Bicyclic iron transporter inhibitors

Abstract

The present invention relates to novel compounds of general formula (I-A) as defined in the present application and pharmaceutical compositions comprising them and their use as medicaments, in particular as inhibitors of iron transporters, more particularly for the prevention and / or treatment of diseases caused by hepcidin deficiency or iron metabolism disorders leading to elevated iron levels, increased iron absorption and / or iron overload. # imgabs0 #

Description

[0001] Introduction

[0002] The present invention relates to novel compounds of general formula (I-A):

[0003]

[0004] and their pharmaceutically acceptable salts. The compounds of general formula (I-A) of the present invention act as ferroportin inhibitors. The novel compounds are particularly suitable for use in medicaments for 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 (I-A) of the present invention are also particularly suitable for the prevention and / or treatment of iron overload, including thalassemia, sickle cell disease and hemochromatosis, and for the prevention and / or treatment of diseases associated with or caused by elevated iron levels, increased iron absorption or iron overload.

[0005] Background and prior art

[0006] Iron is an essential trace element for almost all organisms, especially in relation to growth and blood formation. In this context, the balance of iron metabolism mainly depends on the level of iron recovered from the hemoglobin of senescent red blood cells and the absorption of dietary iron in the duodenum. The released iron is absorbed through the intestine, especially through specific transport systems (DMT-1, ferroportin), transferred into the blood circulation and thus transported to the corresponding tissues and organs (transferrin, transferrin receptor).

[0007] The mammalian body is unable to actively excrete iron. Iron metabolism is largely controlled by hepcidin, a peptide hormone produced in the liver that releases iron through macrophages, hepatocytes and enterocytes. Hepcidin acts on iron absorption in the intestine and placenta and iron release in the reticuloendothelial system. In the body, hepcidin is synthesized in the liver from so-called prohepcidin, which is encoded by the HAMP gene. The formation of hepcidin is directly related to the body's iron level, i.e., if the body obtains sufficient iron and oxygen, more hepcidin is formed; if the iron and oxygen levels are low, or in the case of increased erythropoiesis, less hepcidin is formed. In small intestinal mucosal cells and macrophages, hepcidin binds to ferroportin, which normally transports phagocytosed and recycled iron from the interior of the cell into the blood.

[0008] Ferroportin is a transmembrane protein composed of 571 amino acids, formed in the liver, spleen, kidney, heart, intestine and placenta. In particular, ferroportin is located in the basolateral membrane of enterocytes. Ferroportin bound in this way thus serves to export iron into the blood. In this context, ferroportin most probably transports iron in the form of Fe 2+transferrin in the form of. If hepcidin binds to transferrin, transferrin is transported into the interior of the cell, where it is degraded, thus almost completely blocking the release of recycled iron from the cell by phagocytosis. If transferrin is inactivated, for example by hepcidin, so that it cannot export the iron stored in mucosal cells, the stored iron is lost through feces as the cells are shed naturally. Therefore, when transferrin is inactivated or inhibited, for example by hepcidin, the intestinal absorption of iron is reduced. In addition, transferrin is significantly located in the reticuloendothelial system (RES), to which macrophages also belong. On the other hand, if the serum iron level decreases, the production of hepcidin in hepatocytes of the liver decreases, resulting in a decrease in the released hepcidin, and correspondingly a decrease in the inactivated transferrin, thus allowing more stored iron to be transported into the serum.

[0009] It can be seen that the hepcidin-transferrin system directly regulates iron metabolism, so disorders of the hepcidin regulatory mechanism will directly affect the body's iron metabolism. In principle, the hepcidin-transferrin regulatory mechanism works through the following two opposite principles:

[0010] On the one hand, an increase in hepcidin leads to the inactivation of transferrin, thus blocking the release of stored iron from the cell into the serum, thereby reducing the serum iron level. In pathological conditions, a decrease in the serum iron level leads to a decrease in the hemoglobin level and a reduction in erythropoiesis, and thus to iron deficiency anemia.

[0011] On the other hand, a decrease in hepcidin leads to an increase in active transferrin, thus allowing an increase in the release of stored iron and an increase in iron uptake, for example from food, thereby increasing the serum iron level. In pathological conditions, an increase in iron level leads to iron overload.

[0012] Iron overload states and diseases are characterized by excessive iron levels. Among them, the problem stems from excessive serum iron levels, leading to non-transferrin-bound iron (NTBI). NTBI is rapidly taken up non-specifically by organs, resulting in the accumulation of iron in tissues and organs. Iron overload can lead to many diseases and adverse medical conditions, including heart, liver, and endocrine damage. In addition, the accumulation of iron in the brain has been observed in patients with neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. As a particularly harmful aspect of excessive free iron, the adverse formation of free radicals must be mentioned. In particular, iron(II) ions catalyze the formation of reactive oxygen species (ROS) (especially through the Fenton reaction). These ROS cause damage to DNA, lipids, proteins, and carbohydrates, having a profound impact on cells, tissues, and organs, which is known in the literature and described as oxidative stress.

[0013] In addition to conventional methods of treating iron overload by removing iron from the body, such as using chelating agents, such as deferoxamine (also known as deferoxamine B, N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl}-N-hydroxysuccinamide or ), deferasirox ( 4-(3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzoic acid) and deferiprone ( 3-hydroxy-1,2-dimethylpyridin-4(1H)-one), compounds that act as hepcidin agonists or have an inhibitory or supportive effect on biochemical regulatory pathways in iron metabolism, such as hepcidin-mimetic peptides, have also been described. The treatment method is based on directly acting on the disordered iron metabolism pathway through the main regulator hepcidin by providing a hepcidin mimetic or hepcidin agonist, that is, as a hepcidin substitute or supplement. This method is based on the principle of treating iron overload, that is, too high serum iron levels, by inhibiting ferroportin through the hepcidin inactivation mechanism, thereby blocking excessive iron absorption.

[0014] Ferroportin inhibitors and their preparation methods have been described in WO2017 / 068089, WO2017 / 068090, WO2021 / 191202, WO2022 / 223689 and WO2023 / 046664. In addition, International Application WO2018 / 192973 describes the preparation and crystallization of various specific salts of the selected ferroportin inhibitors described therein and in WO2017 / 068089 and WO2017 / 068090. International Applications WO2021 / 013771, WO2021 / 013772, WO2021 / 078889 and WO2022 / 157185 relate to the use of the selected ferroportin inhibitors described in the above applications in specific medical uses, such as for the treatment of transfusion-dependent thalassemia, the treatment of acute kidney injury, the treatment of sickle cell disease and the treatment of myelodysplastic syndromes.

[0015] WO2020 / 123850A1 describes other ferroportin inhibitors with a broadly defined central heteroaryl bicyclic ring structure and various possible substituents. The compounds of the present invention relate to selected ferroportin inhibitors having a selected central heteroaryl bicyclic ring structure and specific selected substituents on the terminal groups "A" and "B".

[0016] Object of the Invention

[0017] One object of the present invention is to provide new therapeutically effective compounds which can be used for the prevention and treatment of iron metabolism disorders associated with elevated iron levels, such as in particular effective therapies for iron overload. In another object, the new compounds exhibit high efficacy, few side effects, low toxicity, good bioavailability and compatibility in the indications of the present invention. In addition, compared with known iron chelating compounds, these new compounds should be suitable for preventing the occurrence of elevated iron levels, thereby preventing related diseases, rather than removing excess iron from the body when iron overload has already occurred. In another object, the new compounds should have a defined structure (stoichiometry) and should be preparable by a simple synthetic process, exhibiting lower sensitivity and higher long-term efficacy compared to known biomolecular compounds such as antibodies.

[0018] This object is achieved by the development of new compounds as defined herein, such as in particular compounds according to formula (I-A) and (I-B), which have been found to act as ferroportin inhibitors. Thus, the new compounds are suitable for inhibiting iron transport and can thus be effectively used for the prevention and treatment of iron metabolism disorders associated with elevated iron levels, such as in particular iron overload, as well as for the prevention and treatment of diseases caused by hepcidin deficiency, diseases related to or caused by elevated iron levels or iron overload, and diseases related to ineffective hematopoiesis. DETAILED DESCRIPTION OF THE INVENTION

[0020] The inventors have found that specific compounds having the general structural formula (I-A) or (I-B) as defined herein act as ferroportin inhibitors, thereby effectively inhibiting iron transport and are thus particularly suitable for use as medicaments, in particular for the treatment and / or prevention of diseases caused by hepcidin deficiency, diseases related to ineffective hematopoiesis or iron metabolism disorders leading to elevated iron levels, such as in particular iron overload conditions, such as in particular thalassemia and hemochromatosis. Very particularly, the new compounds have been shown to be suitable for the treatment of thalassemia and hemochromatosis. Very particularly, the new compounds have also been shown to be suitable for the treatment of diseases caused by pathological low hepcidin levels and for inhibiting iron transport. In particular, the new compounds described herein exhibit good metabolic stability and good bioavailability, which makes them particularly suitable as pharmaceutical compounds.

[0021] Accordingly, the present invention relates to new compounds of general formula (I-A)

[0022]

[0023] wherein

[0024] l is an integer of 1 or 2;

[0025] L 1 and L 2Each represents a linking group containing 1 to 7 carbon atoms and is independently selected from

[0026] - a straight-chain C1-C3-alkyl–[CH2] m – or –[CH2] n –, where m and n are each independently an integer of 1, 2 or 3,

[0027] - a branched C1-C4-alkyl, and

[0028] - a C3-C6-cycloalkyl that forms a ring with the attached nitrogen atom;

[0029] X 1 is N, S or O; and

[0030] X 2 is N, S or O; provided that X 1 and X 2 one of them is N;

[0031] and wherein

[0032] Y is N or CR 5 ;

[0033] wherein

[0034] R 5 represents

[0035] - H,

[0036] - halogen,

[0037] - a straight-chain or branched C1-C3-alkyl, or

[0038] - a straight-chain or branched C1-C3-haloalkyl;

[0039] A represents the group (a-1)

[0040]

[0041] where * represents the bonding position;

[0042] R 1 and R 2 independently represent

[0043] - hydrogen,

[0044] - halogen,

[0045] - a straight-chain or branched C1-C3-alkyl,

[0046] - a straight-chain or branched C1-C3-haloalkyl, or

[0047] - a straight-chain or branched C1-C3-alkoxy;

[0048] B represents one of the following groups (b-1), (b-2) and (b-3)

[0049]

[0050] where * represents the bonding position;

[0051] R 3 represents 0, 1, 2 or 3 substituents independently selected from

[0052] - straight-chain or branched C1-C3-alkyl,

[0053] - straight-chain or branched C1-C3-haloalkyl,

[0054] - straight-chain or branched C1-C3-alkoxy,

[0055] - unsubstituted or substituted 6-membered aryl,

[0056] - unsubstituted or substituted 5- or 6-membered heteroaryl,

[0057] - unsubstituted or substituted bicyclic heteroaryl,

[0058] - unsubstituted or substituted 3- to 6-membered cycloalkyl,

[0059] - unsubstituted or substituted 5- or 6-membered heterocyclic group,

[0060] - unsubstituted or substituted 5- or 6-membered heterocycloalkyl,

[0061] - unsubstituted or substituted 6-membered arylalkynyl, or

[0062] - unsubstituted or substituted 5- or 6-membered heteroarylalkynyl,

[0063] wherein the substituted aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl, heterocyclic group, heterocycloalkyl, arylalkynyl or heteroarylalkynyl may optionally be substituted by 1, 2 or 3 substituents independently selected from the following

[0064] ○ halogen,

[0065] ○ C1-C3-alkyl,

[0066] ○ C1-C3-haloalkyl, and

[0067] ○ C1-C3-alkoxy;

[0068] R 4 represents

[0069] - hydrogen,

[0070] - unsubstituted or substituted straight-chain or branched C1-C6-alkyl,

[0071] -Dialkyl ether group [R 6 (CH2) x -O-(CH2) y -]

[0072] wherein R 6 represents a C1-C3-alkoxy group, and

[0073] wherein x and y independently represent an integer of 1, 2 or 3,

[0074] -unsubstituted or substituted 3- to 6-membered cycloalkyl group,

[0075] -unsubstituted or substituted 5- or 6-membered heterocyclic group, or

[0076] -unsubstituted or substituted 6-membered aryl group,

[0077] -unsubstituted or substituted 5- or 6-membered heteroaryl group,

[0078] wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group may optionally be substituted by 1 or 2 substituents independently selected from the following

[0079] ○ Halogen,

[0080] ○ C1-C3-alkoxy group,

[0081] ○ C6-cycloalkyloxy group,

[0082] ○ Carboxyl group,

[0083] ○ Aminocarbonyl group,

[0084] ○ Monoalkylaminocarbonyl or dialkylaminocarbonyl group,

[0085] ○ Amino group, including -NH2, monoalkylamino and dialkylamino,

[0086] ○ Unsubstituted or substituted 3- to 6-membered cycloalkyl group,

[0087] ○ Unsubstituted or substituted 5- or 6-membered heterocyclic group,

[0088] ○ Unsubstituted or substituted 6-membered aryl group,

[0089] ○ Unsubstituted or substituted 5- or 6-membered heteroaryl group, and

[0090] ○ Unsubstituted or substituted bicyclic heteroaryl group,

[0091] wherein the substituted cycloalkyl group, heterocyclic group, aryl group, heteroaryl group and bicyclic heteroaryl group may optionally be substituted by 1, 2 or 3 substituents independently selected from the following

[0092] ■ Hydroxyl group,

[0093] ■ Cyano,

[0094] ■ Halogen,

[0095] ■ C1-C3-alkyl,

[0096] ■ C1-C3-haloalkyl,

[0097] ■ C1-C3-alkoxy,

[0098] ■ Carboxyl,

[0099] ■ Amino (-NH2), monoalkylamino or dialkylamino,

[0100] ■ Aminocarbonyl, and

[0101] ■ Monoalkylaminocarbonyl or dialkylaminocarbonyl,

[0102] wherein the monoalkylamino and monoalkylaminocarbonyl may further bear substituents on the monoalkyl chain, and the substituents are selected from

[0103] ● C1-C3-alkoxy,

[0104] ● Unsubstituted or substituted 6-membered aryl, and

[0105] ● Unsubstituted or substituted 5- or 6-membered heteroaryl,

[0106] wherein the substituted aryl or heteroaryl as a substituent on the monoalkyl chain may optionally be substituted by 1, 2 or 3 substituents independently selected from halogen, C1-C3-alkyl and C1-C3-haloalkyl;

[0107] provided that in formula (b-1), when R 3 is absent or when R 3 is methyl, R 4 does not represent hydrogen;

[0108] In formula (b-2) and (b-3), one of D1, D2 and D3 is present and represents

[0109] -Fused 6-membered aryl ring,

[0110] -Fused 5- or 6-membered heteroaryl ring,

[0111] -Fused 5- or 6-membered cycloalkyl ring, or

[0112] -Fused 5- or 6-membered heterocyclic ring;

[0113] And the groups (b-2) and (b-3) bear 0, 1, 2 or 3 substituents, and the substituents are independently selected from

[0114] -Halogen,

[0115] - a straight-chain or branched C1-C3-alkyl group,

[0116] - a straight-chain or branched C1-C3-haloalkyl group,

[0117] - a straight-chain or branched C1-C3-alkoxy group;

[0118] and pharmaceutically acceptable salts thereof.

[0119] In one aspect of the present invention, the compound is characterized by having a selected central bicyclic heterocycle and having a nitrogen-linked substituent R in the benzimidazolyl group of the terminal group B 4 , i.e., forming an "N-substituted" cyclic group B.

[0120] In a particularly preferred aspect, such an "N-substituted" compound is characterized in that, in formula (I-A), the substituent R 4 represents:

[0121] - an unsubstituted or substituted straight-chain or branched C1-C6-alkyl group,

[0122] - a dialkyl ether group [R 6 (CH2) x -O-(CH2) y -]

[0123] wherein R 6 represents a C1-C3-alkoxy group, and

[0124] wherein x and y independently represent an integer of 1, 2 or 3,

[0125] - an unsubstituted or substituted 3- to 6-membered cycloalkyl group,

[0126] - an unsubstituted or substituted 5- or 6-membered heterocyclic group,

[0127] - an unsubstituted or substituted 6-membered aryl group, or

[0128] - an unsubstituted or substituted 5- or 6-membered heteroaryl group,

[0129] wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally be substituted by 1 or 2 substituents independently selected from the following

[0130] ○ halogen,

[0131] ○ C1-C3-alkoxy group,

[0132] ○ C6-cycloalkyloxy group,

[0133] ○ carboxyl group,

[0134] ○ aminocarbonyl,

[0135] ○ Monoalkylaminocarbonyl or dialkylaminocarbonyl,

[0136] ○ Amino group, including -NH2, monoalkylamino and dialkylamino,

[0137] ○ Unsubstituted or substituted 3- to 6-membered cycloalkyl,

[0138] ○ Unsubstituted or substituted 5- or 6-membered heterocyclic group,

[0139] ○ Unsubstituted or substituted 6-membered aryl,

[0140] ○ Unsubstituted or substituted 5- or 6-membered heteroaryl, and

[0141] ○ Unsubstituted or substituted bicyclic heteroaryl,

[0142] Wherein, the substituted cycloalkyl, heterocyclic group, aryl, heteroaryl and bicyclic heteroaryl may optionally be substituted by 1, 2 or 3 substituents independently selected from the following

[0143] ■ Hydroxyl group,

[0144] ■ Cyano group,

[0145] ■ Halogen,

[0146] ■ C1-C3-alkyl,

[0147] ■ C1-C3-haloalkyl,

[0148] ■ C1-C3-alkoxy,

[0149] ■ Carboxyl group,

[0150] ■ Amino (-NH2) or monoalkylamino or dialkylamino,

[0151] ■ Aminocarbonyl, and

[0152] ■ Monoalkylaminocarbonyl or dialkylaminocarbonyl,

[0153] Wherein, monoalkylamino and monoalkylaminocarbonyl may further bear a substituent on the monoalkyl chain, and the substituent is selected from

[0154] ● C1-C3-alkoxy,

[0155] ● Unsubstituted or substituted 6-membered aryl, and

[0156] ● Unsubstituted or substituted 5- or 6-membered heteroaryl,

[0157] Among them, the substituted aryl or heteroaryl as a monoalkyl chain substituent may optionally be substituted by 1, 2 or 3 substituents independently selected from halogen, C1-C3-alkyl and C1-C3-haloalkyl. More preferably, the substituent R 4 is selected from the substituents shown at the corresponding positions in the following examples.

[0158] On the other hand, the compounds of the present invention are characterized by having a selected central bicyclic heterocycle and the group B contains at least 3 rings. Among them, the group B may represent a ring system of at least 3 fused rings, and each fused ring may have the structure defined herein. Embodiments of the group B having at least three rings include compounds in which the group B is represented by the group (b-1), and the group (b-1) bears a substituent R in a cyclic structure 3 , that is, R 3 does not represent hydrogen, but is (substituted or unsubstituted) aryl, heteroaryl, cycloalkyl or heterocyclic ring, or a fused bicyclic ring system, including a benzene ring bearing a fused cycloalkyl or heterocyclic ring defined herein, which may be connected by a direct chemical bond or a C1-C3-alkyl chain or an alkynyl chain defined herein. This means that the expression "the group B contains at least 3 rings" is not limited to a fused tricyclic ring system.

[0159] Therefore, the compounds of the present invention can also be represented by the above formula (I-A), wherein in the group definition according to formula (b-1), when R 3 is absent or when R 3 has the definition as described above, including R 3 is not a substituent in a cyclic structure, but a "chain-like substituent", that is, when selected from a straight-chain or branched C1-C3-alkyl, straight-chain or branched C1-C3-haloalkyl, or straight-chain or branched C1-C3-alkoxy as defined herein, R 4 does not represent hydrogen (but an N-linked substituent).

[0160] In a preferred aspect, the compounds of the present invention are represented by the above formula (I-A), wherein R 4 is not hydrogen, that is, hydrogen is excluded. This means that, more preferably, the substituent R 4 is a group defined in any of the embodiments other than hydrogen as described herein.

[0161] In another preferred aspect, the compounds of the present invention are represented by the above formula (I-A), wherein, in the group definition according to formula (b-1), R 4 does not represent hydrogen (but an N-linked substituent), and R 3 is selected from the substituents having a cyclic structure defined above.

[0162] Another aspect of the present invention relates to a compound of formula (I-A) as defined herein represented by the following formula (I-B)

[0163]

[0164] wherein

[0165] l is an integer of 1 or 2; and

[0166] m and n are independently integers of 1, 2 or 3.

[0167] Term Definitions

[0168] The term "substituted" means that one or more hydrogen atoms on a specified atom or group are replaced by a selected specified group, provided that the normal valence of the specified atom is not exceeded in the given situation.

[0169] The terms "optionally substituted", "optional substituent" or "possible substituent" mean that the number of substituents can be equal to zero or not equal to zero. Unless otherwise specified, an optionally substituted group can be substituted with as many optional substituents as possible, simply by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Generally, the number of optional substituents (if present) can be 1, 2, 3, 4 or 5, especially 1, 2 or 3.

[0170] If used herein, the term "one or more", for example in the definition of the substituents of the compounds of general formulas (I-A) and (I-B) of the present invention, means "1, 2, 3, 4 or 5, especially 1, 2, 3 or 4, more especially 1, 2 or 3, even more especially 1 or 2".

[0171] When used in the claims or the specification, the term "comprising" or "containing" includes "consisting of".

