactivation mechanism, thereby blocking excess iron absorption.

[0011] Ferroportin inhibitors and methods for preparing the same are described in WO 2017 / 068089, WO 2017 / 068090, WO 2021 / 191202, WO 2022 / 223689, and WO 2023 / 046664. 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. International applications WO 2021 / 013771, WO 2021 / 013772, WO 2021 / 078889 and WO 2022 / 157185 relate to selected ferroportin inhibitors described in the above applications in particular medical uses, for example, for treating transfusion-dependent thalassemia, for treating acute kidney injury, for treating sickle cell disease, and for treating myelodysplastic syndromes.

[0012] WO 2020 / 123850 describes additional ferroportin inhibitors having broadly defined central heteroaryl bicyclic ring structures and a wide range of possible substitutions. The compounds of the present invention relate to selected ferroportin inhibitors having selected central heteroaryl bicyclic ring structures and particularly selected substitutions on the terminal groups "A" and "B." Summary of the Invention [Problem to be solved by the invention]

[0013] The objective of the present invention was to provide new therapeutically effective compounds that can be used for effective treatment of iron metabolism disorders associated with elevated iron levels, such as iron overload. In addition, the new compounds should exhibit high efficacy in the indications of the present invention, exhibit few side effects, have low toxicity, and have good bioavailability and compatibility. Furthermore, in contrast to known iron chelating compounds, these new compounds should be suitable for preventing elevated iron levels and thus the development of associated disorders, instead of removing excess iron from the body when iron overload has already occurred. In addition, the new compounds should have a defined structure (stoichiometry), be preparable by simple synthetic processes, and exhibit low sensitivity and improved long-lasting efficacy compared to known biomolecular compounds, such as antibodies. [Means for solving the problem]

[0014] This goal has been achieved by the development of novel compounds as defined herein, such as, in particular, according to formulas (IA) and (IB), 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 INVENTION

[0015] The present inventors have discovered that certain compounds having the general structural formula (IA) or (IB) defined herein act as ferroportin inhibitors, thus effectively inhibiting iron transport, and are therefore particularly suitable for use as pharmaceuticals, particularly 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 iron overload conditions, particularly thalassemia and hemochromatosis. More specifically, the new compounds have been found to be suitable for the treatment of thalassemia and hemochromatosis. The new compounds are also suitable for the treatment of diseases caused by pathologically low hepcidin levels and for use in inhibiting iron transport. In particular, the new compounds described herein exhibit good metabolic stability and good bioavailability, making them particularly suitable as pharmaceutical compounds.

[0016] Thus, the present invention provides compounds of general formula (IA)

[0017] [ka] (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; - Straight chain C1-C3 alkyl group -[CH2] m -or- [CH2] n wherein m and n are independently an integer of 1, 2, or 3; branched C1-C4-alkyl groups, and - C3-C6-cycloalkyl groups which together with the nitrogen atom to which they are attached form a ring are independently selected from; X 1 is N, S or O; X 2 is N, S, or O; However, X 1and X 2 One of them is N; Y is N or 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

[0018] [ka] (where * indicates the bond position; R 1 and R 2 is independent, - hydrogen, - halogen, - linear or branched C1-C3-alkyl, - linear or branched C1-C3-haloalkyl, or - Straight or branched C1-C3 alkoxy represents.) represents; B is the following groups (b-1), (b-2) and (b-3):

[0019] [ka] (where * indicates the bond position; R 3 teeth, - linear or branched C1-C3-alkyl, - linear or branched C1-C3-haloalkyl, - linear or branched C1-C3-alkoxy, - 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 may optionally be Halogen C1-C3-alkyl, C1-C3-haloalkyl, and C1-C3-alkoxy and optionally substituted with 1, 2, or 3 substituents independently selected from: R 4 teeth, - hydrogen, - unsubstituted or substituted straight-chain 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 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, - unsubstituted or substituted 5- or 6-membered heteroaryl represents Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Halogen, C1-C3-alkoxy, C6-cycloalkyloxy, Carboxyl, 〇 Aminocarbonyl, mono- or di-alkylaminocarbonyl, -NH2, amino groups including mono- and dialkylamino, 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 are optionally Hydroxy, Cyano, halogens, 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 substituted with 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 optionally be substituted with 1, 2 or 3 substituents independently selected from halogen, C1-C3-alkyl and C1-C3-haloalkyl. represents one of; However, in formula (b-1), R 3 is non-existent, or R 3 is methyl, R 4 does not represent hydrogen; 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 - halogen, - linear or branched C1-C3-alkyl, - linear or branched C1-C3-haloalkyl, - Straight or branched C1-C3 alkoxy and having 0, 1, 2, or 3 substituents independently selected from: and pharmaceutically acceptable salts thereof.

[0020] In one aspect of the invention, the compound has a selected central bicyclic heterocycle and a nitrogen-bonded substituent R in the benzimidazolyl group of the terminal group B. 4 that is, forming an "N-substituted" cyclic group B.

[0021] In such particularly preferred embodiments, such "N-substituted" compounds are those of formula (IA) in which the substituent R 4 but, - unsubstituted or substituted straight-chain 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 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, - unsubstituted or substituted 5- or 6-membered heteroaryl represents Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Halogen, C1-C3-alkoxy, C6-cycloalkyloxy, Carboxyl, 〇 Aminocarbonyl, mono- or di-alkylaminocarbonyl, -NH2, amino groups including mono- and dialkylamino, 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 The substituted cycloalkyl, heterocyclyl, aryl, heteroaryl and bicyclic heteroaryl groups are optionally Hydroxy, Cyano, halogens, 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 substituted with 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 The substituted aryl or heteroaryl group as a substituent of the monoalkyl chain is optionally substituted with one, two or three substituents independently selected from halogen, C1-C3-alkyl and C1-C3-haloalkyl. Highly preferred is the substituent R 4 is selected from the group of substituents shown at each position in the examples below.

[0022] In a further aspect, the compounds of the present invention are characterized in that they have a selected central bicyclic heterocycle and the B group contains at least three rings. In that, the B group can represent a ring system of at least three fused rings, where each fused ring can have a structure as defined herein. Embodiments having a B group with at least three rings include those in which the B group is a substituent R having a ring structure. 3 That is, R 3 does not represent hydrogen and represents a (substituted or unsubstituted) aryl, heteroaryl, cycloalkyl or heterocyclyl ring, or a fused bicyclic ring system comprising a phenyl ring with a fused cycloalkyl or heterocyclyl as defined herein, which can be attached via a direct bond or a C1-C3-alkyl or alkynyl chain as defined herein. This means that the phrase "group B contains at least three rings" is not limited to fused tricyclic ring systems.

[0023] Therefore, the compounds of the present invention are those in which, in the definition of the group according to formula (b-1), R 3 is non-existent, or R 3 has the meaning defined above (R 3 is not a substituent having a cyclic structure, but is a "straight-chain substituent" (meaning selected from linear or branched C1-C3 alkyl, linear or branched C1-C3 haloalkyl, or linear or branched C1-C3 alkoxy, as defined herein), R 4 does not represent hydrogen (is an N-linked substituent).

[0024] In a preferred embodiment, the compounds of the present invention comprise R 4 In the definition of R 4 is not hydrogen, i.e. hydrogen is excluded. This is very preferably characterized by the formula (IA) as defined above, in which the substituent R 4 is a group as defined in any of the embodiments described anywhere herein, excluding hydrogen.

[0025] In a further preferred embodiment, the compounds of the present invention comprise, in the definition of the group according to formula (b-1), R 4 does not represent hydrogen (represents an N-bonded substituent), and R 3 is selected from the substituents having a cyclic structure as defined above.

[0026] A further aspect of the present invention is a compound of formula (IB)

[0027] [ka] (In the formula, l is an integer of 1 or 2; m and n are independently integers of 1, 2, or 3. The present invention relates to compounds of formula (IA) as defined herein, represented by:

[0028] definition The term "substituted" means that one or more hydrogen atoms on the 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 terms "optionally substituted," "optional substituent(s)," or "possible substituent(s)" mean 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. Generally, 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 "1, 2, 3, 4 or 5, in particular 1, 2, 3 or 4, more particularly 1, 2 or 3, even more particularly 1 or 2", for example in the definition of substituents in compounds of general formula (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 "mentioned herein" or "defined (anywhere) herein," it means that it may be mentioned 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, more 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 a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, or hexyl radical. Methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl radicals are preferred. More preferred are linear or branched "C1-C3-alkyl" radicals, such as, in particular, methyl, ethyl, n-propyl, and isopropyl. Preferred unsubstituted alkyl radicals are selected from methyl and ethyl.

[0036] The C1-C6-alkyl or C1-C6-alkyl group may optionally be substituted with one or two substituents, preferably one substituent. In such cases, the substituted alkyl group is preferably a substituted C1-C3-alkyl group (i.e. a substituted C1-, C2- or C3-alkyl group), more preferably a substituted methyl or ethyl group. Such optional substituents are preferably halogen (which forms a halogen-substituted C1-C3-alkyl group, as defined below and which is also denoted herein as "C1-C3-haloalkyl"), such as preferably difluoroalkyl or trifluoroalkyl, C1-C3-alkoxy, such as preferably methoxy, a cycloalkyloxy group, such as preferably a C6-cycloalkyloxy group (cyclohexyloxy), a carboxyl group [-(C=O)OH], an aminocarbonyl group [NH2(C=O)-], a mono- or di-alkylaminocarbonyl group, such as preferably a methylaminocarbonyl group [CH3NH(C=O)-] or a dimethylaminocarbonyl group [(CH3)2N(C=O)-], -N H2, mono- and di-alkylamino, such as preferably an amino group including mono- or di-methylamino, 3- to 6-membered cycloalkyl containing 3, 4, 5 or 6 carbon atoms (also denoted C3-C6-cycloalkyl), such as preferably cyclopropyl and cyclohexyl, unsubstituted or substituted 5- or 6-membered heterocyclyl, such as preferably substituted 6-membered heterocyclyl, unsubstituted or substituted 6-membered aryl(phenyl), such as preferably unsubstituted 6-membered aryl(phenyl), unsubstituted or substituted 5- or 6-membered heteroaryl, such as preferably unsubstituted 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 substituted with one, two or three 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 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 a 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 -] group (x and y independently represent the integers 1, 2 or 3). 4 Such dialkyl ether groups as 6 and [R 6 (CH2) x -O-CH2) y -] group. 6 represents a substituent selected from the group consisting of C1-C3-alkoxy. 6When represents a hydrogen atom, the dialkyl ether group is unsubstituted and corresponds to an "alkoxy" group as otherwise defined herein. Preferred substituents R 6 is selected from C1-C3-alkoxy groups, such as in particular methoxy and ethoxy.

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

[0041] The term cycloalkyloxy relates 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] The term "carboxyl group" refers to the group [-(C=O)OH].

[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 mono- and dimethylamino groups, more preferred are especially R 4 is a dimethylamino group as a substituent of "substituted C1-C3 alkyl" at position (I).

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

[0045] The term "mono- or dialkylaminocarbonyl group" denotes an aminocarbonyl group [NH2-(C=O)-] in which one or both hydrogens are replaced by a C1-C3-alkyl group. A preferred mono-alkylaminocarbonyl group is the methylaminocarbonyl group [CH3NH(C=O)-]. A preferred di-alkylaminocarbonyl group is the dimethylaminocarbonyl group [(CH3)2N(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 5 to 12-membered heteroaromatic residues that 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 oxazol-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 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, and 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 being preferred.

[0051] In general, the term "heterocyclyl" refers to any group selected from the group consisting of 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, tetrahydrothiophen-2-yl, tetrahydro- These include saturated or unsaturated monocyclic or bicyclic 4- to 8-membered heterocyclic residues containing 1 to 3, preferably 1 to 2, identical or different heteroatoms selected from N, O, and S, including thiophen-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, morpholin-1-yl, morpholin-2-yl, morpholin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, etc. Particularly preferred are 5- or 6-membered heterocyclyl groups, such as pyrrolidinyl, dioxolanyl, dioxanyl, piperidinyl, piperazinyl, and morpholinyl residues, with morpholinyl and piperazinyl groups being especially preferred.

[0052] An aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl or heterocyclyl group can be attached via a direct bond, a C1-C3-alkyl chain, preferably a direct bond or a C1- or C2-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 one, two or three 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 or ethyl, C1-C3-haloalkyl as defined above, such as preferably trifluoromethyl, C1-C3-alkoxy as defined above, such as preferably methoxy and C6-cycloalkyloxy. Particularly preferred are groups in which R 4 Also preferred are methoxy-phenyl and chloro-phenyl groups as substituents of "substituted C1-C3-alkyl" at position R 4 and a pyridinyl group or a methylpiperazinyl group as a substituent of the "substituted C1-C3 alkyl" at position (I).

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

[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] In formula (IA), "l" represents an integer of 1 or 2, and preferably l=1.

[0057] In formula (IA), “L 1 " and "L 2 " each represents a linker group or a so-called spacer, i.e., an "alkyl spacer" 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;

[0058] [ka] or - C3-C6-cycloalkyl groups which together with the nitrogen atom to which they are attached form a ring, such as preferably "L 1 Regarding

[0059] [ka] and preferably "L 2 Regarding

[0060] [ka] Most preferred are 4-membered cycloalkyl groups which, together with the nitrogen atom to which they are attached, form a ring.

[0061] Linker "L 1 " and / or "L 2 " has the meaning of a linear C1-C3-alkyl group, the linker is -[CH2] as defined herein in formula (IA). m - and / or -[CH2] n - may be replaced by the linker "L 1 " and "L 2 " are linear C1-C3-alkyl, the compound has formula (IB)

[0062] [ka] (In the formula, l is an integer of 1 or 2; m and n are independently integers of 1, 2, or 3; All other substituents may have the meaning defined elsewhere herein. It can be represented by:

[0063] In formula (IB), "m" and "n" independently represent an integer of 1, 2 or 3, preferably m=2, preferably n=1 or 2, and even more preferably m and n both represent 2.

[0064] In one aspect of the invention, the linker "L 2 " is defined herein, - Straight chain C1-C3 alkyl group -[CH2] n - (wherein n represents an integer of 1, 2 or 3), branched C1-C4-alkyl groups, and - C3-C6-cycloalkyl groups which together with the nitrogen atom to which they are attached form a ring It means a linker group containing 1 to 7 carbon atoms selected from:

[0065] In formula (IA) and / or (IB), X 1 and X 2 teeth, X 1 =N, S or O; and X 2 = N, S or O; Selected from; However, X 1 and X 2 One of them is N.

[0066] In formula (IA) and / or (IB), Y is N or CR 5 Represents.

[0067] Among them, R 5 is Y=CR 5 represents an optional substituent, and 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.

[0068] In a further embodiment, the compound of the present invention has the following formula (IC), (ID), (IE), (IF) or (IG):

[0069] [ka] wherein the remaining substituents have the meanings defined elsewhere herein. is represented by one of

[0070] Generally, the A group is the (a-1) group.

[0071] [ka] Represents.

[0072] 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:

[0073] Among the (a-1) groups, the following groups are preferred.

[0074] [ka]

[0075] Among these, the (a-1) group having the following structure is more preferred.

[0076] [ka]

[0077] Among these, the (a-1) group having the following structure is most preferred.

[0078] [ka]

[0079] Generally, the B group is selected from the following groups (b-1), (b-2) and (b-3):

[0080] [ka] represents one of the following:

[0081] Among them, the (b-1) group has 0 substituents R 3 (i.e., R 3 represents hydrogen), or one, two or three, preferably one or two, same or different substituents R as defined herein 3 When present, R represents a benzimidazolyl group having the formula 3 preferably represents one substituent as defined anywhere herein.

[0082] As noted above, the substituent R 3 may be selected from so-called "straight-chain substituents", including straight-chain or branched C1-C3-alkyl, straight-chain or branched C1-C3-haloalkyl and straight-chain or branched C1-C3-alkoxy, or R 3 may be selected from the so-called "cyclic substituents", which include 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.

[0083] R 4 is hydrogen, R3 is not absent and is a substituent as defined herein, except for methyl. Preferably, R 4 is hydrogen, R 3 is selected from the group of "cyclic substituents" defined above.

[0084] 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, and the substituted aryl, heteroaryl, and bicyclic heteroaryl groups optionally bear 1, 2, or 3 substituents independently selected from halogen, C-C-alkyl, C-C-haloalkyl, and C-C-alkoxy.

[0085] An aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl or heterocyclyl ring bonded via a C1-C3-alkyl chain, preferably a C1-alkyl chain, is R 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.

[0086] An aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl or heterocyclyl ring attached via an alkynyl chain, e.g., preferably an ethynyl chain, can be R representing an arylalkynyl, heteroarylalkynyl, cycloalkylalkynyl or heterocyclylalkynyl group. 3and "alkynyl" preferably denotes ethynyl. Arylalkynyl groups, such as phenylethynyl groups, and heteroarylalkynyl groups, such as pyridinylethynyl groups, are preferred. The aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl, or heterocyclyl rings therein may have one, two, or three identical or different substituents selected from those defined herein for each group, preferably selected from halogen, such as preferably F, Br, and Cl, C1-C3-alkyl, such as preferably methyl, C1-C3-haloalkyl, such as preferably trifluoromethyl, and C1-C3-alkoxy, such as preferably methoxy, as defined above. Accordingly, such groups are also referred to herein as "unsubstituted or substituted arylalkynyl," "unsubstituted or substituted heteroarylalkynyl," "unsubstituted or substituted cycloalkylalkynyl," and "unsubstituted or substituted heterocyclylalkynyl."

[0087] As explained above, the (b-1) group is preferably a cyclic substituent R 3 which results in a B group containing at least three rings. Examples of possible (b-1) groups with cyclic substituents include: below:

[0088] [ka] Examples include:

[0089] An unsubstituted or substituted aryl ring is directly bonded to R, which represents "unsubstituted or substituted aryl." 3 or R 4 It is generally possible for the substituents to correspond to the above definitions. 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.

[0090] The (b-2) and (b-3) groups represent fused ring systems, and in formulas (b-2) and (b-3), the fused aryl, heteroaryl, cycloalkyl or heterocyclyl ring defined above is present in one of the positions indicated by D1, D2 and D3, preferably forming a fused tricyclic ring system.

[0091] The (b-2) and (b-3) groups may optionally have one, two or three 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, each as defined above. Such optional substituents are also referred to below as R x Such a substituent R on the (b-2) or (b-3) group is represented by X may contain one or more additional substituents, i.e., further N-bonded R 4 Refers to a substituent.

[0092] Examples of possible (b-2) groups having a fused tricyclic structure include the following:

[0093] [ka] Particularly preferred are

[0094] [ka] is.

[0095] Examples of possible (b-3) groups having a fused tricyclic structure include the following:

[0096] [ka] Examples include:

[0097] The compounds of formula (IA) and (IB) of the present invention may contain a substituent R 4R 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 the term "N-alkylated" is understood to include substitution with alkyl groups, dialkyl ether groups as well as cycloalkyl or heterocyclyl groups as defined herein.

[0098] In such cases, especially R 4 The substituents are straight-chain 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.

[0099] R 4 When represents a substituted alkyl group, reference is made to the possible alkyl substituents defined above, with particularly preferred alkyl substituents including alkoxy, unsubstituted cycloalkyl, unsubstituted or substituted 6-membered heterocyclyl, unsubstituted or substituted 6-membered aryl, unsubstituted heteroaryl, and dialkylamino groups.

[0100] R 4 represents a substituted dialkyl ether group, the term "dialkyl ether" as defined above and its possible substituents R 6 and particularly preferred dialkyl ether substituents include alkoxy groups.

[0101] R 4 When represents a substituted cycloalkyl or heterocyclyl group, reference is made to the definitions of possible substituents for such groups elsewhere in this specification, and particularly preferred substituents include C1-C3-alkyl.

[0102] R 4When represents a substituted aryl group, reference is made to the possible aryl (phenyl) substituents defined above, particularly preferred substituents include alkoxy or halogen groups.

