Process for production of ferroportin inhibitors

Abstract

To provide a new process for preparing ferroportin inhibitors.SOLUTION: A process for preparing a compound of formula (I), which comprises reacting a compound of formula (IM-3) with a compound of formula (RM-3).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a compound of formula (I)

[0002] [ka] The present invention relates to a novel process for preparing the compound of formula (I) and its pharmaceutically acceptable salts. The compounds of formula (I) of the present invention act as ferroportin inhibitors and are therefore particularly suitable for use as pharmaceuticals in the prevention and / or treatment of diseases caused by a deficiency of hepcidin or iron metabolism disorders that lead to increased iron levels or increased iron absorption. The compounds of formula (I) of the present invention are further particularly suitable for use in the prevention and / or treatment of iron overload, including thalassemia, sickle cell disease, and hemochromatosis, and for use in the prevention and / or treatment of diseases associated with or caused by increased iron levels, increased iron absorption, or iron overload. [Background technology]

[0003] Iron is an essential trace element for almost all living organisms, particularly in relation to growth and blood formation. The balance of iron metabolism is primarily regulated by iron recovery from hemoglobin in senescent red blood cells and the duodenal absorption of dietary iron. Released iron is taken up via the intestine, particularly via specific transport systems (DMT-1, ferroportin), transferred to the blood circulation, and then transported to the appropriate tissues and organs (transferrin, transferrin receptor).

[0004] Mammalian organisms cannot actively excrete iron. Iron metabolism is essentially controlled by hepcidin, a peptide hormone produced in the liver, through the cellular release of iron from macrophages, hepatocytes, and enterocytes. Hepcidin plays a role in the absorption of iron through the intestine and placenta, and in the release of iron from the reticuloendothelial system. In the body, hepcidin is synthesized in the liver from what is known as prohepcidin, which is encoded by a gene known as the HAMP gene. The formation of hepcidin is directly correlated with the organism's iron level; that is, if the organism is supplied with sufficient iron and oxygen, more hepcidin is formed, and if 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 the transport protein ferroportin, which normally transports phagocytotically recycled iron from the inside of cells into the blood.

[0005] The transport protein ferroportin is a 571 amino acid transmembrane protein formed in the liver, spleen, kidney, heart, intestine, and placenta. In particular, ferroportin is localized to the basolateral membrane of intestinal epithelial cells. Ferroportin bound in this manner therefore acts to excrete iron into the blood. In this case, ferroportin transports iron to Fe 2+Hepcidin most likely transports iron as a ferroportin complex. If hepcidin binds to ferroportin, it is transported to the interior of the cell, where it is degraded, almost completely blocking the release of phagocytically recycled iron from the cell. If ferroportin cannot excrete iron stored in mucosal cells, for example, by being inactivated by hepcidin, the stored iron is lost with the natural shedding of cells through the feces. Therefore, intestinal iron absorption is reduced when ferroportin is inactivated or inhibited, for example, by hepcidin. In addition, ferroportin is significantly localized in the reticuloendothelial system (RES), to which macrophages belong. On the other hand, if serum iron levels decrease, hepcidin production in liver parenchymal cells is reduced, resulting in the release of less hepcidin, and therefore less ferroportin is inactivated, allowing a greater amount of stored iron to be transported into the serum.

[0006] It becomes clear from this that the hepcidin-ferroportin system directly regulates iron metabolism, and that disturbances in the hepcidin regulatory mechanism therefore have a direct effect on iron metabolism in the organism. In principle, the hepcidin-ferroportin regulatory mechanism acts via two opposing principles:

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

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

[0009] Iron overload conditions and diseases are characterized by excessive iron levels. Problems arise from excessive serum iron levels, which lead to non-transferrin-bound iron (NTBI). NTBI is rapidly taken up by organs nonspecifically, leading to iron accumulation in tissues and organs. Iron overload causes many diseases and undesirable medical conditions, including cardiac, hepatic, and endocrine damage. Furthermore, brain iron accumulation has been observed in patients with neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. A particularly harmful aspect of excess free iron is the unwanted formation of radicals. Iron(II) ions, in particular, catalyze the formation of reactive oxygen species (ROS) (especially via the Fenton reaction). These ROS cause damage to DNA, lipids, proteins, and carbohydrates, which has widespread effects in cells, tissues, and organs, leading to the so-called oxidative stress, which is well known and documented.