[0172] If any item in this specification is referred to as "as described herein" or "as defined herein (anywhere)", this means that it can be mentioned anywhere in this specification or has the meaning defined anywhere in this specification.

[0173] The terms used in the claims and the specification have the following meanings:

[0174] "Halogen" or "halogen atom" means a fluorine, chlorine, bromine or iodine atom, especially a fluorine, chlorine or bromine atom, preferably chlorine or fluorine, further preferably bromine or fluorine, more preferably fluorine.

[0175] The term "C1-C6-alkyl" refers to a straight-chain or branched-chain saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl or hexyl. Methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl are preferred. More preferred are straight-chain or branched-chain "C1-C3-alkyls", such as especially methyl, ethyl, n-propyl and isopropyl. Preferred unsubstituted alkyls are selected from methyl and ethyl.

[0176] The C1-C6-alkyl or C1-C6-alkyl group may optionally be substituted by 1 or 2 substituents, preferably by 1 substituent. In this case, the substituted alkyl is preferably a substituted C1-C3-alkyl (i.e., substituted C1-, C2- or C3-alkyl), more preferably substituted methyl or ethyl. Such optional substituents are preferably selected from: halogen (forming a halogen-substituted C1-C3-alkyl as defined below, also referred to herein as "C1-C3-haloalkyl"), such as preferably difluoroalkyl or trifluoroalkyl, C1-C3-alkoxy, such as preferably methoxy, cycloalkoxy, such as preferably C6-cycloalkyloxy (cyclohexyloxy), carboxyl [-(C=O)OH], aminocarbonyl [NH2(C=O)-], monoalkylaminocarbonyl or dialkylaminocarbonyl, such as preferably methylaminocarbonyl [CH3NH(C=O)-] or dimethylaminocarbonyl [(CH3)2N(C=O)-], amino groups containing -NH2, monoalkylamino and dialkylamino, such as preferably monomethylamino or dimethylamino, 3- to 6-membered cycloalkyls containing 3, 4, 5 or 6 carbon atoms (also referred to as C3-C6-cycloalkyls), such as preferably cyclopropyl and cyclohexyl, unsubstituted or substituted 5- or 6-membered heterocyclic groups, such as preferably substituted 6-membered heterocyclic groups, unsubstituted or substituted 6-membered aryls (phenyl), such as preferably unsubstituted 6-membered aryls (phenyl), unsubstituted or substituted 5- or 6-membered heteroaryls, such as preferably unsubstituted 6-membered heteroaryls, and unsubstituted or substituted bicyclic heteroaryls, such as preferably benzimidazolyl.

[0177] Substituted heterocyclyl, aryl, heteroaryl and bicyclic heteroaryl as alkyl substituents may also carry 1, 2 or 3 substituents independently selected from hydroxy, cyano, halogen, C1-C3-alkyl as defined herein, for example preferably methyl, C1-C3-haloalkyl as defined herein, for example preferably difluoroethyl or trifluoromethyl (CF3), C1-C3-alkoxy as defined herein, for example preferably methoxy, carboxyl, amino (-NH2) or monoalkylamino or dialkylamino, aminocarbonyl as defined herein and monoalkylaminocarbonyl or dialkylaminocarbonyl, wherein the monoalkylaminocarbonyl may further carry a 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, wherein the substituted aryl or heteroaryl as a monoalkyl chain substituent may carry 1, 2 or 3 substituents independently selected from halogen, C1-C3-alkyl and C1-C3-haloalkyl, and preferably the further substituent on the monoalkyl chain of the monoalkylaminocarbonyl is selected from halogen-substituted 5- or 6-membered heteroaryl (more preferably fluoropyridyl).

[0178] As used herein, the term "dialkyl ether" or "dialkyl ether group" refers to a C3-C7-alkyl as described above, wherein one CH2 group in the alkyl chain is replaced by -O- to form a group [-(CH2) x -O-(CH2) y -], where x and y independently represent an integer from 1, 2 or 3. The dialkyl ether group as substituent R 4 further carries a substituent R 6 , thereby forming a group [R 6 (CH2) x -O-(CH2) y -]. Wherein, R 6 represents a substituent selected from C1-C3-alkoxy. If R 6 represents a hydrogen atom, the dialkyl ether group is unsubstituted and corresponds to the group "alkoxy" defined separately herein. Preferred substituents R 6 are selected from C1-C3-alkoxy, for example especially methoxy and ethoxy.

[0179] The term "C1-C3-haloalkyl" refers to a straight-chain or branched-chain saturated monovalent C1-C3-alkyl group having the above meaning, wherein one or more hydrogen atoms are replaced by the same or different halogen atoms. In particular, the halogen atom is a chlorine or fluorine atom. More particularly, the halogen atom is a fluorine atom, and even more particularly, all of the halogen atoms are fluorine atoms ("C1-C3-fluoroalkyl"). The C1-C3-haloalkyl 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, with trifluoromethyl (CF3) being particularly preferred.

[0180] The term "C1-C3-alkoxy" refers to a straight-chain or branched-chain saturated monovalent group of the formula (C1-C3-alkyl)O-, wherein the term "C1-C3-alkyl" is as defined above, for example methoxy, ethoxy, n-propoxy or isopropoxy, with methoxy and isopropoxy being particularly preferred.

[0181] The term cycloalkyloxy refers to cycloalkyl-O-, wherein the cycloalkyl as defined below is linked via oxygen (-O-). Cycloalkyloxy includes "C3-C6 cycloalkyloxy", preferably C6-cycloalkyloxy (cyclohexyloxy).

[0182] "Carboxyl" denotes the group [-(C=O)OH].

[0183] The term "monoalkylamino or dialkylamino" denotes an amino group (-NH2), wherein one or two hydrogens are replaced by the same or different C1-C3-alkyl groups. Preferred are methylamino and dimethylamino, more preferably dimethylamino, especially as a substituent of "substituted C1-C3-alkyl" at the 4 R position.

[0184] The term "aminocarbonyl" denotes the group [NH2-(C=O)-].

[0185] The term "monoalkylaminocarbonyl or dialkylaminocarbonyl" denotes aminocarbonyl [NH2-(C=O)-], wherein one or two hydrogens are replaced by C1-C3-alkyl groups. Preferred monoalkylaminocarbonyl is methylaminocarbonyl [CH3NH(C=O)-]. Preferred dialkylaminocarbonyl is dimethylaminocarbonyl [(CH3)2N(C=O)-].

[0186] Generally, the term "aryl" includes aromatic hydrocarbon residues containing 6 to 14 carbon atoms (excluding the carbon atoms on possible substituents), which can be monocyclic or bicyclic, including, for example: phenyl, naphthyl, phenanthryl and anthryl. Preferred is a 6-membered aryl, such as phenyl.

[0187] Generally, the term "heteroaryl" includes heteroaromatic residues containing 4 to 9 ring carbon atoms, which also contain 1 to 3 identical or different heteroatoms selected from S, O, and N in the ring, thus forming 5- to 12-membered heteroaryl groups, which can be monocyclic or bicyclic.

[0188] Monocyclic heteroaryl preferably includes 5- and 6-membered monocyclic heteroaryl groups, such as pyridyl, pyridine-N-oxide, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, or isoxazolyl, including 5-membered heteroaryl groups such as thiazolyl such as thiazol-2-yl, 2-thiazol-2-yl, 2-thiazol-4-yl, thienyl such as thien-3-yl, pyrazolyl such as 1-pyrazol-4-yl, 3-pyrazol-5-yl, imidazolyl such as imidazol-2-yl, 2-imidazol-4-yl, 1-imidazol-4-yl, triazolyl such as 1-triazol-3-yl, 1-triazol-4-yl, such as 1,2,4-triazol-3-yl or 1,2,3-triazol-4-yl, oxazolyl such as 2-oxazol-4-yl, 2-oxazol-5-yl, isoxazolyl such as isoxazol-4-yl, oxadiazolyl such as 1,2,4-oxadiazol-3-yl, tetrazolyl; and 6-membered heteroaryl groups such as pyridyl such as pyridin-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-pyridin-4-yl, 2-pyridin-6-yl, 3-pyridin-5-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl. Preferred heteroaryl groups are pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl.

[0189] Bicyclic heteroaryl preferably includes indolizinyl, indolyl, benzo[b]thienyl, benzo[b]furyl, indazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinazolinyl, quinoxalinyl, and benzimidazolyl such as benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl. Benzimidazolyl is preferred.

[0190] Generally, the term "cycloalkyl" includes alicyclic rings containing 3 to 8, more preferably 3 to 6 ring carbon atoms. Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, with cyclopropyl and cyclohexyl being preferred.

[0191] Generally, the term "heterocyclic group" includes 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 azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydrothienyl, oxathiolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, thianyl, dithianyl, trithianyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, etc., such as azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophene-2-yl, tetrahydrothiophene-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 heterocyclic groups, such as pyrrolidinyl, dioxolanyl, dioxanyl, piperidinyl, piperazinyl, and morpholinyl, and particularly preferred are morpholinyl and piperazinyl.

[0192] An aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl, or heterocyclic group can be linked by a direct chemical bond, a C1-C3-alkyl chain (preferably a direct chemical bond or a C1- or C2-alkyl chain), or an alkynyl chain such as preferably an ethynyl chain (-C≡C-), or an aryl, heteroaryl, cycloalkyl, or heterocyclic group can be fused to an aromatic ring to form a fused ring system as defined herein.

[0193] An aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl, or heterocyclic group, including fused aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl, and heterocyclic groups, can bear 1, 2, or 3 identical or different substituents independently selected from the halogens 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-cycloalkoxy. Particularly preferred are methoxyphenyl and chlorophenyl, especially as substituents for "substituted C1-C3-alkyl" at the R 4 position. Also preferred are pyridyl or methylpiperazinyl as substituents for "substituted C1-C3-alkyl" at the R 4 position.

[0194] An aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl, or heterocyclic group can also bear 1, 2, or 3 substituents as defined above for the possible substituents of an alkyl group.

[0195] An aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl or heterocyclic group as defined herein may form one of group A and / or group B as defined herein.

[0196] In formula (I-A), "l" represents an integer of 1 or 2, preferably l = 1.

[0197] In formula (I-A), "L 1 " and "L 2 " each represent a linking group or a spacer group, namely an "alkyl spacer group", which contains 1 to 7 carbon atoms. Such an alkyl spacer group or linking group "L 1 " and "L 2 " are independently selected from

[0198] - straight-chain C1-C3-alkyl –[CH2] m – or –[CH2] n –, where m and n are independently integers of 1, 2 or 3; or

[0199] - branched C1-C4-alkyl, such as preferably 2-dimethylethyl

[0200]

[0201] - C3-C6-cycloalkyl that forms a ring with the attached nitrogen atom. For example, "L 1 " is preferably

[0202] And

[0203] "L 2 " is preferably

[0204]

[0205] Most preferably a 4-membered cycloalkyl that forms a ring with the attached nitrogen atom.

[0206] If the linking group "L 1 " and / or "L 2 " has the meaning of a straight-chain C1-C3-alkyl, then in formula (I-A) the linking group can be replaced by –[CH2] m – and / or –[CH2] n – as defined herein. If the linking groups "L 1 " and "L 2 " are both straight-chain C1-C3-alkyl, then the compound can be represented by formula (IB)

[0207]

[0208] Where

[0209] l is an integer of 1 or 2;

[0210] m and n are independently integers of 1, 2 or 3; and

[0211] All other substituents may have the meanings defined anywhere herein.

[0212] In formula (I-B), "m" and "n" independently represent integers of 1, 2 or 3, preferably m = 2 and preferably n = 1 or 2, even more preferably both m and n represent 2.

[0213] In one aspect of the present invention, the linking group "L 2 " has the meaning of a linking group containing 1 to 7 carbon atoms, selected from

[0214] - straight-chain C1-C3-alkyl–[CH2] n –, where n represents an integer of 1, 2 or 3,

[0215] - branched-chain C1-C4-alkyl, and

[0216] - C3-C6-cycloalkyl that forms a ring with the attached nitrogen atom as defined herein.

[0217] In formula (I-A) and / or (I-B), X 1 and X 2 are selected from:[[]]

[0218] X 1 = N, S or O; and

[0219] X 2 = N, S or O;

[0220] Provided that one of X 1 and X 2 is N.

[0221] In formula (I-A) and / or (I-B)

[0222] Y represents N or CR 5 .

[0223] Wherein, in the case of Y = CR 5 R 5 represents an optional substituent, R 5 is preferably selected from halogen, straight-chain or branched-chain C1-C3-alkyl and straight-chain or branched-chain C1-C3-haloalkyl as defined above. If no substituent is present, R 5 represents hydrogen.

[0224] In another aspect, the compounds of the present invention are represented by one of the following formulas (I-C), (I-D), (I-E), (I-F) or (I-G):

[0225]

[0226] Among them, the remaining substituents have the meanings defined anywhere in this text.

[0227] Generally, group A represents group (a-1)

[0228]

[0229] This group (a-1) is a pyridyl group, which bears 0 substituents (R 1 / R 2 represents hydrogen) or 1 or 2 identical or different substituents R 1 / R 2 , and the said substituents are independently selected from the halogens defined above such as preferably F, Br and Cl, C1-C3-alkyls such as preferably methyl, C1-C3-haloalkyls defined above such as preferably trifluoromethyl, and C1-C3-alkoxys defined above such as preferably methoxy.

[0230] Group (a-1) is preferably the following groups:

[0231]

[0232] Group (a-1) is more preferably the following structures:

[0233]

[0234] Group (a-1) is most preferably the following structures:

[0235]

[0236] Generally, group B represents one of the following groups (b-1), (b-2) and (b-3)

[0237]

[0238] Among them, group (b-1) represents a benzimidazole group, which bears 0 substituents R 3 (i.e., R 3 represents hydrogen) or 1, 2 or 3, preferably 1 or 2 identical or different substituents R 3 as defined herein. If present, R 3 preferably represents 1 substituent defined anywhere in this text.

[0239] As described above, the substituent R 3 can be selected from "chain-like substituents", including linear or branched C1-C3-alkyls, linear or branched C1-C3-haloalkyls and linear or branched C1-C3-alkoxys, or R 3It may be selected from "cyclic substituents", including aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl and heterocyclic groups as described above, which are connected by a direct chemical bond or through a C1-C3-alkyl chain, preferably a C1-alkyl chain, or an alkynyl chain such as preferably an ethynyl chain.

[0240] When R 4 is hydrogen, R 3 is not absent but is a substituent as defined herein, excluding methyl. Preferably, when R 4 is hydrogen, R 3 is selected from the "cyclic substituents" as defined above.

[0241] 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 heterocyclic, unsubstituted or substituted 5- or 6-membered heterocycloalkyl, unsubstituted or substituted 6-membered arylalkynyl, or unsubstituted or substituted 5- or 6-membered heteroarylalkynyl, wherein the substituted aryl, heteroaryl and bicyclic heteroaryl may bear 1, 2 or 3 substituents independently selected from halogen, C1-C3-alkyl, C1-C3-haloalkyl and C1-C3-alkoxy.

[0242] An aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl or heterocyclic group connected by a C1-C3-alkyl chain (preferably a C1-alkyl chain) corresponds to R 3 representing arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein "alkyl" preferably represents C1-C3-alkyl. Preferably heterocycloalkylalkyl, such as piperazinylmethyl or morpholinylmethyl.

[0243] An aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl or heterocyclic ring connected by an alkynyl chain (such as preferably an ethynyl chain) corresponds to R 3 representing arylalkynyl, heteroarylalkynyl, cycloalkylalkynyl or heterocycloalkynyl, wherein "alkynyl" preferably represents ethynyl. Preferably arylalkynyl such as phenylethynyl and heteroarylalkynyl such as pyridyl ethynyl. Wherein the aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl or heterocyclic ring may bear 1, 2 or 3 identical or different substituents selected from those defined herein for each group, preferably selected from the halogen as defined above such as preferably F, Br and Cl, C1-C3-alkyl such as preferably methyl, the C1-C3-haloalkyl as defined above such as preferably trifluoromethyl, and the C1-C3-alkoxy as defined above such as preferably methoxy. Therefore, such groups are also defined herein as "unsubstituted or substituted arylalkynyl", "unsubstituted or substituted heteroarylalkynyl", "unsubstituted or substituted cycloalkylalkynyl" and "unsubstituted or substituted heterocycloalkynyl".

[0244] As described above, the group (b-1) preferably bears a cyclic substituent R 3 , such that the group B contains at least 3 rings. Possible examples of the group (b-1) with a cyclic substituent include:

[0245]

[0246]

[0247] Generally, unsubstituted or substituted aryl rings can be directly linked, corresponding to R 3 or R 4 representing "unsubstituted or substituted aryl". Possible substituents are as defined above. In particular for the aryl directly linked to the group B, such as as the substituent R 4 , preferred substituents are selected from halogen, more preferably Cl, and C1-C3-alkoxy, more preferably methoxy.

[0248] The groups (b-2) and (b-3) represent fused ring systems, wherein in formulas (b-2) and (b-3), a fused aryl, heteroaryl, cycloalkyl or heterocyclic ring as described above is present at one of the positions shown by D1, D2 and D3, preferably forming a fused tricyclic ring system.

[0249] The groups (b-2) and (b-3) may optionally bear 1, 2 or 3 identical or different substituents independently selected from halogen, straight-chain or branched C1-C3-alkyl, straight-chain or branched C1-C3-haloalkyl and straight-chain or branched C1-C3-alkoxy, each substituent being as described above. Such optional substituents are also denoted by R x herein. The substituent R x on the group (b-2) or (b-3) refers to one or more additional substituents other than the N-linked R 4 substituent.

[0250] Examples of possible groups (b-2) having a fused tricyclic structure include:

[0251] Particularly preferred

[0252] Examples of possible groups (b-3) having a fused tricyclic structure include:

[0253]

[0254] The compounds of formulas (I-A) and (I-B) of the present invention are characterized by containing the substituent R 4, forming an “N - substituted” cyclic group B. In an embodiment of the present invention, where R 4 is not a directly - attached substituted or unsubstituted aryl, the “N - substituted” cyclic group B can be referred to as an “N - alkylated” (cyclic) group B. Herein, the term “N - alkylated” should be understood to include being substituted by an alkyl, a dialkyl ether group, and a cycloalkyl or heterocyclic group as defined herein.

[0255] In this case, in particular, R 4 substituent represents a straight - chain or branched C1 - C6 - alkyl, a dialkyl ether group as described above [R 6 (CH2) x -O-(CH2) y -], a 3 - to 6 - membered cycloalkyl or a 5 - or 6 - membered heterocyclic group, which may be substituted or unsubstituted.

[0256] In the case where R 4 represents a substituted alkyl, referring to the possible substituents of the alkyl as described above, among which the particularly preferred substituents of the alkyl include an alkoxy group, an unsubstituted cycloalkyl, an unsubstituted or substituted 6 - membered heterocyclic group, an unsubstituted or substituted 6 - membered aryl, an unsubstituted heteroaryl, and a dialkylamino group.

[0257] In the case where R 4 represents a substituted dialkyl ether group, referring to the definition of “dialkyl ether” and the possible substituents R 6 as described above, among which the particularly preferred substituents of the dialkyl ether include an alkoxy group.

[0258] In the case where R 4 represents a substituted cycloalkyl or heterocyclic group, referring to the definition of the possible substituents of such groups anywhere in this text, among which the particularly preferred substituents include C1 - C3 - alkyl.

[0259] In the case where R 4 represents a substituted aryl, referring to the possible substituents of the aryl - (phenyl -) as described above, among which the particularly preferred substituents include an alkoxy group or a halogen.

[0260] Preferably, the substituents of R 4 aryl, alkyl, dialkyl ether group, cycloalkyl, and heterocyclic group can be substituted by 1 or 2 substituents, especially the substituents defined above for phenyl, C1 - C3 - alkyl, and dialkyl ether.

[0261] In one aspect, the compounds (I - A) and (I - B) of the present invention contain the group (b - 1) as defined herein, which bears a substituent R 4 that is not hydrogen but a group as defined herein for R 4 .

[0262] On the other hand, the compounds (I-A) and (I-B) of the present invention contain the group (b-2).

[0263] In such an embodiment, the following group (b-2) is preferred:

[0264]

[0265] Among them, the following groups are more preferred:

[0266]

[0267] wherein R 4 has the meaning defined anywhere herein (including or excluding hydrogen). Examples of the group (b-2) include:

[0268]

[0269] Among these examples of the group (b-2), those groups having a fused dioxane ring are preferred.

[0270] If used anywhere herein, for example, in formulas (a-1), (b-1), (b-2) and (b-3), "*" represents the bonding position.