[0103] Preferably, R 4 Substituents Aryl, alkyl, dialkylether, cycloalkyl and heterocyclyl may be substituted with one or two substituents, in particular those defined above for phenyl, C1-C3-alkyl and dialkylether.

[0104] In one embodiment, compounds (IA) and (IB) of the present invention have R 4 The substituent R is a group as defined herein for 4 and (b-1) group as defined herein, having the formula:

[0105] In a further embodiment, compounds (IA) and (IB) of the present invention comprise a (b-2) group.

[0106] In such embodiments, the following (b-2) group:

[0107] [ka] are preferred, among which the following groups are preferred:

[0108] [ka] (In the formula, R 4 has the meaning defined anywhere in this specification (including or excluding hydrogen). is even more preferred. Examples of such (b-2) groups include:

[0109] [ka] Examples include:

[0110] Among these examples of the (b-2) group, those having a condensed dioxane ring are preferred.

[0111] As used elsewhere herein, for example in formulas (a-1), (b-2) and (b-3), "*" indicates the point of attachment.

[0112] A further aspect is A is the (a-1) group

[0113] [ka] (where * indicates the bond position; R 1 and R 2 is independent, - hydrogen, - halogen, - linear or branched C1-C3-alkyl, - linear or branched C1-C3-haloalkyl, or - Straight or branched C1-C3 alkoxy represents.) represents; B is the following group (b-1), (b-2) and (b-3):

[0114] [ka] (where * indicates the bond position; R 3 teeth, - linear or branched C1-C3-alkyl, - linear or branched C1-C3-haloalkyl, - linear or branched C1-C3-alkoxy, - 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 The substituted aryl, heteroaryl and bicyclic heteroaryl groups are optionally Halogen C1-C3-alkyl, C1-C3-haloalkyl, and C1-C3-alkoxy and optionally substituted with 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 an integer of 1, 2, or 3; - 3- to 6-membered cycloalkyl, or - 5- or 6-membered heterocyclyl, - 6-membered aryl represents Alkyl, cycloalkyl, heterocyclyl and aryl are optionally C1-C3-alkoxy, Carboxyl, 〇 Aminocarbonyl, mono- or di-alkylaminocarbonyl, an amino (-NH2) or mono- or di-alkylamino group, 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 The substituted aryl, heteroaryl and bicyclic heteroaryl groups are optionally Hydroxy, Cyano, halogens, 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 substituted with 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 optionally be substituted with 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 - 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 It relates to compounds of formula (IA) and (IB) as defined above.

[0115] A further aspect is A is the (a-1) group

[0116] [ka] (where * indicates the bond position; R 1 and R 2 is independent, - hydrogen, - halogen, - linear or branched C1-C3-alkyl, - linear or branched C1-C3-haloalkyl, or - Straight or branched C1-C3 alkoxy represents.) represents; B is the following group (b-1), (b-2) and (b-3):

[0117] [ka] (where * indicates the bond position; R 3 teeth, - linear or branched C1-C3-alkyl, - linear or branched C1-C3-haloalkyl, - linear or branched C1-C3-alkoxy, 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 The substituted phenyl, heteroaryl and bicyclic heteroaryl groups are optionally Halogen C1-C3-alkyl, C1-C3-haloalkyl, and C1-C3-alkoxy and optionally substituted with 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 an integer of 1, 2, or 3; - a 5- or 6-membered unsubstituted heterocyclyl, or - unsubstituted or substituted phenyl represents The substituents on the phenyl are: Halogens, and C1-C3-alkoxy Selected from; Alkyl is optionally Halogen, C1-C3-alkoxy, C6-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 The substituted heterocyclyl, aryl, heteroaryl and bicyclic heteroaryl groups are optionally halogens, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, aminocarbonyl, and Mono-alkylaminocarbonyl and optionally substituted with 1, 2, or 3 substituents independently selected from Mono-alkylaminocarbonyl groups may have further substituents on the monoalkyl chain selected from halogen-substituted 5- or 6-membered heteroaryls. 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 - 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.

[0118] A further aspect is the following A group:

[0119] [ka] and the remaining substituents have the meanings defined anywhere herein or in the context of any of the above aspects and embodiments.

[0120] A further aspect is the following group B:

[0121] [ka] (In the formula, R 4 represents a substituent defined anywhere herein, except hydrogen, and / or R 3 represents one substituent selected from the group of "cyclic substituents" defined above. and the remaining substituents have the meanings defined anywhere herein or in the context of any of the above aspects and embodiments.

[0122] A further aspect is the following group B:

[0123] [ka] (In the formula, R 4 represents a substituent defined anywhere herein. and the remaining substituents have the meanings defined anywhere herein or in the context of any of the above aspects and embodiments.

[0124] Further embodiments include the following A and B groups:

[0125] [ka] In the preferred (b-1) group shown above, R 4 represents a substituent defined anywhere herein, except hydrogen, and / or R 3 represents one substituent selected from the group of "cyclic substituents" defined above, and the remaining substituents have the meanings defined elsewhere herein or in the context of any of the above aspects and embodiments, of formula (IF) or (IG) as defined above:

[0126] [ka] The present invention relates to the compound

[0127] In a further aspect of the invention, there is provided a compound of formula (IA), (IB), (IC), (ID), (IE), (IF) or (IG) as defined anywhere herein, wherein one or more of the substituents defined therein are particularly selected as follows: the halogen substituents are selected from F, Cl and Br; preferably F and Cl; and / or the linear or branched C1-C6-alkyl substituents are selected from methyl, ethyl, propyl, isopropyl, n-butyl and isobutyl; preferably methyl, ethyl and propyl, more preferably methyl or ethyl; 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 represents a substituted or unsubstituted C1-C3-alkyl group, preferably a substituted or unsubstituted C1- or C2-alkyl group; and / or - the bicyclic heteroaryl group is selected from the benzimidazolyl group; It is preferable that the present invention is characterized by the above.

[0128] In a further aspect of the invention, for compounds of formula (IA), (IB), (IC), (ID), (IE), (IF) or (IG) as defined anywhere herein, it is preferred that the possible substituents are selected from any combination of one or more of the following definitions: [1]R 1 and R 2 one of which represents hydrogen and the other is selected from F, Cl, methyl, ethyl, difluoroethyl, trifluoromethyl, methoxy and ethoxy; preferably F, Cl, methyl, trifluoromethyl and methoxy, with F being most preferred. [2]R 3 but, - linear or branched C1-C3-alkyl, preferably ethyl, propyl or isopropyl; - linear or branched C1-C3-haloalkyl, preferably difluoroethyl or trifluoromethyl; - linear or branched C1-C3-alkoxy, preferably methoxy or ethoxy or the group of "straight chain substituents" including - unsubstituted or substituted phenyl; - unsubstituted or substituted 5- or 6-membered heteroaryl; - unsubstituted or substituted bicyclic heteroaryl; - 6-membered heterocyclyl; - 6-membered heterocyclylalkyl; - phenylethynyl; and - Pyridinylethynyl A group of "cyclic substituents" including is selected from The substituted phenyl, heteroaryl and bicyclic heteroaryl groups are optionally halogen, preferably F or Cl; C1-C3-alkyl, preferably methyl or ethyl; C1-C3-haloalkyl, preferably difluoroethyl or trifluoromethyl; and C1-C3-alkoxy, preferably methoxy or ethoxy and optionally substituted with 1, 2, or 3 substituents independently selected from R 3 is preferably selected from the group of "cyclic substituents". [3]R 4 but, - unsubstituted or substituted 6-membered aryl, preferably phenyl; and - straight-chain or branched C1-C6-alkyl, preferably methyl or ethyl, optionally bearing one substituent selected from C1-C3-alkoxy, preferably methoxy or isopropoxy, dialkylamino, preferably dimethylamino, heterocyclyl, preferably morpholinyl or N-substituted C1-C3-alkylpiperazin-1-yl, unsubstituted or substituted 6-membered aryl, preferably phenyl, methoxy-phenyl and chloro-phenyl, and unsubstituted or substituted 6-membered heteroaryl, preferably pyridinyl; and - Dialkyl ether group [R 6 (CH2) x -O-CH2) y -](In the formula, R 6 represents a C1-C3 alkoxy group, preferably a methoxy group; x and y independently represent the integers 1, 2 or 3, preferably x and / or y represent 2. is selected from. or R 4 but, - linear or branched C1-C6-alkyl, preferably methyl or ethyl, optionally bearing one substituent selected from C1-C3-alkoxy, preferably methoxy or isopropoxy, heterocyclyl, preferably morpholinyl, and unsubstituted or substituted 6-membered aryl, preferably phenyl, methoxy-phenyl and chloro-phenyl; and - Dialkyl ether group [R 6 (CH2) x -O-CH2) y -](In the formula, R 6represents a C1-C3 alkoxy group, preferably a methoxy group; x and y independently represent the integers 1, 2 or 3, preferably x and / or y represent 2. is selected from. [4]R 5 but, - hydrogen, halogens, preferably F and Cl; linear or branched C1-C3-alkyl, preferably methyl; and - linear or branched C1-C3-haloalkyl, preferably difluoroethyl and trifluoromethyl is selected from. [5]L 1 and L 2 became independent, - Straight chain C1-C3 alkyl group -[CH2] m -or- [CH2] n - (wherein m and n are independently an integer of 1, 2 or 3, preferably m and n are independently 1 or 2, more preferably m and n are both 2); - branched C1-C4-alkyl groups, preferably 2-dimethylethyl groups; and - C3-C6-cycloalkyl groups which together with the nitrogen atom to which they are attached form a ring, preferably groups which together with the nitrogen atom to which they are attached form a tetracyclic or hexacyclic ring, preferably groups which together with the nitrogen atom to which they are attached form a tetracyclic ring. represents a linker group selected from

[0129] In a particularly preferred embodiment, the compounds according to the invention are selected from compounds according to formulae (IA), (IB), (IC), (IE) and (IF) as defined above, including in particular the following compounds:

[0130] [Table 1] JPEG2025535398000034.jpg145164

[0131] In any case, the following compounds of WO 2020 / 123850 are excluded from the present invention:

[0132] [ka] JPEG2025535398000036.jpg111159

[0133] The present invention relates to novel ferroportin inhibitor compounds as defined anywhere herein, including pharmaceutically acceptable salts thereof. In a further aspect, the present invention also includes solvates, hydrates and polymorphs of the compounds defined herein and their pharmaceutically acceptable salts.

[0134] Salts, solvates or hydrates of compounds of formula (IA), (IB), (IC), (IE), (IF), or (IG) as defined anywhere herein may exist in amorphous, polymorphic, crystalline and / or semi-crystalline (partially crystalline) form, as well as in the form of solvates (or hydrates) of salts. Preferably, the salts, solvates or hydrates of the invention exist in crystalline and / or semi-crystalline (partially crystalline) form.

[0135] The preferred crystallinity of the salt or salt solvate of the present invention can be determined by conventional analytical methods, for example, by using various X-ray methods that allow clear and simple analysis of salt compounds in particular. In particular, the crystallinity grade can be determined or confirmed by, for example, using powder X-ray diffraction (reflection) as described in the following examples, or by, for example, using powder X-ray diffraction (transmission) as described in the following examples (both abbreviated as PXRD below). In the case of crystalline solids with the same chemical composition, the resulting different crystal lattices are summarized by the term polymorphism.

[0136] Pharmaceutically acceptable salts of the compounds according to the invention include, for example, salts with suitable anions, such as carboxylates, which may include formates or acetates, as well as sulfonates, sulfates, chlorides, bromides, iodides, phosphates, tartrates, methanesulfonates, hydroxyethanesulfonates, glycinates, maleates, propionates, fumarates, toluenesulfonates, benzenesulfonates, trifluoroacetates, 1,5-naphthalenedisulfonates, salicylates, benzoates, lactates, malate salts, 3-hydroxy-2-naphthoate-2-, citrates and acetate salts. HCl salts are preferred.

[0137] Pharmaceutically acceptable salts of the compounds according to the invention further include, for example, salts with suitable pharmaceutically acceptable bases, such as alkali or alkaline earth hydroxides, for example NaOH, KOH, Ca(OH), Mg(OH), and the like, amine compounds, 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.

[0138] The novel compounds of the present invention may exist as solvates and / or hydrates, which may be formed by the attraction, association, adsorption, adhesion, embedding or complexation of solvent molecules into the crystalline lattice of the salts of the present invention. The solvent molecules that may be embedded in the crystalline lattice may be derived from the solvent used for crystallization and water derived from the relative humidity.

[0139] The degree to which a selected solvent or water forms a solvate or hydrate in a process step or during a crystallization step depends on the combination of process conditions, the various interactions between the selected compound, the counteranion derived from the selected acid, and the selected solvent, as well as humidity conditions. Salt solvates or hydrates may be preferred because solvent or water molecules in the crystal structure are bound by strong intermolecular forces, which may represent an element of the structure formation of these crystals, which may, in part, improve the stability of the salt. However, solvent and / or water molecules also exist in certain crystal lattices bound by fairly weak intermolecular forces. Such molecules are incorporated into the crystal structure formation to some extent, but with low energy effect. The solvent and / or water content of the solvate also depends on the drying and ambient conditions (i.e., relative humidity). Stable solvates or hydrates usually have a well-defined stoichiometric ratio between the active compound (i.e., salt) and the solvent or water. In many cases, these ratios do not fully satisfy the stoichiometric ratio and usually approach a lower value compared to theory due to certain crystal defects. The ratio of organic molecules to solvent or water molecules for weaker bound water can vary considerably, ranging, for example, from di-, tri-, or tetra-hydrates. On the other hand, in amorphous solids, the molecular structural classification of solvent and / or water is not stoichiometric; the classification can only be stoichiometric by chance. In some cases, layer structures are formed, and the embedded solvent or water molecules cannot be determined in a defined form, making it impossible to classify the exact stoichiometry of the solvent or water molecules.

[0140] The solvent and / or water content in amorphous solids and crystalline solvates or hydrates can generally be determined by conventional methods, for example by using the well-known Karl-Fischer titration method, by performing dynamic water vapor sorption (DVS) measurements, by performing thermogravimetry (TG-FTIR), by elemental or structural analysis methods, for example 1H NMR spectroscopy or Raman spectroscopy (FT-Raman spectroscopy) may also provide information about the extent of solvate or hydrate formation and / or may be used to confirm or verify the results of Karl-Fischer (KF), DVS or TG-FTIR measurements.

[0141] Examples of solvates and / or hydrates according to the present invention include, for example, hemi-(0.5), mono-, sesqui-(1.5), di-, tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, deca-solvates or hydrates, respectively. Additional intermediate degrees of solvation are also possible, for example, solvation with 2.5, 3.5, 4.5, etc. solvent and / or water molecules.

[0142] Preferred examples of solvates and / or hydrates include those containing about 0.5, 1, 1.5, 2.5, 3, 4, and 7 solvent / water molecules. More preferred examples of solvates and / or hydrates include those containing about 0.5, 1, 1.5, 2.5, 3, 4, 6, and 7 solvent / water molecules. More preferred are hemi- and mono-solvates / hydrates containing about 0.5 or 1 solvent / water molecule, with hemi- and mono-hydrates being particularly preferred. Anhydrous salts are also preferred. It is further possible for solvent and / or water residues to remain in the salt in non-stoichiometric amounts.

[0143] The formation of salts of the compounds of the invention can be carried out in particular by the methods described in international application WO 2018 / 192973.

[0144] As described therein, solvents used for crystallization include acetonitrile, dichloromethane (DCM), alcohols, such as, in particular, methanol, ethanol, 2-propanol (iso-propanol), aldehydes, ketones, in particular acetone, ethers, such as tetrahydrofuran (THF) or dioxane, esters, such as ethyl acetate, or alkanes, such as, in particular, pentane, hexane, heptane or cyclohexane, and water, and mixtures thereof. Preferred solvents used for crystallization are selected from the group consisting of acetonitrile, dichloromethane, methanol, ethanol, 2-propanol, ethyl acetate, THF, water, and mixtures thereof.

[0145] Particularly preferred solvents used for crystallization are selected from the group consisting of acetonitrile, methanol, ethanol, 2-propanol, ethyl acetate, THF, water, and mixtures thereof. Preferred water / solvent mixtures include mixtures of water, acetonitrile, and methanol or ethanol, with a mixture of water, acetonitrile, and methanol being preferred.

[0146] In principle, salts, solvates, hydrates, and polymorphs of the compounds according to the invention can be prepared by any commonly applied crystallization technique, including evaporation crystallization, cooling crystallization, crystallization by addition of an antisolvent, seeded crystallization, template crystallization, or melt crystallization.

[0147] In a particularly preferred embodiment, salts, solvates, or hydrates of the compounds defined elsewhere herein are prepared using particularly preferred solvent mixtures in preparative high performance liquid chromatography (HPLC).The preparation of such salts, solvates, or hydrates has the advantage that the reaction product from compound synthesis can be purified while simultaneously transferring the compound according to the present invention to the desired phase.In such cases, suitable anions can be selected from formic acid, acetic acid, or lactic acid.Each anion is added to the HPLC solution at 0.05% by weight, 0.075% by weight, 0.1% by weight, 0.2% by weight, 0.3% by weight, 0.4% by weight, or 0.5% by weight, with 0.1% by weight being preferred.Preparative HPLC can then be carried out.

[0148] The novel compounds according to formula (IA), (IB), (IC), (ID) (IE), (IF) or (IG) as defined anywhere in this specification have been found to act as ferroportin inhibitors and are therefore suitable for pharmaceutical use, for example, in particular for use as ferroportin inhibitors.

[0149] As already explained above, ferroportin is an iron transport protein responsible for the uptake of released iron via the intestine and its transport into the blood circulation, thereby delivering iron to the appropriate tissues and organs. Inactivation or inhibition of ferroportin prevents iron export, thereby reducing intestinal iron absorption. Therefore, ferroportin inhibition in the sense of the present invention includes inhibition of iron transport from cells to the blood circulation and inhibition of iron absorption in the intestine. Inhibition of iron transport and / or iron reflux can be achieved by various mechanisms, including, for example, inhibition of the iron transport activity of ferroportin and thus inhibition of iron reflux, induction of internalization, degradation and / or reduction of ferroportin, and administration of hepcidin agonists, i.e., compounds that compete with hepcidin or inhibit the binding of hepcidin to ferroportin.

[0150] 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 Examples below. Furthermore, ferroportin inhibition can be determined by measuring ferroportin internalization and / or degradation in a ferroportin internalization and degradation assay (FACS), or by examining ferroportin ubiquitination and degradation, each of which is described in more detail in the Examples below. Furthermore, ferroportin inhibition can be determined by measuring hepcidin agonist activity, for example, by determining hepcidin binding ability to ferroportin in a hepcidin internalization assay (J774), as described in more detail in the Examples below. 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 Examples below. Additionally, ferroportin inhibition can be determined by determining the activity of a compound with respect to its ability to block ferroportin-mediated iron export, for example, using an assay to measure inhibition of iron efflux, as described in more detail in the Examples below.

[0151] Thus, ferroportin inhibition in the sense 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: IC50 of 100 or less (≦100), preferably 50 or less (≦50), 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 as follows: "+ comparable to hepcidin," "+ / - intermediate effect," and "+ / + / - stronger intermediate effect." Preferred effects are "+" or "+ / + / -," with "+" being most preferred. 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.

[0152] 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 blockage 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 blockage of iron overload in beta2-microglobulin-deficient mice via measurement of total iron in the spleen or liver; and testing for improvement of anemia, ineffective erythropoiesis, and iron overload in a mouse model of beta-thalassemia intermedia.

[0153] 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.

[0154] Furthermore, as already explained above, ferroportin inhibition can be brought about, for example, by hepcidin, and thus hepcidin is an essential regulator of iron absorption, inhibiting ferroportin and thus blocking iron transport and absorption from cells into blood circulation.It has also 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.

[0155] The compounds defined in the present invention are therefore also suitable for use in inhibiting iron transport from cells into the circulation and inhibiting iron absorption in the intestine, as well as for use as hepcidin mimetics or hepcidin agonists.

[0156] Due to the activity of the compounds defined herein as ferroportin inhibitors, the compounds of the present invention are particularly suitable for use in inhibiting ferroportin-mediated iron transport, thereby preventing and / or treating 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 present 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.