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

[0011] The ferroportin inhibitor according to formula (I) of the present invention and a method for preparing the same are described in WO2017 / 068089 and WO2017 / 068090. The preparation method described therein involves 12 process steps, including several chromatographic process steps, resulting in a time-consuming, cost-intensive, and labor-intensive, low-efficiency preparation process. The process described therein is further characterized by a relatively low yield, and some of the process steps create safety and technical issues due to the formation of significant by-products.

[0012] Furthermore, International Application WO2018 / 192973 describes the preparation and crystallization of various specific salts of selected ferroportin inhibitors as described therein and in WO2017 / 068089 and WO2017 / 068090.

[0013] WO2011 / 029832 describes a process for preparing thiazole and oxazole compounds acting as hepcidin antagonists, which are described as being suitable for use in the treatment of iron deficiency diseases, according to synthetic route 3. The process described therein involves multiple process steps, including chromatographic separation and purification steps, and is therefore unfavorable from the viewpoint of efficiency.

[0014] A.C. Veronese et al. (One-Pot Synthesis of 2-Vinylimidazole Derivatives by Reaction of α-Hydroxyimino-β-dicarbonyl Compounds with Allylamine; 1985) describe a one-pot synthesis reaction to obtain 2-vinylimidazole derivatives, but do not mention compounds according to formula (I), (II) or (II') and selected intermediates of the present invention or processes for their preparation. Summary of the Invention [Problem to be solved by the invention]

[0015] The object of the present invention was to provide a new method for preparing selected ferroportin inhibitors defined by the general formula (I) of the present invention and their pharmaceutically acceptable salts. The new method should be improved in at least one of the following aspects: increased yield, process efficiency, reduced process steps, improved source of supply, for example, by using commercially available or less expensive starting compounds, or by using starting and intermediate compounds that can be prepared in a time-, cost-, and labor-efficient manner, by avoiding chromatographic process steps as much as possible, increasing operational safety, avoiding significant or harmful by-products, avoiding dangerous reaction components such as Sn reagents, and reducing intermediate isolation steps as much as possible. A further object of the present invention was to provide a new process that provides ferroportin inhibitor compounds with an improved impurity profile and / or higher purity compared to compounds available by known methods.

[0016] Accordingly, a further object of the present invention relates to providing ferroportin inhibitor compounds of high purity and with improved impurity profiles. [Means for solving the problem]

[0017] A further aspect relates to providing new ferroportin inhibitor compounds, which has been solved with novel compounds according to formula (II').

[0018] The object has been solved by providing a new and improved process for preparing selected ferroportin inhibitors as defined by the general formula (I) of the present invention and their pharmaceutically acceptable salts. [Brief explanation of the drawings]

[0019] [Figure 1] FIG. 1 shows the PXRD pattern of compound (II) in the form of the 3HCl salt (polymorph PM1). [Figure 2] FIG. 1 shows the PXRD pattern of compound (II) in the form of the 3HCl salt (polymorph PM2). [Figure 3] FIG. 1 shows the PXRD pattern of Compound (II) in the form of the 3HCl salt (polymorph PM3). [Figure 4] FIG. 1 shows the PXRD pattern of compound (II) in the form of the H2SO4 salt. [Figure 5] FIG. 1 shows the PXRD pattern of compound (II) in the form of a 1H3PO4 salt. [Figure 6] FIG. 1 shows an HPLC chromatogram showing the impurity profile of Compound (II) in the form of the 3HCl salt (polymorph PM1) prepared by the process according to Example 4, followed by solvent extraction (Process Variant 1). [Figure 7] FIG. 1 shows an HPLC chromatogram showing the impurity profile of compound (II) in the form of the 3HCl salt (polymorph PM1) prepared by the process according to Example 4, followed by oil separation (Process Variant 2). [Figure 8] FIG. 1 shows an HPLC chromatogram illustrating the impurity profile of Compound (II) 3HCl (polymorph PM1) obtained by the process described in WO2017068090A1 (preparation of Example Compound No. 127). DETAILED DESCRIPTION OF THE INVENTION

[0020] In a first aspect, the present invention provides a compound of general formula (I)

[0021] [ka] A novel process for preparing the compound of formula (I), comprising: The compound of formula (IM-3) is reacted with a compound of formula (RM-3)