[0271] On the other hand, it relates to the compounds of the above formulas (I-A) and (I-B), wherein

[0272] A represents the group (a-1)

[0273]

[0274] wherein * represents the bonding position;

[0275] R 1 and R 2 independently represent

[0276] - hydrogen,

[0277] - halogen,

[0278] - straight-chain or branched C1-C3-alkyl,

[0279] - straight-chain or branched C1-C3-haloalkyl, or

[0280] - straight-chain or branched C1-C3-alkoxy;

[0281] B represents one of the following groups (b-1), (b-2) and (b-3)

[0282]

[0283] wherein * represents the bonding position;

[0284] R 3 represents 0, 1, 2 or 3 substituents independently selected from

[0285] - a straight-chain or branched C1-C3-alkyl group,

[0286] - a straight-chain or branched C1-C3-haloalkyl group,

[0287] - a straight-chain or branched C1-C3-alkoxy group,

[0288] - an unsubstituted or substituted 6-membered aryl group,

[0289] - an unsubstituted or substituted 5- or 6-membered heteroaryl group,

[0290] - an unsubstituted or substituted bicyclic heteroaryl group,

[0291] - a 3- to 6-membered cycloalkyl group,

[0292] - a 5- or 6-membered heterocyclic group,

[0293] - a 5- or 6-membered heterocycloalkyl group, or

[0294] - a 6-membered arylalkynyl group

[0295] wherein the substituted aryl, heteroaryl and bicyclic heteroaryl groups may optionally be substituted with 1, 2 or 3 substituents independently selected from

[0296] ○ halogen,

[0297] ○ C1-C3-alkyl,

[0298] ○ C1-C3-haloalkyl, and

[0299] ○ C1-C3-alkoxy;

[0300] R 4 represents

[0301] - a straight-chain or branched C1-C6-alkyl group,

[0302] - a dialkyl ether group [R 6 (CH2) x -O-(CH2) y -]

[0303] wherein R 6 represents C1-C3-alkoxy, and

[0304] wherein x and y independently represent an integer of 1, 2 or 3,

[0305] - a 3- to 6-membered cycloalkyl group,

[0306] - a 5- or 6-membered heterocyclic group, or

[0307] -6-aryl

[0308] wherein the alkyl, cycloalkyl, heterocyclic group, and aryl group may optionally be substituted with 1 or 2 substituents independently selected from the following

[0309] ○ C1-C3-alkoxy

[0310] ○ carboxyl

[0311] ○ aminocarbonyl

[0312] ○ monoalkylaminocarbonyl or dialkylaminocarbonyl

[0313] ○ amino (-NH2), monoalkylamino or dialkylamino

[0314] ○ 3- to 6-membered cycloalkyl, and

[0315] ○ 5- or 6-membered heterocyclic group

[0316] ○ unsubstituted or substituted 6-membered aryl

[0317] ○ unsubstituted or substituted 5- or 6-membered heteroaryl, and

[0318] ○ unsubstituted or substituted bicyclic heteroaryl

[0319] wherein the substituted aryl, heteroaryl, and bicyclic heteroaryl groups may optionally be substituted with 1, 2, or 3 substituents independently selected from the following

[0320] ■ hydroxy

[0321] ■ cyano

[0322] ■ halogen

[0323] ■ C1-C3-alkyl

[0324] ■ C1-C3-haloalkyl

[0325] ■ C1-C3-alkoxy

[0326] ■ carboxyl

[0327] ■ amino (-NH2), monoalkylamino or dialkylamino

[0328] ■ aminocarbonyl, and

[0329] ■ monoalkylaminocarbonyl or dialkylaminocarbonyl

[0330] wherein the monoalkylamino and monoalkylaminocarbonyl may further bear a substituent on the monoalkyl chain, and the substituent is selected from

[0331] ● C1-C3-alkoxy,

[0332] ● unsubstituted or substituted 6-membered aryl, and

[0333] ● unsubstituted or substituted 5- or 6-membered heteroaryl,

[0334] wherein the substituted aryl or heteroaryl as a monoalkyl chain substituent may optionally be substituted with 1, 2 or 3 substituents independently selected from halogen, C1-C3-alkyl and C1-C3-haloalkyl;

[0335] In formulas (b-2) and (b-3), one of D1, D2 and D3 is present and represents

[0336] - a fused 6-membered aryl ring,

[0337] - a fused 5- or 6-membered heteroaryl ring,

[0338] - a fused 5- or 6-membered cycloalkyl ring, or

[0339] - a fused 5- or 6-membered heterocyclic ring;

[0340] Groups (b-2) and (b-3) bear 0, 1, 2 or 3 substituents independently selected from

[0341] - halogen,

[0342] - straight-chain or branched C1-C3-alkyl,

[0343] - straight-chain or branched C1-C3-haloalkyl,

[0344] - straight-chain or branched C1-C3-alkoxy.

[0345] On the other hand, it relates to the compounds of formulas (I-A) and (I-B) above, wherein

[0346] A represents group (a-1)

[0347]

[0348] where * represents the bonding position;

[0349] R 1 and R 2 independently represent

[0350] - hydrogen,

[0351] - halogen,

[0352] - straight-chain or branched C1-C3-alkyl,

[0353] - straight-chain or branched C1-C3-haloalkyl, or

[0354] - straight-chain or branched C1-C3-alkoxy;

[0355] B represents one of the following groups (b-1), (b-2) and (b-3)

[0356]

[0357] where * represents the bonding position;

[0358] R 3 represents 0, 1, 2 or 3 substituents independently selected from

[0359] - straight-chain or branched C1-C3-alkyl,

[0360] - straight-chain or branched C1-C3-haloalkyl,

[0361] - straight-chain or branched C1-C3-alkoxy,

[0362] - unsubstituted or substituted phenyl,

[0363] - unsubstituted or substituted 5- or 6-membered heteroaryl,

[0364] - unsubstituted or substituted bicyclic heteroaryl,

[0365] - 6-membered heterocyclic group,

[0366] - 6-membered heterocycloalkyl,

[0367] - phenylethynyl, or

[0368] - pyridinylethynyl,

[0369] wherein the substituted phenyl, heteroaryl and bicyclic heteroaryl may optionally be substituted by 1, 2 or 3 substituents independently selected from the following

[0370] ○ halogen,

[0371] ○ C1-C3-alkyl,

[0372] ○ C1-C3-haloalkyl, and

[0373] ○ C1-C3-alkoxy;

[0374] R 4 represents

[0375] - straight-chain or branched C1-C6-alkyl,

[0376] - dialkyl ether group [R 6 (CH2) x -O-(CH2) y -]

[0377] wherein R 6 represents a C1-C3-alkoxy group, and

[0378] wherein x and y independently represent an integer of 1, 2 or 3,

[0379] - a 5- or 6-membered unsubstituted heterocyclic group, or

[0380] - a substituted or unsubstituted phenyl group,

[0381] wherein the substituents of the phenyl group are selected from

[0382] ○ halogen, and

[0383] ○ C1-C3-alkoxy group; and

[0384] wherein the alkyl group may optionally be substituted by 1 or 2 substituents independently selected from the following

[0385] ○ halogen,

[0386] ○ C1-C3-alkoxy group,

[0387] ○ C6-cycloalkyloxy group,

[0388] ○ carboxyl group,

[0389] ○ aminocarbonyl group,

[0390] ○ monoalkylaminocarbonyl group,

[0391] ○ dialkylamino group,

[0392] ○ 3- to 6-membered cycloalkyl group,

[0393] ○ unsubstituted or substituted 5- or 6-membered heterocyclic group,

[0394] ○ unsubstituted or substituted 6-membered aryl group,

[0395] ○ unsubstituted or substituted 5- or 6-membered heteroaryl group, and

[0396] ○ unsubstituted or substituted bicyclic heteroaryl group,

[0397] wherein the substituted heterocyclic group, aryl group, heteroaryl group and bicyclic heteroaryl group may optionally be substituted by 1, 2 or 3 substituents independently selected from the following

[0398] ■ halogen,

[0399] ■ C1-C3-alkyl group,

[0400] ■ C1-C3-haloalkyl group,

[0401] ■ C1-C3-alkoxy group,

[0402] ■ aminocarbonyl group, and

[0403] ■ Monoalkylaminocarbonyl,

[0404] wherein the monoalkylaminocarbonyl may further bear a substituent on the monoalkyl chain, and the substituent is selected from halogen-substituted 5- or 6-membered heteroaryl;

[0405] And, in formulae (b-2) and (b-3), one of D1, D2 and D3 is present and represents

[0406] - fused phenyl ring,

[0407] - fused 6-membered heteroaryl ring,

[0408] - fused 6-membered cycloalkyl ring, or

[0409] - fused 5- or 6-membered heterocyclic ring;

[0410] And, the groups (b-2) and (b-3) bear 0 or 1 substituent selected from the following:

[0411] - halogen,

[0412] - straight-chain or branched C1-C3-alkyl,

[0413] - straight-chain or branched C1-C3-haloalkyl, and

[0414] - straight-chain or branched C1-C3-alkoxy.

[0415] On the other hand, it relates to compounds of the above formulae (I-A), (I-B), (I-C), (I-D), (I-E), (I-F) or (I-G) having the following group A,

[0416]

[0417] and wherein the remaining substituents have the meanings defined anywhere in this text or in any of the above aspects and embodiments.

[0418] On the other hand, it relates to compounds of the above formulae (I-A), (I-B), (I-C), (I-D), (I-E), (I-F) or (I-G) having the following group B,

[0419]

[0420] wherein R 4 represents a substituent other than hydrogen defined anywhere in this text, and / or wherein R 3 represents 1 substituent selected from the above-defined "cyclic substituents", and wherein the remaining substituents have the meanings defined anywhere in this text or in any of the above aspects and embodiments.

[0421] On the other hand, it relates to compounds of the above formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F) or (I-G) having the following group B,

[0422]

[0423] wherein R 4 represents a substituent defined anywhere herein, and wherein the remaining substituents have the meanings defined anywhere herein or in the context of any of the above aspects and embodiments.

[0424] On the other hand, it relates to compounds of the above formula (I-F) or (I-G):

[0425]

[0426] which have the following groups A and B:

[0427]

[0428] wherein, in the above-mentioned preferred group (b-1), R 4 represents a substituent other than hydrogen defined anywhere herein, and / or wherein R 3 represents a substituent selected from the above-defined "cyclic substituents", and wherein the remaining substituents have the meanings defined anywhere herein or in any of the above aspects and embodiments.

[0429] In another aspect of the present invention, preferably, the compounds of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F) or (I-G) defined anywhere herein are characterized in that one or more of the defined substituents are specifically selected from the following:

[0430] - The halogen substituents are selected from F, Cl and Br; preferably selected from F and Cl; and / or

[0431] - The straight-chain or branched C1-C6-alkyl substituents are selected from methyl, ethyl, propyl, isopropyl, n-butyl and isobutyl; preferably selected from methyl, ethyl and propyl, more preferably selected from methyl or ethyl; and / or

[0432] - The C1-C3-alkoxy substituents are selected from methoxy and ethoxy; and / or

[0433] - The C1-C3-haloalkyl substituents are selected from difluoroethyl (-CH2-CHF2) and trifluoromethyl (CF3); and /

[0434] or

[0435] - R 4The substituted alkyl at the position represents a substituted or unsubstituted C1-C3-alkyl, preferably a substituted or unsubstituted C1- or C2-alkyl; and / or

[0436] - The bicyclic heteroaryl is selected from benzimidazolyl.

[0437] In another aspect of the present invention, preferably, for the compounds of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F) or (I-G) defined anywhere herein, the possible substituents are selected from one of the following definitions or any combination of two or more of the following definitions:

[0438] [1] One of R 1 and R 2 represents hydrogen, and the other is selected from F, Cl, methyl, ethyl, difluoroethyl, trifluoromethyl, methoxy and ethoxy; preferably selected from F, Cl, methyl, trifluoromethyl and methoxy, and most preferably F.

[0439] [2] R 3 is selected from

[0440] "Chain-like substituents", including:

[0441] - Straight-chain or branched C1-C3-alkyl, preferably ethyl, propyl or isopropyl;

[0442] - Straight-chain or branched C1-C3-haloalkyl, preferably difluoroethyl or trifluoromethyl;

[0443] - Straight-chain or branched C1-C3-alkoxy, preferably methoxy or ethoxy; or

[0444] "Cyclic substituents", including:

[0445] - Unsubstituted or substituted phenyl;

[0446] - Unsubstituted or substituted 5- or 6-membered heteroaryl;

[0447] - Unsubstituted or substituted bicyclic heteroaryl;

[0448] - 6-membered heterocyclic group;

[0449] - 6-membered heterocyclic group alkyl;

[0450] - Phenyl ethynyl; and

[0451] - Pyridyl ethynyl,

[0452] wherein the substituted phenyl, heteroaryl and bicyclic heteroaryl may optionally be substituted by 1, 2 or 3 substituents independently selected from the following

[0453] ○ Halogen, preferably F or Cl;

[0454] ○ C1-C3-alkyl, preferably methyl or ethyl;

[0455] ○ C1-C3-haloalkyl, preferably difluoroethyl or trifluoromethyl; and

[0456] ○ C1-C3-alkoxy, preferably methoxy or ethoxy;

[0457] wherein R 3 is preferably selected from "cyclic substituents".

[0458] [3]R 4 is selected from

[0459] - unsubstituted or substituted 6-membered aryl, preferably phenyl; and

[0460] - straight-chain or branched C1-C6-alkyl, preferably methyl or ethyl, which may carry 1 substituent selected from: C1-C3-alkoxy, preferably methoxy or isopropoxy; dialkylamino, preferably dimethylamino;

[0461] heterocyclic group, preferably morpholinyl or N-substituted C1-C3-alkylpiperazin-1-yl; unsubstituted or substituted 6-membered aryl, preferably phenyl, methoxyphenyl and chlorophenyl; unsubstituted or substituted 6-membered heteroaryl, preferably pyridyl; and

[0462] - dialkyl ether group [R 6 (CH2) x -O-(CH2) y -], where R 6 represents C1-C3-alkoxy, preferably methoxy; wherein, x and y independently represent an integer of 1, 2 or 3, preferably x and / or y represents 2;

[0463] or

[0464] R 4 is selected from

[0465] - straight-chain or branched C1-C6-alkyl, preferably methyl or ethyl, which may carry 1 substituent selected from the following: C1-C3-alkoxy, preferably methoxy or isopropoxy; heterocyclic group, preferably morpholinyl; unsubstituted or substituted 6-membered aryl, preferably phenyl, methoxyphenyl and chlorophenyl; and

[0466] - dialkyl ether group [R 6 (CH2) x -O-(CH2) y -], where R 6 represents C1-C3-alkoxy, preferably methoxy; wherein, x and y independently represent an integer of 1, 2 or 3, preferably x and / or y represents 2.

[0467] [4]R 5 selected from

[0468] - hydrogen,

[0469] - halogen, preferably F and Cl;

[0470] - straight-chain or branched C1-C3-alkyl, preferably methyl; and

[0471] - straight-chain or branched C1-C3-haloalkyl, preferably difluoroethyl and trifluoromethyl.

[0472] [5]L 1 and L 2 independently represent a linking group selected from the following

[0473] - straight-chain C1-C3-alkyl–[CH2] m – or –[CH2] n –, where m and n are independently integers of 1, 2 or 3, preferably m and n are independently 1 or 2, more preferably both m and n represent 2;

[0474] - branched C1-C4-alkyl, preferably 2-dimethylethyl; and

[0475] - C3-C6-cycloalkyl forming a ring with the attached nitrogen atom, preferably a group forming a 4-ring or 6-ring with the attached nitrogen atom, preferably a group forming a 4-ring with the attached nitrogen atom.

[0476] In a particularly preferred aspect, the compounds of the present invention are selected from the compounds defined by the above formulas (I-A), (I-B), (I-C), (I-E) and (I-F), specifically including the following compounds:

[0477]

[0478]

[0479]

[0480] In any case, the present invention does not include the following compounds in WO2020 / 123850:

[0481]

[0482]

[0483]

[0484] The present invention relates to novel compounds which are inhibitors of transferrin receptor, as defined anywhere herein, including pharmaceutically acceptable salts thereof. In another aspect, the present invention also includes solvates, hydrates and polymorphs of the compounds defined herein and their pharmaceutically acceptable salts.

[0485] Salts, solvates or hydrates of the compounds of formula (I-A), (I-B), (I-C), (I-E), (I-F) or (I-G) as defined anywhere herein may exist in amorphous, polymorphic, crystalline and / or semi-crystalline (partially crystalline) form, or in the form of a solvate (or hydrate) of a salt. The salts, solvates or hydrates of the present invention preferably exist in crystalline and / or semi-crystalline (partially crystalline) form.

[0486] The preferred crystallinity of the salts or solvates of the salts of the present invention can be determined using conventional analytical methods, for example, in particular, using various X-ray methods which enable clear and simple analysis of salt compounds. Specifically, the crystallinity can be determined or confirmed by using the powder X-ray diffraction (reflection) method as described in the following examples, or using the powder X-ray diffraction (transmission) method as described in the following examples (both hereinafter referred to simply as PXRD). For crystalline solids of the same chemical composition, different final crystal lattices are collectively referred to by the term "polymorph".

[0487] Pharmaceutically acceptable salts of the compounds of the present invention include, for example, salts formed with suitable anions, such as carboxylates, which may include formates, acetates, and also sulfonates, sulfates, chlorides, bromides, iodides, phosphates, tartrates, methanesulfonates, hydroxyethanesulfonates, glycine salts, maleates, propionates, fumarates, toluenesulfonates, benzenesulfonates, trifluoroacetates, 1,5-naphthalenedisulfonates, salicylates, benzoates, lactates, malates, 2-(3-hydroxy-2-naphthoate) salts, citrates and acetates. The HCl salt is preferred.

[0488] Pharmaceutically acceptable salts of the compounds of the present invention also include, for example, salts formed with suitable pharmaceutically acceptable bases, such as alkali metal or alkaline earth metal hydroxides such as NaOH, KOH, Ca(OH)2, Mg(OH)2, etc., amine compounds such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, ethanolamine, diethanolamine, triethanolamine, methylglucamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine, 2-amino-2-methyl-1-propanol, 2-amino-2-methyl-1,3-propanediol, 2-amino-2-hydroxymethyl-1,3-propanediol (TRIS), etc.

[0489] The novel compounds of the present invention may exist in the form of solvates and / or hydrates, which may be formed by the attraction, association, adsorption, adhesion, embedding or complexation of solvent molecules in the crystal lattice of the salts of the present invention. The solvent molecules that can be embedded in the crystal lattice may be derived from the solvent used during crystallization or from water in the relative humidity.

[0490] The extent to which the selected solvent or water forms solvates or hydrates during a process step or crystallization step depends on the combination of various interactions between the process conditions and the selected compound, the counteranion of the selected acid, the selected solvent and the humidity conditions. Solvates or hydrates of salts may be preferred because the solvent or water molecules in the crystal structure are bound by strong intermolecular forces and may thus be an element in the formation of these crystal structures, which may to some extent improve the stability of the salt. However, there are also solvents and / or water molecules bound by rather weak intermolecular forces in certain crystal lattices. Such molecules are more or less involved in the formation of the crystal structure but have a smaller impact on the energy. The solvent and / or water content of the solvate also depends on the drying and environmental conditions (i.e., relative humidity). In the case of stable solvates or hydrates, there is usually a definite stoichiometric ratio between the active compound (i.e., the salt) and the solvent or water. In many cases, these ratios do not exactly match the stoichiometric values and are usually lower than the theoretical values due to certain crystal defects. For weakly bound water, the ratio of organic molecules to solvent or water molecules can vary widely, for example, it may be a dihydrate, trihydrate or tetrahydrate. On the other hand, in amorphous solids, the molecular structure classification of the solvent and / or water is non-stoichiometric; however, this classification may also only accidentally match the stoichiometry. In some cases, the exact stoichiometry of the solvent or water molecules cannot be determined because a layered structure is formed, making it impossible to determine the embedded solvent or water molecules in a definite form.

[0491] The solvent and / or water content in amorphous solids as well as in crystalline solvates or hydrates can generally be determined by conventional methods, such as using the well-known Karl Fischer titration, performing dynamic vapor sorption (DVS) measurements, performing thermogravimetric measurements (TG-FTIR). Elemental analysis or structural analysis methods such as 1 1H NMR spectroscopy or Raman spectroscopy (FT Raman spectroscopy) can provide information on the degree of solvate or hydrate formation and / or can be used to confirm or verify the results of Karl Fischer (KF), DVS or TG-FTIR measurements.

[0492] Examples of the solvates and / or hydrates of the present invention include, for example, hemi (0.5), mono, sesqui (1.5), di, tri, tetra, penta, hexa, hepta, octa, nona, deca, etc. solvates or hydrates, respectively. Intermediate degrees of solvation may also exist, such as solvation with 2.5, 3.5, 4.5, etc. amounts of solvent and / or water molecules.

[0493] Exemplary preferred solvates and / or hydrates include solvates / hydrates formed with about 0.5, 1, 1.5, 2.5, 3, 4, and 7 solvent / water molecules. Further exemplary preferred solvates and / or hydrates include solvates / hydrates formed with about 0.5, 1, 1.5, 2.5, 3, 4, 6, and 7 solvent / water molecules. More preferably, hemisolvates / hydrates and monosolvates / hydrates formed with about 0.5 or 1 solvent / water molecule are preferred, with hemihydrates and monohydrates being particularly preferred. The anhydrous salt is also preferred. In addition, solvent and / or water residues may also remain in the salt in non-stoichiometric amounts.

[0494] The formation of the salts of the compounds of the present invention can in particular be carried out by the methods described in International Application WO2018 / 192973.

[0495] As described therein, solvents for crystallization include acetonitrile, dichloromethane (DCM), alcohols such as in particular methanol, ethanol, 2-propanol (isopropanol), aldehydes, ketones especially 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 crystallization solvents are selected from acetonitrile, dichloromethane, methanol, ethanol, 2-propanol, ethyl acetate, THF, water and mixtures thereof.

[0496] Particularly preferred crystallization solvents are selected from 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 mixtures of water, acetonitrile and methanol being preferred.

[0497] In principle, the salts, solvates, hydrates and polymorphs of the compounds of the present invention can be prepared by any conventional crystallization technique, including evaporation crystallization, cooling crystallization, anti-solvent addition crystallization, seeding crystallization, template crystallization or melt crystallization.