[0157] Among these, 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.

[0158] 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 the compounds are believed to be effective by limiting iron deposition or accumulation in tissues or cells.

[0159] 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.

[0160] Diseases associated with ineffective erythropoiesis include, inter alia, myelodysplastic syndromes (MDS, myelodysplasia) and polycythemia vera, as well as congenital dyserythropoietic anemia.

[0161] 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), including 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 leukemia, 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.

[0162] 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.

[0163] The compounds of the present invention may further be suitable for use in the prevention and treatment of diseases caused by a deficiency of hepcidin.

[0164] In view of that, a further object of the present 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 in particular.

[0165] 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 pharmaceutically 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 present invention, the remainder being formed by pharmacologically acceptable carriers and / or auxiliary substances and / or solvents and / or optionally further pharmaceutically active compounds, respectively.

[0166] Among them, pharmaceutically acceptable carriers, auxiliary substances, or solvents are common pharmaceutical carriers, auxiliary substances, or solvents, including various organic or inorganic carriers and / or auxiliary materials, as they are commonly used for pharmaceutical purposes, especially for solid pharmaceutical preparations. Examples include excipients such as sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate; binders such as cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, 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, talc, calcium carbonate, calcium carbonate, calcium carbonate, calcium carbonate, calcium carbonate, calcium carbonate, calcium carbonate, calcium carbonate, calcium carbonate, calcium carbonate, calcium carbonate, magnesium stearate, talc, calcium carbonate ... magnesium stearate, tal flavoring agents 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, etc.

[0167] Liquid pharmaceutical formulations, such as solutions, suspensions, and gels, typically contain a liquid carrier, such as water and / or a pharmaceutically acceptable organic solvent. Furthermore, such liquid formulations may also contain, for example, pH adjusters, emulsifiers or dispersants, buffers, preservatives, wetting agents, gelatinizing agents (e.g., methylcellulose), dyes, and / or flavoring agents, as defined above. The composition may be isotonic, i.e., have the same osmotic pressure as blood. The isotonicity of the composition can be adjusted by using sodium chloride and other pharmaceutically acceptable agents, such as dextrose, maltose, boric acid, sodium tartrate, propylene glycol, and other inorganic or organic soluble substances. The viscosity of the liquid composition can be adjusted with a pharmaceutically acceptable thickener, such as methylcellulose. Other suitable thickeners include, for example, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, carbomer, etc. The preferred concentration of the thickener depends on the drug selected.

[0168] To extend the shelf life of the liquid composition, a pharmaceutically acceptable preservative can be used. For example, several preservatives can be used, including parabens, thimerosal, chlorobutanol, and benzalkonium chloride, but benzyl alcohol may be preferred.

[0169] The pharmaceutical compositions are suitable, for example, for intravenous, intraperitoneal, intramuscular, intravaginal, buccal, percutaneous, subcutaneous, mucocutaneous, oral, rectal, transdermal, topical, intradermal, intragastric or intradermal administration and may be provided, for example, in the form of pills, tablets, enteric-coated tablets, film tablets, layer tablets, sustained-release preparations for oral, subcutaneous or cutaneous 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, inhalable powders, microcrystalline preparations, inhalation sprays, dustings, drops, nasal drops, nasal sprays, aerosols, ampoules, solutions, juices, suspensions, infusions or injection solutions, etc.

[0170] A further aspect 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 pharmaceutically 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 pharmaceutically 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.

[0171] A further aspect of the present invention relates to the use of the compounds 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 compounds of the present invention and at least one additional pharmaceutically active compound (drug). Combination therapy in fixed dose combination therapy includes the co-administration of the compounds of the present invention and at least one additional pharmaceutically active compound in a fixed dose formulation. Combination therapy in free dose combination therapy includes the co-administration of the compounds of the present invention and at least one additional pharmaceutically 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 pharmaceutically 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, e.g., n-acetylcysteine, an antidiabetic drug, e.g., a GLP-1 receptor agonist, an antibiotic, e.g., vancomycin (VAN) or tobramycin, malaria, or a combination thereof. 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), antiviral drugs such as interferon-alpha or ribavirin, or immunosuppressants (cyclosporin A or cyclosporin A derivatives), iron supplements, vitamin supplements, erythropoiesis stimulators, anti-inflammatory biological agents, antithrombolytic agents, statins, hypertensive agents, and inotropic compounds.

[0172] A further aspect of the invention relates to the use of the above combinations 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 this application.

[0173] A further aspect of the present invention relates to the use of the compounds as defined herein, either on their own or in combination therapy as described above, in combination with blood transfusion.

[0174] The compounds, medicaments and / or combined preparations according to the invention may be administered orally, parenterally and intravenously.

[0175] For this purpose, the compounds according to the invention are preferably provided in the form of medicaments or pharmaceutical compositions in the form of pills, tablets, e.g. enteric-coated tablets, film tablets and layer tablets, sustained-release formulations for oral administration, depot formulations, dragees, granules, emulsions, suspensions, microcapsules, microformulations, nanoformulations, liposomal formulations, capsules, e.g. enteric-coated capsules, powders, microcrystalline formulations, dusting powders, drops, ampoules, solutions, suspensions, infusion or injection solutions, or in the form of preparations suitable for inhalation.

[0176] In a preferred embodiment of the invention, the compounds are administered in the form of tablets or capsules, as defined above, which may be present, for example, in an acid-resistant form or with a pH-dependent coating.

[0177] 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 patient's age, body weight, condition, severity of the disease, or type of administration.

[0178] Therefore, a further aspect of the present invention 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 of the indications, conditions, disorders or diseases as defined above.

[0179] A further aspect 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 associated with or leading to elevated iron levels and in particular iron overload, diseases associated with or caused by elevated iron levels or iron overload, iron storage diseases associated with or leading to elevated iron levels, and diseases associated with ineffective erythropoiesis, comprising the step of administering to a patient (human or animal) in need thereof a compound, medicament, composition or combined preparation as defined above.

[0180] Among these are diseases associated with, related to, caused by or leading to elevated iron levels or iron overload as defined above.

[0181] A further aspect of the present invention relates to the use of a compound 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.

[0182] Compounds according to the invention of general structural formula (IA) and (IB) can be prepared essentially as shown in the following general synthetic schemes I, II and III: General synthetic scheme I:

[0183] [ka] (wherein the leaving group Q can be NHBoc or NBoc, and the positions of "XH" and "NH2" can be interchanged to prepare the so-called "iso compounds" described herein).

[0184] [ka] (wherein the structures shown as "(b1 / b2 / b3)" represent structures b-1, b-2 or b-3 as defined herein).

[0185] General synthetic scheme II:

[0186] [ka] (Wherein the formula, the positions of "XH" and "NH2" can be interchanged to prepare the so-called "isocompounds" described herein, and the structures shown as "(b1 / b2 / b3)" represent structures b-1, b-2, or b-3 as defined herein.)

[0187] General Synthetic Scheme III:

[0188] [ka] (wherein the leaving group Q can be OBn, and the positions of "XH" and "NH2" can be interchanged to prepare the so-called "iso compounds" described herein).

[0189] [ka] (wherein the structures shown as "(b1 / b2 / b3)" represent structures b-1, b-2 or b-3 as defined herein).

[0190] In particular, the following general procedures describe suitable preparative processes for preferred compounds of the present invention:

[0191] Synthesis of intermediates: General Scheme 1:

[0192] [ka] wherein R is one substituent R as defined herein. 1 or R 2 indicates.)

[0193] General Scheme 2:

[0194] [ka] wherein R is one substituent R as defined herein. 1 or R 2 indicates.)

[0195] General Scheme 3:

[0196] [ka] wherein R is one substituent R as defined herein. 1 or R 2 indicates.)

[0197] General Scheme 4:

[0198] [ka] (In the formula, R 4 may have the meaning defined elsewhere in this specification.

[0199] General Scheme 5:

[0200] [ka] wherein R is one substituent R as defined herein. 1 or R 2 indicates.)

[0201] Synthesis of compounds of the present invention: General Scheme 6:

[0202] [ka] (In the formula, R 1 and R 4 may have the meaning defined elsewhere in this specification.

[0203] General Scheme 7:

[0204] [ka] (In the formula, R 1 and R 4 may have the meaning defined elsewhere in this specification.

[0205] General Scheme 8:

[0206] [ka] (In the formula, R 1 and R 4 may have the meaning defined elsewhere in this specification.

[0207] General Scheme 9:

[0208] [ka] (In the formula, R 1 and R 4 may have the meaning defined elsewhere in this specification.

[0209] In a further aspect, the present invention covers intermediate compounds obtainable by the preparation methods described herein, such as intermediate compounds obtained from the individual steps of the general reaction schemes described above and in more detail herein. Details of the preparation conditions are provided in the examples below. [Example]

[0210] The present invention is illustrated in more detail by the following examples, which are merely illustrative and one skilled in the art will be able to extend the specific examples further to the claimed compounds.

[0211] Pharmacological assays 1. Hepcidin Internalization Assay (J774) This cellular assay allows for quantification of hepcidin binding to ferroportin (Fpn) through microscopic detection of the internalization of fluorescently labeled hepcidin into J774 cells. J774 is a murine 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 the 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. Therefore, microscopic detection of cell-associated TMR fluorescence is a measure of hepcidin binding to Fpn and the internalization of hepcidin and Fpn. When 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.

[0212] 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). 5J774 cells were plated at 1000 cells / ml and grown at 37°C in 5% CO2. After overnight incubation, cells were washed three times with prewarmed DMEM with phenol red. After the final wash, 30 μl / well of DMEM with phenol red was added, and 10 μl / well of a dilution series of test compounds was added in triplicate. J774 cells were preincubated with test compounds for 15 minutes at 37°C in 5% CO2, followed by the addition of TMR-hepcidin at a final concentration of 25 nM. Cells were incubated in a total volume of 50 μl at 37°C in 5% CO2 for 2 hours, then Hoechst 33342 dye was added to a final concentration of 0.5 μg / ml to stain the nuclei and further incubated at 37°C in 5% CO2 for 10 minutes. Cells were washed three times with PBS and fixed in 100 μl of 4% paraformaldehyde in PBS at room temperature for 15 minutes. After removing the paraformaldehyde solution, the cells were washed three times with PBS, leaving 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 taken per well, and the fluorescence channels covered approximately 1500 cells per well. The acquired image data were analyzed using 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. 50Sum(Mean) values ​​were calculated on the raw data using "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.

[0213] [Table 2] JPEG2025535398000052.jpg218131JPEG2025535398000053.jpg211131

[0214] 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, as detected by a dose-dependent decrease in the TMR FP signal, as described in detail below.

[0215] 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, and 0.1% BSA is plated at 16 μl per well in a 384-well black, low-volume, round-bottom plate (Corning, catalog 3677). 8 μl of serially diluted test compound is added in duplicate to reach final Fpn and TMR-hepcidin concentrations of 1 μM and 20 nM, respectively. The plate is incubated at room temperature for 90 minutes, and parallel (S) and perpendicular (P) fluorescence is measured using a Synergy H1 fluorescence reader (BioTek). FP values ​​are calculated in mP according to the following formula:

[0216]

number

[0217] I C 50 The IC value is determined using the calculated mP value as described for the hepcidin internalization assay. 50 is approximately 0.37±0.067 μM.

[0218] 3. Inhibition of Ferroportin-Mediated Iron Export Activity in the Iron Response Assay 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 the 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 reporter gene activity. Meanwhile, 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.

[0219] 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 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 plated at 1.8 × 10 cells per well in 50 μl of 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), and 4 μg / ml doxycycline (Clontech, catalog 631311) in 384-well PDL-coated plates. 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, catalog K1085) to the cells. After incubating the plates in the dark at 18°C ​​for 60 minutes, 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 blue / green fluorescence ratio, calculated as a measure of BLA activity, is calculated, and the EC 50 Determine the EC value of hepcidin in this assay. 50 is approximately 0.096±0.063 μM (n=37).

[0220] 4. Ferroportin Internalization and Degradation Assay The HEK-293 cell line #354 (described in Example 3) was 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 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 were tested for their dose-dependent effects on Fpn-GFP mean fluorescence intensity (MFI) in HEK-293 cell line #354 as described below.

[0221] HEK#354 cells were harvested from approximately 80% confluent cultures and plated at 0.6 × 10 cells per well in 50 μl of DMEM / F12 GlutaMAX™ medium (Invitrogen, Catalog 31331-028) containing 10% FBS (Clontech, Catalog 631106), 1% penicillin-streptomycin (Invitrogen, Catalog 15140-122), 200 μg / ml hygromycin B (Invitrogen, Catalog 10687-010), 5 μg / ml blasticidin (Invitrogen, Catalog R210-01), and 4 μg / ml doxycycline (Clontech, Catalog 631311) in 384-well plates (Greiner; Catalog 781091). 6 Cells are seeded at 1000 cells / ml and grown at 37°C in 5% CO2. After overnight incubation, 10 μl / well of a serially diluted test compound is 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, catalog P4864), and analyzed using a flow cytometer (CANTO™ II, BD Biosciences) equipped with a high-throughput sampler. Live HEK#354 cells are gated as a propidium iodide-negative population and analyzed for Fpn-GFP expression. The MFI of Fpn-GFP over 2000 viable cells for each compound dilution is calculated using FlowJo (Tree Star's, Oregon), 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.

[0222] 5. Ferroportin Ubiquitination and Degradation Exposure of ferroportin (Fpn)-expressing cells to hepcidin is known to induce Fpn ubiquitination and subsequent internalization and degradation (Qiao, 2012). The ability of Fpn inhibitors to induce Fpn ubiquitination and degradation was investigated by immunoprecipitation assay using the J774 murine macrophage cell line, which expresses Fpn upon iron treatment.

[0223] J774 cells (DSMZ, catalog ACC170) are seeded at 0.8 x 10 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% CO. 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 overnight with control agarose beads at 4 °C for 1 h to pre-clear the lysate and reduce nonspecific signal. The unbound lysate is then incubated overnight with 12 µg per reaction of affinity-purified anti-Fpn antibody F308, which is directed against a GST fusion protein of mouse Fpn amino acids 224–308. Immune complexes are captured by pipetting 14 μl of precipitated Pierce Protein A / G Plus agarose beads (Life Technologies, catalog 20423) per reaction, and the slurry is incubated with gentle tilting for 1.5 hours at 4° C. The beads are washed, and immune complexes are directly eluted with 75 μl of SDS NuPAGE LDS sample buffer (Life Technologies, catalog NP0007) containing DTT (Life Technologies, catalog NP0009).

[0224] After immunoprecipitation, samples were analyzed by Western blotting using rabbit anti-mouse MTP1 antiserum (Alpha Diagnostic International, catalog MTP11-A) and mouse anti-mono- and polyubiquitin conjugated monoclonal antibodies (Enzo Lifesciences, catalog BML-PW8810) to detect ferroportin and ubiquitin, respectively. Mouse monoclonal anti-rabbit IgG light chain (Abcam, catalog ab99697) and anti-mouse IgG H&L (Abcam, catalog ab6789) HRP conjugate were used as secondary antibodies.

[0225] 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.

[0226] Cells were plated in 24-well plates (Greiner, catalog 662160) containing 350,000 cells / well and incubated in 100 μM of growth medium containing 500 μM L-ascorbic acid (Sigma Aldrich, catalog 795437). 58 Fe(sulfate 58Incubate cells overnight with Fe(II), Vifor Pharma, batch number ROR3085. Wash cells once with 500 μl of iron uptake buffer (IUB; PIPES 40 mM, catalog P1851, glucose monohydrate 10 mM, catalog 49158, sodium chloride 260 mM, catalog 71379, potassium chloride 20 mM, catalog P9541, magnesium sulfate 2 mM, catalog 63138, Sigma-Aldrich) and then twice with removal buffer (2 min incubation, BPDS 100 μM, catalog 11890, and NaSO 500 μM, catalog 157953, Sigma-Aldrich, in IUB). Add serial dilutions of hepcidin (Bachem) or ferroportin inhibitor (4 μM–0.0064 μM, 5-fold dilutions) in a total volume of 0.6 ml per well. The cells are incubated at 37°C in 5% CO for 20 hours. The supernatant is 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.

[0227] 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.

[0228] 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 eluent, or by preparative HPLC (if otherwise stated).

[0229] Abbreviation EtOAc ethyl acetate CH2Cl2 Dichloromethane 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 milliliter 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

[0230] chemical nomenclature Chemical names of intermediate and final example compounds were generated by using Chem Draw Professional 17.0.

[0231] All R f Values ​​are based on the following TLC plates: Merck, TLC silica gel 60 F 254 was determined using

[0232] Preparation details Intermediates A. tert-Butyl (3-((4-hydroxypyridin-3-yl)amino)-3-oxopropyl)carbamate

[0233] [ka] To a solution of 3-aminopyridin-4-ol (5.00 g, 44.0 mmol, 1 equiv.) in N,N-dimethylformamide (90 mL) was added 3-((tert-butoxycarbonyl)amino)propanoic acid (8.42 g, 44.0 mmol, 1 equiv.), triethylamine (12.4 mL, 88.1 mmol), and HATU (20.7 g, 52.9 mmol, 1.2 equiv.). The reaction mixture was stirred at 23 °C for 16 h. The solution was diluted with water and extracted with ethyl acetate (3 ×). The combined organic phases were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude oil was purified by flash column chromatography (heptane / EtOAc, 0 to 100% EtOAc) to afford the title tert-butyl (3-((4-hydroxypyridin-3-yl)amino)-3-oxopropyl)carbamate (11.7 g, 41.6 mmol, 94%) as a white foam. LCMS (ESI) m / z = 282.2. 1H NMR (400 MHz, DMSO) δ 11.47 (s, 1H), 9.02 (s, 1H), 8.83 - 8.59 (m, 1H), 7.63 (dd, J = 7.1, 1.6 Hz, 1H), 6.76 (t, J = 5.7 Hz, 1H), 6.23 (d, J = 7.1 Hz, 1H), 3.22 - 3.13 (m, 3H), 2.57 - 2.49 (m, 2H), 1.35 (s, 9H) ppm.

[0234] B. tert-Butyl (2-(oxazolo[4,5-c]pyridin-2-yl)ethyl)carbamate

[0235] [ka] To a suspension of polymer-supported triphenylphosphine (loading 1.6 mmol / g, 7.75 g, 12.4 mmol, 2 equiv.) in dichloromethane (60 mL) was added hexachloroethane (1.83 g, 7.73 mmol, 1.25 equiv.) and triethylamine (4.31 mL, 30.9 mmol, 5 equiv.). The suspension was stirred for 5 minutes, after which tert-butyl (3-((4-hydroxypyridin-3-yl)amino)-3-oxopropyl)carbamate (1.74 g, 6.19 mmol, 1.0 equiv.) was added. The mixture was stirred at rt for 1 hour. Additional 1,1,1,2,2,2-hexachloroethane (1.10 g) and triethylamine (1.42 mL) were added, and stirring was continued at 23 °C for 16 hours. The reaction mixture was diluted with dichloromethane and acetonitrile and then filtered. The filtrate was concentrated, and the resulting crude oil was purified by flash column chromatography (heptane / EtOAc, 0 to 100% EtOAc) to afford the desired tert-butyl (2-(oxazolo[4,5-c]pyridin-2-yl)ethyl)carbamate (1.12 g, 4.25 mmol, 69%). LCMS (ESI) m / z = 264.1. 1H NMR (400 MHz, DMSO) δ 8.97 (s, 1H), 8.51 (d, J = 5.5 Hz, 1H), 7.02 (t, J = 6.0 Hz, 1H), 3.41 (q, J = 6.5 Hz, 2H), 3.07 (t, J = 6.7 Hz, 2H), 1.30 (s, 9H) ppm.