[0022] [ka] to provide a compound of formula (I); (In the formula, X 1 is N, S or O; and X 2 is N, S or O; However, X 1 and X 2 One of the is N and the other is X 1 and X 2 is the condition that they are different; m is an integer of 1, 2, or 3; n is an integer of 1, 2, 3, or 4; o is an integer of 1, 2, 3, or 4; A represents a CH- group, a CH2-CH- group, or a CH2-CH2-CH- group; R 1 and R 2 teeth, -hydrogen and - C1-C4 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of: R 3 teeth, -halogen, -Cyano, -C1-C4-alkyl, -C1-C3-halogenoalkyl; -C1-C4-alkoxy, and -Carboxyl group represents 0, 1, 2, or 3 substituents which may be independently selected from the group consisting of: R 4 teeth, -hydrogen, -halogen, -C1-C3-alkyl, and -C1~C3-halogenoalkyl selected from the group consisting of: R 5 teeth, -aryl, which may carry 1 to 3 substituents, and -monocyclic or bicyclic heteroaryl, which may bear 1 to 3 substituents selected from the group consisting of: R 6 teeth, -hydrogen, -halogen, - C1-C4-alkyl optionally substituted by 1 or 2 substituents; -C1~C3-halogenoalkyl (selected from the group consisting of:

[0023] definition The term "substituted" means that one or more hydrogen atoms on the specified atom or group are replaced with a selection from the indicated group, provided that the normal valence for the specified atom at the time is not exceeded. Combinations of substituents and / or variables are permissible.

[0024] The term "optionally substituted" or "optional substituent(s)" means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, an optionally substituted group can be substituted with as many optional substituents as can be accommodated by replacing hydrogen atoms with non-hydrogen substituents on any available carbon or nitrogen atom. Commonly, the number of optional substituents, when present, can be 1, 2, 3, 4, or 5, particularly 1, 2, or 3.

[0025] As used herein, the term "one or more" means "1, 2, 3, 4 or 5, in particular 1, 2, 3 or 4, more in particular 1, 2 or 3, even more in particular 1 or 2", for example in the definition of substituents of compounds of general formula (I) of the present invention.

[0026] The term "comprising" when used in the claims or the specification includes "consisting of."

[0027] Within this specification, if any item is referred to as "as described herein" or "as defined (anywhere) herein," that means that it may have the meaning as described anywhere herein or as defined anywhere herein.

[0028] Terms as described herein have the following meanings:

[0029] The term "halogen" or "halogen atom" means a fluorine, chlorine, bromine or iodine atom, in particular a fluorine, chlorine or bromine atom, preferred selections relating to chlorine or fluorine, more preferred selections relating to bromine or fluorine, most preferred being fluorine.

[0030] The term "C1-C4-alkyl" means a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3 or 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, or an isomer thereof. The term "C1-C3-alkyl" means a linear or branched saturated monovalent hydrocarbon radical having 1, 2 or 3 carbon atoms, such as methyl, ethyl, n-propyl or isopropyl.

[0031] The C1-C4- or C1-C3-alkyl groups may be optionally substituted by one or two substituents, preferably one substituent, which are preferably selected from the group consisting of halogen (forming a halogen-substituted C1-C4- or C1-C3-alkyl group as defined below), C3-C6-cycloalkyl, preferably containing 3, 4, 5 or 6 carbon atoms, such as, preferably, cyclopropyl, mono- or bicyclic heteroaryl as defined below, such as, preferably, a benzimidazolyl group, an amino group as defined below, a carboxyl group, an aminocarbonyl group as defined below.

[0032] The term "C1-C3-halogenoalkyl" means a linear or branched saturated monovalent hydrocarbon radical, wherein the term "C1-C3-alkyl" has the meaning as defined above, and wherein one or more hydrogen atoms are replaced by halogen atoms, whether identical or different. In particular, said halogen atoms are fluorine atoms. More in particular, all halogen atoms are fluorine atoms ("C1-C3-fluoroalkyl"). Said C1-C3-halogenoalkyl radicals are, 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, wherein the trifluoromethyl radical is particularly preferred.

[0033] The term "C1-C4-alkoxy" means a linear or branched saturated monovalent radical of the formula (C1-C4-alkyl)-O-, where the term "C1-C4-alkyl" is as previously defined, for example a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy radical, or an isomer thereof, with methoxy being particularly preferred.

[0034] The term "carboxyl group" refers to the group [-(C=O)-OH].

[0035] The term "aminocarbonyl" refers to the group [NH2-(C=O)-].

[0036] The term "amino group" includes amino (-NH2), mono- or dialkylamino (alkyl-NH-, (alkyl)2N-), where for "alkyl" reference may be made to the above definitions of C1-C4-alkyl and C1-C3-alkyl. Preferred are the amino group (-NH2) and mono- or dimethylamino. Most preferred is the amino group (-NH2).