[0498] In a particularly preferred embodiment, salts, solvates or hydrates of the compounds defined anywhere herein are prepared in preparative high performance liquid chromatography (HPLC) using a particularly preferred solvent mixture. The advantage of preparing salts, solvates or hydrates in this way is that reaction products from the compound synthesis can be purified while the compounds of the invention can be transferred to the desired phase. In this case, suitable anions may be selected from formate, acetate or lactate. The corresponding anions are added to the HPLC solution in a proportion of 0.05 wt.%, 0.075 wt.%, 0.1 wt.%, 0.2 wt.%, 0.3 wt.%, 0.4 wt.% or 0.5 wt.%, preferably 0.1 wt.%. Subsequently, preparative HPLC can be carried out.

[0499] It has been found that the novel compounds of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F) or (I-G) defined anywhere herein act as ferroportin inhibitors and are thus suitable for use as medicaments, in particular as ferroportin inhibitors.

[0500] As described above, ferroportin is an iron-transporting protein responsible for absorbing the iron released by intestinal absorption and transferring it to the blood circulation, thereby delivering iron to the appropriate tissues and organs. Inactivation or inhibition of ferroportin will hinder the output of iron, thereby reducing the intestinal absorption of iron. Thus, for the purposes of the present invention, ferroportin inhibition includes inhibiting the transport of iron from cells to the blood circulation and inhibiting the intestinal absorption of iron. Among them, the inhibition of iron transport and / or iron recirculation can be achieved by different mechanisms, including for example inhibiting the iron transport activity of ferroportin to inhibit iron recirculation, triggering the internalization, degradation and / or reduction of ferroportin, administering hepcidin agonists, i.e., compounds competing with hepcidin or using compounds that inhibit the binding of hepcidin to ferroportin.

[0501] Transferrin inhibition can be determined by measuring the inhibition of transferrin-mediated iron transport activity in an iron response assay (BLAzer assay), the details of which are described in the following examples. Additionally, transferrin inhibition can be determined by measuring the internalization and / or degradation of transferrin in a transferrin internalization and degradation assay (FACS), or by examining the ubiquitination and degradation of transferrin, which are described in more detail in the following examples. Further, transferrin inhibition can be determined by measuring the activity as a hepcidin agonist, for example, by determining the binding ability of hepcidin to transferrin in a hepcidin internalization assay (J774), the details of which are described in the following examples. Additionally, transferrin inhibition can be determined by confirming the inhibition of the binding of hepcidin to transferrin, for example, in a biophysical transferrin-hepcidin binding assay (Hep Bind FP), the details of which are described in the following examples. Moreover, transferrin inhibition can be determined by measuring the ability of a compound to block the export of iron through transferrin, for example, using a test that measures iron efflux inhibition, the details of which are described in the following examples.

[0502] Thus, for the purposes of the present invention, transferrin inhibition can be particularly defined as exhibiting transferrin inhibitory activity in at least one of the above test methods, specifically manifested as:

[0503] Inhibiting transferrin-mediated iron transport activity in an iron response assay (Blazer assay): IC 50 value [μM] not exceeding 100 (≤100), preferably not exceeding 50 (≤50), more preferably less than 50 (<50).

[0504] Transferrin internalization and degradation assay (FACS): EC 50 value [μM] not exceeding 100 (≤100), preferably not exceeding 50 (≤50), more preferably less than 50 (<50).

[0505] Transferrin ubiquitination and degradation: The effects observed in a protein immunoblot are "+ equivalent to hepcidin", "+ / - moderate effect", and "+ / + / - stronger moderate effect", preferably the effect is "+" or "+ / + / -", and most preferably the effect is "+".

[0506] Hepcidin internalization assay (J774): IC 50 value [μM] not exceeding 100 (≤100), preferably not exceeding 50 (≤50), more preferably less than 50 (<50).

[0507] Biophysical transferrin-hepcidin binding assay: IC 50The value [μM] does not exceed 100 (≤100), preferably does not exceed 50 (≤50), more preferably is less than 50 (<50).

[0508] Inhibiting iron efflux: IC 50 The value does not exceed 100 (≤100), preferably does not exceed 50 (≤50), more preferably is less than 50 (<50).

[0509] The ferroportin inhibitory effect can also be measured in in vivo models, the details of which are described in the following examples. Suitable in vivo models can include, for example, examining hypoferremia in untreated mice by measuring reduced serum iron; examining prevention of iron absorption in anemic rats by measuring serum iron inhibition; examining correction of hyperferremia in β2-microglobulin-deficient mice by measuring reduced serum iron; examining prevention of iron overload in β2-microglobulin-deficient mice by measuring total iron content in the spleen or liver; examining improvement of anemia, ineffective hematopoiesis, and iron overload in an intermediate β-thalassemia mouse model.

[0510] The activity of the compounds of the present invention as ferroportin inhibitors can be particularly measured by the methods described in the following examples.

[0511] As further explained above, the ferroportin inhibitory effect can be achieved, for example, by hepcidin, an important regulator of iron absorption, which inhibits ferroportin, thereby blocking the transport of iron from cells to the blood circulation and iron absorption. It has also been found that several compounds defined herein can act as hepcidin mimetics or hepcidin agonists, which also fall within the meaning of the ferroportin inhibitory effect of the present invention.

[0512] Therefore, the compounds defined in the present invention are also suitable for inhibiting the transport of iron from cells to the blood circulation and inhibiting intestinal iron absorption, and are also suitable for acting as hepcidin mimetics or hepcidin agonists.

[0513] Due to the activity of the compounds defined herein as ferroportin inhibitors, the compounds of the present invention are also particularly suitable for inhibiting ferroportin-mediated iron transport, and thus for preventing and / or treating iron metabolism disorders leading to elevated iron levels, diseases associated with or caused by elevated iron levels, increased iron absorption, or iron overload, such as especially tissue iron overload, diseases associated with ineffective hematopoiesis, or diseases caused by reduced hepcidin levels. In addition, the compounds of the present invention are suitable for adjuvant therapy by restricting the amount of iron available to pathogenic microorganisms such as Vibrio vulnificus, thereby preventing or treating infections caused by said pathogenic microorganisms.

[0514] Among them, diseases associated with, caused by, or resulting in elevated iron levels, increased iron absorption, iron overload (such as tissue iron overload), or ineffective hematopoiesis 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 anemia.

[0515] Diseases associated with, caused by, or resulting in elevated iron levels, increased iron absorption, iron overload (such as tissue iron overload) also include neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, in which the compounds of the present invention are believed to act by limiting or increasing iron deposition in tissues or cells.

[0516] The compounds of the present invention are also suitable for preventing and / or treating free radical, reactive oxygen species (ROS) formation, and oxidative stress caused by excessive iron or iron overload, as well as preventing and / or treating cardiac, hepatic, and endocrine damage caused by excessive iron or iron overload, and can also be used for preventing and / or treating inflammation triggered by excessive iron or iron overload.

[0517] Diseases associated with ineffective hematopoiesis particularly include myelodysplastic syndromes (MDS, myelodysplasia), polycythemia vera, and congenital dyserythropoietic anemia.

[0518] Other diseases, disorders, and / or conditions include iron overload caused by gene mutations involved in sensing systemic iron stores such as hepcidin (Hamp1), hemochromatosis protein (HFE), hemojuvelin (HJV), and transferrin receptor 2 (TFR2), such as diseases particularly associated with HFE and HJV gene mutations, chronic hemolysis-related diseases, sickle cell disease, erythrocyte membrane diseases, glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency), erythropoietic porphyria, Friedreich's ataxia, and subgroups of iron overload such as transfusion-related iron overload, iron poisoning, pulmonary hemosiderosis, osteopenia, insulin resistance, African iron overload, Hallervorden-Spatz disease, hyperferritinemia, ceruloplasmin deficiency, neonatal hemochromatosis, and erythrocyte diseases including thalassemia (including α-thalassemia, β-thalassemia, and δ-thalassemia), intermediate thalassemia, sickle cell disease, and myelodysplastic syndromes.

[0519] Other diseases and / or disorders and / or conditions associated with elevated iron levels include, but are not limited to, diseases with elevated iron levels, including ataxia, Friedreich's ataxia, age-related macular degeneration, age-related cataract, age-related retinal diseases, and neurodegenerative diseases such as pantothenate kinase-associated neurodegeneration, restless legs syndrome, and Huntington's disease.

[0520] The compounds of the present invention may also be suitable for the prevention and treatment of diseases caused by hepcidin deficiency.

[0521] In view of this, another object of the present invention relates to a medicament comprising one or more of the compounds defined above, for example, in particular, a medicament for the prevention and treatment of any of the above-mentioned indications, conditions, disorders or diseases.

[0522] Another object of the present invention relates to pharmaceutical compositions and medicaments which comprise one or more of the compounds of the present invention as defined above and optionally one or more pharmaceutically acceptable carriers and / or adjuvants and / or solvents. Another object of the present invention relates to pharmaceutical compositions and medicaments which comprise one or more of the compounds of the present invention as defined above and optionally one or more other pharmaceutically active compounds. The pharmaceutical composition comprises, for example, up to 99% by weight or up to 90% by weight or up to 80% by weight or up to 70% by weight of the compound of the present invention, the remainder being formed respectively by a pharmaceutically acceptable carrier and / or adjuvant and / or solvent and / or optionally other pharmaceutically active compounds.

[0523] Among them, pharmaceutically acceptable carriers, adjuvants or solvents are common pharmaceutical carriers, adjuvants or solvents, including various organic or inorganic carriers and / or excipients commonly used for pharmaceutical purposes, especially those 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, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, starch; disintegrants such as starch, hydrolyzed starch, carboxymethylcellulose, calcium carboxymethylcellulose, hydroxypropyl starch, sodium starch glycolate, sodium bicarbonate, calcium phosphate, calcium citrate; lubricants such as magnesium stearate, talc, sodium lauryl sulfate; flavoring agents such as citric acid, menthol, glycine, orange powder; preservatives such as sodium benzoate, sodium bisulfite, parabens (such as methyl paraben, ethyl paraben, propyl paraben, butyl paraben); stabilizers such as citric acid, sodium citrate, acetic acid and polycarboxylic acids from the titriplex series such as diethylenetriaminepentaacetic acid (DTPA); suspending agents such as methylcellulose, polyvinylpyrrolidone, aluminum stearate; dispersants; diluents such as water, organic solvents; waxes, fats and oils such as beeswax, cocoa butter; polyethylene glycol; white petrolatum, etc.

[0524] Liquid pharmaceutical preparations, such as solutions, suspensions, and gels, generally contain a liquid carrier, such as water and / or a pharmaceutically acceptable organic solvent. In addition, such liquid preparations may also contain pH regulators, emulsifiers or dispersants, buffers, preservatives, wetting agents, gelling agents (such as methylcellulose), dyes, and / or flavoring agents, such as those defined above. The compositions can be isotonic, i.e., they can have the same osmotic pressure as blood. The isotonic pressure of the compositions can be adjusted by using sodium chloride and other pharmaceutically acceptable agents such as glucose, maltose, boric acid, sodium tartrate, propylene glycol, and other inorganic or organic soluble substances. The viscosity of the liquid compositions can be adjusted by pharmaceutically acceptable thickening agents such as methylcellulose. Other suitable thickening agents include, for example, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, etc. The preferred concentration of the thickening agent will depend on the thickening agent selected.

[0525] Pharmaceutically acceptable preservatives can be used to extend the shelf life of the liquid compositions. Benzyl alcohol is suitable, although a variety of preservatives can also be used, including, for example, parabens, thimerosal, chlorobutanol, and benzalkonium chloride.

[0526] The above-mentioned pharmaceutical compositions are suitable for, for example, intravenous, intraperitoneal, intramuscular, vaginal, buccal, transdermal, subcutaneous, mucocutaneous, oral, rectal, transdermal, topical, intradermal, intragastric, or intradermal administration, and are provided, for example, in the form of pills, tablets, enteric-coated tablets, film-coated tablets, layer tablets, sustained-release preparations for oral, subcutaneous, or dermal administration (especially as patches), depot preparations, dragees, suppositories, gels, ointments, syrups, granules, suppositories, emulsions, dispersions, microcapsules, microformulations, nanformulations, liposomal preparations, capsules, enteric-coated capsules, powders, inhaled powders, microcrystalline preparations, inhaled sprays, dusting powders, drops, nasal drops, nasal sprays, aerosols, ampoules, solutions, juices, suspensions, infusion solutions, or injection solutions.

[0527] Another aspect of the present invention relates to a pharmaceutical or combination preparation comprising one or more of the compounds defined above and at least one other pharmaceutically active compound, said other pharmaceutically active compound being, for example, especially a compound for preventing and treating iron overload and its related symptoms (preferably an iron chelating compound), or a pharmaceutically active compound for preventing and treating any of the above-mentioned diseases, disorders, or conditions, such as especially a compound for preventing and treating thalassemia, hemochromatosis, neurodegenerative diseases (such as Alzheimer's disease or Parkinson's disease) and their related symptoms.

[0528] Another aspect of the present invention relates to the use of the compounds as defined above per se in combination therapy (fixed-dose or free-dose combinations for sequential use) with one or two other active ingredients (medicaments). Such combination therapy includes co-administering the compounds of the present invention with at least one other pharmaceutically active compound (medicament). The combination therapy in fixed-dose combination therapy includes co-administering the compounds of the present invention with at least one other pharmaceutically active compound in a fixed-dose formulation. The combination therapy in free-dose combination therapy includes co-administering the compounds of the present invention and at least one other pharmaceutically active compound at the free doses of the respective compounds, which can be carried out by co-administering the respective compounds simultaneously or by sequentially using the respective compounds over a period of time. At least one other pharmaceutically active compound (medicament) particularly includes medicaments for reducing iron overload (such as Tmprss6-ASO) or iron chelators, in particular curcumin, SSP-004184, deferiprone, deferasirox, desferrioxamine and / or deferiprone, or antioxidants such as N-acetylcysteine, antidiabetic drugs such as GLP-1 receptor agonists, antibiotics such as vancomycin (Van) or tobramycin, drugs for treating malaria, anticancer agents, antifungal drugs, drugs for treating neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (such as dopamine agonists such as levodopa), antiviral drugs such as interferon-α or ribavirin, immunosuppressants (cyclosporine A or derivatives of cyclosporine A), iron supplements, vitamin supplements, erythropoiesis-stimulating agents, anti-inflammatory biologics, antithrombotic drugs, statins, vasopressors and inotropic agents.

[0529] Another aspect of the present invention relates to the use of the above combination for the prevention and / or treatment of diseases caused by hepcidin deficiency or iron metabolism disorders, such as in particular iron overload states, such as in particular thalassemia and hemochromatosis and other diseases described in the present application.

[0530] Another aspect of the present invention relates to the use of the compounds as defined herein per se or the above combination therapy in combination with blood transfusion.

[0531] The compounds, medicaments and / or pharmaceutical preparations of the present invention can be administered orally, parenterally and intravenously.

[0532] For this purpose, the compounds of the present invention are preferably in the form of pills, tablets such as enteric-coated tablets, film-coated tablets and layer tablets, sustained-release preparations for oral administration, depot preparations, dragees, granules, emulsions, dispersions, microcapsules, micro-formulations, nano-formulations, liposomal formulations, capsules such as enteric-coated capsules, powders, microcrystalline formulations, dusting powders, drops, ampoules, solutions, suspensions, infusions or injection solutions, or in the form of preparations suitable for inhalation, and are present in the medicament or pharmaceutical composition.

[0533] In a preferred embodiment of the present invention, the compound is administered in the form of the above-mentioned tablets or capsules. The tablets or capsules can be present, for example, in an acid-resistant form or in the form of a pH-dependent coating.

[0534] The compound of the present invention, as the active substance, can be administered, for example, in a unit dose of 0.001 mg to 500 mg per kilogram of body weight, for example, 1 to 4 times a day. However, the dose can be increased or decreased according to the patient's age, weight, condition, disease severity, or type of administration.

[0535] Therefore, another aspect of the present invention relates to the use of the compounds, drugs, compositions, and fixed-dose combinations defined above for the preparation of a medicament, in particular for the prevention and treatment of any of the above-mentioned indications, conditions, disorders, or diseases, especially for oral or parenteral administration.

[0536] Another aspect of the present invention relates to a method of prevention and treatment as defined above, for example, especially for the prevention and / or treatment of iron metabolism disorders associated with or leading to elevated iron levels, 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 hematopoiesis. The method comprises administering to a patient (human or animal) in need thereof the compounds, drugs, compositions, or fixed-dose combinations defined above.

[0537] Among them, the diseases associated with, caused by, or leading to elevated iron levels or iron overload are as defined above.

[0538] Another aspect of the present invention relates to the use of the compounds defined above for the preparation of a medicament, in particular for the prevention and treatment of any of the above-mentioned indications, conditions, disorders, or diseases.

[0539] The compounds of the general structural formulas (I-A) and (I-B) of the present invention can be prepared substantially according to the following general synthetic schemes I, II, and III:

[0540] General synthetic scheme I:

[0541]

[0542] (Wherein the leaving group Q can be NHBoc or NBoc, and the positions of "XH" and "NH2" can be interchanged to prepare the "iso-compounds" described herein).

[0543]

[0544]

[0545] (Wherein, the structure represented by "(b1 / b2 / b3)" represents the structures b-1, b-2 or b-3 defined herein).

[0546] General synthetic scheme II:

[0547]

[0548] (Wherein the positions of "XH" and "NH2" can be interchanged to prepare the "hetero-compounds" described herein, and the structure represented by "(b1 / b2 / b3)" represents the structures b-1, b-2 or b-3 defined herein)

[0549] General synthetic scheme III:

[0550]

[0551] (Wherein, the leaving group Q can be OBn, and wherein the positions of "XH" and "NH2" can be interchanged to prepare the "hetero-compounds" described herein)

[0552]

[0553] (Wherein, the structure represented by "(b1 / b2 / b3)" represents the structures b-1, b-2 or b-3 defined herein).

[0554] In particular, the following general procedure describes a suitable method for preparing the preferred compounds of the present invention: Synthesis of intermediates:

[0555] General scheme 1:

[0556]

[0557] (Wherein R represents a substituent R defined herein 1 or R 2 ).

[0558] General scheme 2:

[0559]

[0560] (Wherein R represents a substituent R defined herein 1 or R 2 )

[0561] General scheme 3:

[0562]

[0563] (Wherein R represents a substituent R defined herein 1 or R 2)。

[0564] General scheme 4:

[0565]

[0566] (where R 4 may have any meaning defined anywhere herein).

[0567] General scheme 5:

[0568]

[0569] (where R represents a substituent R defined herein 1 or R 2 ). Synthesis of the compounds of the present invention:

[0570] General scheme 6:

[0571]

[0572] (where R 1 and R 4 may have any meaning defined anywhere herein).

[0573] General scheme 7:

[0574]

[0575] (where R 1 and R 4 may have any meaning defined anywhere herein).

[0576] General scheme 8:

[0577]

[0578] (where R 1 and R 4 may have any meaning defined anywhere herein).

[0579] General scheme 9:

[0580]

[0581] (where R 1 and R 4 may have any meaning defined anywhere herein).

[0582] In another aspect, the present invention encompasses intermediate compounds obtainable by the preparation methods described herein, such as, in particular, intermediate compounds resulting from the individual steps of the general reaction schemes described above, which will be described in further detail herein. Details of the preparation conditions are provided in the following examples. Examples

[0583] The present invention is illustrated in more detail by the following examples. These examples are for illustrative purposes only, and those skilled in the art can extend these specific examples to other compounds claimed.

[0584] Pharmacological tests

[0585] 1. Hepcidin Internalization Assay (J774)

[0586] This cellular assay quantitatively analyzes the binding of hepcidin to ferroportin (Fpn) by microscopically detecting the internalization of fluorescently labeled hepcidin into J774 cells. J774 is a murine macrophage cell line that has been shown to endogenously express Fpn after incubation with iron (Knutson et al., 2005). The binding of hepcidin to Fpn triggers the internalization and degradation of both hepcidin and Fpn. However, the 6-carboxytetramethylrhodamine (TMR) fluorophore attached to hepcidin remains bound to the cells after degradation of the hepcidin peptide chain. Thus, the binding of hepcidin to Fpn and the extent of hepcidin and Fpn internalization can be measured by microscopically detecting the TMR fluorescence intensity associated with the cells. If TMR-hepcidin cannot bind to Fpn, the TMR fluorescence intensity of the cells remains at a low level (Dürrenberger et al., 2013). The following is a method for evaluating the role of small molecule Fpn inhibitor compounds in this assay in vitro.