[0236] C. 2-(2-((tert-butoxycarbonyl)amino)ethyl)oxazolo[4,5-c]pyridine-5-oxide

[0237] [ka] tert-Butyl (2-(oxazolo[4,5-c]pyridin-2-yl)ethyl)carbamate (3.04 g, 11.5 mmol, 1 equiv.) was dissolved in dichloromethane (100 mL). After cooling the solution to 0° C., mCPBA (75% Wt, 5.31 g, 23.1 mmol, 2 equiv.) was added. After 2 h, the ice bath was removed and stirring was continued at 23° C. until LCMS showed complete conversion of sm. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was suspended in methanol. The solid was filtered off, washed with methanol, and dried under vacuum to give the desired 2-(2-((tert-butoxycarbonyl)amino)ethyl)oxazolo[4,5-c]pyridine-5-oxide (1.78 g, 6.37 mmol, 55%) as an off-white solid. LCMS (ESI) m / z = 280.3. 1H NMR (400 MHz, DMSO) δ 8.77 (d, J = 1.8 Hz, 1H), 8.20 (dd, J = 7.0, 1.8 Hz, 1H), 7.80 (d, J = 7.1 Hz, 1H), 7.02 (t, J = 5.9 Hz, 1H), 3.39 (q, J = 6.4 Hz, 2H), 3.04 (t, J = 6.6 Hz, 2H), 1.31 (s, 9H) ppm.

[0238] D. tert-Butyl (2-(4-(((3-fluoropyridin-2-yl)methyl)amino)oxazolo[4,5-c]pyridin-2-yl)ethyl)carbamate

[0239] [ka] To a solution of 2-(2-((tert-butoxycarbonyl)amino)ethyl)oxazolo[4,5-c]pyridine-5-oxide (1.78 g, 6.37 mmol, 1 equiv.) and (3-fluoropyridin-2-yl)methanamine dihydrochloride (1.90 g, 9.56 mmol, 1.5 equiv.) in anhydrous tetrahydrofuran (60 mL) was added DIPEA (4.12 g, 5.55 mL, 31.9 mmol, 5 equiv.) and bromotri(pyrrolidin-1-yl)phosphonium(l2-fluoraneyl)pentafluorophosphate (V) (4.47 g, 9.56 mmol, 1.5 equiv.). The reaction mixture was stirred at 23 °C until LC / MS showed complete consumption of sm. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CHCl / MeOH / NH 90 / 9 / 1) to give the desired tert-butyl (2-(4-(((3-fluoropyridin-2-yl)methyl)amino)oxazolo[4,5-c]pyridin-2-yl)ethyl)carbamate (2.31 g, 5.96 mmol, 94%). LCMS (ESI) m / z = 388.6. 1H NMR (400 MHz, DMSO) δ 8.31 (dd, J = 4.9, 1.8 Hz, 1H), 7.92 - 7.84 (m, 1H), 7.73 (ddd, J = 10.0, 8.3, 1.3 Hz, 1H), 7.42 (dt, J = 8.6, 4.5 Hz, 1H), 7.28 (d, J = 6.6 Hz, 1H), 7.00 (t, J = 5.9 Hz, 1H), 4.97 (s, 1H), 3.41 - 3.36 (m, 2H), 3.06 (t, J = 6.6 Hz, 2H), 1.29 (s, 9H) ppm.

[0240] E. 2-(2-Aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine

[0241] [ka] tert-Butyl (2-(4-(((3-fluoropyridin-2-yl)methyl)amino)oxazolo[4,5-c]pyridin-2-yl)ethyl)carbamate (2.31 g, 5.96 mmol, 1 equiv.) was dissolved in dichloromethane (60 mL) and then treated with HCl in dioxane (4 N, 14.9 mL, 59.6 mmol, 10 equiv.). The reaction mixture was neutralized with 7 N ammonia in methanol and then concentrated. The crude mixture was purified by flash column chromatography (CHCl / 1 N NH in MeOH, 90 / 10) to afford the desired 2-(2-aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (1.45 g, 5.05 mmol, 85%) as a pale yellow oil. LCMS (ESI) m / z = 288.2. 1H NMR (400 MHz, DMSO) δ 8.35 (dt, J = 4.7, 1.5 Hz, 1H), 7.85 (d, J = 5.7 Hz, 1H), 7.67 (ddd, J = 10.3, 8.3, 1.3 Hz, 1H), 7.37 (dt, J = 8.5, 4.4 Hz, 1H), 7.18 (t, J = 5.6 Hz, 1H), 6.91 (d, J = 5.7 Hz, 1H), 4.83 (dd, J = 5.6, 1.8 Hz, 2H), 3.07 - 2.91 (m, 4H) ppm.

[0242] F. tert-Butyl 3-((4-hydroxypyridin-3-yl)carbamoyl)azetidine-1-carboxylate

[0243] [ka] To a solution of 3-aminopyridin-4-ol (3.00 g, 27.2 mmol, 1 equiv.) in DMF (50 mL) was added 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (5.48 g, 27.2 mmol, 1 equiv.), triethylamine (7.59 mL, 54.5 mmol, 2 equiv.), and HATU (12.4 g, 1.2 equiv., 32.7 mmol). The reaction mixture was stirred at 23 °C for 16 h. The solution was diluted with water and extracted with ethyl acetate (3x). The combined organic phase was washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude oil was purified by flash column chromatography (CH2Cl2 / MeOH, 0-15% MeOH) to afford the desired tert-butyl 3-((4-hydroxypyridin-3-yl)carbamoyl)azetidine-1-carboxylate (1.82 g, 6.20 mmol, 22.8%) as a white foam. LCMS (ESI) m / z = 288.2 [M-tBuOH]. 1H NMR (400 MHz, DMSO) δ 11.45 (s, 1H), 9.25 (s, 1H), 8.71 (d, J = 3.5 Hz, 1H), 7.63 (d, J = 7.1 Hz, 1H), 6.22 (d, J = 7.1 Hz, 1H), 3.99 - 3.84 (m, 4H), 3.75 (tt, J = 8.7, 5.7 Hz, 1H), 1.37 (s, 9H) ppm.

[0244] G. tert-Butyl 3-(oxazolo[4,5-c]pyridin-2-yl)azetidine-1-carboxylate

[0245] [ka] To polymer-supported triphenylphosphine (loading 1.6 mmol / g, 7.75 g, 12.4 mmol, 2 equiv.) in dichloromethane (60 mL) was added hexachloroethane (1.84 g, 7.76 mmol, 1.25 equiv.) and triethylamine (4.32 mL, 31.0 mmol, 5 equiv.). The suspension was stirred for 5 minutes, after which solid tert-butyl (3-((4-hydroxypyridin-3-yl)amino)-3-oxopropyl)carbamate (1.82 g, 6.20 mmol, 1 equiv.) was added. The mixture was stirred at rt for 1 hour. Additional 1,1,1,2,2,2-hexachloroethane (1.10 g) and triethylamine (1.42 mL) were added, and stirring was continued at 23 °C for 16 hours. The reaction mixture was diluted with dichloromethane and acetonitrile and then filtered. The filtrate was concentrated and then purified by flash column chromatography (heptane / EtOAc, 0 to 100% EtOAc) to give the desired tert-butyl 3-(oxazolo[4,5-c]pyridin-2-yl)azetidine-1-carboxylate (1.28 g, 4.65 mmol, 75%). LCMS (ESI) m / z = 276.2. 1H NMR (400 MHz, DMSO) δ 9.03 (d, J = 1.0 Hz, 1H), 8.55 (d, J = 5.6 Hz, 1H), 7.82 (dd, J = 5.5, 1.0 Hz, 1H), 4.28 (d, J = 8.4 Hz, 2H), 4.23 - 4.14 (m, 3H), 3.09 (qd, J = 7.3, 3.3 Hz, 1H), 1.39 (s, 9H) ppm.

[0246] H. 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)oxazolo[4,5-c]pyridine 5-oxide

[0247] [ka] tert-Butyl 3-(oxazolo[4,5-c]pyridin-2-yl)azetidine-1-carboxylate (1.28 g, 4.65 mmol, 1 equiv.) was dissolved in dichloromethane (45 mL). After cooling the solution to 0° C., mCPBA (75% Wt, 2.14 g, 9.30 mmol, 2 equiv.) was added. After 2 h, the ice bath was removed, and stirring was continued at 23° C. until LCMS showed complete conversion of sm. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was suspended in methanol. The solid was filtered off, washed with methanol, and dried under vacuum to give the desired 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)oxazolo[4,5-c]pyridine 5-oxide (716 mg, 2.46 mmol, 53%) as an off-white solid. LCMS (ESI) m / z = 292.2. 1H NMR (400 MHz, DMSO) δ 8.83 (dd, J = 1.8, 0.6 Hz, 1H), 8.23 ​​(dd, J = 7.1, 1.8 Hz, 1H), 7.85 (dd, J = 7.1, 0.7 Hz, 1H), 4.31 - 4.22 (m, 2H), 4.20 - 4.09 (m, 3H), 1.39 (s, 9H) ppm.

[0248] I. tert-Butyl 3-(4-(((3-fluoropyridin-2-yl)methyl)amino)oxazolo[4,5-c]pyridin-2-yl)azetidine-1-carboxylate

[0249] [ka] To a solution of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)oxazolo[4,5-c]pyridine 5-oxide (716 mg, 2.46 mmol, 1 equiv.) and (3-fluoropyridin-2-yl)methanamine dihydrochloride (734 mg, 3.69 mmol, 1.5 equiv.) in anhydrous tetrahydrofuran (25 mL) was added DIPEA (2.14 mL, 12.3 mmol, 5 equiv.) and bromotri(pyrrolidin-1-yl)phosphonium(l2-fluoranyl)pentafluorophosphate (V) (1.73 g, 3.69 mmol, 1.5 equiv.). The reaction mixture was stirred at 23 °C until LC / MS showed complete consumption of sm. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH / NH3 90 / 9 / 1) to afford the desired tert-butyl 3-(4-(((3-fluoropyridin-2-yl)methyl)amino)oxazolo[4,5-c]pyridin-2-yl)azetidine-1-carboxylate (978 mg, 2.45 mmol, 99%). LCMS (ESI) m / z = 400.3. 1H NMR (400 MHz, DMSO) δ 8.34 (dt, J = 4.7, 1.5 Hz, 1H), 7.89 (d, J = 5.8 Hz, 1H), 7.67 (ddd, J = 10.3, 8.3, 1.3 Hz, 1H), 7.41 - 7.32 (m, 2H), 6.95 (d, J = 5.8 Hz, 1H), 4.85 (dd, J = 5.7, 1.8 Hz, 2H), 4.31 - 4.24 (m, 2H), 4.18 - 4.06 (m, 3H), 1.39 (s, 9H) ppm.

[0250] J. 2-(Azetidin-3-yl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine

[0251] [ka] tert-Butyl 3-(4-(((3-fluoropyridin-2-yl)methyl)amino)oxazolo[4,5-c]pyridin-2-yl)azetidine-1-carboxylate (978 mg, 2.45 mmol, 1 equiv.) was dissolved in dichloromethane (20 mL) and then treated with HCl in dioxane (4N, 6.12 mL, 24.5 mmol, 10 equiv.). After complete conversion of sm, the reaction mixture was concentrated under reduced pressure. The crude material was purified by SCX-column eluting with 7N ammonia in methanol to give the desired 2-(azetidin-3-yl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (530 mg, 1.77 mmol, 72%) as an oil. LCMS (ESI) m / z = 300.2. 1H NMR (400 MHz, DMSO) δ 8.36 (d, J = 4.7 Hz, 1H), 7.93 (d, J = 5.8 Hz, 1H), 7.70 (ddd, J = 10.1, 8.3, 1.3 Hz, 2H), 7.39 (dt, J = 8.5, 4.4 Hz, 3H), 6.99 (d, J = 5.8 Hz, 2H), 4.90 - 4.86 (m, 3H), 4.48 - 4.39 (m, 1H), 4.34 (d, J = 8.1 Hz, 4H) ppm.

[0252] K. Oxazolo[4,5-c]pyridine

[0253] [ka] 3-Aminopyridin-4-ol (1.50 g, 1 equiv., 13.6 mmol) was placed in a microwave vial and suspended in trimethyl orthoformate (14.9 mL, 136 mmol, 10 equiv.). Acetic acid (1.17 mL, 20.4 mmol, 1.5 equiv.) was added, the vial was sealed, and subjected to microwave irradiation (160 °C, 30 min). The reaction mixture was concentrated, and the residue was purified by flash chromatography (50% EtOAc in hexanes to 100% EtOAc) to afford the desired oxazolo[4,5-c]pyridine (1.17 g, 9.74 mmol, 72%) as a colorless oil that crystallized upon standing. LCMS (ESI) m / z = 121.1. 1H NMR (400 MHz, DMSO) δ 9.12 (d, J = 1.0 Hz, 1H), 8.89 (s, 1H), 8.60 (d, J = 5.6 Hz, 1H), 7.89 (dd, J = 5.6, 1.0 Hz, 1H) ppm.

[0254] L. Oxazolo[4,5-c]pyridine 5-oxide

[0255] [ka] Oxazolo[4,5-c]pyridine (4.66 g, 38.8 mmol, 1 equiv.) was dissolved in dichloromethane (40.0 mL). After cooling the solution to 0 °C, mCPBA (75% wt, 17.9 g, 77.6 mmol, 2.0 equiv.) was added. After 2 h, the ice bath was removed, and stirring was continued at 23 °C until TLC indicated complete conversion of sm. The reaction mixture was concentrated to approximately 20 mL, filtered, and the filtrate was directly subjected to flash column chromatography (CHCl / MeOH, MeOH 0–20%) to afford the desired oxazolo[4,5-c]pyridine 5-oxide (4.02 g, 38.8 mmol, 76%) as a beige solid. LCMS (ESI) m / z = 137.2. 1H NMR (400 MHz, DMSO) δ 9.79 (s, 1H), 8.79 (d, J = 2.9 Hz, 1H), 8.29 (d, J = 1.6 Hz, 1H), 7.86 (dd, J = 7.7, 2.9 Hz, 1H), 6.17 (d, J = 7.7 Hz, 1H) ppm.

[0256] M-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine

[0257] [ka] To a solution of oxazolo[4,5-c]pyridine 5-oxide (240 mg, 1.76 mmol, 1 equiv.) and (3-fluoropyridin-2-yl)methanamine dihydrochloride (526 mg, 2.64 mmol, 1.5 equiv.) in anhydrous tetrahydrofuran (9 mL) was added DIPEA (1.14 g, 1.54 mL, 8.82 mmol, 5 equiv.) and bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (V) (1.24 g, 2.64 mmol, 1.5 equiv.). The reaction mixture was stirred at 23 °C until TLC showed complete consumption of sm. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (heptane / EtOAc, 0 to 100% EtOAc) to afford the desired N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (315 mg, 1.29 mmol, 73%) as an off-white solid. LCMS(ESI) m / z = 245.2. 1H NMR (400 MHz, DMSO) δ 8.66 (s, 1H), 8.36 (dt, J = 4.6, 1.5 Hz, 1H), 7.94 (d, J = 5.8 Hz, 1H), 7.69 (ddd, J = 10.1, 8.3, 1.3 Hz, 1H), 7.38 (p, J = 4.4 Hz, 2H), 7.00 (d, J = 5.8 Hz, 1H), 4.88 (dd, J = 5.7, 1.8 Hz, 2H) ppm.

[0258] N. 2-Bromo-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine

[0259] [ka] Under an inert atmosphere, N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (250 mg, 1 equiv., 1.02 mmol) was dissolved in tetrahydrofuran (8 mL) and cooled to −78° C. LiHMDS (360 mg, 2.15 mL, 1 molar, 2.1 equiv., 2.15 mmol) was added dropwise. The reaction mixture was allowed to warm to −40° C. within 60 minutes. The orange solution was then recooled to −78° C. and then treated with N-bromosuccinimide (237 mg, 1.33 mmol, 1.3 equiv.) in one portion. The reaction mixture was allowed to warm to 23° C. overnight. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and then extracted with EtOAc (3×). 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 (heptane / EtOAc, 0–100% EtOAc) to afford the desired 2-bromo-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (80 mg, 0.25 mmol, 24%) as a slightly red solid. LCMS (ESI) m / z = 325.2, 323.2. 1H NMR (400 MHz, DMSO) δ 8.33 (dt, J = 4.7, 1.6 Hz, 1H), 7.90 (d, J = 5.8 Hz, 1H), 7.67 (ddd, J = 9.9, 8.3, 7.53 (t, J = 5.7 Hz, 1H), 7.36 (dt, J = 8.6, 4.4 Hz, 1H), 6.96 (d, J = 5.8 Hz, 1H), 4.82 (dd, J = 5.7, 1.8 Hz, 2H) ppm.

[0260] ON-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazolo[4,5-c]pyridin-4-amine

[0261] [ka] 2-Bromo-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (75 mg, 0.23 mmol, 1 equiv.), tributyl(vinyl)tin (88 μL, 0.30 mmol, 1.3 equiv.), and bis(triphenylphosphine)palladium(II) chloride (16 mg, 23 μmol, 10 mol%) were suspended in 1,4-dioxane (3 mL). After degassing the reaction mixture with nitrogen for 5 minutes, the reaction mixture was heated to 110° C. After TLC (approximately 1 h) showed complete conversion of sm, the reaction mixture was cooled to rt and filtered through a short pad of Celite. The filter cake was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / THF) to afford the desired N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazolo[4,5-c]pyridin-4-amine (48 mg, 0.18 mmol, 77%) as an off-white solid. LCMS (ESI) = 271.2. 1H NMR (400 MHz, DMSO) δ 8.35 (dt, J = 4.6, 1.5 Hz, 1H), 7.92 (d, J = 5.7 Hz, 1H), 7.68 (ddd, J = 10.1, 8.4, 1.3 Hz, 1H), 7.40 - 7.33 (m, 2H), 6.94 (d, J = 5.7 Hz, 1H), 6.81 (dd, J = 17.5, 11.2 Hz, 1H), 6.36 (dd, J = 17.6, 0.9 Hz, 1H), 5.93 (dd, J = 11.2, 1.0 Hz, 1H), 4.85 (dd, J = 5.7, 1.8 Hz, 2H) ppm.

[0262] P. 2-Bromo-1-(2-methoxyethyl)-1H-benzo[d]imidazole

[0263] [ka] Under an inert atmosphere, 2-bromo-1H-benzo[d]imidazole (3.00 g, 1 eq, 15.2 mmol) was dissolved in N,N-dimethylformamide (30 mL) at 23 °C to give a clear solution. Sodium hydride (0.73 g, 60% Wt, 1.2 eq, 18.3 mmol) was added portionwise. The reaction mixture was stirred for 10 minutes, and then 1-bromo-2-methoxyethane (2.54 g, 1.72 mL, 1.2 eq, 18.3 mmol) was added. The reaction mixture was stirred at 23 °C for 16 hours. The reaction mixture was diluted with ethyl acetate and washed several times with water and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the desired 2-bromo-1-(2-methoxyethyl)-1H-benzo[d]imidazole (3.06 g, 12.0 mmol, 79%). LCMS (ESI) m / z = 257.1, 255.1. 1H NMR (400 MHz, DMSO) δ 7.66 - 7.55 (m, 2H), 7.25 (dtd, J = 21.7, 7.4, 1.3 Hz, 2H), 4.43 (t, J = 5.3 Hz, 2H), 3.68 (t, J = 5.3 Hz, 2H), 3.21 (s, 3H) ppm.

[0264] Q. 1-(2-Methoxyethyl)-2-vinyl-1H-benzo[d]imidazole

[0265] [ka] 2-Bromo-1-(2-methoxyethyl)-1H-benzo[d]imidazole (1.00 g, 3.92 mmol, 1 equiv.), tributyl(vinyl)tin (1.26 mL, 4.31 mmol, 1.1 equiv.), and bis(triphenylphosphine)palladium(II) chloride (138 mg, 196 μmol, 5 mol%) were suspended in 1,4-dioxane (40 mL). After degassing the reaction mixture with nitrogen for 5 minutes, the reaction mixture was heated to 110 °C. After 1 h, TLC showed complete conversion of sm. The reaction mixture was cooled to rt and filtered through a short pad of Celite. The filter cake was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / THF) to afford the desired 1-(2-methoxyethyl)-2-vinyl-1H-benzo[d]imidazole (581 mg, 2.87 mmol, 73%) as an orange gel. LCMS (ESI) m / z = 203.3. 1H NMR (400 MHz, DMSO) δ 7.63 - 7.49 (m, 2H), 7.25 - 7.14 (m, 2H), 7.02 (dd, J = 17.0, 11.0 Hz, 1H), 6.40 (dd, J = 17.1, 2.2 Hz, 1H), 5.64 (dd, J = 11.0, 2.2 Hz, 1H), 4.47 (t, J = 5.2 Hz, 2H), 3.60 (t, J = 5.2 Hz, 2H), 3.16 (s, 3H) ppm.