[0037] The term "aryl" includes aromatic hydrocarbon residues containing 6 to 14 carbon atoms (excluding the carbon atoms of possible substituents), which may be monocyclic or bicyclic, including, for example: phenyl, naphthyl, phenanthrenyl and anthracenyl, which may optionally be substituted by one, two or three identical or different substituents selected from: hydroxy, halogen as defined above, such as, for example, preferably F, Br and Cl, cyano, carboxyl as defined above, amino as defined above, C1-C4-alkyl or C1-C3-alkyl as defined above, for example, preferably methyl, C1-C3-halogenoalkyl as defined above, for example, preferably trifluoromethyl, and C1-C4-alkoxy as defined above, for example, preferably methoxy.

[0038] Optionally substituted phenyl is preferred, such as unsubstituted phenyl and phenyl substituted with 1 to 3, more preferably 1 or 2, substituents which may be the same or different, wherein the 1 to 3 phenyl substituents are in particular selected from the group as defined above.

[0039] The term "monocyclic or bicyclic heteroaryl" includes heteroaromatic hydrocarbon residues containing 4 to 9 ring carbon atoms, which additionally preferably contain 1 to 3 of the same or different heteroatoms from the series S, O, N in the ring, thus forming preferably 5- to 12-membered heteroaromatic residues, which are preferably monocyclic but may also be bicyclic. Preferred aromatic heterocyclic residues include: pyridyl (pyridinyl), pyridyl-N-oxide, pyridazinyl, pyrimidyl, pyrazinyl, thienyl (thiophenyl), furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl or isoxazolyl, indolizinyl, indolyl, benzo[b]thienyl, benzo[b]furyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolinyl, quinoxalinyl.From the group of the 5-membered heteroaryl, for example thiazolyl, for example thiazol-2-yl, 2-thiazol-2-yl, 2-thiazol-4-yl, thienyl (thiophenyl), for example thien-3-yl, pyrazolyl, for example 1-pyrazol-4-yl, 3-pyrazol-5-yl, imidazolyl, for example imidazol-2-yl, 2-imidazol-4-yl, 1-imidazol-4-yl, triazolyl, for example 1-triazol-3-yl, 1-triazol-4-yl, for example 1,2,4-triazol-3-yl or 1,2,3-triazol-4-yl, oxazolyl, for example 2-oxazol-4-yl, 2-oxazol-5-yl, oxadiazolyl, for example 1,2,4-oxadiazolyl From the group of the aryl-3-yl, and 6-membered heteroaryls, for example, pyridyl (pyridinyl), for example, pyrid-1-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 2-pyrid-4-yl, 2-pyrid-6-yl, 3-pyrid-5-yl (pyridin-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-pyridin-4-yl, 2-pyridin-6-yl, 3-pyridin-5-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, and from the group of bicyclic heteroaromatic residues, in particular benzimidazolyl, for example, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, and 5- or 6-membered aromatic heterocycles are preferred.

[0040] The heteroaryl groups described above can carry one or more, preferably one, two or three, more preferably one or two identical or different substituents, especially selected from hydroxy, halogen as defined above, such as preferably F, Br and Cl, cyano, carboxyl as defined above, amino as defined above, C1-C4-alkyl or C1-C3-alkyl as defined above, such as preferably methyl, C1-C3-halogenoalkyl as defined above, such as preferably trifluoromethyl, and C1-C4-alkoxy as defined above, such as preferably methoxy.

[0041] Particularly preferred monocyclic or bicyclic heteroaryl groups are pyridinyl groups carrying one, two or three substituents selected from the group defined above. Preferably, the pyridinyl group carries one or two substituents, more preferably one substituent. The one, two or three optional pyridinyl substituents are preferably selected from C1-C3-alkyl as defined above, such as, in particular, methyl, halogen as defined above, such as, in particular, fluorine and bromine (fluorine is most preferred), and C1-C3-halogenoalkyl as defined above, such as, in particular, trifluoromethyl. Most preferred are groups of the formula

[0042] [ka] (In the formula, * indicates the bond position, and R y represents a substituent selected from C1-C3-alkyl, for example, preferably methyl, halogen, for example, preferably fluorine or bromine, and C1-C3-halogenoalkyl, for example, preferably trifluoromethyl, where more preferred is fluorine or bromine, most preferred is fluorine), which forms a group represented by Ry.