[0587] Harvest J774 cells from a culture that is approximately 80% confluent at 8×10 5Cells were seeded at a density of 50 cells / ml in complete medium (DMEM, 10% fetal bovine serum, 1% penicillin-streptomycin) containing 200 μM Fe(III)NTA (nitrilotriacetic acid), 100 μl per well, in a 96-well MicroClear plate (Greiner; catalog number 655090), and cultured at 37 °C in 5% CO2. After overnight incubation, the cells were washed 3 times with pre-warmed phenol red-free DMEM. After the last wash, 30 μl of phenol red-free DMEM was added to each well, followed by 10 μl of serially diluted test compound, with 3 replicates per concentration. The J774 cells were pre-incubated with the test compound at 37 °C in 5% CO2 for 15 minutes, and then TMR-hepcidin was added at a final concentration of 25 nM. The cells were incubated at 37 °C in 5% CO2 for 2 hours in a total volume of 50 μl, and then Hoechst 33342 dye was added at a final concentration of 0.5 μg / ml to stain the cell nuclei, and incubation was continued at 37 °C in 5% CO2 for 10 minutes. The cells were washed 3 times with PBS, then fixed with 100 μl of PBS containing 4% paraformaldehyde at room temperature for 15 minutes. After removing the paraformaldehyde solution, the cells were washed 3 times with PBS, 100 μl was retained in each well, and the plate was sealed with a foil plate seal. TMR (excitation wavelength 530 - 550 nm / emission wavelength 575 - 625 nm / exposure time 400 ms) and Hoechst 33342 (excitation wavelength 360 - 370 nm / emission wavelength 420 - 460 nm / exposure time 10 ms) fluorescence images were acquired using a ScanR plate imager (Olympus) equipped with a 20x high numerical aperture objective lens. Four images were acquired per well, and the fluorescence channels covered approximately 1500 cells per well. The acquired image data was analyzed using ScanR image analysis software. Image analysis included detecting cell nuclei (Hoechst 33342 fluorescence), identifying cell-associated regions, applying virtual channels and thresholds to reduce rolling ball background, and then applying the Sum(Mean) algorithm to measure the TMR fluorescence intensity associated with the cells, which was used as a quantitative indicator of internalized TMR-hepcidin. Using Prism 5 software (GraphPad Software Inc., version 5.02), the IC 50 values were calculated from the Sum(Mean) raw data by "log(inhibitor) vs. response" curve fitting. For each data set, the fitting results of the "log(inhibitor) vs. response (three parameters)" model were compared with the fitting results of the "log(inhibitor) vs. response - variable slope (four parameters)" model, and the IC 50 data of the preferred model was adopted. The IC 50 data of the Fpn inhibitors tested in the hepcidin internalization assay are listed in Table 1. In this assay, the IC 50 data of unlabeled hepcidin is 5050 is 0.015 ± 0.011 μM.

[0588] Table 1 shows the average (AVE) IC of multiple measurements of Fpn inhibitors tested in the hepcidin internalization assay 50 Data

[0589] Table 1

[0590]

[0591]

[0592]

[0593] 2. Biophysical ferroportin - hepcidin binding assay

[0594] This biophysical assay was developed to more directly confirm the inhibition of hepcidin binding to ferroportin (Fpn). Incubating TMR - hepcidin with purified human Fpn isolated from Pichia pastoris cells expressing human Fpn with a C - terminal FLAG affinity tag (Bonaccorsi di Patti, 2014) results in an increase in the fluorescence polarization (FP) of the TMR - hepcidin ligand. The inhibition of the binding of the small - molecule Fpn inhibitor to TMR - hepcidin and Fpn was tested by detecting the decrease in the TMR FP signal with dose, as described below.

[0595] 1.3 μM human Fpn and 30 nM TMR - hepcidin were dissolved in FP assay buffer containing 50 mM Tris - HCl pH 7.3, 200 mM NaCl, 0.02% DDM, 0.1% BSA. The mixture was seeded into 384 - well black low - volume round bottom plates (Corning, catalog number 3677) at 16 μl per well. 8 μl of serially diluted test compounds were added to bring the final concentrations of Fpn and TMR - hepcidin to 1 μM and 20 nM, respectively, with 2 replicates for each concentration. After incubation at room temperature for 90 minutes, parallel (S) and perpendicular (P) fluorescence were measured using a Synergy H1 fluorescence reader (BioTek).

[0596] The FP value in mP was calculated according to the following formula.

[0597]

[0598] Following the method described in the hepcidin internalization assay, the IC value was determined based on the calculated mP values. 50 value. In this assay, the IC of unlabeled hepcidin 50 was approximately 0.37 ± 0.067 μM.

[0599] 3. Inhibitory effect on ferroportin-mediated iron export activity in iron response assays

[0600] In this assay, intracellular iron levels are indirectly measured by monitoring the activity of a β-lactamase (BLA) reporter gene fused to the human ferritin promoter and an iron-responsive element (IRE) in the 5'-untranslated region of ferritin mRNA. Expression of ferroportin (Fpn) in such cell lines leads to iron efflux and a decrease in iron levels, which is reflected in a decrease in reporter gene activity. On the other hand, inhibition of Fpn-mediated iron efflux leads to an increase in intracellular iron levels, manifested as an increase in reporter gene activity. The following is a method for testing the dose-dependent effect of small molecule Fpn inhibitor compounds in an in vitro iron response assay.

[0601] The HEK-293 cell line #354 was 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 number 631068), and (ii) a human ferritin promoter-BLA reporter gene into the HEK-293 Tet-ON Advanced cell line (Clontech). To construct the ferritin-BLA reporter gene construct, a 1.4 kb human ferritin H promoter fragment was amplified by PCR from human genomic DNA (forward primer 5'-CAGGTTTGTGAGCATCCTGAA-3'; reverse primer 5'-GGCGGCGACTAAGGAGAGG-3') and inserted upstream of the BLA gene in the pcDNA TM 6.2 / cGeneBLAzer TM -DEST plasmid (Invitrogen, catalog number 12578-043), thereby replacing the original CMV promoter, and placing the IRE that regulates ferritin gene translation approximately 170 bp upstream of the reporter gene start codon. Cells #354 were harvested from cultures at approximately 80% confluence and seeded at a density of 1.8×10 5 cells / ml in DMEM / F12 GlutaMAX containing 10% fetal bovine serum (Clontech, catalog number 631106), 1% penicillin-streptomycin, 200 μg / ml hygromycin B (Invitrogen, catalog number 10687-010), 5 μg / ml blasticidin (Invitrogen, catalog number R210-01), 4 μg / ml doxycycline (Clontech, catalog number 631311) TMIn a medium (Invitrogen, catalog number 31331 - 028), 50 μl per well, inoculated into a 384 - well PDL - coated plate, and cultured at 37 °C under 5% CO₂ conditions. After overnight incubation, 10 μl of serially diluted test compounds were added to each well, with 4 replicates for each concentration. Then the plate was further incubated overnight at 37 °C under 5% CO₂ conditions. The cells were washed 3 times with HBSS, and 25 μl was retained in each well. BLA activity was detected by adding 5 μl / well of GeneBlazer reagent CCF4 - AM (Invitrogen, catalog number K1085) to the cells. After incubating the plate for 60 minutes at 18 °C in the dark, the blue and green fluorescence signals were measured using a Safire2 fluorescence plate reader (Tecan) at an excitation wavelength of 410 nm, emission wavelengths of 458 nm (blue) and 522 nm (green). The blue / green fluorescence ratio was calculated as a measure of BLA activity, and the EC 50 value was determined according to the method described in the hepcidin internalization assay based on the calculated blue / green fluorescence ratio. In this assay, the EC 50 of hepcidin was approximately 0.096 ± 0.063 μM (n = 37).

[0602] 4. Ferroportin internalization and degradation assay

[0603] The ability of compounds to induce ferroportin (Fpn) internalization and degradation was measured by fluorescence - activated cell sorting (FACS) using the HEK - 293 cell line #354 (described in Example 3). HEK - 293 #354 cells were cultured in a medium containing doxycycline to induce cell - surface expression of the human Fpn - GFP fusion protein. Data from 10 independent experiments showed that culturing HEK #354 cells in the presence of 4 μg / ml doxycycline for 48 hours could induce an average of 42.6% ± 6.4% of Fpn - GFP - positive cells. The following is the method for testing the dose - dependent effect of small - molecule Fpn inhibitor compounds on the mean fluorescence intensity (MFI) of Fpn - GFP on the HEK - 293 cell line #354.

[0604] HEK #354 cells were harvested from a culture at approximately 80% confluence and inoculated at a density of 0.6×10 6 cells / ml into DMEM / F12 GlutaMAX containing 10% fetal bovine serum (Clontech, catalog number 631106), 1% penicillin - streptomycin (Invitrogen, catalog number 15140 - 122), 200 μg / ml hygromycin B (Invitrogen, catalog number 10687 - 010), 5 μg / ml blasticidin (Invitrogen, catalog number R210 - 01), 4 μg / ml doxycycline (Clontech, catalog number 631311)TM In a medium (Invitrogen, catalog number 31331-028), 50 μl per well, seeded in a 384-well plate (Greiner; catalog number 781091), and cultured at 37 °C under 5% CO2. After overnight incubation, 10 μl of a series of diluted test compounds was added to each well, with 4 replicates for each concentration, and then the plate was incubated overnight at 37 °C under 5% CO2. The cells were washed once with FACS buffer (PBS containing 1% fetal bovine serum, 2 mM EDTA, and 0.05% NaN3), harvested with FACS buffer containing 0.5 μg / ml propidium iodide (Sigma, catalog number P4864), and analyzed on a flow cytometer (CANTO tm II, BD Biosciences) equipped with a high-throughput sampler. Live HEK #354 cells were set as the propidium iodide-negative population, and the expression of Fpn-GFP was analyzed. The mean fluorescence intensity (MFI) of Fpn-GFP in >2000 live cells for each compound dilution was calculated using FlowJo (Tree Star's, Oregon), and the potency of Fpn inhibitors to induce Fpn-GFP internalization and degradation was calculated as described in the hepcidin internalization assay. In this assay, the mean EC 50 value of hepcidin was approximately 0.004 ± 0.002 μM.

[0605] 5. Ferroportin ubiquitination and degradation

[0606] It is known that exposing cells expressing ferroportin (Fpn) to hepcidin triggers the ubiquitination of Fpn, followed by internalization and degradation (Qiao, 2012). Using the J774 mouse macrophage cell line expressing Fpn after iron treatment, the potential of Fpn inhibitors to induce Fpn ubiquitination and degradation was investigated by immunoprecipitation assay.

[0607] J774 cells (DSMZ, catalog number ACC170) were seeded at 0.8×10 6Cells were seeded at a density of cells / ml in 15 ml of medium (DMEM Gibco cat. no. 11971-025, 10% heat-inactivated fetal bovine serum Gibco cat. no. 10500-064, 1% penicillin-streptomycin Gibco cat. no. 15140-122) containing 200 μM Fe(III)-NTA, seeded in a 10 cm tissue culture dish (Greiner cat. no. 664160), and cultured overnight at 37 °C and 5% CO2. The cells were incubated with synthetic human hepcidin (Bachem, cat. no. H-5926) or an Fpn inhibitor compound for 10 minutes or 120 minutes. After washing the cells, the cells were lysed with ice-cold lysis buffer (Pierce, Life Technoligies, cat. no. 87787), which contained 1X HALT protease inhibitor cocktail (Life technologies, cat. no. 78429) and 10 mM iodoacetamide (Sigma, cat. no. I6125) to stabilize ubiquitinated proteins. Immunoprecipitation was performed using the Pierce Classic IP Kit (Life Technologies, cat. no. 26146) according to the manufacturer's protocol. Briefly, 2 mg of protein in 1.25 ml of IP lysis buffer was mixed and incubated with control agarose beads at 4 °C for 1 hour to clear the lysate and reduce non-specific signals. Then the unbound lysate was incubated overnight with 12 μg of affinity-purified anti-Fpn antibody F308 against the GST fusion protein of mouse Fpn amino acids 224-308 per reaction. The immune complexes were captured by pipetting 14 μl of precipitated Pierce Protein A / G Plus agarose beads (Life Technologies, cat. no. 20423) per reaction, and the slurry was gently inverted and incubated at 4 °C for 1.5 hours. The beads were washed and then the immune complexes were directly eluted with 75 μl of SDS NuPAGE LDS sample buffer (LifeTechnologies, cat. no. NP0007) containing DTT (Life Technologies, cat. no. NP0009).

[0608] After immunoprecipitation, the samples were analyzed by Western blot analysis to detect ferroportin and ubiquitin using rabbit anti-mouse MTP1 antiserum (Alpha Diagnostic International, cat. no. MTP11-A) and mouse anti-monoubiquitinated and polyubiquitinated conjugates monoclonal antibody (Enzo Lifesciences, cat. no. BML-PW8810), respectively. Mouse monoclonal anti-rabbit IgG light chain (Abcam, cat. no. ab99697) and anti-mouse IgG H&L (Abcam, cat. no. ab6789) HRP conjugates were used as secondary antibodies.

[0609] 6. Inhibitory effect of transferrin inhibitors on iron efflux

[0610] The activity of hepcidin and transferrin inhibitor compounds to block the ability of iron to be exported through transferrin was tested on T47D cells (ECACC, catalog number 85102201) as described below.

[0611] Cells were seeded in 24-well plates (Greiner, catalog number 662160), with 350,000 cells per well, and in growth medium containing 500 μM L-ascorbic acid (Sigma Aldrich, catalog number 795437), incubated overnight with 100 μM 58 Fe( 58 Fe(II)-sulfate, Vifor Pharma batch number ROR 3085). Cells were washed once with 500 μl of iron uptake buffer (IUB; 40 mM PIPES, catalog number P1851, 10 mM glucose monohydrate, catalog number 49158, 260 mM sodium chloride, catalog number 71379, 20 mM potassium chloride, catalog number P9541, 2 mM magnesium sulfate, catalog number 63138, Sigma Aldrich), then incubated for 2 minutes with removal buffer (containing 100 μM BPDS, catalog number 11890 and 500 μM Na2S2O4, catalog number 157953, Sigma Aldrich, dissolved in IUB), and washed twice with IUB. Serial dilutions of hepcidin (Bachem) or transferrin inhibitor (4 μM - 0.0064 μM, 5-fold dilution) with a total volume of 0.6 ml were added to each well. Cells were incubated at 37 °C and 5% CO2 for 20 hours. The supernatant was collected, and the 58 Fe content was measured using inductively coupled plasma mass spectrometry (ICP-MS, Thermo Scientific, Element 2). The cell pellet was harvested for protein concentration determination. The results were plotted as nanograms of 58 Fe per milligram of protein in the cell lysate versus the supernatant.

[0612] Preparation of the example compounds

[0613] General experimental details

[0614] Commercially available reagents and solvents (HPLC grade) can be used without further purification. 1 1H NMR spectra were recorded on a Bruker DRX500 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.

[0615] The compound was purified by flash column chromatography on normal phase silica gel using a suitable SNAP column and gradient on a Biotage Isolera system. Alternatively, the compound was purified under reverse phase conditions using a Biotage Isolera system with a suitable C18 SNAP column and reverse phase eluent, or by preparative HPLC (except as otherwise noted).

[0616] Abbreviations

[0617] EtOAc: Ethyl acetate

[0618] CH2Cl2: Dichloromethane

[0619] Et2O: Diethyl ether

[0620] MeOH: Methanol

[0621] EtOH: Ethanol

[0622] brine: Saturated aqueous sodium chloride solution

[0623] Chloroform-d: Deuterochloroform

[0624] DMSO-d6: Deuterated dimethyl sulfoxide

[0625] s: Singlet

[0626] br s: Broad singlet

[0627] d: Doublet

[0628] dd: Double doublet

[0629] dt: Double triplet

[0630] td: Triple doublet

[0631] hept.: Heptet

[0632] m: Multiplet

[0633] q: Quartet

[0634] δ: Chemical shift

[0635] ppm: Parts per million

[0636] M: Molarity

[0637] mM: Millimolarity

[0638] μmol: Micromole

[0639] g: Gram

[0640] mg: Milligram

[0641] l: liter

[0642] mL: milliliter

[0643] h: hour

[0644] min: minute

[0645] %-w / w: weight percentage

[0646] TLC: thin layer chromatography

[0647] UHPLC: ultra-high performance liquid chromatography

[0648] MS: mass spectrometry

[0649] ESI: electrospray ionization

[0650] m / z: mass-to-charge ratio

[0651] H + : proton

[0652] MHz: megahertz

[0653] s.m.: starting material

[0654] Jones Reagent: H2SO4 solution of CrO3, CrO3: chromium trioxide

[0655] HCl: hydrochloric acid

[0656] H2SO4: sulfuric acid

[0657] NH4Cl: ammonium chloride

[0658] Na2SO4: sodium sulfate

[0659] NaOH: sodium hydroxide

[0660] Bn: benzyl

[0661] MS Mass spectra: mass spectra

[0662] ESI: electrospray ionization

[0663] SNAP: brand name of Biotage column for flash column chromatography

[0664] R f : retention factor

[0665] TLC: thin layer chromatography

[0666] Chemical nomenclature

[0667] The chemical names of the intermediate and final example compounds were generated by ChemDraw Professional 17.0. All R f values were determined using the following TLC plates: Merck, silica gel 60F 254 TLC plates.

[0668] Preparation details

[0669] Intermediate

[0670] A. tert-Butyl (3-((4-hydroxypyridin-3-yl)amino)-3-oxopropyl)carbamate

[0671]

[0672] To a solution of 3-aminopyridin-4-ol (5.00 g, 44.0 mmol, 1 eq.) in N,N-dimethylformamide (90 mL) was added 3-((tert-butoxycarbonyl)amino)propanoic acid (8.42 g, 44.0 mmol, 1 eq.), triethylamine (12.4 mL, 88.1 mmol), and HATU (20.7 g, 52.9 mmol, 1.2 eq.). The reaction mixture was stirred at 23 °C for 16 h. The solution was diluted with water and extracted with ethyl acetate (3 times). 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 / ethyl acetate, 0 - 100% ethyl acetate) to give the title compound, tert-butyl (3-((4-hydroxypyridin-3-yl)amino)-3-oxopropyl)carbamate (11.7 g, 41.6 mmol, 94%) as a white foam.

[0673] LCMS (ESI) m / z = 282.2. 1 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.

[0674] B. tert-Butyl (2-(oxazolo[4,5-c]pyridin-2-yl)ethyl)carbamate

[0675]

[0676] To a suspension of polymer-supported triphenylphosphine (loading 1.6 mmol / g, 7.75 g, 12.4 mmol, 2 eq.) in dichloromethane (60 mL) was added hexachloroethane (1.83 g, 7.73 mmol, 1.25 eq.) and triethylamine (4.31 mL, 30.9 mmol, 5 eq.). The suspension was stirred for 5 minutes, then (3-((4-hydroxypyridin-3-yl)amino)-3-oxopropyl)carbamic acid tert-butyl ester (1.74 g, 6.19 mmol, 1.0 eq.) was added. The mixture was stirred at room temperature for 1 hour. Another portion of 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, then filtered. The filtrate was concentrated and the resulting crude oil was purified by flash column chromatography (heptane / ethyl acetate, 0 - 100% ethyl acetate) to give the desired tert-butyl (2-(oxazolo[4,5-c]pyridin-2-yl)ethyl)carbamate (1.12 g, 4.25 mmol, 69%).

[0677] LCMS (ESI) m / z = 264.1. 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.

[0678] C. tert-Butyl (2-((tert-butoxycarbonyl)amino)ethyl)oxazolo[4,5-c]pyridine 5-oxide

[0679]

[0680] tert-Butyl (2-(oxazolo[4,5-c]pyridin-2-yl)ethyl)carbamate (3.04 g, 11.5 mmol, 1 eq.) was dissolved in dichloromethane (100 mL). The solution was cooled to 0 °C and m-chloroperbenzoic acid (mCPBA, 75% Wt, 5.31 g, 23.1 mmol, 2 eq.) was added. After 2 hours, the ice bath was removed and stirring was continued at 23 °C until LCMS showed complete conversion of the starting material. 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 product was suspended in methanol. The solid was filtered, washed with methanol and dried in vacuo to give the desired tert-butyl (2-((tert-butoxycarbonyl)amino)ethyl)oxazolo[4,5-c]pyridine 5-oxide (1.78 g, 6.37 mmol, 55%) as an off-white solid.

[0681] LCMS(ESI) m / z = 280.3. 1 H 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.

[0682] D. tert-Butyl (2-(4-(((3-fluoropyridin-2-yl)methyl)amino)oxazolo[4,5-c]pyridin-2-yl)ethyl)carbamate

[0683]

[0684] To a dry THF (60 mL) solution of 2-(2-((tert-butoxycarbonyl)amino)ethyl)oxazolo[4,5-c]pyridine 5-oxide (1.78 g, 6.37 mmol, 1 eq.) and (3-fluoropyridin-2-yl)methanamine dihydrochloride (1.90 g, 9.56 mmol, 1.5 eq.) was added DIPEA (4.12 g, 5.55 mL, 31.9 mmol, 5 eq.) and bromotris(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) (4.47 g, 9.56 mmol, 1.5 eq.). The reaction mixture was stirred at 23 °C until LC / MS showed complete consumption of the starting materials. 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 product was purified by flash column chromatography (CH2Cl2 / MeOH / NH3 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%).

[0685] LCMS(ESI) m / z = 388.6. 1 H 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.

[0686] E. 2-(2-Aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine

[0687]

[0688] Dissolve 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 eq.) in dichloromethane (60 mL), and then treat with 4N hydrogen chloride dioxane solution (14.9 mL, 59.6 mmol, 10 eq.). The reaction mixture was neutralized with 7N methanol ammonia solution and then concentrated. The crude mixture was purified by flash column chromatography (CH2Cl2 / methanol solution of 1N NH3, 90 / 10) to give 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.

[0689] LCMS (ESI) m / z = 288.2. 1 H 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.

[0690] F. tert-Butyl 3-((4-hydroxypyridin-3-yl)carbamoyl)azetidine-1-carboxylate

[0691]

[0692] To a solution of 3-aminopyridin-4-ol (3.00 g, 27.2 mmol, 1 eq.) in DMF (50 mL), 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (5.48 g, 27.2 mmol, 1 eq.), triethylamine (7.59 mL, 54.5 mmol, 2 eq.), and HATU (12.4 g, 32.7 mmol, 1.2 eq.) were added. The reaction mixture was stirred at 23 °C for 16 h. The solution was diluted with water and extracted with ethyl acetate (3 times). 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 (CH2Cl2 / MeOH, 0 - 15% MeOH) to give 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.