[0266] R. 2-Bromo-1-(cyclopropylmethyl)-1H-benzo[d]imidazole

[0267] [ka] Under an inert atmosphere, 2-bromo-1H-benzo[d]imidazole (3.00 g, 15.2 mmol, 1 equiv.) was dissolved in N,N-dimethylformamide (30 mL) at 23° C. to give a clear solution. Sodium hydride (60% Wt, 0.73 g, 18.3 mmol, 1.2 equiv.) was added portionwise. The reaction mixture was stirred for 10 minutes, after which (bromomethyl)-cyclopropane (2.47 g, 18.3 mmol, 1.2 equiv.) was added. The reaction mixture was stirred at 23° C. for 16 hours. The reaction mixture was quenched with water (5 mL) and then concentrated under reduced pressure. The concentrate was resuspended in ethyl acetate, filtered, and concentrated again. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to give the desired 2-bromo-1-(cyclopropylmethyl)-1H-benzo[d]imidazole (2.42 g, 9.64 mmol, 63%). LCMS (ESI) m / z = 253.1, 251.1. 1H NMR (400 MHz, DMSO) δ 7.72 - 7.63 (m, 1H), 7.62 - 7.57 (m, 1H), 7.32 - 7.17 (m, 2H), 4.15 (d, J = 7.0 Hz, 2H), 1.33 - 1.18 (m, 1H), 0.55 - 0.40 (m, 4H) ppm.

[0268] S. 1-(Cyclopropylmethyl)-2-vinyl-1H-benzo[d]imidazole

[0269] [ka] 2-Bromo-1-(cyclopropylmethyl)-1H-benzo[d]imidazole (1.00 g, 3.98 mmol, 1 equiv.), tributyl(vinyl)tin (1.29 mL, 4.18 mmol), and bis(triphenylphosphine)palladium(II) chloride (140 mg, 199 μmol, 5 mol%) were suspended in 1,4-dioxane (40 mL). After degassing the reaction mixture with nitrogen for 5 minutes, the reaction mixture was heated to 110 °C. After 1 hour, TLC showed complete conversion of sm. The reaction mixture was cooled to 23 °C and filtered through a short pad of Celite. The filter cake was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / THF) to give the desired 1-(cyclopropylmethyl)-2-vinyl-1H-benzo[d]imidazole (522 mg, 2.63 mmol, 66%) as a slightly yellow gel. LCMS (ESI) m / z = 199.2. 1H NMR (400 MHz, DMSO) δ 7.59 (dd, J = 6.5, 2.3 Hz, 2H), 7.25 - 7.14 (m, 2H), 7.05 (dd, J = 17.0, 10.9 Hz, 1H), 6.42 (dd, J = 17.0, 2.2 Hz, 1H), 5.67 (dd, J = 10.9, 2.2 Hz, 1H), 4.23 (d, J = 6.9 Hz, 2H), 1.32 - 1.10 (m, 1H), 0.51 - 0.33 (m, 4H) ppm.

[0270] T. 2-Bromo-1-(2-(2-methoxyethoxy)ethyl)-1H-benzo[d]imidazole

[0271] [ka] Under an inert atmosphere, 2-bromo-1H-benzo[d]imidazole (3.00 g, 15.2 mmol, 1 equiv.) was dissolved in N,N-dimethylformamide (30 mL) at 23 °C to give a clear solution. Sodium hydride (60% Wt, 0.73 g, 18.3 mmol, 1.2 equiv.) was added portionwise. The reaction mixture was stirred for 10 minutes, after which 1-bromo-2-(2-methoxyethoxy)ethane (3.34 g, 18.3 mmol, 1.2 equiv.) was added. The reaction mixture was stirred overnight. The reaction mixture was quenched with water (5 mL) and then concentrated under reduced pressure. The concentrate was resuspended in ethyl acetate, filtered, and concentrated again. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the desired 2-bromo-1-(2-(2-methoxyethoxy)ethyl)-1H-benzo[d]imidazole (1.95 g, 6.52 mmol, 43%) as a colorless oil. LCMS (ESI) m / z = 299.2. 1H NMR (400 MHz, DMSO) δ 7.60 (ddt, J = 13.3, 7.8, 0.8 Hz, 2H), 7.30 - 7.16 (m, 2H), 4.41 (t, J = 5.4 Hz, 2H), 3.75 (t, J = 5.4 Hz, 2H), 3.51 - 3.43 (m, 2H), 3.35 - 3.28 (m, 2H), 3.12 (s, 3H) ppm.

[0272] U. 1-(2-(2-Methoxyethoxy)ethyl)-2-vinyl-1H-benzo[d]imidazole

[0273] [ka] 2-Bromo-1-(2-(2-methoxyethoxy)ethyl)-1H-benzo[d]imidazole (1.00 g, 3.34 mmol, 1 equiv.), tributyl(vinyl)tin (1.13 mL, 3.38 mmol, 1.1 equiv.), and bis(triphenylphosphine)palladium(II) chloride (235 mg, 334 μmol, 10 mol%) were suspended in 1,4-dioxane (30 mL). After the reaction mixture was degassed with nitrogen for 5 minutes, the reaction mixture was heated to 110°C. After TLC showed complete conversion of sm (approximately 1 h), the reaction mixture was cooled to 23°C and filtered through a short pad of Celite. The filter cake was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / THF) to give the desired 1-(2-(2-methoxyethoxy)ethyl)-2-vinyl-1H-benzo[d]imidazole (632 mg, 2.57 mmol, 77%) as a slightly yellow gel.

[0274] V. 2-Bromo-1-(2-isopropoxyethyl)-1H-benzo[d]imidazole

[0275] [ka] Under an inert atmosphere, 2-bromo-1H-benzo[d]imidazole (3.00 g, 15.2 mmol, 1 equiv.) was dissolved in N,N-dimethylformamide (30 mL) at 23° C. to give a clear solution. Sodium hydride (60% Wt, 0.73 g, 18.3 mmol, 1.2 equiv.) was added portionwise. The reaction mixture was stirred for 10 minutes, after which 2-(2-bromoethoxy)propane (3.05 g, 18.3 mmol, 1.2 equiv.) was added. The reaction mixture was stirred at 23° C. for 16 hours. The reaction mixture was quenched with water (5 mL) and then concentrated under reduced pressure. The concentrate was resuspended in ethyl acetate, filtered, and concentrated again. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH) to afford the desired 2-bromo-1-(2-isopropoxyethyl)-1H-benzo[d]imidazole (3.30 g, 11.7 mmol, 77%) as a colorless oil that crystallized on standing. LCMS (ESI) m / z = 285.3, 283.3. 1H NMR (400 MHz, DMSO) δ 7.64 - 7.52 (m, 2H), 7.23 (dtd, J = 22.3, 7.4, 1.3 Hz, 2H), 4.37 (t, J = 5.4 Hz, 2H), 3.68 (t, J = 5.5 Hz, 2H), 3.43 (hept, J = 6.0 Hz, 1H), 0.92 (d, J = 6.0 Hz, 6H) ppm.

[0276] W. 1-(2-Isopropoxyethyl)-2-vinyl-1H-benzo[d]imidazole

[0277] [ka] 2-Bromo-1-(2-isopropoxyethyl)-1H-benzo[d]imidazole (1.00 g, 3.53 mmol, 1 equiv.), tributyl(vinyl)tin (1.14 mL, 3.88 mmol, 1.1 equiv.), and bis(triphenylphosphine)palladium(II) chloride (248 mg, 353 μmol, 10 mol%) were suspended in 1,4-dioxane (30 mL). After degassing the reaction mixture with nitrogen for 5 minutes, the reaction mixture was heated to 110°C. After TLC showed complete conversion of sm (approximately 1 h), the reaction mixture was cooled to 23°C and filtered through a short pad of Celite. The filter cake was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / THF) to give the desired 1-(2-isopropoxyethyl)-2-vinyl-1H-benzo[d]imidazole (660 mg, 2.87 mmol, 81%) as a slightly yellow gel. LCMS (ESI) m / z = 231.3. 1H NMR (400 MHz, DMSO) δ 7.62 - 7.49 (m, 2H), 7.24 - 7.13 (m, 2H), 7.03 (dd, J = 17.1, 11.0 Hz, 1H), 6.38 (dd, J = 17.1, 2.2 Hz, 1H), 4.42 (t, J = 5.2 Hz, 2H), 3.62 (t, J = 5.3 Hz, 2H), 3.39 (hept, J = 6.0 Hz, 1H), 0.91 (d, J = 6.1 Hz, 6H) ppm.

[0278] X. 4-(2-(2-bromo-1H-benzo[d]imidazol-1-yl)ethyl)morpholine

[0279] [ka] Under an inert atmosphere, 2-bromo-1H-benzo[d]imidazole (1.00 g, 5.08 mmol, 1 equiv.) was dissolved in anhydrous N,N-dimethylformamide (10 mL). After cooling the solution to 0 °C, sodium hydride (60% Wt, 305 mg, 7.61 mmol, 1.5 equiv.) was added. After 10 min, 4-(2-bromoethyl)morpholine (1.48 g, 7.61 mmol, 1.5 equiv.) was carefully added. The reaction mixture was allowed to warm slowly to 23 °C within 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate (5 ×). The combined organic phases were washed with water (2 ×) and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / MeOH, 0-10% MeOH) to afford the title 4-(2-(2-bromo-1H-benzo[d]imidazol-1-yl)ethyl)morpholine (1.25 g, 4.03 mmol, 79%). LCMS (ESI) m / z = 310.1. 1H NMR (400 MHz, DMSO) δ 7.60 (ddt, J = 11.3, 7.8, 0.9 Hz, 2H), 7.24 (dtd, J = 24.4, 7.3, 1.2 Hz, 2H), 4.34 (t, J = 6.4 Hz, 2H), 3.51 - 3.48 (m, 4H), 2.63 (t, J = 6.5 Hz, 2H), 2.45 - 2.37 (m, 4H) ppm.

[0280] Y. 4-(2-(2-vinyl-1H-benzo[d]imidazol-1-yl)ethyl)morpholine

[0281] [ka] 4-(2-(2-Bromo-1H-benzo[d]imidazol-1-yl)ethyl)morpholine (555 mg, 1.79 mmol, 1 equiv.), tributyl(vinyl)tin (624 mg, 575 μL, 1.97 mmol, 1.1 equiv.), and bis(triphenylphosphine)palladium(II) chloride (62.8 mg, 89.5 μmol, 5 mol%) were suspended in 1,4-dioxane (15 mL). The reaction mixture was degassed with nitrogen for 5 minutes, after which the reaction mixture was heated to 110° C. After TLC showed complete conversion of sm (approximately 4 h), the reaction mixture was cooled to 23° C. and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / THF) to afford the desired 4-(2-(2-vinyl-1H-benzo[d]imidazol-1-yl)ethyl)morpholine (321 mg, 1.25 mmol, 69.7%) as a slightly yellow solid. LCMS (ESI) m / z = 258.2. 1H NMR (400 MHz, DMSO) δ 7.61 - 7.55 (m, 2H), 7.25 - 7.16 (m, 2H), 7.03 (dd, J = 17.0, 11.0 Hz, 1H), 6.41 (dd, J = 17.0, 2.2 Hz, 1H), 5.67 (dd, J = 10.9, 2.2 Hz, 1H), 4.42 (t, J = 6.4 Hz, 2H), 3.50 (t, J = 4.6 Hz, 5H), 2.59 (t, J = 6.4 Hz, 2H), 2.41 (dd, J = 5.6, 3.7 Hz, 4H) ppm.

[0282] Z. 1-Benzyl-2-bromo-1H-benzo[d]imidazole

[0283] [ka] Under an inert atmosphere, 2-bromo-1H-benzo[d]imidazole (2.00 g, 10.2 mmol, 1 equiv.) was dissolved in N,N-dimethylformamide (20 mL) at 23° C. to give a clear solution. Sodium hydride (60% Wt, 609 mg, 15.2 mmol, 1.5 equiv.) was added portionwise. The reaction mixture was stirred for 10 minutes, after which benzyl bromide (2.60 g, 15.2 mmol, 1.5 equiv.) was added. The reaction mixture was stirred at 23° C. for 16 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3×). 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 (heptane / EtOAc) to afford the desired 1-benzyl-2-bromo-1H-benzo[d]imidazole (2.55 g, 8.88 mmol, 88%) as an off-white solid. LCMS(ESI) m / z=287.1.

[0284] AA. 1-Benzyl-2-vinyl-1H-benzo[d]imidazole

[0285] [ka] 1-Benzyl-2-bromo-1H-benzo[d]imidazole (500 mg, 1.74 mmol, 1 equiv.), tributyl(vinyl)tin (590 μL, 1.92 mmol, 1.1 equiv.), and bis(triphenylphosphine)palladium(II) chloride (61.1 mg, 87.1 μmol, 5 mol%) were suspended in 1,4-dioxane (17 mL). After the reaction mixture was degassed with nitrogen for 5 minutes, the reaction mixture was heated to 110°C. After TLC showed complete conversion of sm (approximately 2 h), the reaction mixture was cooled to 23°C and filtered through a short pad of Celite. The filter cake was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / THF) to give the desired 1-benzyl-2-vinyl-1H-benzo[d]imidazole (230 mg, 982 μmol, 56%) as a slightly yellow gel. LCMS (ESI) m / z = 235.2. 1H NMR (400 MHz, DMSO) δ 7.66 - 7.60 (m, 1H), 7.58 - 7.53 (m, 1H), 7.34 - 7.28 (m, 2H), 7.27 - 7.23 (m, 1H), 7.23 - 7.17 (m, 2H), 7.14 - 7.10 (m, 2H), 7.08 - 7.01 (m, 1H), 6.43 (dd, J = 17.0, 2.1 Hz, 1H), 5.66 (dd, J = 10.9, 2.1 Hz, 1H), 5.61 (s, 2H) ppm.

[0286] BB. 2-Bromo-1-(3-methoxybenzyl)-1H-benzo[d]imidazole

[0287] [ka] Under an inert atmosphere, 2-bromo-1H-benzo[d]imidazole (2.00 g, 10.2 mmol, 1 equiv.) was dissolved in N,N-dimethylformamide (20 mL) at 23 °C to give a clear solution. Sodium hydride (60% Wt, 609 mg, 15.2 mmol, 1.5 equiv.) was added portionwise. The reaction mixture was stirred for 10 minutes, after which 1-(bromomethyl)-3-methoxybenzene (2.13 mL, 15.2 mmol, 1.5 equiv.) was added. The reaction mixture was stirred at 23 °C for 16 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (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 (heptane / EtOAc) to afford the desired 2-bromo-1-(3-methoxybenzyl)-1H-benzo[d]imidazole (1.43 g, 4.51 mmol, 44%) as an off-white solid. LCMS (ESI) m / z = 317.2. 1H NMR (400 MHz, DMSO) δ 7.69 - 7.56 (m, 2H), 7.32 - 7.20 (m, 3H), 6.87 (ddd, J = 8.2, 2.7, 0.9 Hz, 1H), 6.80 (t, J = 2.1 Hz, 1H), 6.68 (ddd, J = 7.6, 1.7, 0.9 Hz, 1H), 5.50 (s, 2H), 3.71 (s, 3H) ppm.

[0288] CC. 1-(3-Methoxybenzyl)-2-vinyl-1H-benzo[d]imidazole

[0289] [ka] 2-Bromo-1-(3-methoxybenzyl)-1H-benzo[d]imidazole (507 mg, 1.60 mmol, 1 equiv.), tributyl(vinyl)tin (514 μL, 1.76 mmol, 1.1 equiv.), and bis(triphenylphosphine)palladium(II) chloride (56.1 mg, 79.9 μmol, 5 mol%) were suspended in 1,4-dioxane (17 mL). After degassing the reaction mixture with nitrogen for 5 minutes, the reaction mixture was heated to 110°C. After TLC showed complete conversion of sm (approximately 2 h), the reaction mixture was cooled to 23°C and filtered through a short pad of Celite. The filter cake was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / THF) to give the desired 1-(3-methoxybenzyl)-2-vinyl-1H-benzo[d]imidazole (280 mg, 1.06 mmol, 66%) as a slightly yellow gel. LCMS (ESI) m / z = 265.2. 1H NMR (400 MHz, DMSO) δ 7.68 - 7.50 (m, 2H), 7.20 (tt, J = 4.7, 2.8 Hz, 3H), 7.06 (ddd, J = 17.0, 11.0, 1.1 Hz, 1H), 6.82 (dd, J = 8.4, 2.5 Hz, 1H), 6.71 (t, J = 2.0 Hz, 1H), 6.43 (dt, J = 17.0, 1.6 Hz, 1H), 5.66 (dt, J = 10.9, 1.6 Hz, 1H), 5.57 (s, 2H), 3.68 (d, J = 1.1 Hz, 3H) ppm.

[0290] DD. 1-Bromo-1-(3-chlorobenzyl)-1H-benzo[d]imidazole

[0291] [ka] Under an inert atmosphere, 2-bromo-1H-benzo[d]imidazole (2.00 g, 10.2 mmol, 1 equiv.) was dissolved in N,N-dimethylformamide (20 mL) at 23 °C to give a clear solution. Sodium hydride (60% Wt, 609 mg, 15.2 mmol, 1.5 equiv.) was added portionwise. The reaction mixture was stirred for 10 minutes, after which 1-(bromomethyl)-3-chlorobenzene (2.00 mL, 15.2 mmol, 1.5 equiv.) was added. The reaction mixture was stirred at 23 °C for 16 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (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 (heptane / EtOAc) to afford the desired 2-bromo-1-(3-chlorobenzyl)-1H-benzo[d]imidazole (2.57 g, 7.99 mmol, 79%) as an off-white solid. LCMS (ESI) m / z = 321.1. 1H NMR (400 MHz, DMSO) δ 7.69 - 7.57 (m, 2H), 7.39 - 7.33 (m, 2H), 7.31 - 7.19 (m, 3H), 7.10 - 7.01 (m, 1H), 5.54 (s, 2H) ppm.

[0292] EE. 1-(3-chlorobenzyl)-2-vinyl-1H-benzo[d]imidazole

[0293] [ka] 2-Bromo-1-(3-chlorobenzyl)-1H-benzo[d]imidazole (800 mg, 2.49 mmol, 1 equiv.), tributyl(vinyl)tin (800 μL, 2.74 mmol, 1.1 equiv.), and bis(triphenylphosphine)palladium(II) chloride (87.3 mg, 124 μmol, 5 mol%) were suspended in 1,4-dioxane (18 mL). After degassing the reaction mixture with nitrogen for 5 minutes, the reaction mixture was heated to 110°C. After TLC showed complete conversion of sm (approximately 2 h), the reaction mixture was cooled to 23°C and filtered through a short pad of Celite. The filter cake was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The crude material was purified by flash column chromatography (CH2Cl2 / THF) to give the desired 1-(3-chlorobenzyl)-2-vinyl-1H-benzo[d]imidazole (451 mg, 1.68 mmol, 68%) as a slightly yellow gel. 1H NMR (400 MHz, DMSO) δ 7.67 - 7.61 (m, 1H), 7.59 - 7.55 (m, 1H), 7.35 - 7.30 (m, 2H), 7.24 - 7.18 (m, 3H), 7.11 - 6.96 (m, 2H), 6.44 (dd, J = 17.0, 2.1 Hz, 1H), 5.68 (dd, J = 11.0, 2.1 Hz, 1H), 5.64 (s, 2H) ppm.

[0294] FF. 3-(benzyloxy)-N-(4-hydroxypyridin-3-yl)propanamide

[0295] [ka] To a solution of 3-aminopyridin-4-ol (3.06 g, 27.7 mmol, 1 equiv.) in DMF (80 mL) was added 3-(benzyloxy)propanoic acid (5.00 g, 27.7 mmol, 1 equiv.), triethylamine (5.62 g, 7.73 mL, 55.5 mmol, 2 equiv.), and HATU (12.7 g, 33.3 mmol, 1.2 equiv.). The reaction mixture was stirred at 23 °C for 16 h. The solution was diluted with water and extracted with ethyl acetate (3 ×). The combined organic phase was washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude oil was purified by flash column chromatography (CH2Cl2 / MeOH, 0-15% MeOH) to afford the desired 3-(benzyloxy)-N-(4-hydroxypyridin-3-yl)propanamide (6.78 g, 24.9 mmol, 90%) as a white foam. LCMS (ESI) m / z = 273.1. 1H NMR (400 MHz, DMSO) δ 9.33 (s, 1H), 8.82 (d, J = 1.5 Hz, 1H), 7.77 (dd, J = 7.0, 1.6 Hz, 1H), 7.39 - 7.31 (m, 4H), 7.29 - 7.21 (m, 1H), 6.43 (d, J = 7.0 Hz, 1H), 4.50 (s, 2H), 3.71 (t, J = 6.1 Hz, 2H), 2.74 (t, J = 6.1 Hz, 2H) ppm.

[0296] GG. 2-(2-(benzyloxy)ethyl)oxazolo[4,5-c]pyridine

[0297] [ka] To polymer-supported triphenylphosphine (polymer-supported, loading 1.6 mmol / g, 12.6 g) in dichloromethane (100 mL) was added hexachloroethane (2.97 g, 12.5 mmol, 1.25 equiv.) and triethylamine (5.07 g, 6.99 mL, 50.1 mmol, 5 equiv.). After stirring the suspension for 5 minutes, solid 3-(benzyloxy)-N-(4-hydroxypyridin-3-yl)propanamide (2.73 g, 10.0 mmol, 1 equiv.) was added. The mixture was stirred at rt for 1 hour. Additional hexachloroethane (1.78 g, 0.75 equiv.) and triethylamine (2.33 mL) were added, and stirring was continued at 23 °C for 16 hours. The reaction mixture was diluted with dichloromethane and acetonitrile and then filtered. The filtrate was concentrated under reduced pressure and then purified by flash column chromatography (heptane / EtOAc, 0 to 100% EtOAc) to afford the desired 2-(2-(benzyloxy)ethyl)oxazolo[4,5-c]pyridine (1.68 g, 6.61 mmol, 66%) as a yellow oil that crystallized on standing. LCMS (ESI) m / z = 255.2. 1H NMR (400 MHz, DMSO) δ 9.01 (d, J = 0.9 Hz, 1H), 8.54 (d, J = 5.5 Hz, 1H), 7.80 (dd, J = 5.5, 1.0 Hz, 1H), 7.35 - 7.22 (m, 5H), 4.53 (s, 2H), 3.93 (t, J = 6.3 Hz, 2H), 3.30 (t, J = 6.4 Hz, 2H) ppm.

[0298] HH. 2-(2-(benzyloxy)ethyl)oxazolo[4,5-c]pyridine 5-oxide

[0299] [ka] 2-(2-(benzyloxy)ethyl)oxazolo[4,5-c]pyridine (1.68 g, 6.61 mmol, 1 equiv.) was dissolved in dichloromethane (60 mL). The solution was cooled to 0 °C, and then mCPBA (75% Wt, 3.04 g, 13.2 mmol, 2 equiv.) was added. After 2 h, the ice bath was removed, and stirring was continued at 23 °C until LCMS showed complete conversion of sm. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was recrystallized in methanol. The solid was filtered off, washed with methanol, and dried under vacuum to give the desired 2-(2-(benzyloxy)ethyl)oxazolo[4,5-c]pyridine 5-oxide (1.30 g, 4.81 mmol, 73%) as an off-white solid. LCMS (ESI) m / z = 271.3. 1H NMR (400 MHz, DMSO) δ 8.79 (d, J = 1.8 Hz, 1H), 8.21 (dd, J = 7.0, 1.8 Hz, 1H), 7.81 (d, J = 7.0 Hz, 1H), 7.35 - 7.20 (m, 5H), 4.51 (s, 2H), 3.89 (t, J = 6.3 Hz, 2H), 3.27 (t, J = 6.3 Hz, 2H) ppm.

[0300] II. 2-(2-(benzyloxy)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine

[0301] [ka] To a solution of 2-(2-(benzyloxy)ethyl)oxazolo[4,5-c]pyridine 5-oxide (1.30 g, 4.81 mmol, 1 equiv.) and (3-fluoropyridin-2-yl)methanamine dihydrochloride (1.44 g, 7.21 mmol, 1.5 equiv.) in anhydrous tetrahydrofuran (50 mL) was added N,N-diisopropylethylamine (3.11 g, 4.19 mL, 24.0 mmol, 5 equiv.) and bromotri(pyrrolidin-1-yl)phosphonium(l2-fluoranyl)pentafluorophosphate (V) (3.37 g, 7.21 mmol, 1.5 equiv.). The reaction mixture was stirred at 23 °C until LC / MS showed complete consumption of sm. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CHCl / MeOH / NH 90 / 9 / 1) to give the desired 2-(2-(benzyloxy)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (1.76 g, 4.65 mmol, 97%). LCMS (ESI) m / z = 379.4. 1H NMR (400 MHz, DMSO) δ 8.34 (dt, J = 4.7, 1.5 Hz, 1H), 7.87 (d, J = 5.8 Hz, 1H), 7.67 (ddd, J = 10.1, 8.4, 1.3 Hz, 1H), 7.36 (dt, J = 8.6, 4.4 Hz, 1H), 7.33 - 7.23 (m, 5H), 7.19 (t, J = 5.6 Hz, 1H), 6.91 (d, J = 5.7 Hz, 1H), 4.83 (dd, J = 5.6, 1.7 Hz, 2H), 4.51 (s, 2H), 3.88 (t, J = 6.4 Hz, 2H), 3.22 (t, J = 6.4 Hz, 2H) ppm.

[0302] JJ. 2-(4-(((3-fluoropyridin-2-yl)methyl)amino)oxazolo[4,5-c]pyridin-2-yl)ethan-1-ol

[0303] [ka] 2-(2-(benzyloxy)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (500 mg, 1.32 mmol, 1 equiv.) was dissolved in dichloromethane (12 mL). The colorless solution was treated with boron tribromide dimethyl sulfide complex (1 M in dichloromethane, 3.96 mL, 3.96 mmol, 1 equiv.) in two portions (2 equiv. immediately + 1 equiv. after 30 min). The reaction mixture was stirred at 23 °C until TLC showed complete conversion of sm. The reaction mixture was quenched by slowly adding saturated aqueous sodium bicarbonate solution. The mixture was stirred for 30 min, and then the two phases were separated. The aqueous phase was extracted with dichloromethane (3 × ). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (CHCl / MeOH, MeOH 0–20%) to afford the desired 2-(4-(((3-fluoropyridin-2-yl)methyl)amino)oxazolo[4,5-c]pyridin-2-yl)ethan-1-ol (180 mg, 624 μmol, 47%) as a colorless oil that crystallized on standing. LCMS (ESI) m / z = 289.2. 1H NMR (400 MHz, DMSO) δ 8.37 (dt, J = 4.7, 1.5 Hz, 1H), 7.87 (d, J = 5.8 Hz, 1H), 7.69 (ddd, J = 10.3, 8.3, 1.3 Hz, 1H), 7.38 (dt, J = 8.6, 4.4 Hz, 1H), 7.20 (t, J = 5.6 Hz, 1H), 6.93 (d, J = 5.7 Hz, 1H), 4.93 (t, J = 5.5 Hz, 1H), 4.85 (dd, J = 5.7, 1.8 Hz, 2H), 3.87 (q, J = 6.1 Hz, 2H), 3.07 (t, J = 6.4 Hz, 2H) ppm.

[0304] KK. N-((3-fluoropyridin-2-yl)methyl)-2-(2-iodoethyl)oxazolo[4,5-c]pyridin-4-amine

[0305] [ka] Triphenylphosphine (1.11 g, 4.24 mmol, 1.3 equiv) was dissolved in dichloromethane (7 mL). Iodine (1.08 g, 4.24 mmol, 1.3 equiv) was added portionwise. After 10 min, imidazole (300 mg, 4.40 mmol, 1.35 equiv) was added. After an additional 10 min, the reaction mixture was cooled to 0 °C, and 2-(4-(((3-fluoropyridin-2-yl)methyl)amino)oxazolo[4,5-c]pyridin-2-yl)ethan-1-ol (940 mg, 1 equiv, 3.26 mmol) was added. After TLC showed complete conversion of sm, the reaction was quenched by the addition of saturated aqueous sodium thiosulfate solution. The reaction mixture was separated, and the aqueous phase was re-extracted with dichloromethane (3x). The combined organic phase was washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (heptane / Et0Ac) to give the desired N-((3-fluoropyridin-2-yl)methyl)-2-(2-iodoethyl)oxazolo[4,5-c]pyridin-4-amine (450 mg, 1.13 mmol, 35%) as a white solid. 1H NMR (400 MHz, DMSO) δ 8.35 (dt, J = 4.7, 1.5 Hz, 1H), 7.89 (d, J = 5.8 Hz, 1H), 7.68 (ddd, J = 10.1, 8.3, 1.3 Hz, 1H), 7.40 - 7.31 (m, 2H), 6.96 (d, J = 5.8 Hz, 1H), 4.85 (dd, J = 5.6, 1.8 Hz, 2H), 3.73 - 3.46 (m, 4H) ppm.

[0306] Example Compounds Example Compound No. 1: N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazolo[4,5-c]pyridin-4-amine

[0307] [ka] 2-(2-aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (303 mg, 1.05 mmol, 1 equiv.), 1-(2-methoxyethyl)-2-vinyl-1H-benzo[d]imidazole (213 mg, 1.05 mmol, 1 equiv.), and ammonium acetate (97.6 mg, 1.27 mmol, 1.2 equiv.) were suspended in acetonitrile (10 mL). The reaction mixture was heated to 50° C. for 24 h. The reaction mixture was dry-loaded onto silica and purified by flash column chromatography (CHCl / MeOH 0–20% MeOH) to afford N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazolo[4,5-c]pyridin-4-amine (205 mg, 419 μmol, 39.7%) as a brownish oil. LCMS (ESI) m / z = 490.8. 1 H NMR (400 MHz, DMSO) δ 8.36 (dt, J = 4.7, 1.5 Hz, 1H), 7.88 (d, J = 5.8 Hz, 1H), 7.69 (ddd, J = 10.3, 8.3, 1.3 Hz, 1H), 7.52 - 7.45 (m, 2H), 7.42 - 7.34 (m, 1H), 7.21 - 7.07 (m, 3H), 6.91 (d, J = 5.8 Hz, 1H), 4.85 (dd, J = 5.6, 1.7 Hz, 2H), 4.35 (t, J = 5.3 Hz, 2H), 3.61 (t, J = 5.2 Hz, 2H), 3.17 (s, 3H), 3.10 (d, J = 11.8 Hz, 6H), 3.02 (td, J = 6.1, 1.7 Hz, 2H) ppm.

[0308] Example Compound No. 2: 2-(2-((2-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine

[0309] [ka] 2-(2-aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (200 mg, 696 μmol, 1 equiv.), 1-(cyclopropylmethyl)-2-vinyl-1H-benzo[d]imidazole (138 mg, 696 μmol, 1 equiv.), and ammonium acetate (64.4 mg, 835 μmol, 1.2 equiv.) were suspended in acetonitrile (7 mL). The reaction mixture was heated to 50° C. for 24 hours. The reaction mixture was dry-loaded onto silica and purified by flash column chromatography (CHCl / MeOH 0–20% MeOH) to afford 2-(2-((2-(1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (132 mg, 272 μmol, 39%) as a brownish oil. LCMS (ESI) m / z = 486.5. 1H NMR (400 MHz, DMSO) δ 8.34 (dt, J = 4.7, 1.5 Hz, 1H), 7.86 (d, J = 5.7 Hz, 1H), 7.67 (ddd, J = 10.3, 8.3, 1.3 Hz, 1H), 7.52 - 7.44 (m, 2H), 7.36 (dt, J = 8.6, 4.4 Hz, 1H), 7.18 - 7.07 (m, 3H), 6.90 (d, J = 5.8 Hz, 1H), 4.83 (dd, J = 5.7, 1.8 Hz, 2H), 4.07 (d, J = 6.9 Hz, 2H), 3.09 (d, J = 6.0 Hz, 6H), 3.01 (td, J = 6.5, 1.6 Hz, 2H), 1.17 (tq, J = 9.8, 3.6 Hz, 1H), 0.49 - 0.34 (m, 4H) ppm.

[0310] Example Compound No. 3: N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(2-(2-methoxyethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazolo[4,5-c]pyridin-4-amine

[0311] [ka] 2-(2-aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (200 mg, 696 μmol, 1 equiv.), 1-(2-(2-methoxyethoxy)ethyl)-2-vinyl-1H-benzo[d]imidazole (171 mg, 696 μmol, 1 equiv.), and ammonium acetate (64.4 mg, 835 μmol, 1.2 equiv.) were suspended in acetonitrile (7 mL). The reaction mixture was heated to 50° C. for 24 hours. The reaction mixture was dry-loaded onto silica and purified by flash column chromatography (CHCl / MeOH 0–20% MeOH) to afford N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(2-(2-methoxyethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazolo[4,5-c]pyridin-4-amine (25 mg, 47 μmol, 7%) as a brownish oil. LCMS (ESI) m / z = 534.7. 1 H NMR (400 MHz, DMSO) δ 8.34 (dt, J = 4.7, 1.5 Hz, 1H), 7.87 (d, J = 5.8 Hz, 1H), 7.67 (ddd, J = 10.1, 8.4, 1.3 Hz, 1H), 7.48 (td, J = 7.7, 1.3 Hz, 2H), 7.36 (dt, J = 8.6, 4.5 Hz, 1H), 7.18 - 7.07 (m, 3H), 6.90 (d, J = 5.8 Hz, 1H), 4.83 (dd, J = 5.6, 1.8 Hz, 2H), 4.34 (t, J = 5.3 Hz, 2H), 3.68 (t, J = 5.3 Hz, 2H), 3.45 - 3.36 (m, 2H), 3.33 - 3.23 (m, 2H), 3.16 - 3.12 (m, 6H), 3.10 (s, 3H), 3.06 (t, J = 4.2 Hz, 3H) ppm.

[0312] Example Compound No. 4: N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(2-isopropoxyethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazolo[4,5-c]pyridin-4-amine

[0313] [ka] 2-(2-aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (200 mg, 1,696 μmol, 1 equiv.), 1-(2-isopropoxyethyl)-2-vinyl-1H-benzo[d]imidazole (160 mg, 696 μmol, 1 equiv.), and ammonium acetate (64.4 mg, 835 μmol, 1.2 equiv.) were suspended in acetonitrile (7 mL). The reaction mixture was heated to 50° C. for 24 hours. The reaction mixture was dry-loaded onto silica and purified by flash column chromatography (CHCl / MeOH 0–20% MeOH) to afford N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(2-isopropoxyethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazolo[4,5-c]pyridin-4-amine (88 mg, 0.17 mmol, 24%) as a dark yellow oil. LCMS (ESI) m / z = 518.5. 1H NMR (400 MHz, DMSO) δ 8.34 (dt, J = 4.7, 1.5 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.67 (ddd, J = 9.9, 8.3, 1.3 Hz, 1H), 7.49 - 7.44 (m, 2H), 7.36 (dt, J = 8.6, 4.4 Hz, 1H), 7.17 - 7.06 (m, 3H), 6.89 (d, J = 5.8 Hz, 1H), 4.83 (dd, J = 5.6, 1.7 Hz, 2H), 4.30 (t, J = 5.3 Hz, 2H), 3.61 (t, J = 5.3 Hz, 2H), 3.38 (p, J = 6.1 Hz, 1H), 3.12 - 3.00 (m, 8H), 0.90 (d, J = 6.0 Hz, 6H) ppm.

[0314] Example Compound No. 5: N-((3-fluoropyridin-2-yl)methyl)-2-(1-(2-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)ethyl)azetidin-3-yl)oxazolo[4,5-c]pyridin-4-amine

[0315] [ka] 2-(azetidin-3-yl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (100 mg, 334 μmol, 1 equiv.), 1-(2-methoxyethyl)-2-vinyl-1H-benzo[d]imidazole (67.6 mg, 334 μmol, 1 equiv.), and ammonium acetate (30.9 mg, 401 μmol, 1.2 equiv.) were suspended in acetonitrile (3 mL). The reaction mixture was heated to 50° C. for 24 hours. The reaction mixture was dry-loaded onto silica and purified by flash column chromatography (CHCl / MeOH 0–20% MeOH) to afford the desired N-((3-fluoropyridin-2-yl)methyl)-2-(1-(2-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)ethyl)azetidin-3-yl)oxazolo[4,5-c]pyridin-4-amine (60 mg, 0.12 mmol, 36%) as a colorless oil. LCMS (ESI) m / z = 502.6. 1 H NMR (400 MHz, DMSO) δ 8.34 (dt, J = 4.7, 1.5 Hz, 1H), 7.87 (d, J = 5.8 Hz, 1H), 7.56 - 7.44 (m, 2H), 7.40 - 7.31 (m, 1H), 7.23 (t, J = 5.6 Hz, 1H), 7.19 - 7.09 (m, 2H), 6.92 (d, J = 5.8 Hz, 1H), 4.83 (dd, J = 5.6, 1.7 Hz, 2H), 4.37 (t, J = 5.2 Hz, 2H), 3.93 (p, J = 7.3 Hz, 1H), 3.66 (t, J = 7.5 Hz, 2H), 3.62 (t, J = 5.2 Hz, 2H), 3.44 (t, J = 6.9 Hz, 2H), 3.17 (s, 3H), 2.99 - 2.85 (m, 4H) ppm.

[0316] Example Compound No. 6: N-((3-fluoropyridin-2-yl)methyl)-2-(1-(2-(1-(2-(2-methoxyethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)ethyl)azetidin-3-yl)oxazolo[4,5-c]pyridin-4-amine

[0317] [ka] 2-(azetidin-3-yl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (100 mg, 334 μmol, 1 equiv.), 1-(2-(2-methoxyethoxy)ethyl)-2-vinyl-1H-benzo[d]imidazole (82.3 mg, 334 μmol, 1 equiv.), and ammonium acetate (30.9 mg, 401 μmol, 1.2 equiv.) were suspended in acetonitrile (3 mL). The reaction mixture was heated to 50° C. for 24 hours. The reaction mixture was dry-loaded onto silica and then purified by flash column chromatography (CHCl / MeOH 0–20% MeOH) to afford the desired N-((3-fluoropyridin-2-yl)methyl)-2-(1-(2-(1-(2-(2-methoxyethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)ethyl)azetidin-3-yl)oxazolo[4,5-c]pyridin-4-amine (57 mg, 0.10 mmol, 31%) as a colorless oil. LCMS (ESI) m / z = 546.7. 1H NMR (400 MHz, DMSO) δ 8.34 (dt, J = 4.7, 1.5 Hz, 1H), 7.57 - 7.45 (m, 2H), 7.36 (dt, J = 8.6, 4.4 Hz, 1H), 7.23 (t, J = 5.6 Hz, 1H), 7.18 - 7.09 (m, 2H), 6.92 (d, J = 5.7 Hz, 1H), 4.83 (dd, J = 5.6, 1.8 Hz, 2H), 4.37 (t, J = 5.2 Hz, 2H), 3.94 (p, J = 7.3 Hz, 1H), 3.73 - 3.64 (m, 4H), 3.50 - 3.39 (m, 4H), 3.12 (s, 3H), 3.01 - 2.87 (m, 4H) ppm. -CH2- signals are obscured by H2O signals.