[0693] LCMS (ESI) m / z = 288.2 [M-tBuOH]. 1 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.

[0694] G. tert-Butyl 3-(oxazolo[4,5-c]pyridin-2-yl)azetidine-1-carboxylate

[0695]

[0696] To a suspension of polymer-supported triphenylphosphine (loading 1.6 mmol / g, 7.75 g, 12.4 mmol, 2 eq.) in dichloromethane (60 mL) was added hexachloroethane (1.84 g, 7.76 mmol, 1.25 eq.) and triethylamine (4.32 mL, 31.0 mmol, 5 eq.). The suspension was stirred for 5 minutes, then solid tert-butyl (3-((4-hydroxypyridin-3-yl)amino)-3-oxopropyl)carbamate (1.82 g, 6.20 mmol, 1 eq.) was added. The mixture was stirred at room temperature for 1 hour. Another portion of 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 / ethyl acetate, 0 - 100% ethyl acetate) to afford the desired tert-butyl 3-(oxazolo[4,5-c]pyridin-2-yl)azetidine-1-carboxylate (1.28 g, 4.65 mmol, 75%).

[0697] LCMS(ESI) m / z = 276.2. 1 H 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.

[0698] H. 2-(1-(tert-Butoxycarbonyl)azetidin-3-yl)oxazolo[4,5-c]pyridine 5-oxide

[0699]

[0700] tert-Butyl 3-(oxazolo[4,5-c]pyridin-2-yl)azetidine-1-carboxylate (1.28 g, 4.65 mmol, 1 eq.) was dissolved in dichloromethane (45 mL). The solution was cooled to 0 °C and m-chloroperbenzoic acid (75% Wt, 2.14 g, 9.30 mmol, 2 eq.) was added. After 2 h, the ice bath was removed and stirring was continued at 23 °C until LCMS indicated complete conversion of the starting material. 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 product was suspended in methanol. The solid was filtered, washed with methanol and dried in vacuo 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.

[0701] LCMS (ESI) m / z = 292.2. 1 H 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.

[0702] I. tert-Butyl 3-(4-(((3-fluoropyridin-2-yl)methyl)amino)oxazolo[4,5-c]pyridin-2-yl)azetidine-1-carboxylate

[0703]

[0704] To a dry solution of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)oxazolo[4,5-c]pyridine 5-oxide (716 mg, 2.46 mmol, 1 eq.) and (3-fluoropyridin-2-yl)methanamine dihydrochloride (734 mg, 3.69 mmol, 1.5 eq.) in tetrahydrofuran (25 mL) was added DIPEA (2.14 mL, 12.3 mmol, 5 eq.) and bromotris(pyrrolidin-1-yl)phosphonium hexafluorophosphate (V) (1.73 g, 3.69 mmol, 1.5 eq.). The reaction mixture was stirred at 23 °C until LC / MS showed complete consumption of the starting materials. 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 product 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%).

[0705] LCMS(ESI) m / z = 400.3. 1 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.

[0706] J. 2-(Azetidin-3-yl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine

[0707]

[0708] 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 eq.) was dissolved in dichloromethane (20 mL), and then treated with 4N hydrogen chloride dioxane solution (6.12 mL, 24.5 mmol, 10 eq.). After complete conversion of the starting material, the reaction mixture was concentrated under reduced pressure. The crude product was purified by a strong cation exchange column (SCX-column) and eluted with 7N methanolic ammonia solution 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.

[0709] LCMS (ESI) m / z = 300.2. 1 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.

[0710] K. Oxazolo[4,5-c]pyridine

[0711]

[0712] 3-Aminopyridin-4-ol (1.50 g, 1 eq., 13.6 mmol) was added to a microwave reaction vial and suspended in trimethyl orthoformate (14.9 mL, 136 mmol, 10 eq.). Acetic acid (1.17 mL, 20.4 mmol, 1.5 eq.) was added, the reaction vial was sealed and subjected to microwave irradiation (160 °C, 30 min). The reaction mixture was concentrated and the residue was purified by flash column chromatography (50% ethyl acetate in hexane to 100% ethyl acetate) to give the desired oxazolo[4,5-c]pyridine (1.17 g, 9.74 mmol, 72%) as a colorless oil which crystallized upon standing.

[0713] LCMS (ESI) m / z = 121.1. 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.

[0714] L. Oxazolo[4,5-c]pyridine 5-oxide

[0715]

[0716] Dissolve oxazolo[4,5-c]pyridine (4.66 g, 38.8 mmol, 1 eq.) in dichloromethane (40.0 mL). Cool the solution to 0 °C and add m-chloroperbenzoic acid (75% wt, 17.9 g, 77.6 mmol, 2.0 eq.). Remove the ice bath after 2 hours and continue stirring at 23 °C until thin-layer chromatography (TLC) shows complete conversion of the starting material. Concentrate the reaction mixture to about 20 mL, filter, and purify the filtrate directly by flash column chromatography (CH2Cl2 / MeOH, 0 - 20% MeOH) to obtain the desired oxazolo[4,5-c]pyridine 5-oxide (4.02 g, 38.8 mmol, 76%) as a beige solid.

[0717] LCMS (ESI) m / z = 137.2. 1 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.

[0718] M.N-((3-Fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine

[0719]

[0720] To a dry THF (9 mL) solution of oxazolo[4,5-c]pyridine 5-oxide (240 mg, 1.76 mmol, 1 eq.) and (3-fluoropyridin-2-yl)methanamine dihydrochloride (526 mg, 2.64 mmol, 1.5 eq.), add DIPEA (1.14 g, 1.54 mL, 8.82 mmol, 5 eq.) and bromotris(pyrrolidin-1-yl)phosphonium hexafluorophosphate (V) (1.24 g, 2.64 mmol, 1.5 eq.). Stir the reaction mixture at 23 °C until TLC shows complete consumption of the starting material. Dilute the reaction mixture with ethyl acetate and wash with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and brine. Dry the organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the crude product by flash column chromatography (heptane / ethyl acetate, 0 - 100% ethyl acetate) to obtain 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.

[0721] LCMS(ESI) m / z = 245.2. 1 H 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.

[0722] N.2 - Bromo - N - ((3 - fluoropyridin - 2 - yl)methyl)oxazolo[4,5 - c]pyridin - 4 - amine

[0723]

[0724] Under an inert atmosphere, N - ((3 - fluoropyridin - 2 - yl)methyl)oxazolo[4,5 - c]pyridin - 4 - amine (250 mg, 1 eq., 1.02 mmol) was dissolved in tetrahydrofuran (8 mL) and cooled to - 78 °C. Lithium bis(trimethylsilyl)amide LiHMDS (360 mg, 2.15 mL, 1 M, 2.1 eq., 2.15 mmol) was added dropwise. The reaction mixture was warmed to - 40 °C over 60 minutes. Subsequently, the orange solution was recooled to - 78 °C and then treated at once with N - bromosuccinimide (237 mg, 1.33 mmol, 1.3 eq.). The reaction mixture was warmed to 23 °C overnight. The reaction was quenched by adding saturated aqueous ammonium chloride solution and then extracted with ethyl acetate (3 times). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (heptane / ethyl acetate, 0 - 100% ethyl acetate) to give 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.

[0725] LCMS(ESI) m / z = 325.2, 323.2. 1 H 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, 1.3 Hz, 1H), 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.

[0726] O.N-((3-Fluoropyridin-2-yl)methyl)-2-vinyloxazolo[4,5-c]pyridin-4-amine

[0727]

[0728] 2-Bromo-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (75 mg, 0.23 mmol, 1 eq.), tributyl(vinyl)tin (88 μL, 0.30 mmol, 1.3 eq.) and bis(triphenylphosphine)palladium(II) chloride (16 mg, 23 μmol, 10 mol%) were suspended in 1,4-dioxane (3 mL). The reaction mixture was degassed with nitrogen for 5 minutes and then heated to 110 °C. After TLC showed complete conversion of the starting material (ca. 1 h), the reaction mixture was cooled to room temperature and filtered through a short pad of Celite. The cake was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The crude product was purified by flash column chromatography (CH2Cl2 / THF) to give 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.

[0729] LCMS (ESI) = 271.2. 1 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.

[0730] P. 2-Bromo-1-(2-methoxyethyl)-1H-benzo[d]imidazole

[0731]

[0732] 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 in portions. 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 product 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%).

[0733] LCMS(ESI) m / z = 257.1, 255.1. 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.

[0734] Q. 1-(2-Methoxyethyl)-2-vinyl-1H-benzo[d]imidazole

[0735]

[0736] 2-Bromo-1-(2-methoxyethyl)-1H-benzo[d]imidazole (1.00 g, 3.92 mmol, 1 eq.), tributyl(vinyl)tin (1.26 mL, 4.31 mmol, 1.1 eq.) and bis(triphenylphosphine)palladium(II) chloride (138 mg, 196 μmol, 5 mol%) were suspended in 1,4-dioxane (40 mL). The reaction mixture was degassed with nitrogen for 5 minutes and then heated to 110 °C. After 1 hour, TLC showed complete conversion of the starting material. The reaction mixture was cooled to room temperature and filtered through a short pad of celite. The cake was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The crude product was purified by flash column chromatography (CH2Cl2 / THF) to give the desired 1-(2-methoxyethyl)-2-vinyl-1H-benzo[d]imidazole (581 mg, 2.87 mmol, 73%) as an orange gel.

[0737] LCMS(ESI) m / z = 203.3. 11H NMR (400 MHz, DMSO) δ 7.63–7.49 (m, 2H), 7.25–7.14 (m,

[0738] 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.

[0739] R. 2-Bromo-1-(cyclopropylmethyl)-1H-benzo[d]imidazole

[0740]

[0741] Under an inert atmosphere, 2-bromo-1H-benzo[d]imidazole (3.00 g, 15.2 mmol, 1 eq.) was dissolved in N,N-dimethylformamide (30 mL) at 23 °C to form a clear solution. Sodium hydride (60% Wt, 0.73 g, 18.3 mmol, 1.2 eq.) was added in portions. The reaction mixture was stirred for 10 minutes and then (bromomethyl)cyclopropane (2.47 g, 18.3 mmol, 1.2 eq.) 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 product 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%).

[0742] LCMS (ESI) m / z=253.1, 251.1. 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.

[0743] S. 1-(Cyclopropylmethyl)-2-vinyl-1H-benzo[d]imidazole

[0744]

[0745] 2-Bromo-1-(cyclopropylmethyl)-1H-benzo[d]imidazole (1.00 g, 3.98 mmol, 1 eq.), 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). The reaction mixture was degassed with nitrogen for 5 minutes and then heated to 110 °C. After 1 hour, TLC showed complete conversion of the starting material. The reaction mixture was cooled to 23 °C and filtered through a short pad of celite. The cake was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The crude product was purified by flash column chromatography (CH2Cl2 / THF) to afford the desired 1-(cyclopropylmethyl)-2-vinyl-1H-benzo[d]imidazole (522 mg, 2.63 mmol, 66%) as a slightly yellow gel.

[0746] LCMS (ESI) m / z = 199.2. 1 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.

[0747] T. 2-Bromo-1-(2-(2-methoxyethoxy)ethyl)-1H-benzo[d]imidazole

[0748]

[0749] Under an inert atmosphere, 2-bromo-1H-benzo[d]imidazole (3.00 g, 15.2 mmol, 1 eq.) 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 eq.) was added in portions. The reaction mixture was stirred for 10 minutes and then 1-bromo-2-(2-methoxyethoxy)ethane (3.34 g, 18.3 mmol, 1.2 eq.) 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 product 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.

[0750] LCMS(ESI) m / z = 299.2. 1 H 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.

[0751] U. 1-(2-(2-Methoxyethoxy)ethyl)-2-vinyl-1H-benzo[d]imidazole

[0752]

[0753] 2-Bromo-1-(2-(2-methoxyethoxy)ethyl)-1H-benzo[d]imidazole (1.00 g, 3.34 mmol, 1 eq.), tributyl(vinyl)tin (1.13 mL, 3.38 mmol, 1.1 eq.), and bis(triphenylphosphine)palladium(II) chloride (235 mg, 334 μmol, 10 mol%) were suspended in 1,4-dioxane (30 mL). The reaction mixture was degassed with nitrogen for 5 minutes and then heated to 110 °C. After TLC showed complete conversion of the starting material (ca. 1 h), the reaction mixture was cooled to 23 °C and filtered through a short pad of Celite. The cake was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The crude product was purified by flash column chromatography (CH2Cl2 / THF) to afford the desired 1-(2-(2-methoxyethoxy)ethyl)-2-vinyl-1H-benzo[d]imidazole (632 mg, 2.57 mmol, 77%) as a pale yellow gel.

[0754] V. 2-Bromo-1-(2-isopropoxyethyl)-1H-benzo[d]imidazole

[0755]

[0756] Under an inert atmosphere, 2-bromo-1H-benzo[d]imidazole (3.00 g, 15.2 mmol, 1 eq.) was dissolved in N,N-dimethylformamide (30 mL) at 23 °C to form a clear solution. Sodium hydride (60% Wt, 0.73 g, 18.3 mmol, 1.2 eq.) was added in portions. The reaction mixture was stirred for 10 minutes and then 2-(2-bromoethoxy)propane (3.05 g, 18.3 mmol, 1.2 eq.) 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 product was purified by flash column chromatography (CH2Cl2 / MeOH) to give the desired 2-bromo-1-(2-isopropoxyethyl)-1H-benzo[d]imidazole (3.30 g, 11.7 mmol, 77%) as a colorless oil that crystallized upon standing.

[0757] LCMS (ESI) m / z = 285.3, 283.3. 1 H 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.

[0758] W. 1-(2-Isopropoxyethyl)-2-vinyl-1H-benzo[d]imidazole

[0759]

[0760] 2-Bromo-1-(2-isopropoxyethyl)-1H-benzo[d]imidazole (1.00 g, 3.53 mmol, 1 eq.), tributyl(vinyl)tin (1.14 mL, 3.88 mmol, 1.1 eq.), and bis(triphenylphosphine)palladium(II) chloride (248 mg, 353 μmol, 10 mol%) were suspended in 1,4-dioxane (30 mL). The reaction mixture was degassed with nitrogen for 5 minutes and then heated to 110 °C. After TLC showed complete conversion of the starting material (ca. 1 hour), the reaction mixture was cooled to 23 °C and filtered through a short pad of Celite. The cake was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The crude product 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.

[0761] LCMS(ESI) m / z = 231.3. 1 H 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.

[0762] X. 4-(2-(2-Bromo-1H-benzo[d]imidazol-1-yl)ethyl)morpholine

[0763]

[0764] Under an inert atmosphere, 2-bromo-1H-benzo[d]imidazole (1.00 g, 5.08 mmol, 1 eq.) was dissolved in dry N,N-dimethylformamide (10 mL). The solution was cooled to 0 °C, and then sodium hydride (60% Wt, 305 mg, 7.61 mmol, 1.5 eq.) was added. After 10 minutes, 4-(2-bromoethyl)morpholine (1.48 g, 7.61 mmol, 1.5 eq.) was carefully added. The reaction mixture was slowly warmed to 23 °C over 16 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (5 times). The combined organic phases were washed with water (2 times) and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (CH2Cl2 / MeOH, 0 - 10% MeOH) to give the title compound 4-(2-(2-bromo-1H-benzo[d]imidazol-1-yl)ethyl)morpholine (1.25 g, 4.03 mmol, 79%).

[0765] LCMS(ESI) m / z = 310.1. 1 H 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.

[0766] Y. 4-(2-(2-Vinyl-1H-benzo[d]imidazol-1-yl)ethyl)morpholine

[0767]

[0768] 4-(2-(2-Bromo-1H-benzo[d]imidazol-1-yl)ethyl)morpholine (555 mg, 1.79 mmol, 1 eq.), tributyl(vinyl)tin (624 mg, 575 μL, 1.97 mmol, 1.1 eq.), 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 and then heated to 110 °C. After TLC showed complete conversion of the starting material (ca. 4 h), the reaction mixture was cooled to 23 °C and concentrated under reduced pressure. The crude product 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.

[0769] LCMS (ESI) m / z = 258.2. 1 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.

[0770] Z.1-Benzyl-2-bromo-1H-benzo[d]imidazole

[0771]

[0772] Under an inert atmosphere, 2-bromo-1H-benzo[d]imidazole (2.00 g, 10.2 mmol, 1 eq.) 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 eq.) was added portionwise. The reaction mixture was stirred for 10 minutes and then benzyl bromide (2.60 g, 15.2 mmol, 1.5 eq.) was added. The reaction mixture was stirred at 23 °C for 16 h. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 times). The combined organic phases were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (heptane / ethyl acetate) to afford the desired 1-benzyl-2-bromo-1H-benzo[d]imidazole (2.55 g, 8.88 mmol, 88%) as an off-white solid.

[0773] LCMS(ESI) m / z = 287.1.

[0774] AA. 1-Benzyl-2-vinyl-1H-benzo[d]imidazole

[0775]

[0776] 1-Benzyl-2-bromo-1H-benzo[d]imidazole (500 mg, 1.74 mmol, 1 eq.), tributyl(vinyl)tin (590 μL, 1.92 mmol, 1.1 eq.), and bis(triphenylphosphine)palladium(II) chloride (61.1 mg, 87.1 μmol, 5 mol%) were suspended in 1,4-dioxane (17 mL). The reaction mixture was degassed with nitrogen for 5 minutes and then heated to 110 °C. After TLC showed complete conversion of the starting material (ca. 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 product 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.

[0777] LCMS(ESI) m / z = 235.2. 1 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.

[0778] BB. 2-Bromo-1-(3-methoxybenzyl)-1H-benzo[d]imidazole

[0779]

[0780] Under an inert atmosphere, 2-bromo-1H-benzo[d]imidazole (2.00 g, 10.2 mmol, 1 eq.) 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 eq.) was added in portions. The reaction mixture was stirred for 10 minutes and then 1-(bromomethyl)-3-methoxybenzene (2.13 mL, 15.2 mmol, 1.5 eq.) 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 times). The combined organic phases were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (heptane / ethyl acetate) to give the desired 2-bromo-1-(3-methoxybenzyl)-1H-benzo[d]imidazole (1.43 g, 4.51 mmol, 44%) as an off-white solid.

[0781] LCMS (ESI) m / z = 317.2. 1 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.

[0782] CC. 1-(3-Methoxybenzyl)-2-vinyl-1H-benzo[d]imidazole

[0783]

[0784] 2-Bromo-1-(3-methoxybenzyl)-1H-benzo[d]imidazole (507 mg, 1.60 mmol, 1 eq.), tributyl(vinyl)tin (514 μL, 1.76 mmol, 1.1 eq.) and bis(triphenylphosphine)palladium(II) chloride (56.1 mg, 79.9 μmol, 5 mol%) were suspended in 1,4-dioxane (17 mL). The reaction mixture was degassed with nitrogen for 5 minutes and then heated to 110 °C. After TLC showed complete conversion of the starting material (ca. 2 h), the reaction mixture was cooled to 23 °C and filtered through a short pad of celite. The cake was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The crude product 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.

[0785] LCMS(ESI) m / z = 265.2. 1 H 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.

[0786] DD. 1-Bromo-1-(3-chlorobenzyl)-1H-benzo[d]imidazole

[0787]

[0788] Under an inert atmosphere, 2-bromo-1H-benzo[d]imidazole (2.00 g, 10.2 mmol, 1 eq.) was dissolved in N,N-dimethylformamide (20 mL) at 23 °C to obtain a clear solution. Sodium hydride (60% Wt, 609 mg, 15.2 mmol, 1.5 eq.) was added in portions. The reaction mixture was stirred for 10 minutes and then 1-(bromomethyl)-3-chlorobenzene (2.00 mL, 15.2 mmol, 1.5 eq.) 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 times). The combined organic phases were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (heptane / ethyl acetate) to give the desired 2-bromo-1-(3-chlorobenzyl)-1H-benzo[d]imidazole (2.57 g, 7.99 mmol, 79%) as an off-white solid.

[0789] LCMS(ESI) m / z = 321.1. 1 H 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.

[0790] EE. 1-(3-Chlorobenzyl)-2-vinyl-1H-benzo[d]imidazole

[0791]

[0792] 2-Bromo-1-(3-chlorobenzyl)-1H-benzo[d]imidazole (800 mg, 2.49 mmol, 1 eq.), tributyl(vinyl)tin (800 μL, 2.74 mmol, 1.1 eq.), and bis(triphenylphosphine)palladium(II) chloride (87.3 mg, 124 μmol, 5 mol %) were suspended in 1,4-dioxane (18 mL). The reaction mixture was degassed with nitrogen for 5 min and then heated to 110 °C. After TLC showed complete conversion of the starting material (ca. 2 h), the reaction mixture was cooled to 23 °C and filtered through a short pad of Celite. The cake was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The crude product was purified by flash column chromatography (CH2Cl2 / THF) to afford the desired 1-(3-chlorobenzyl)-2-vinyl-1H-benzo[d]imidazole (451 mg, 1.68 mmol, 68%) as a slightly yellow gel.

[0793] 1 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.