[0318] Example Compound No. 7: N-((3-fluoropyridin-2-yl)methyl)-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)oxazolo[4,5-c]pyridin-4-amine

[0319] [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 (51.8 mg, 148 μmol, 1 equivalent) and sodium hydroxide (63 mg, 30% Wt, 474 μmol, 3.2 equivalents) were dissolved in water (1.5 mL). N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazolo[4,5-c]pyridin-4-amine (40.0 mg, 148 μmol, 1 equivalent) was added, and the reaction mixture was heated to 80°C for 48 hours. After the reaction mixture was cooled to 23°C, the pH was adjusted to pH = 7 using 3N hydrochloric acid. The reaction mixture was concentrated and purified by flash column chromatography (CHCl / MeOH 0→20% MeOH) followed by an SCX-column (1-7N NH in MeOH) to afford the desired N-((3-fluoropyridin-2-yl)methyl)-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)oxazolo[4,5-c]pyridin-4-amine (15 mg, 27 μmol, 19%) as a pale yellow solid. LCMS (ESI) m / z = 548.6. 1 H NMR (400 MHz, DMSO) δ 8.20 (dt, J = 4.7, 1.5 Hz, 1H), 7.87 (d, J = 5.5 Hz, 1H), 7.73 (ddd, J = 9.9, 8.3, 1.3 Hz, 1H), 7.36 (dt, J = 8.6, 4.4 Hz, 1H), 6.94 (d, J = 12.8 Hz, 2H), 6.56 (d, J = 5.5 Hz, 1H), 5.63 (d, J = 1.7 Hz, 2H), 4.27 - 4.15 (m, 8H), 3.15 (s, 3H), 3.05 - 2.92 (m, 6H), 2.90 (d, J = 5.9 Hz, 2H) ppm.

[0320] Example Compound No. 8: N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(2-morpholinoethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazolo[4,5-c]pyridin-4-amine

[0321] [ka] 2-(2-aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (150 mg, 522 μmol, 1 equiv.), 4-(2-(2-vinyl-1H-benzo[d]imidazol-1-yl)ethyl)morpholine (134 mg, 522 μmol, 1 equiv.), and ammonium acetate (48.3 mg, 627 μmol, 1.2 equiv.) were suspended in acetonitrile (5 mL). The reaction mixture was heated to 50° C. overnight. The reaction mixture was concentrated onto silica and then purified by flash column chromatography (CHCl / MeOH 0–20% MeOH) to afford N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(2-morpholinoethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazolo[4,5-c]pyridin-4-amine (32.3 mg, 59.3 μmol, 11.4%) as a yellowish solid. LCMS (ESI) m / z = 545.1. 1H NMR (400 MHz, DMSO) δ 8.34 (ddt, J = 4.8, 3.1, 1.5 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.67 (ddd, J = 10.0, 8.3, 1.3 Hz, 1H), 7.49 - 7.43 (m, 2H), 7.36 (dt, J = 8.5, 4.4 Hz, 1H), 7.17 - 7.07 (m, 3H), 6.89 (d, J = 5.7 Hz, 1H), 4.83 (dd, J = 5.6, 1.7 Hz, 2H), 4.25 (t, J = 6.5 Hz, 2H), 3.49 (t, J = 4.6 Hz, 4H), 3.11 - 3.04 (m, 6H), 3.04 - 2.98 (m, 2H), 2.56 (t, J = 6.5 Hz, 2H), 2.38 (dd, J = 5.6, 3.4 Hz, 4H) ppm.

[0322] Example Compound No. 9: 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)oxazolo[4,5-c]pyridin-4-amine

[0323] [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 (163 mg, 370 μmol, 1 equivalent) and sodium hydroxide (207 mg, 30% Wt, 1.55 mmol, 4.2 equivalents) were dissolved in water (3 mL). N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazolo[4,5-c]pyridin-4-amine (100 mg, 370 μmol, 1 equivalent) was added, and the reaction mixture was heated to 80°C for 48 hours. After the reaction mixture was cooled to 23°C, the pH was adjusted to pH = 7 using 3N hydrochloric acid. The reaction mixture was concentrated and purified by reverse-phase column chromatography (HO / (CHCN / MeOH)+0.1% TFA, 95 / %→5 / 95) followed by SCX-column (1-7N NH in MeOH) to afford the desired 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)oxazolo[4,5-c]pyridin-4-amine (25.0 mg, 41.5 μmol, 11.2%) as a yellow solid. LCMS (ESI) m / z = 603.6. 1 H NMR (400 MHz, DMSO) δ 8.20 (dt, J = 4.7, 1.5 Hz, 1H), 7.86 (d, J = 5.4 Hz, 1H), 7.77 - 7.69 (m, 1H), 7.36 (s, 1H), 7.04 - 6.89 (m, 3H), 6.56 (d, J = 5.5 Hz, 1H), 5.62 (d, J = 1.6 Hz, 2H), 4.23 - 4.18 (m, 4H), 4.13 (t, J = 6.7 Hz, 2H), 3.49 (t, J = 4.6 Hz, 4H), 3.02 - 2.94 (m, 6H), 2.93 - 2.88 (m, 2H), 2.54 - 2.49 (m, 2H), 2.39-2.34 (m, 4H) ppm.

[0324] Example Compound No. 10 2-(2-((2-(1-benzyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine

[0325] [ka] 2-(2-aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (100 mg, 348 μmol, 1 equiv.), 1-benzyl-2-vinyl-1H-benzo[d]imidazole (92.0 mg, 348 μmol, 1 equiv.), and ammonium acetate (32.2 mg, 418 μmol, 1.2 equiv.) were suspended in acetonitrile (2.5 mL). The reaction mixture was heated to 50° C. overnight. The reaction mixture was concentrated onto silica and then purified by flash column chromatography (CHCl / MeOH 0–20% MeOH) to afford 2-(2-((2-(1-benzyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (35.1 mg, 67.3 μmol, 19%) as a brownish oil. LCMS (ESI) m / z = 522.5. 1H NMR (400 MHz, DMSO) δ 8.33 (dt, J = 4.7, 1.5 Hz, 1H), 7.86 (d, J = 5.7 Hz, 1H), 7.67 (ddd, J = 10.0, 8.3, 1.3 Hz, 1H), 7.57 - 7.49 (m, 1H), 7.47 - 7.40 (m, 1H), 7.40 - 7.33 (m, 1H), 7.31 - 7.22 (m, 3H), 7.19 - 7.11 (m, 3H), 7.11 - 7.05 (m, 2H), 6.89 (d, J = 5.8 Hz, 1H), 5.47 (s, 2H), 4.83 (dd, J = 5.6, 1.7 Hz, 2H), 3.14 - 3.06 (m, 6H), 3.01 (t, J = 6.4 Hz, 2H) ppm.

[0326] Example Compound No. 11 N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(3-methoxybenzyl)-1H-benzo[d]-imidazol-2-yl)ethyl)amino)ethyl)oxazolo[4,5-c]pyridin-4-amine

[0327] [ka] 2-(2-aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (100 mg, 348 μmol, 1 equiv.), 1-(2-methoxybenzyl)-2-vinyl-1H-benzo[d]imidazole (81.6 mg, 348 μmol, 1 equiv.), and ammonium acetate (32.2 mg, 418 μmol, 1.2 equiv.) were suspended in acetonitrile (2.5 mL). The reaction mixture was heated to 50° C. overnight. The reaction mixture was concentrated onto silica and then purified by flash column chromatography (CHCl / MeOH 0-20% MeOH) to afford N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(2-methoxybenzyl)-1H-benzo[d]-imidazol-2-yl)ethyl)amino)ethyl)oxazolo[4,5-c]pyridin-4-amine (52.2 mg, 92.8 μmol, 27%) as a brownish oil. LCMS (ESI) m / z = 552.6. 1 H NMR (400 MHz, DMSO) δ 8.33 (dt, J = 4.7, 1.5 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.67 (ddd, J = 10.1, 8.3, 1.3 Hz, 1H), 7.55 - 7.49 (m, 1H), 7.46 - 7.40 (m, 1H), 7.36 (dt, J = 8.6, 4.4 Hz, 1H), 7.22 - 7.09 (m, 4H), 6.89 (d, J = 5.8 Hz, 1H), 6.81 (ddd, J = 8.3, 2.7, 0.9 Hz, 1H), 6.67 (t, J = 2.0 Hz, 1H), 6.60 - 6.55 (m, 1H), 5.43 (s, 2H), 4.83 (dd, J = 5.6, 1.7 Hz, 2H), 3.66 (s, 3H), 3.11 - 3.04 (m, 6H), 3.00 (t, J = 6.3 Hz, 2H) ppm.

[0328] Example Compound No. 12: 2-(2-((2-(1-(3-chlorobenzyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine

[0329] [ka] 2-(2-aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (175 mg, 609 μmol, 1 equiv.), 1-(3-chlorobenzyl)-2-vinyl-1H-benzo[d]imidazole (164 mg, 609 μmol, 1 equiv.), and ammonium acetate (56.3 mg, 731 μmol, 1.2 equiv.) were suspended in acetonitrile (5 mL). The reaction mixture was heated to 50° C. overnight. The reaction mixture was concentrated onto silica and then purified by flash column chromatography (CHCl / MeOH 0-20% MeOH) to afford 2-(2-((2-(1-(3-chlorobenzyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (65.1 mg, 117 μmol, 19.2%) as a brownish oil. LCMS (ESI) m / z = 557.2. 1H NMR (400 MHz, DMSO) δ 8.33 (dt, J = 4.7, 1.5 Hz, 1H), 7.87 (d, J = 5.8 Hz, 1H), 7.67 (ddd, J = 10.0, 8.3, 1.3 Hz, 1H), 7.56 - 7.51 (m, 1H), 7.49 - 7.40 (m, 1H), 7.40 - 7.33 (m, 1H), 7.34 - 7.30 (m, 2H), 7.22 - 7.09 (m, 4H), 7.04 - 6.96 (m, 1H), 6.90 (d, J = 5.8 Hz, 1H), 5.50 (s, 2H), 4.84 (dd, J = 5.6, 1.7 Hz, 2H), 3.22 - 3.11 (m, 6H), 3.05 (t, J = 6.9 Hz, 2H) ppm.

[0330] Example Compound No. 13: 2-(2-((2-(1-(cyclopropylmethyl)-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)oxazolo[4,5-c]pyridin-4-amine

[0331] [ka] N-((3-fluoropyridin-2-yl)methyl)-2-(2-iodoethyl)oxazolo[4,5-c]pyridin-4-amine (125 mg, 314 μmol, 1 equiv.) and 2-(1-(cyclopropylmethyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethan-1-amine dihydrochloride (109 mg, 314 μmol, 1 equiv.) were suspended in acetonitrile (2 mL). N,N-Diisopropyl-ethylamine (130 mg, 175 μL, 1.00 mmol, 3.2 equiv.) was added, and the reaction mixture was heated to 60 °C for 48 h. The reaction mixture was concentrated and then purified by reverse-phase column chromatography (HO / (CHCN / MeOH)+0.1% TFA, 95 / % a 5 / 95) followed by an SCX-column (1-7N NH in MeOH) to afford the desired 2-(2-((2-(1-(cyclopropylmethyl)-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)oxazolo[4,5-c]pyridin-4-amine (33.4 mg, 61.4 μmol, 20%) as a yellow solid. LCMS (ESI) m / z = 544.6. 1H NMR (400 MHz, DMSO) δ 8.33 (s, 1H), 7.85 (d, J = 5.7 Hz, 1H), 7.67 (ddd, J = 10.1, 8.3, 1.3 Hz, 1H), 7.36 (dt, J = 8.6, 4.4 Hz, 1H), 7.14 (t, J = 5.6 Hz, 1H), 7.03 - 6.96 (m, 2H), 6.91 - 6.86 (m, 2H), 4.83 (dd, J = 5.6, 1.7 Hz, 2H), 4.20 (tt, J = 5.3, 2.7 Hz, 4H), 3.96 (t, J = 7.7 Hz, 2H), 3.07 - 3.03 (m, 4H), 2.99 (q, J = 6.8 Hz, 2H), 2.91 (t, J = 6.4 Hz, 2H), 1.17 - 1.07 (m, 1H), 0.43 (ddd, J = 8.2, 6.0, 4.1 Hz, 2H), 0.34 (ddt, J = 9.8, 6.4, 3.1 Hz, 2H) ppm.

[0332] Example Compound No. 14: 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)oxazolo[4,5-c]pyridin-4-amine

[0333] [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 (148 mg, 370 μmol, 1 equiv.) and sodium hydroxide (30% Wt, 207 mg, 1.55 mmol, 4.2 equiv.) were dissolved in water (4 mL). N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazolo[4,5-c]pyridin-4-amine (100 mg, 370 μmol, 1 equiv.) was added, and the reaction mixture was heated to 80°C for 48 hours. After the reaction mixture was cooled to rt, the pH was adjusted to pH = 7 using 3N hydrochloric acid. The reaction mixture was concentrated and purified by flash column chromatography (CHCl / MeOH, 0→20% MeOH) followed by an SCX-column (1-7N NH in MeOH) to afford the desired 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)oxazolo[4,5-c]pyridin-4-amine (65.0 mg, 116 μmol, 31%) as a pale yellow solid. LCMS (ESI) m / z = 561.7. 1 H NMR (400 MHz, DMSO) δ 8.20 (dd, J = 4.7, 1.4 Hz, 1H), 7.81 (d, J = 5.5 Hz, 1H), 7.72 (ddd, J = 9.9, 8.3, 1.3 Hz, 1H), 7.36 (dt, J = 8.6, 4.4 Hz, 1H), 6.93 (s, 1H), 6.92 (s, 1H), 6.52 (d, J = 5.5 Hz, 1H), 5.63 - 5.55 (m, 2H), 4.25 - 4.15 (m, 4H), 4.10 (t, J = 6.7 Hz, 2H), 2.97 (td, J = 8.6, 3.5 Hz, 6H), 2.89 (t, J = 6.4 Hz, 2H), 2.48 - 2.42 (m, 2H), 2.14 (s, 6H) ppm.

[0334] Example Compound No. 15: N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazolo[4,5-c]pyridin-4-amine

[0335] [ka] 2-(1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine (93.4 mg, 370 μmol, 1 equivalent) and sodium hydroxide (30% Wt, 59.2 mg, 444 μmol, 1.2 equivalent) were dissolved in water (4 mL). N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazolo[4,5-c]pyridin-4-amine (100 mg, 370 μmol, 1 equivalent) was added, and the reaction mixture was heated to 80° C. for 48 hours. After the reaction mixture was cooled to rt, the pH was adjusted to pH=7 using 3N hydrochloric acid. The reaction mixture was concentrated and purified by flash column chromatography (CHCl / MeOH, 0→20% MeOH) followed by an SCX-column (1-7N NH in MeOH) to afford the desired N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazolo[4,5-c]pyridin-4-amine (32 mg, 61 μmol, 17%) as a pale yellow solid. LCMS (ESI) m / z = 523.5. 1H NMR (400 MHz, DMSO) δ 8.47 (dd, J = 5.0, 1.7 Hz, 1H), 8.20 (d, J = 4.7 Hz, 1H), 7.93 (d, J = 5.5 Hz, 1H), 7.81 - 7.71 (m, 2H), 7.51 (td, J = 6.2, 2.4 Hz, 2H), 7.38 (dt, J = 8.6, 4.4 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.28 (dd, J = 7.6, 4.9 Hz, 1H), 7.15 (tt, J = 7.3, 5.6 Hz, 2H), 6.65 (d, J = 5.5 Hz, 1H), 5.67 (s, 2H), 5.58 (s, 2H), 3.57 - 3.50 (m, 4H), 3.38 (t, J = 7.0 Hz, 2H), 3.30 (t, J = 6.9 Hz, 2H) ppm.

[0336] Example Compound No. 16: N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-phenethyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazolo[4,5-c]pyridin-4-amine

[0337] [ka] 2-(1-Phenethyl-1H-benzo[d]imidazol-2-yl)ethan-1-amine hydrochloride (112 mg, 370 μmol, 1 equiv.) and sodium hydroxide (30% Wt, 109 mg, 814 μmol, 2.2 equiv.) were dissolved in water (4 mL). N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazolo[4,5-c]pyridin-4-amine (100 mg, 370 μmol, 1 equiv.) was added, and the reaction mixture was heated to 80° C. for 48 hours. After the reaction mixture was cooled to room temperature, the pH was adjusted to pH=7 using 3N hydrochloric acid. The reaction mixture was concentrated and purified by flash column chromatography (CHCl / MeOH, 0→20% MeOH) followed by an SCX-column (1-7N NH in MeOH) to give the desired N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-phenethyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazolo[4,5-c]pyridin-4-amine (68.2 mg, 127 μmol, 34%) as a pale yellow solid. LCMS (ESI) m / z = 536.7. 1 H NMR (400 MHz, DMSO) δ 8.33 (dt, J = 4.7, 1.5 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.67 (ddd, J = 10.1, 8.3, 1.4 Hz, 1H), 7.47 (ddd, J = 7.0, 4.8, 1.4 Hz, 2H), 7.36 (dt, J = 8.6, 4.5 Hz, 1H), 7.24 - 7.09 (m, 6H), 7.07 - 7.04 (m, 2H), 6.89 (d, J = 5.8 Hz, 1H), 4.83 (dd, J = 5.7, 1.7Hz, 2H), 4.36 (t, J = 7.2 Hz, 2H), 3.07 - 2.94 (m, 6H), 2.87 (t, J = 7.0 Hz, 2H), 2.65 (t, J = 6.9 Hz, 2H) ppm.

[0338] Example Compound No. 17: N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazolo[4,5-c]pyridin-4-amine

[0339] [ka] 2-(1-Phenyl-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (115 mg, 370 μmol, 1 equiv.) and sodium hydroxide (30% Wt, 158 mg, 1.18 mmol, 3.2 equiv.) were dissolved in water (4 mL). N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazolo[4,5-c]pyridin-4-amine (100 mg, 370 μmol, 1 equiv.) was added, and the reaction mixture was heated to 80° C. for 48 hours. After cooling the reaction mixture to room temperature, the pH was adjusted to pH=7 using 3N hydrochloric acid. The reaction mixture was concentrated and purified by flash column chromatography (CHCl / MeOH, 0→20% MeOH) followed by an SCX-column (1-7N NH in MeOH) to afford the desired N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazolo[4,5-c]pyridin-4-amine (53.2 mg, 105 μmol, 28%) as a pale yellow solid. LCMS (ESI) m / z = 508.5 ppm. 1H NMR (400 MHz, DMSO) δ 8.33 (dt, J = 4.7, 1.5 Hz, 1H), 7.67 (ddd, J = 10.0, 8.3, 1.3 Hz, 1H), 7.63 - 7.57 (m, 3H), 7.56 - 7.48 (m, 3H), 7.36 (dt, J = 8.6, 4.4 Hz, 1H), 7.22 - 7.12 (m, 3H), 7.08 - 7.03 (m, 1H), 6.87 (d, J = 5.8 Hz, 1H), 4.82 (dd, J = 5.6, 1.7 Hz, 2H), 3.04 - 2.90 (m, 6H), 2.84 (t, J = 6.6 Hz, 2H) ppm.

[0340] Example Compound No. 18: 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)oxazolo[4,5-c]pyridin-4-amine

[0341] [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 (168 mg, 370 μmol, 1 equivalent) and sodium hydroxide (30% Wt, 207 mg, 1.55 mmol, 4.2 equivalents) were dissolved in water (4 mL). N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazolo[4,5-c]pyridin-4-amine (100 mg, 370 μmol, 1 equivalent) was added, and the reaction mixture was heated to 80°C for 48 hours. After cooling the reaction mixture to rt, the pH was adjusted to pH = 7 using 3N hydrochloric acid. The reaction mixture was concentrated and purified by flash column chromatography (CHCl / MeOH, 0→20% MeOH) followed by an SCX-column (1-7N NH in MeOH) to afford the desired 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)oxazolo[4,5-c]pyridin-4-amine (48.1 mg, 78.1 μmol, 21%) as a yellowish solid. LCMS (ESI) m / z = 616.8 ppm. 1 H NMR (400 MHz, DMSO) δ 8.21 (dt, J = 4.7, 1.5 Hz, 1H), 7.78 - 7.67 (m, 2H), 7.36 (dt, J = 8.7, 4.4 Hz, 1H), 6.94-6.93 (m, 2H), 6.44 (d, J = 5.6 Hz, 1H), 5.59 (s, 2H), 4.23 - 4.17 (m, 4H), 4.11 (t, J = 6.5 Hz, 2H), 2.94 (ddt, J = 22.5, 14.3, 7.0 Hz, 8H), 2.43 - 2.31 (m, 4H), 2.27 - 2.18 (m, 4H), 2.07 (s, 3H) ppm. -CH2- is masked by the DMSO solvent signal.

[0342] Example Compound No. 19: 2-(2-((2-(1-ethyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine

[0343] [ka] 2-(1-Ethyl-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (97.0 mg, 370 μmol, 1 equiv.) and sodium hydroxide (30% Wt, 158 mg, 1.18 mmol, 3.2 equiv.) were dissolved in water (4 mL). N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazolo[4,5-c]pyridin-4-amine (100 mg, 370 μmol, 1 equiv.) was added, and the reaction mixture was heated to 80° C. for 48 hours. After the reaction mixture was cooled to room temperature, the pH was adjusted to pH=7 using 3N hydrochloric acid. The reaction mixture was concentrated and purified by flash column chromatography (CHCl / MeOH, 0→20% MeOH) followed by an SCX-column (1-7N NH in MeOH) to afford the desired 2-(2-((2-(1-ethyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (74.0 mg, 161 μmol, 44%) as an off-white solid. LCMS (ESI) m / z = 460.5. 1H NMR (400 MHz, DMSO) δ 8.34 (dt, J = 4.7, 1.5 Hz, 1H), 7.89 (d, J = 5.8 Hz, 1H), 7.68 (ddd, J = 10.0, 8.3, 1.3 Hz, 1H), 7.50 (t, J = 8.2 Hz, 2H), 7.37 (dt, J = 8.6, 4.4 Hz, 1H), 7.21 - 7.15 (m, 2H), 7.12 (td, J = 7.6, 1.2 Hz, 1H), 6.93 (d, J = 5.8 Hz, 1H), 4.84 (dd, J = 5.6, 1.8 Hz, 2H), 4.22 (q, J = 7.2 Hz, 2H), 3.41 - 3.25 (m, 8H), 3.17 (t, J = 7.0 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H) ppm.

[0344] Example Compound No. 20: 2-(2-((2-(1-(2-(dimethylamino)ethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine

[0345] [ka] 2-(2-(2-aminoethyl)-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethan-1-amine trihydrochloride (240 mg, 703 μmol, 1 equiv.) and sodium hydroxide (30% Wt, 394 mg, 2.95 mmol, 4.2 equiv.) were dissolved in water (4 mL). N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazolo[4,5-c]pyridin-4-amine (190 mg, 703 μmol, 1 equiv.) was added, and the reaction mixture was heated to 80° C. for 48 hours. After the reaction mixture was cooled to rt, the pH was adjusted to pH=7 using 3N hydrochloric acid. The reaction mixture was concentrated and purified by RP18 flash column chromatography (water / methanol+0.1% NH, 5% to 95% methanol) to afford the desired 2-(2-((2-(1-(2-(dimethylamino)ethyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (34.0 mg, 67.6 μmol, 10%) as a pale yellow solid. LCMS (ESI) m / z = 503.2. 1 H NMR (400 MHz, DMSO) δ 8.16 (d, J = 4.6 Hz, 1H), 7.88 (d, J = 5.5 Hz, 1H), 7.73 (t, J = 9.3 Hz, 1H), 7.54 (dd, J = 18.3, 7.8 Hz, 2H), 7.34 (dt, J = 8.7, 4.4 Hz, 1H), 7.19 (dt, J = 20.8, 7.3 Hz, 2H), 6.60 (d, J = 5.5 Hz, 1H), 5.64 (s, 2H), 4.35 (t, J = 6.7 Hz, 2H), 4.08 (s, 2H), 3.05 (p, J = 5.4 Hz, 4H), 2.61 (t, J = 6.6 Hz, 2H), 2.19 (s, 6H) ppm.

[0346] Example Compound No. 21: 2-(2-((2-(1-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)oxazolo[4,5-c]pyridin-4-amine formate

[0347] [ka] 2-(1-Ethyl-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)ethan-1-amine dihydrochloride (118 mg, 370 μmol, 1 equivalent) and sodium hydroxide (30% Wt, 158 mg, 1.18 mmol, 3.2 equivalents) were dissolved in water (4 mL). N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazolo[4,5-c]pyridin-4-amine (100 mg, 370 μmol, 1 equivalent) was added, and the reaction mixture was heated to 80°C for 48 hours. After cooling to room temperature, the pH was adjusted to pH = 7 using 3N hydrochloric acid. The reaction mixture was concentrated and purified by preparative RP18 HPLC (water / acetonitrile / methanol with 0.1% formic acid, 5→95% acetonitrile / methanol) to afford the desired 2-(2-((2-(1-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)oxazolo[4,5-c]pyridin-4-amineformate (23.6 mg, 45.6 μmol, 12%) as a white solid. LCMS(ESI) m / z = 536.6. 1H NMR (400 MHz, DMSO) δ 8.34 (dt, J = 4.7, 1.5 Hz, 1H), 8.20 (s, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.67 (ddd, J = 10.1, 8.3, 1.3 Hz, 1H), 7.36 (dt, J = 8.6, 4.4 Hz, 1H), 6.99 - 6.87 (m, 3H), 4.83 (dd, J = 5.6, 1.7 Hz, 2H), 4.20 (tq, J = 6.9, 3.0 Hz, 4H), 4.08 (q, J = 7.1 Hz, 2H), 3.05 (t, J = 6.9 Hz, 2H), 2.93 (t, J = 6.9 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H) ppm.

[0348] Example Compound No. 22: N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazolo[4,5-c]pyridin-4-amine formate

[0349] [ka] 2-(1-Methyl-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (91.8 mg, 370 μmol, 1 equiv.) and sodium hydroxide (30% Wt, 158 mg, 1.18 mmol, 3.2 equiv.) were dissolved in water (4 mL). N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazolo[4,5-c]pyridin-4-amine (100 mg, 370 μmol, 1 equiv.) was added, and the reaction mixture was heated to 80° C. for 48 hours. After the reaction mixture was cooled to room temperature, the pH was adjusted to pH=7 using 3N hydrochloric acid. The reaction mixture was concentrated and purified by preparative RP18 HPLC (water / acetonitrile / methanol with 0.1% formic acid, 5→95% acetonitrile / methanol) to afford the desired N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazolo[4,5-c]pyridin-4-amineformate (38.8 mg, 45.6 μmol, 24%) as a white solid. LCMS(ESI) m / z = 446.7. 1 H NMR (400 MHz, DMSO) δ 8.34 (dt, J = 4.7, 1.5 Hz, 1H), 8.20 (s, 1H), 7.86 (d, J = 5.7 Hz, 1H), 7.67 (ddd, J = 10.0, 8.4, 1.3 Hz, 1H), 7.50 - 7.41 (m, 2H), 7.36 (dt, J = 8.6, 4.4 Hz, 1H), 7.16 (ddd, J = 7.9, 5.2, 1.3 Hz, 2H), 7.10 (td, J = 7.5, 1.3 Hz, 1H), 6.90 (d, J = 5.7 Hz, 1H), 4.83 (dd, J = 5.6, 1.8 Hz, 2H), 3.71 (s, 3H), 3.16 - 2.96 (m, 8H) ppm.

[0350] Example Compound No. 23: 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)oxazolo[4,5-c]pyridin-4-amine formate

[0351] [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 (136 mg, 370 μmol, 1 equiv.) and sodium hydroxide (30% Wt, 158 mg, 1.18 mmol, 3.2 equiv.) were dissolved in water (4 mL). N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazolo[4,5-c]pyridin-4-amine (100 mg, 370 μmol, 1 equiv.) was added, and the reaction mixture was heated to 80°C for 48 hours. After cooling to room temperature, the pH was adjusted to pH = 7 using 3N hydrochloric acid. The reaction mixture was concentrated and purified by preparative RP18 HPLC (water / acetonitrile / methanol with 0.1% formic acid, 5→95% acetonitrile / methanol) to afford the desired 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)oxazolo[4,5-c]pyridin-4-amineformate (40.2 mg, 71.1 μmol, 19%) as a white solid. LCMS(ESI) m / z = 566.8. 1H NMR (400 MHz, DMSO) δ 8.33 (dt, J = 4.7, 1.5 Hz, 1H), 8.18 (s, 1H), 7.85 (d, J = 5.8 Hz, 1H), 7.67 (ddd, J = 10.1, 8.3, 1.3 Hz, 1H), 7.58 (dd, J = 8.3, 6.7 Hz, 2H), 7.54 - 7.48 (m, 1H), 7.47 - 7.43 (m, 2H), 7.36 (dt, J = 8.6, 4.4 Hz, 1H), 7.13 (t, J = 5.6 Hz, 1H), 7.03 (s, 1H), 6.88 (d, J = 5.7 Hz, 1H), 6.44 (s, 1H), 4.82 (dd, J = 5.6, 1.7 Hz, 2H), 4.33 - 4.19 (m, 4H), 3.03 - 2.89 (m, 6H), 2.79 (t, J = 7.0 Hz, 2H) ppm.

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 - C that forms 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, or O; However, X １ and X ２ One of the is N, Y is N or 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】 (wherein * indicates a bonding position; R １ and R ２ is independent, - hydrogen, - 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.) represents; B is the following groups (b-1), (b-2) and (b-3): 【Chemistry 3】 (wherein * indicates a bonding position; R ３ teeth, - Linear or branched C １ ~C ３ - alkyl, - Linear or branched C １ ~C ３ -haloalkyl, - Linear or branched C １ ~C ３ -alkoxy, 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 may optionally be Halogen ○ C １ ~C ３ - alkyl, ○ C １ ~C ３ -haloalkyl, and ○ C １ ~C ３ -alkoxy and optionally substituted with 1, 2, or 3 substituents independently selected from: R ４ teeth, - hydrogen, - 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, unsubstituted or substituted 5- or 6-membered heteroaryl represents Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Halogen, ○ C １ ~C ３ -alkoxy, ○ C ６ -cycloalkyloxy, Carboxyl, Aminocarbonyl, mono- or di-alkylaminocarbonyl, ○ -NH ２ , 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 are optionally 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 substituted with 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 groups as substituents of the monoalkyl chain may optionally be selected from the group consisting of halogen, C １ ~C ３ -Alkyl and C １ ~C ３ -haloalkyl. represents one of: However, in formula (b-1), R ３ is absent, or R ３ is methyl, R ４ does not represent hydrogen; 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 has 0, 1, 2 or 3 substituents independently selected from and pharmaceutically acceptable salts thereof.

2. In the definition of the group according to formula (b-1), R ３ is absent, or R ３ is a straight chain or branched C １ ~C ３ - alkyl, linear or branched C １ ~C ３ -haloalkyl, or straight or branched C １ ~C ３ -alkoxy, R ４ 2. The compound of claim 1, wherein does not represent hydrogen.

3. R ４ 3. The compound according to claim 1 or 2, wherein hydrogen is excluded from the definition of

4. Compounds according to formula (IB) 【Chemistry 4】 (In the formula, l is an integer of 1 or 2; m and n are independently an integer of 1, 2, or 3.

4. The compound of claim 1, 2 or 3, selected from the group consisting of:

5. 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. 3- to 6-membered cycloalkyl, or - 5- or 6-membered heterocyclyl, - 6-membered aryl represents Alkyl, cycloalkyl, heterocyclyl and aryl are optionally ○ C １ ~C ３ -alkoxy, Carboxyl, Aminocarbonyl, mono- or di-alkylaminocarbonyl, ○ -NH ２ , amino groups, including mono- and dialkylamino; 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 The substituted aryl, heteroaryl and bicyclic heteroaryl groups are optionally 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 substituted with 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 optionally be selected from the group consisting of halogen, C １ ~C ３ -Alkyl and C １ ~C ３ -optionally substituted with 1, 2 or 3 substituents independently selected from haloalkyl; 5. A compound according to any one of claims 1 to 4 and pharmaceutically acceptable salts thereof.

6. A is a group (a-1) 【Chemistry 5】 (wherein * indicates a bonding position; R １ and R ２ is independent, - hydrogen, - 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.) represents; B is the following groups (b-1), (b-2) and (b-3): 【Chemistry 6】 (wherein * indicates a bonding position; R ３ teeth, - Linear or branched C １ ~C ３ - alkyl, - Linear or branched C １ ~C ３ -haloalkyl, - Linear or branched C １ ~C ３ -alkoxy, 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 The substituted aryl, heteroaryl and bicyclic heteroaryl groups are optionally Halogen ○ C １ ~C ３ - alkyl, ○ C １ ~C ３ -haloalkyl, and ○ C １ ~C ３ -alkoxy and optionally substituted with 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, - 6-membered aryl represents Alkyl, cycloalkyl, heterocyclyl and aryl are optionally ○ C １ ~C ３ -alkoxy, Carboxyl, 〇 Aminocarbonyl, mono- or di-alkylaminocarbonyl, ○-NH ２ , amino groups, including mono- and dialkylamino; 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 The substituted aryl, heteroaryl and bicyclic heteroaryl groups are optionally 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 substituted with 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 groups as substituents of the monoalkyl chain may optionally be selected from the group consisting of 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 6. A compound according to any one of claims 1 to 5 and pharmaceutically acceptable salts thereof.

7. A is a group (a-1) 【Chemistry 7】 (wherein * indicates a bonding position; R １ and R ２ is independent, - hydrogen, - 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.) represents; B is the following groups (b-1), (b-2) and (b-3): 【Chemistry 8】 (wherein * indicates a bonding position; R ３ teeth, - Linear or branched C １ ~C ３ - alkyl, - Linear or branched C １ ~C ３ -haloalkyl, - Linear or branched C １ ~C ３ -alkoxy, 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 The substituted phenyl, heteroaryl and bicyclic heteroaryl groups are optionally Halogen ○ C １ ~C ３ - alkyl, ○ C １ ~C ３ -haloalkyl, and ○ C １ ~C ３ -alkoxy and optionally substituted with 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. - 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 optionally Halogen, ○ C １ ~C ３ -alkoxy, ○ C ６ -cycloalkyloxy, Carboxyl, 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 The substituted heterocyclyl, aryl, heteroaryl and bicyclic heteroaryl groups are optionally - halogens, ・C １ ~C ３ - alkyl, ・C １ ~C ３ -haloalkyl, ・C １ ~C ３ -alkoxy, aminocarbonyl, and Mono-alkylaminocarbonyl and optionally substituted with 1, 2, or 3 substituents independently selected from Monoalkylaminocarbonyl groups may have further substituents on the monoalkyl chain selected from halogen-substituted 5- or 6-membered heteroaryls. 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 having 0 or 1 substituent selected from 7. A compound according to any one of claims 1 to 6 and pharmaceutically acceptable salts thereof.

8. Formula (IC), (ID), (IE), (IF) or (IG) 【Chemistry 9】 wherein the remaining substituents have the meanings defined in any one of claims 1 to 7.

8. The compound of claim 1, wherein the compound is a pharmaceutically acceptable salt thereof.

9. The B group is a (b-1) or (b-2) group; preferably the following structure: 【Chemistry 10】 Preferably 【Chemistry 11】 is a (b-2) group having the formula: and / or The A group has the following structure: 【Chemistry 12】 Preferably 【Chemistry 13】 having 9. A compound according to any one of claims 1 to 8 and pharmaceutically acceptable salts thereof.

10. 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 １ ~C ３ represents an alkyl group; and / or the bicyclic heteroaryl group is selected from benzimidazolyl groups, 10. A compound according to any one of claims 1 to 9 and pharmaceutically acceptable salts thereof.

11. 【Table 1】 11. The compound of any one of claims 1 to 10, selected from: and pharmaceutically acceptable salts thereof.

12. 12. A compound according to any one of claims 1 to 11, and pharmaceutically acceptable salts thereof in the form of hydrates and solvates, and polymorphs of said salts, hydrates and solvates.

13. 13. A compound according to any one of claims 1 to 12 for use as a pharmaceutical.

14. - for use as a ferroportin inhibitor or in inhibiting iron transport mediated by ferroportin, and / or - for use in increasing iron levels or increasing iron absorption and / or in the prevention and / or treatment of iron metabolism disorders leading to iron overload, 14. A compound according to any one of claims 1 to 13.

15. - for use in the prevention and / or treatment of diseases associated with or caused by elevated iron levels, increased iron absorption or iron overload selected from thalassemia, including alpha-thalassemia, beta-thalassemia and delta-thalassemia, hemoglobinopathies, hemoglobin E disease, hemoglobin H disease, hemochromatosis, hemolytic anemia, including in particular sickle cell anemia, or congenital dyserythropoietic anemia; and / or - for use in the prevention and / or treatment of diseases associated with ineffective erythropoiesis, such as myelodysplastic syndromes (MDS, myelodysplasia), polycythemia vera and congenital dyserythropoietic anemia; and / or - for use in the prevention and / or treatment of diseases caused by a decrease in hepcidin levels; and / or - for use in the prevention and / or treatment of infections caused by pathogenic microorganisms, such as the bacterium Vibrio vulnificus, in adjuvant therapy by limiting the amount of iron available to said pathogenic microorganisms; and / or - for use in the prevention and / or treatment of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, by limiting the deposition or accumulation of iron in tissues or cells; and / or - for use in the prevention and / or treatment of the formation of radicals, reactive oxygen species (ROS) and oxidative stress; and / or - for use in the prevention and / or treatment of cardiac, hepatic and endocrine damage caused by iron overload; and / or - inflammation caused by excess iron, 15. A compound according to any one of claims 1 to 14.

16. one or more of the compounds defined in any one of claims 1 to 12; one or more compounds selected from pharmaceutical carriers, adjuvants and solvents; and / or at least one additional pharmaceutically active compound, preferably selected from active compounds for the prevention and treatment of iron overload, thalassemia or hemochromatosis, active compounds for the prevention and treatment of neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease and related conditions, and iron chelating compounds; and a pharmaceutical composition comprising:

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

18. 13. A compound as defined in any one of claims 1 to 12 for use in combination therapy comprising co-administration of a compound as defined in any one of claims 1 to 12 with at least one further pharmaceutically active compound, The co-administration of the combination therapy may be performed in a fixed dose combination therapy by co-administration of a compound as defined in any one of claims 1 to 12 and at least one additional pharmaceutically active compound in a fixed dose formulation; or The co-administration of the combination therapy may be performed in a free dose combination therapy by co-administration of the compound defined in any one of claims 1 to 12 and the 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 distributed over a period of time; The one or more additional pharmaceutically active compounds are preferably active compounds for reducing iron overload, including Tmprss6-ASO, iron chelators, curcumin, SSP-004184, deferithrin, deferasirox, deferoxamine and / or deferiprone; and / or antioxidants, such as n-acetylcysteine; antidiabetic drugs, such as GLP-1 receptor agonists; antibiotics, such as vancomycin (Van) or tobramycin; anti-inflammatory drugs, such as anti-inflammatory drugs, ... the pharmaceutically active compound may be selected from: drugs for treating neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease; anti-cancer drugs; anti-fungal drugs; drugs for treating neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, including dopamine agonists, such as levodopa; anti-viral drugs, such as interferon-α or ribavirin; immunosuppressants, such as cyclosporin A or cyclosporin A derivatives; iron supplements; vitamin supplements; erythropoiesis stimulators; anti-inflammatory biological agents; anti-thrombolytic drugs; statins; hypertensive drugs; and inotropic compounds.

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