[0794] FF. 3-(Benzyloxy)-N-(4-hydroxypyridin-3-yl)propanamide

[0795]

[0796] To a solution of 3-aminopyridin-4-ol (3.06 g, 27.7 mmol, 1 eq.) in DMF (80 mL) was added 3-(benzyloxy)propanoic acid (5.00 g, 27.7 mmol, 1 eq.), triethylamine (5.62 g, 7.73 mL, 55.5 mmol, 2 eq.), and HATU (12.7 g, 33.3 mmol, 1.2 eq.). The reaction mixture was stirred at 23 °C for 16 h. The solution was diluted with water and extracted with ethyl acetate (3 times). 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 (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.

[0797] LCMS (ESI) m / z = 273.1. 11H 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.

[0798] GG. 2-(2-(Benzyloxy)ethyl)oxazolo[4,5-c]pyridine

[0799]

[0800] To the polymer-supported triphenylphosphine (polymer-supported, loading 1.6 mmol / g, 12.6 g) suspended in dichloromethane (100 mL) was added hexachloroethane (2.97 g, 12.5 mmol, 1.25 eq.) and triethylamine (5.07 g, 6.99 mL, 50.1 mmol, 5 eq.). The suspension was stirred for 5 minutes, and then solid 3-(benzyloxy)-N-(4-hydroxypyridin-3-yl)propanamide (2.73 g, 10.0 mmol, 1 eq.) was added. The mixture was stirred at room temperature for 1 hour. Another portion of hexachloroethane (1.78 g, 0.75 eq.) 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 / ethyl acetate, 0 - 100% ethyl acetate) to give the desired 2-(2-(benzyloxy)ethyl)oxazolo[4,5-c]pyridine (1.68 g, 6.61 mmol, 66%) as a yellow oil that crystallized upon standing.

[0801] LCMS (ESI) m / z = 255.2. 1 1H NMR (400 MHz, DMSO) δ 9.01 (d, J = 0.9 Hz, 1H), 8.54 (d, J =

[0802] 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.

[0803] HH. 2-(2-(Benzyloxy)ethyl)oxazolo[4,5-c]pyridine 5-oxide

[0804]

[0805] Dissolve 2-(2-(benzyloxy)ethyl)oxazolo[4,5-c]pyridine (1.68 g, 6.61 mmol, 1 eq.) in dichloromethane (60 mL). Cool the solution to 0 °C and add meta-chloroperoxybenzoic acid (75% Wt, 3.04 g, 13.2 mmol, 2 eq.). Remove the ice bath after 2 hours and continue stirring at 23 °C until LCMS shows complete conversion of the starting material. Dilute the reaction mixture with dichloromethane, wash with saturated aqueous sodium bicarbonate and brine, dry over sodium sulfate, filter and concentrate under reduced pressure. Recrystallize the crude product from methanol. Filter the solid, wash with methanol and dry in vacuo 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.

[0806] LCMS (ESI) m / z = 271.3. 1 H 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.

[0807] II. 2-(2-(Benzyloxy)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine

[0808]

[0809] To a solution of 2-(2-(benzyloxy)ethyl)oxazolo[4,5-c]pyridine 5-oxide (1.30 g, 4.81 mmol, 1 eq.) and (3-fluoropyridin-2-yl)methanamine dihydrochloride (1.44 g, 7.21 mmol, 1.5 eq.) in dry tetrahydrofuran (50 mL) was added N,N-diisopropylethylamine (3.11 g, 4.19 mL, 24.0 mmol, 5 eq.) and bromotris(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) (3.37 g, 7.21 mmol, 1.5 eq.). The reaction mixture was stirred at 23 °C until LC / MS showed complete consumption of the starting materials. 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 product was purified by flash column chromatography (CH2Cl2 / MeOH / NH3 90 / 9 / 1) to afford 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%).

[0810] LCMS (ESI) m / z = 379.4. 1 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.

[0811] JJ. 2-(4-(((3-fluoropyridin-2-yl)methyl)amino)oxazolo[4,5-c]pyridin-2-yl)ethan-1-ol

[0812]

[0813] Dissolve 2-(2-(benzyloxy)ethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (500 mg, 1.32 mmol, 1 eq.) in dichloromethane (12 mL). Treat this colorless solution with boron tribromide dimethyl sulfide complex (1 M in dichloromethane, 3.96 mL, 3.96 mmol, 1 eq.), adding it in two portions (2 eq. first, then 1 eq. after 30 minutes). Stir the reaction mixture at 23 °C until TLC shows complete conversion of the starting material. Quench the reaction mixture by slowly adding saturated aqueous sodium bicarbonate. Stir the mixture for 30 minutes, then separate the two phases. Extract the aqueous phase with dichloromethane (3 times). Dry the combined organic phases over sodium sulfate, filter, and concentrate under reduced pressure. Purify the crude product by flash column chromatography (CH2Cl2 / MeOH, 0 - 20% MeOH) 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 crystallizes upon standing.

[0814] LCMS(ESI) m / z = 289.2. 1 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.

[0815] KK. N-((3-fluoropyridin-2-yl)methyl)-2-(2-iodoethyl)oxazolo[4,5-c]pyridin-4-amine

[0816]

[0817] Dissolve triphenylphosphine (1.11 g, 4.24 mmol, 1.3 eq.) in dichloromethane (7 mL). Add iodine (1.08 g, 4.24 mmol, 1.3 eq.) in portions. After 10 minutes, add imidazole (300 mg, 4.40 mmol, 1.35 eq.). After another 10 minutes, cool the reaction mixture to 0 °C and add 2-(4-(((3-fluoropyridin-2-yl)methyl)amino)oxazolo[4,5-c]pyridin-2-yl)ethan-1-ol (940 mg, 1 eq., 3.26 mmol). After TLC showed complete conversion of the starting material, quench the reaction with saturated aqueous sodium thiosulfate solution. Separate the reaction mixture, and re-extract the aqueous phase with dichloromethane (3 times). Wash the combined organic phases with water and brine, dry over sodium sulfate, filter and concentrate under reduced pressure. Purify the crude product by flash column chromatography (heptane / ethyl acetate) to afford 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.

[0818] 1 H 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.

[0819] Example compound

[0820] Example compound 1:

[0821] 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

[0822]

[0823] 2-(2-Aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (303 mg, 1.05 mmol, 1 eq.), 1-(2-methoxyethyl)-2-vinyl-1H-benzo[d]imidazole (213 mg, 1.05 mmol, 1 eq.) and ammonium acetate (97.6 mg, 1.27 mmol, 1.2 eq.) were suspended in acetonitrile (10 mL). The reaction mixture was heated to 50 °C and reacted for 24 h. The reaction mixture was loaded onto a silica gel column by dry loading and purified by flash column chromatography (CH2Cl2 / MeOH, 0 - 20% MeOH) to give 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 brown oil.

[0824] LCMS(ESI) m / z = 490.8. 1 1H 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.

[0825] Example Compound 2:

[0826] 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

[0827]

[0828] 2-(2-Aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (200 mg, 696 μmol, 1 eq.), 1-(cyclopropylmethyl)-2-vinyl-1H-benzo[d]imidazole (138 mg, 696 μmol, 1 eq.), and ammonium acetate (64.4 mg, 835 μmol, 1.2 eq.) were suspended in acetonitrile (7 mL). The reaction mixture was heated to 50 °C and reacted for 24 hours. The reaction mixture was loaded onto a silica gel column by dry loading and purified by flash column chromatography (CH2Cl2 / MeOH, 0 - 20% MeOH) to obtain 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 brown oil.

[0829] LCMS(ESI) m / z = 486.5. 1 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.

[0830] Example Compound 3:

[0831] 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

[0832]

[0833] 2-(2-Aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (200 mg, 696 μmol, 1 eq.), 1-(2-(2-methoxyethoxy)ethyl)-2-vinyl-1H-benzo[d]imidazole (171 mg, 696 μmol, 1 eq.), and ammonium acetate (64.4 mg, 835 μmol, 1.2 eq.) were suspended in acetonitrile (7 mL). The reaction mixture was heated to 50 °C and reacted for 24 h. The reaction mixture was loaded onto a silica gel column by dry loading and purified by flash column chromatography (CH2Cl2 / MeOH, 0 - 20% MeOH) to obtain 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 brown oil.

[0834] LCMS(ESI) m / z = 534.7. 1 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), 7.48 (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.

[0835] Example Compound 4:

[0836] 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

[0837]

[0838] 2-(2-Aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (200 mg, 696 μmol, 1 eq.), 1-(2-isopropoxyethyl)-2-vinyl-1H-benzo[d]imidazole (160 mg, 696 μmol, 1 eq.) and ammonium acetate (64.4 mg, 835 μmol, 1.2 eq.) were suspended in acetonitrile (7 mL). The reaction mixture was heated to 50 °C and reacted for 24 h. The reaction mixture was loaded onto a silica gel column by dry loading and purified by flash column chromatography (CH2Cl2 / MeOH, 0 - 20% MeOH) to obtain 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.

[0839] LCMS(ESI) m / z = 518.5. 1 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.

[0840] Example Compound 5:

[0841] 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

[0842]

[0843] 2-(Azetidin-3-yl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (100 mg, 334 μmol, 1 eq.), 1-(2-methoxyethyl)-2-vinyl-1H-benzo[d]imidazole (67.6 mg, 334 μmol, 1 eq.) and ammonium acetate (30.9 mg, 401 μmol, 1.2 eq.) were suspended in acetonitrile (3 mL). The reaction mixture was heated to 50 °C and reacted for 24 h. The reaction mixture was loaded onto a silica gel column by dry loading and purified by flash column chromatography (CH2Cl2 / MeOH, 0 - 20% MeOH) to give 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.

[0844] LCMS(ESI) m / z = 502.6. 1 1H NMR (400 MHz, DMSO) δ 8.34 (dt, J = 4.7, 1.5 Hz, 1H), 7.87 (d, J = 5.8 Hz, 1H), 7.56–7.44 (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.

[0845] Example Compound 6:

[0846] 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

[0847]

[0848] 2-(Azetidin-3-yl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (100 mg, 334 μmol, 1 eq.), 1-(2-(2-methoxyethoxy)ethyl)-2-vinyl-1H-benzo[d]imidazole (82.3 mg, 334 μmol, 1 eq.) and ammonium acetate (30.9 mg, 401 μmol, 1.2 eq.) were suspended in acetonitrile (3 mL). The reaction mixture was heated to 50 °C and reacted for 24 h. The reaction mixture was loaded onto a silica gel column by dry loading and then purified by flash column chromatography (CH2Cl2 / MeOH, 0 - 20% MeOH) to give 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.

[0849] LCMS(ESI) m / z = 546.7. 1 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 were covered by H2O signals.

[0850] Example Compound 7:

[0851] 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

[0852]

[0853] 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 eq.) and sodium hydroxide (63 mg, 30% Wt, 474 μmol, 3.2 eq.) were dissolved in water (1.5 mL). N-((3-Fluoropyridin-2-yl)methyl)-2-vinyl-oxazolo[4,5-c]pyridin-4-amine (40.0 mg, 148 μmol, 1 eq.) was added and the reaction mixture was heated to 80 °C for 48 h. After the reaction mixture was cooled to 23 °C, the pH was adjusted to 7 with 3 N hydrochloric acid. The reaction mixture was concentrated and purified by flash column chromatography (CH2Cl2 / MeOH, 0 - 20% MeOH), followed by purification through a strong cation exchange column (methanol solution of 1 - 7 N NH3) to give 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.

[0854] LCMS(ESI) m / z = 548.6. 1 1H 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.

[0855] Example Compound 8:

[0856] 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

[0857]

[0858] 2-(2-Aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (150 mg, 522 μmol, 1 eq.), 4-(2-(2-ethenyl-1H-benzo[d]imidazol-1-yl)ethyl)morpholine (134 mg, 522 μmol, 1 eq.) and ammonium acetate (48.3 mg, 627 μmol, 1.2 eq.) were suspended in acetonitrile (5 mL). The reaction mixture was heated at 50 °C overnight. The reaction mixture was concentrated onto silica gel and then purified by flash column chromatography (CH2Cl2 / MeOH, 0 - 20% MeOH) to give 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 pale yellow solid.

[0859] LCMS(ESI) m / z = 545.1. 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.

[0860] Example Compound 9:

[0861] 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

[0862]

[0863] Dissolve 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 eq.) and sodium hydroxide (207 mg, 30% Wt, 1.55 mmol, 4.2 eq.) in water (3 mL). Add N-((3-fluoropyridin-2-yl)methyl)-2-vinyl-oxazolo[4,5-c]pyridin-4-amine (100 mg, 370 μmol, 1 eq.), and heat the reaction mixture to 80 °C for 48 h. After the reaction mixture is cooled to 23 °C, adjust the pH to 7 with 3 N hydrochloric acid. Concentrate the reaction mixture and purify it by reverse-phase column chromatography (H2O / (CH3CN / MeOH) + 0.1% TFA, 95 / 5 - 5 / 95), followed by purification through a strong cation exchange column (methanol solution of 1 - 7 N NH3) to obtain 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.

[0864] LCMS(ESI) m / z = 603.6. 1 1H 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.

[0865] Example Compound 10:

[0866] 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

[0867]

[0868] 2-(2-Aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (100 mg, 348 μmol, 1 eq.), 1-benzyl-2-vinyl-1H-benzo[d]imidazole (92.0 mg, 348 μmol, 1 eq.) and ammonium acetate (32.2 mg, 418 μmol, 1.2 eq.) were suspended in acetonitrile (2.5 mL). The reaction mixture was heated at 50 °C overnight. The reaction mixture was concentrated onto silica gel and then purified by flash column chromatography (CH2Cl2 / 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 brown oil.

[0869] LCMS(ESI) m / z = 522.5. 1 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.

[0870] Example Compound 11:

[0871] 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

[0872]

[0873] 2-(2-Aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (100 mg, 348 μmol, 1 eq.), 1-(3-methoxybenzyl)-2-vinyl-1H-benzo[d]imidazole (81.6 mg, 348 μmol, 1 eq.), and ammonium acetate (32.2 mg, 418 μmol, 1.2 eq.) were suspended in acetonitrile (2.5 mL). The reaction mixture was heated at 50 °C overnight. The reaction mixture was concentrated onto silica gel and then purified by flash column chromatography (CH2Cl2 / MeOH, 0 - 20% MeOH) to afford 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 (52.2 mg, 92.8 μmol, 27%) as a brown oil.

[0874] LCMS(ESI) m / z = 552.6. 1 1H 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.

[0875] Example Compound 12:

[0876] 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

[0877]

[0878] 2-(2-Aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)oxazolo[4,5-c]pyridin-4-amine (175 mg, 609 μmol, 1 eq.), 1-(3-chlorobenzyl)-2-vinyl-1H-benzo[d]imidazole (164 mg, 609 μmol, 1 eq.) and ammonium acetate (56.3 mg, 731 μmol, 1.2 eq.) were suspended in acetonitrile (5 mL). The reaction mixture was heated at 50 °C overnight. The reaction mixture was concentrated onto silica gel and then purified by flash column chromatography (CH2Cl2 / MeOH, 0 - 20% MeOH) to give 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 brown oil.

[0879] LCMS(ESI) m / z = 557.2. 1 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.

[0880] Example Compound 13:

[0881] 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

[0882]

[0883] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-iodoethyl)oxazolo[4,5-c]pyridin-4-amine (125 mg, 314 μmol, 1 eq.) 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 eq.) were suspended in acetonitrile (2 mL). N,N-Diisopropylethylamine (130 mg, 175 μL, 1.00 mmol, 3.2 eq.) 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 (H2O / (CH3CN / MeOH) + 0.1% TFA, 95 / 5 - 5 / 95), followed by purification through a strong cation exchange column (methanol solution of 1 - 7N NH3) 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.

[0884] LCMS(ESI) m / z = 544.6. 1 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.

[0885] Example Compound 14:

[0886] 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

[0887]

[0888] Dissolve 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 eq.) and sodium hydroxide (30% Wt, 207 mg, 1.55 mmol, 4.2 eq.) in water (4 mL). Add N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazolo[4,5-c]pyridin-4-amine (100 mg, 370 μmol, 1 eq.), and heat the reaction mixture to 80 °C for 48 h. After the reaction mixture is cooled to room temperature, adjust the pH to 7 with 3 N hydrochloric acid. Concentrate the reaction mixture, purify it by flash column chromatography (CH2Cl2 / MeOH, 0 - 20% MeOH), and then purify it by strong cation exchange column (methanol solution of 1 - 7 N NH3) to obtain 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.

[0889] 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.

[0890] Example Compound 15:

[0891] 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

[0892]

[0893] Dissolve 2-(1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-2-yl)ethan-1-amine (93.4 mg, 370 μmol, 1 eq.) and sodium hydroxide (30% Wt, 59.2 mg, 444 μmol, 1.2 eq.) in water (4 mL). Add N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazolo[4,5-c]pyridin-4-amine (100 mg, 370 μmol, 1 eq.), and heat the reaction mixture to 80 °C for 48 h. After the reaction mixture is cooled to room temperature, adjust the pH to 7 with 3 N hydrochloric acid. Concentrate the reaction mixture and purify it by flash column chromatography (CH2Cl2 / MeOH, 0 - 20% MeOH), followed by purification through a strong cation exchange column (methanol solution of 1 - 7 N NH3) to obtain 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.

[0894] LCMS (ESI) m / z = 523.5. 1 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.

[0895] Example Compound 16:

[0896] N-((3-Fluoropyridin-2-yl)methyl)-2-(2-((2-(1-phenylethyl-1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)oxazolo[4,5-c]pyridin-4-amine

[0897]

[0898] Dissolve 2-(1-phenylethyl-1H-benzo[d]imidazol-2-yl)ethan-1-amine hydrochloride (112 mg, 370 μmol, 1 eq.) and sodium hydroxide (30% Wt, 109 mg, 814 μmol, 2.2 eq.) in water (4 mL). Add N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazolo[4,5-c]pyridin-4-amine (100 mg, 370 μmol, 1 eq.), and heat the reaction mixture to 80 °C for 48 h. After the reaction mixture is cooled to room temperature, adjust the pH to 7 with 3N hydrochloric acid. Concentrate the reaction mixture and purify it by flash column chromatography (CH2Cl2 / MeOH, 0 - 20% MeOH), followed by purification through a strong cation exchange column (methanol solution of 1 - 7N NH3) to obtain the desired N-((3-fluoropyridin-2-yl)methyl)-2-(2-((2-(1-phenylethyl-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.

[0899] 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, 1.7 Hz, 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.

[0900] Example Compound 17:

[0901] 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

[0902]

[0903] Dissolve 2-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (115 mg, 370 μmol, 1 eq.) and sodium hydroxide (30% Wt, 158 mg, 1.18 mmol, 3.2 eq.) in water (4 mL). Add N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazolo[4,5-c]pyridin-4-amine (100 mg, 370 μmol, 1 eq.), and heat the reaction mixture to 80 °C for 48 h. After cooling the reaction mixture to room temperature, adjust the pH to 7 with 3 N hydrochloric acid. Concentrate the reaction mixture and purify it by flash column chromatography (CH2Cl2 / MeOH, 0 - 20% MeOH), followed by purification through a strong cation exchange column (methanol solution of 1 - 7 N NH3) to obtain 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.

[0904] LCMS (ESI) m / z = 508.5 ppm. 1 H 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.

[0905] Example Compound 18:

[0906] 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

[0907]

[0908] Dissolve 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 eq.) and sodium hydroxide (30% Wt, 207 mg, 1.55 mmol, 4.2 eq.) in water (4 mL). Add N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazolo[4,5-c]pyridin-4-amine (100 mg, 370 μmol, 1 eq.), and heat the reaction mixture to 80 °C for 48 h. After cooling the reaction mixture to room temperature, adjust the pH to 7 with 3N hydrochloric acid. Concentrate the reaction mixture and purify it by flash column chromatography (CH2Cl2 / MeOH, 0 - 20% MeOH), followed by purification through a strong cation exchange column (methanolic solution of 1 - 7N NH3) to obtain 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 pale yellow solid.

[0909] LCMS(ESI) m / z = 616.8 ppm. 1 1H 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 covered by the DMSO solvent signal.

[0910] Example Compound 19:

[0911] 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

[0912]

[0913] Dissolve 2-(1-Ethyl-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (97.0 mg, 370 μmol, 1 eq.) and sodium hydroxide (30% Wt, 158 mg, 1.18 mmol, 3.2 eq.) in water (4 mL). Add N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazolo[4,5-c]pyridin-4-amine (100 mg, 370 μmol, 1 eq.), and heat the reaction mixture to 80 °C for 48 h. After the reaction mixture is cooled to room temperature, adjust the pH to 7 with 3N hydrochloric acid. Concentrate the reaction mixture, purify it by flash column chromatography (CH2Cl2 / MeOH, 0 - 20% MeOH), and then purify it by strong cation exchange column (methanol solution of 1 - 7N NH3) to obtain 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.

[0914] LCMS(ESI) m / z = 460.5. 1 H 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.

[0915] Example Compound 20:

[0916] 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

[0917]

[0918] Dissolve 2-(2-(2-aminoethyl)-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethan-1-amine trihydrochloride (240 mg, 703 μmol, 1 eq.) and sodium hydroxide (30% Wt, 394 mg, 2.95 mmol, 4.2 eq.) in water (4 mL). Add N-((3-fluoropyridin-2-yl)methyl)-2-vinyloxazolo[4,5-c]pyridin-4-amine (190 mg, 703 μmol, 1 eq.), and heat the reaction mixture to 80 °C for 48 h. After the reaction mixture is cooled to room temperature, adjust the pH to 7 with 3N hydrochloric acid. Concentrate the reaction mixture and purify it by RP18 flash column chromatography (water / methanol + 0.1% NH3, 5%-95% methanol) to obtain 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.

[0919] LCMS(ESI) m / z = 503.2. 1 1H 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.

[0920] Example Compound 21:

[0921] 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

[0922]

[0923] 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 eq.) and sodium hydroxide (30% Wt, 158 mg, 1.18 mmol, 3.2 eq.) were dissolved in water (4 mL). N-((3-Fluoropyridin-2-yl)methyl)-2-vinyl oxazolo[4,5-c]pyridin-4-amine (100 mg, 370 μmol, 1 eq.) was added and the reaction mixture was heated to 80 °C for 48 h. After the reaction mixture was cooled to room temperature, the pH was adjusted to 7 with 3 N hydrochloric acid. The reaction mixture was concentrated and purified by preparative RP18 HPLC (water / acetonitrile / methanol + 0.1% formic acid, 5% - 95% acetonitrile / methanol) to give 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-amine formate (23.6 mg, 45.6 μmol, 12%) as a white solid.

[0924] LCMS (ESI) m / z = 536.6. 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 = 5.8 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.

[0925] Example Compound 22:

[0926] 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

[0927]

[0928] 2-(1-Methyl-1H-benzo[d]imidazol-2-yl)ethan-1-amine dihydrochloride (91.8 mg, 370 μmol, 1 eq.) and sodium hydroxide (30% Wt, 158 mg, 1.18 mmol, 3.2 eq.) 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 eq.) was added and the reaction mixture was heated to 80 °C for 48 h. After the reaction mixture was cooled to room temperature, the pH was adjusted to 7 with 3 N hydrochloric acid. The reaction mixture was concentrated and purified by preparative RP18 HPLC (water / acetonitrile / methanol + 0.1% formic acid, 5% - 95% acetonitrile / methanol) to give 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-amine formate (38.8 mg, 45.6 μmol, 24%) as a white solid.

[0929] 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.

[0930] Example Compound 23:

[0931] 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

[0932]

[0933] 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 eq.) and sodium hydroxide (30% Wt, 158 mg, 1.18 mmol, 3.2 eq.) 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 eq.) was added and the reaction mixture was heated to 80 °C for 48 h. After the reaction mixture was cooled to room temperature, the pH was adjusted to 7 with 3 N hydrochloric acid. The reaction mixture was concentrated and purified by preparative RP18 HPLC (water / acetonitrile / methanol + 0.1% formic acid, 5%-95% acetonitrile / methanol) to give 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-amine formate (40.2 mg, 71.1 μmol, 19%), as a white solid.

[0934] LCMS (ESI) m / z = 566.8. 1 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. A compound according to formula (I-A) wherein l is an integer of 1 or 2; L 1 and L 2 each represent a linking group containing from 1 to 7 carbon atoms and are independently selected from -linear C1-C3-alkyl–[CH2] m –or–[CH2] n –, where m and n are each independently an integer of 1, 2 or 3, - branched C1-C4-alkyl, and - C3-C6-cycloalkyl forming a ring with the attached nitrogen atom; X 1 is N, S or O; and X 2 is N, S or O; provided that X 1 and X 2 one of them is N; and wherein Y is N or CR 5 ; wherein R 5 means -H， - halogen, - straight-chain or branched C1-C3-alkyl, or - straight-chain or branched C1-C3-haloalkyl; A represents the group (a-1) where * represents the bonding position; R 1 and R 2 each independently represents - hydrogen, - halogen, - straight-chain or branched C1-C3-alkyl, - straight-chain or branched C1-C3-haloalkyl, or - straight-chain or branched C1-C3-alkoxy; B represents one of the following groups (b-1), (b-2) and (b-3) where * represents the bonding position; R 3 represents 0, 1, 2 or 3 substituents, independently selected from - straight-chain or branched C1-C3-alkyl, - straight-chain or branched C1-C3-haloalkyl, - straight-chain 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 heterocyclic group, - unsubstituted or substituted 5- or 6-membered heterocycloalkyl, - unsubstituted or substituted 6-membered arylalkynyl, or - an unsubstituted or substituted 5- or 6-membered heteroaryl alkynyl, wherein, the substituted aryl, heteroaryl, bicyclic heteroaryl, cycloalkyl, heterocyclic group, heterocycloalkyl, arylalkynyl or heteroarylalkynyl may optionally be substituted by 1, 2 or 3 substituents independently selected from the following ○ halogen, ○ C1-C3-alkyl, ○ C1-C3-haloalkyl, and ○ C1-C3-alkoxy; R 4 represent - hydrogen, - unsubstituted or substituted straight-chain or branched C1-C6-alkyl, -Dialkyl ether group [R 6 (CH2) x -O-(CH2) y -] wherein R 6 represents a C1-C3-alkoxy group, and wherein 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 heterocyclic group, or - unsubstituted or substituted 6-membered aryl, - unsubstituted or substituted 5- or 6-membered heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl may optionally be substituted by 1 or 2 substituents independently selected from the following ○ halogen, ○ C1-C3-alkoxy, ○ C6-cycloalkyloxy, ○ carboxyl, ○ aminocarbonyl, ○ monoalkylaminocarbonyl or dialkylaminocarbonyl, ○ amino, including -NH2, monoalkylamino and dialkylamino, ○ unsubstituted or substituted 3- to 6-membered cycloalkyl, ○ unsubstituted or substituted 5- or 6-membered heterocyclic group, ○ unsubstituted or substituted 6-membered aryl, ○ unsubstituted or substituted 5- or 6-membered heteroaryl, and ○ unsubstituted or substituted bicyclic heteroaryl, wherein the substituted cycloalkyl, heterocyclic group, aryl, heteroaryl and bicyclic heteroaryl may optionally be substituted by 1, 2 or 3 substituents independently selected from the following ■ hydroxyl, ■ cyano, ■ halogen, ■ C1-C3-alkyl, ■ C1-C3-haloalkyl, ■ C1-C3-alkoxy, ■ carboxyl, ■ amino (-NH2), monoalkylamino or dialkylamino, ■ aminocarbonyl, and ■ monoalkylaminocarbonyl or dialkylaminocarbonyl, wherein the monoalkylamino and monoalkylaminocarbonyl may further carry a substituent on the monoalkyl chain, and the substituent is selected from ● C1-C3-alkoxy, ● unsubstituted or substituted 6-membered aryl, and ● unsubstituted or substituted 5- or 6-membered heteroaryl, Wherein, the substituted aryl or heteroaryl as a monoalkyl chain substituent may optionally be substituted with 1, 2 or 3 substituents independently selected from halogen, C1-C3-alkyl and C1-C3-haloalkyl; Provided that, in formula (b-1), when R 3 is absent or when R 3 is methyl, R 4 does not represent hydrogen; In formulae (b-2) and (b-3), one of D1, D2 and D3 is present and represents - a fused 6-membered aryl ring, - a fused 5- or 6-membered heteroaryl ring, - a fused 5- or 6-membered cycloalkyl ring, or - a fused 5- or 6-membered heterocyclic ring; And the groups (b-2) and (b-3) bear 0, 1, 2 or 3 substituents independently selected from - halogen, - straight-chain or branched C1-C3-alkyl, - straight-chain or branched C1-C3-haloalkyl, - straight-chain or branched C1-C3-alkoxy; And pharmaceutically acceptable salts thereof.

2. The compound according to claim 1, wherein In the definition of the group of formula (b-1), when R 3 is absent or when R 3 is selected from straight-chain or branched C1-C3-alkyl, straight-chain or branched C1-C3-haloalkyl, or straight-chain or branched C1-C3-alkoxy, R 4 does not represent hydrogen.

3. The compound according to claim 1 or 2, wherein hydrogen is not included in the definition of R 4 .

4. The compound according to claim 1, 2 or 3, which is selected from the compounds according to formula (I-B) Wherein l is an integer of 1 or 2; and m and n are independently integers of 1, 2 or 3; And pharmaceutically acceptable salts thereof.

5. The compound according to any one of claims 1 to 4, wherein R 4 denotes - straight-chain or branched C1-C6-alkyl, -Dialkyl ether group [R 6 (CH2) x -O-(CH2) y -] wherein R 6 represents a C1-C3-alkoxy group, and wherein x and y independently represent integers of 1, 2 or 3, - 3- to 6-membered cycloalkyl, - 5- or 6-membered heterocyclic, or - 6-membered aryl, Among them, The alkyl, cycloalkyl, heterocyclic and aryl may optionally be substituted with 1 or 2 substituents independently selected from the following ○ C1-C3-alkoxy, ○ carboxyl, ○ aminocarbonyl, ○ monoalkylaminocarbonyl or dialkylaminocarbonyl, ○ amino, including -NH2, monoalkylamino and dialkylamino ○ 3- to 6-membered cycloalkyl, ○ 5- or 6-membered heterocyclic, ○ unsubstituted or substituted 6-membered aryl, ○ unsubstituted or substituted 5- or 6-membered heteroaryl, and ○ unsubstituted or substituted bicyclic heteroaryl, Wherein, the substituted aryl, heteroaryl and bicyclic heteroaryl may optionally be substituted with 1, 2 or 3 substituents independently selected from the following ■ hydroxy, ■ cyano, ■ halogen, ■ C1-C3-alkyl, ■ C1-C3-haloalkyl, ■ C1-C3-alkoxy, ■ carboxyl, ■ amino (-NH2), monoalkylamino or dialkylamino, ■ aminocarbonyl, and ■ monoalkylaminocarbonyl or dialkylaminocarbonyl, Wherein, the monoalkylamino and monoalkylaminocarbonyl may further bear a substituent on the monoalkyl chain, and the substituent is selected from ● C1-C3-alkoxy, ● unsubstituted or substituted 6-membered aryl, and ● unsubstituted or substituted 5- or 6-membered heteroaryl, Wherein, the substituted aryl or heteroaryl as a monoalkyl chain substituent may optionally be substituted with 1, 2 or 3 substituents independently selected from halogen, C1-C3-alkyl and C1-C3-haloalkyl; And pharmaceutically acceptable salts thereof.

6. The compound according to any one of claims 1 to 5, wherein A represents the group (a-1) where * represents the bonding position; R 1 and R 2 each independently represents - hydrogen, - halogen, - straight-chain or branched C1-C3-alkyl, - straight-chain or branched C1-C3-haloalkyl, or - straight-chain or branched C1-C3-alkoxy; B represents one of the following groups (b-1), (b-2) and (b-3) where * represents the bonding position; R 3 represents 0, 1, 2 or 3 substituents, independently selected from - straight-chain or branched C1-C3-alkyl, - straight-chain or branched C1-C3-haloalkyl, - straight-chain 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 heterocyclic group, - 5- or 6-membered heterocycloalkyl, or - 6-membered arylalkynyl, Among them, The substituted aryl, heteroaryl and bicyclic heteroaryl may optionally be substituted with 1, 2 or 3 substituents independently selected from the following ○ halogen, ○ C1-C3-alkyl, ○ C1-C3-haloalkyl, and ○ C1-C3-alkoxy; R 4 represent - straight-chain or branched C1-C6-alkyl, -Dialkyl ether group [R 6 (CH2) x -O-(CH2) y -] wherein R 6 represents a C1-C3-alkoxy group, and wherein x and y independently represent an integer of 1, 2 or 3, - 3- to 6-membered cycloalkyl, or - 5- or 6-membered heterocyclic group, - 6-membered aryl, wherein the alkyl, cycloalkyl, heterocyclic group and aryl may optionally be substituted with 1 or 2 substituents independently selected from the following ○ C1-C3-alkoxy, ○ carboxyl, ○ aminocarbonyl, ○ monoalkylaminocarbonyl or dialkylaminocarbonyl, ○ amino, including -NH2, monoalkylamino and dialkylamino ○ 3- to 6-membered cycloalkyl, ○ 5- or 6-membered heterocyclic group, ○ unsubstituted or substituted 6-membered aryl, ○ unsubstituted or substituted 5- or 6-membered heteroaryl, and ○ unsubstituted or substituted bicyclic heteroaryl, wherein the substituted aryl, heteroaryl and bicyclic heteroaryl may optionally be substituted with 1, 2 or 3 substituents independently selected from the following ■ hydroxyl, ■ cyano, ■ halogen, ■ C1-C3-alkyl, ■ C1-C3-haloalkyl, ■ C1-C3-alkoxy, ■ carboxyl, ■ amino (-NH2), monoalkylamino or dialkylamino, ■ aminocarbonyl, and ■ monoalkylaminocarbonyl or dialkylaminocarbonyl, wherein the monoalkylamino and monoalkylaminocarbonyl may further bear a substituent on the monoalkyl chain, and the substituent is selected from ● C1-C3-alkoxy, ● unsubstituted or substituted 6-membered aryl, and ● unsubstituted or substituted 5- or 6-membered heteroaryl, wherein the substituted aryl or heteroaryl as a substituent on the monoalkyl chain may optionally be substituted with 1, 2 or 3 substituents independently selected from halogen, C1-C3-alkyl and C1-C3-haloalkyl; In formula (b-2) and (b-3), one of D1, D2 and D3 is present and represents - fused 6-membered aryl ring, - fused 5- or 6-membered heteroaryl ring, - fused 5- or 6-membered cycloalkyl ring, or - fused 5- or 6-membered heterocyclic ring; Group (b-2) and (b-3) bear 0, 1, 2 or 3 substituents independently selected from - halogen, - straight-chain or branched C1-C3-alkyl, - straight-chain or branched C1-C3-haloalkyl, - straight-chain or branched C1-C3-alkoxy; and its pharmaceutically acceptable salts.

7. The compound according to any one of claims 1 to 6, wherein A represents group (a-1) where * represents the bonding position; R 1 and R 2 each independently represents - hydrogen, - halogen, - straight-chain or branched C1-C3-alkyl, - straight-chain or branched C1-C3-haloalkyl, or - straight-chain or branched C1-C3-alkoxy; B represents one of the following groups (b-1), (b-2) and (b-3) wherein * represents the bonding position; R 3 represents 0, 1, 2 or 3 substituents, independently selected from - a straight-chain or branched C1-C3-alkyl group, - a straight-chain or branched C1-C3-haloalkyl group, - a straight-chain or branched C1-C3-alkoxy group, - an unsubstituted or substituted phenyl group, - an unsubstituted or substituted 5- or 6-membered heteroaryl group, - an unsubstituted or substituted bicyclic heteroaryl group, - a 6-membered heterocyclic group, - a 6-membered heterocycloalkyl group, - phenylethynyl, or - pyridyl ethynyl, Among them, The substituted phenyl, heteroaryl and bicyclic heteroaryl groups may optionally be substituted by 1, 2 or 3 substituents independently selected from the following ○ halogen, ○ C1-C3-alkyl, ○ C1-C3-haloalkyl, and ○ C1-C3-alkoxy; R 4 denotes - a straight-chain or branched C1-C6-alkyl group, -Dialkyl ether group [R 6 (CH2) x -O-(CH2) y -] wherein R 6 represents a C1-C3-alkoxy group, and wherein x and y independently represent an integer of 1, 2 or 3, - an unsubstituted 5- or 6-membered heterocyclic group, or - a substituted or unsubstituted phenyl group, wherein the substituents of the phenyl group are selected from ○ halogen, and ○ C1-C3-alkoxy; and wherein the alkyl group may optionally be substituted by 1 or 2 substituents independently selected from the following ○ halogen, ○ C1-C3-alkoxy, ○ C6-cycloalkyloxy, ○ carboxyl, ○ aminocarbonyl, ○ monoalkylaminocarbonyl, ○ dialkylamino, ○ 3- to 6-membered cycloalkyl, ○ an unsubstituted or substituted 5- or 6-membered heterocyclic group, ○ an unsubstituted or substituted 6-membered aryl group, ○ an unsubstituted or substituted 5- or 6-membered heteroaryl group, and ○ an unsubstituted or substituted bicyclic heteroaryl group, wherein the substituted heterocyclic group, aryl group, heteroaryl group and bicyclic heteroaryl group may optionally be substituted by 1, 2 or 3 substituents independently selected from the following ■ halogen, ■ C1-C3-alkyl, ■ C1-C3-haloalkyl, ■ C1-C3-alkoxy, ■ aminocarbonyl, and ■ monoalkylaminocarbonyl, wherein the monoalkylaminocarbonyl may further bear a substituent on the monoalkyl chain, and the substituent is selected from a halogen-substituted 5- or 6-membered heteroaryl group; In formulae (b-2) and (b-3), one of D1, D2 and D3 is present and represents - a fused benzene ring, - a fused 6-membered heteroaryl ring, - a fused 6-membered cycloalkyl ring, or - a fused 5- or 6-membered heterocyclic ring; Groups (b-2) and (b-3) bear 0 or 1 substituent selected from - halogen, - a straight-chain or branched C1-C3-alkyl group, - a straight-chain or branched C1-C3-haloalkyl group, and - a straight-chain or branched C1-C3-alkoxy group; and its pharmaceutically acceptable salts.

8. The compound according to any one of claims 1 to 7, which is represented by one of formulae (I-C), (I-D), (I-E), (I-F) or (I-G) Among them, The remaining substituents have the definitions as described in any one of claims 1 to 7; and its pharmaceutically acceptable salts.

9. The compound according to any one of claims 1 to 8, wherein - group B is group (b-1) or (b-2); Preferably, group (b-2) having the following structure: Preferably and / or The structure of group A is as follows: Preferably and its pharmaceutically acceptable salts.

10. The compound according to any one of claims 1 to 9, wherein - the halogen substituents are selected from F, Cl and Br; and / or - The straight-chain or branched C1-C6-alkyl substituents are selected from methyl, ethyl, propyl, isopropyl, n-butyl, and isobutyl; 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 alkyl substituted in the position represents substituted C1-C3-alkyl; and / or - The bicyclic heteroaryl group is selected from benzimidazolyl; and its pharmaceutically acceptable salts.

11. The compound according to any one of claims 1 to 10, which is selected from: and its pharmaceutically acceptable salts.

12. The compound according to any one of claims 1 to 11 and its pharmaceutically acceptable salts, which are in the form of hydrates, solvates, and polymorphs of its salts, hydrates, and solvates.

13. The compound according to any one of claims 1 to 12, which is used as a medicine.

14. The compound according to any one of claims 1 to 13, - is used as an inhibitor of transferrin or for the inhibition of transferrin-mediated iron transport; and / or - for the prevention and / or treatment of iron metabolism disorders leading to elevated iron levels, increased iron absorption, and / or iron overload.

15. The compound according to any one of claims 1 to 14, - for the prevention and / or treatment of diseases associated with or caused by elevated iron levels, increased iron absorption, or iron overload, said diseases being selected from thalassemia, including α-thalassemia, β-thalassemia, and δ-thalassemia; hemoglobinopathy; hemoglobin E disease; hemoglobin H disease; hemochromatosis; hemolytic anemia, especially including sickle cell anemia or congenital dyserythropoietic anemia; and / or - for the prevention and / or treatment of diseases associated with ineffective hematopoiesis, such as myelodysplastic syndrome (MDS, myelodysplasia), polycythemia vera, and congenital dyserythropoietic anemia; and / or - for the prevention and / or treatment of diseases caused by reduced hepcidin levels; and / or - for the prevention and / or treatment of infections caused by a pathogenic microorganism by restricting the amount of iron available to the pathogenic microorganism, such as Vibrio vulnificus, in adjuvant therapy; and / or - for the prevention and / or treatment of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, by restricting the deposition or increase of iron in tissues or cells; and / or - for the prevention and / or treatment of the formation of free radicals, reactive oxygen species (ROS), and oxidative stress; and / or - for the prevention and / or treatment of heart, liver, and endocrine damage caused by iron overload; and / or - inflammation caused by iron excess.

16. A pharmaceutical composition, which comprises one or more compounds according to any one of claims 1 to 12 and - one or more compounds selected from pharmaceutical carriers, excipients, and solvents, and / or - at least one additional pharmaceutically active compound, which is 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 their related symptoms, and iron chelating compounds.

17. The pharmaceutical composition according to claim 16, which is in a form suitable for oral or parenteral administration.

18. The use of a compound according to any one of claims 1 to 12 for combination therapy, which comprises co-administering a compound according to any one of claims 1 to 12 with at least one further pharmaceutically active compound, wherein the co-administration in the combination therapy can be effected in a fixed-dose combination therapy by co-administering a compound according to any one of claims 1 to 12 with at least one further pharmaceutically active compound in a fixed-dose formulation; or the co-administration in the combination therapy can be effected in a free-dose combination therapy by co-administering a compound according to any one of claims 1 to 12 and at least one further pharmaceutically active compound at the free doses of the respective compounds, either by simultaneous administration of the respective compounds or by sequential use of the respective compounds over a period of time; and wherein one or more of the further pharmaceutically active compounds are preferably: active compounds for reducing iron overload, including Tmprss6-ASO, iron chelators, curcumin, SSP-004184, diflurane, deferasirox, desferrioxamine and / or deferiprone; and / or pharmaceutically active compounds selected from: antioxidants such as N-acetylcysteine; antidiabetic drugs such as GLP-1 receptor agonists; antibiotics such as vancomycin (Van) or tobramycin; antimalarial drugs; anticancer agents; antifungal drugs; drugs for treating neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, including dopamine agonists such as levodopa; antiviral drugs such as interferon-α or ribavirin; immunosuppressive agents such as cyclosporin A or cyclosporin A derivatives; iron supplements; vitamin supplements; erythropoiesis-stimulating agents; anti-inflammatory biologics; antithrombotic drugs; statins; vasopressors; and inotropic agents.

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