[0043] Aspects of the present invention In a first aspect, the present invention provides a new process for preparing compounds of general formula (I) as defined herein, wherein an intermediate compound of formula (IM-3) is reacted with a compound of formula (RM-3) to give a compound of formula (I):

[0044] [ka] The present invention provides a compound of the formula:

[0045] So, "A" is [ ] mrepresents a CH-, CH2-CH-, or CH2-CH2-CH- group, depending on the desired resulting alkylene chain length defined by m = 1. Using an "A" group that is a CH- group results in a chain length where m = 1. Using an "A" group that is a CH2-CH- group results in a chain length where m = 2. Using an "A" group that is a CH2-CH2-CH- group results in a chain length where m = 3.

[0046] The process steps are preferably carried out under alkaline conditions at elevated temperatures between 30° C. and 90° C. Alkaline conditions can be achieved by adding a suitable base, including inorganic and organic bases such as those described below. Preferred bases are lithium hydroxide and sodium hydroxide.

[0047] In a second aspect of the present invention, the novel process comprises reacting an intermediate compound of formula (IM-2) with a compound of formula (RM-2)

[0048] [ka] The compound of formula (IM-3) can further comprise the additional step of preparing an intermediate compound of formula (IM-3) by reacting the compound of formula (IM-3) with a compound of formula (IM-4) (In the formula, X 1 ,X 2 ,o,A,R 1 , R 4 and R 5 have the meanings defined above).

[0049] The process step for preparing intermediate compound (IM-3) can be carried out before the process step for preparing compound (I) as shown above. The process step is preferably carried out using methylmorpholine and ethyl chloroformate in DCM (dichloromethane). The reaction is preferably carried out under cooling, preferably at a temperature below 10°C.

[0050] The compound (RM-2) used in said process step is preferably in the form of a salt, such as in particular the HCl salt.

[0051] The resulting intermediate compound (IM-3) can be extracted by aqueous HCl extraction at pH 1 and crystallized from water, followed by conventional filtration and drying steps to isolate intermediate compound (IM-3).

[0052] In a third aspect of the present invention, the novel process comprises converting compound (RM-1) to compound (IM-1), followed by ester cleavage.

[0053] [ka] (In the formula, R y represents hydrogen or halogen, for example, preferably chlorine, and X 1 , X 2 , A and R 4 has the meaning as defined elsewhere in this specification) The compound may further comprise the additional step of preparing an intermediate compound of formula (IM-2) by

[0054] Thus, ester cleavage can be carried out by ester hydrolysis using conventional methods. Preferably, ester cleavage of compound (IM-1) is carried out using a suitable base, including inorganic and organic bases such as those described below. Preferred bases are lithium hydroxide and sodium hydroxide.

[0055] The reaction can be carried out in any suitable solvent, including those listed below. Preferably, THF (tetrahydrofuran) and water are used, and the reaction is preferably carried out at room temperature (23° C.±3° C.).

[0056] In a fourth aspect of the present invention, the novel process is represented by the following reaction scheme a):

[0057] [ka] (In the formula, X 1 , X 2 , A and R 4 has the meaning as defined elsewhere in this specification) The method may include a step of preparing an intermediate compound of formula (IM-1) according to the following formula:

[0058] The process steps for preparing compound (IM-1) are preferably carried out at an elevated temperature >40° C. Any suitable solvent may be used, including those listed below. Preferably, the reaction is carried out in THF.

[0059] Furthermore, the reaction is carried out using a suitable catalyst, including, for example, Pd(PPh3)4, Pd2(dba)3, Pd(OAc)2 / PPh3, Pd(dppf)Cl2 x DCM, Pd / C. It is particularly preferred to use Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium(0)) as the catalyst in the reaction.

[0060] Alternatively, the preparation of (IM-1) can be carried out by direct use of bromo-alkenes in gas form or in the form of commercially available solutions in organic solvents.

[0061] In an alternative embodiment, the intermediate compound of formula (IM-2) is R y is prepared by converting compound (RM-1) having the meaning of Cl to compound (IM-1), followed by ester cleavage as described above:

[0062] [ka] (In the formula, X 1 , X 2 , A and R 4has the meaning as defined elsewhere herein).

[0063] Thus, the process steps for preparing (IM-1) are shown in Reaction Scheme b):

[0064] [ka] This can be carried out using tributyl(vinyl)tin as described below in step 1-a'.

[0065] In a further alternative embodiment of the present invention, the step of preparing the intermediate compound of formula (IM-1) comprises the step of reacting R y has the meaning of Cl with vinylboronic acid pinacol ester to form compound (IM-1) according to reaction scheme c):

[0066] [ka] (In the formula, X 1 , X 2 , A and R 4 has the meaning as defined elsewhere herein).

[0067] This process step is advantageous because no tin (Sn) reagents are required, which results in reduced environmental damage, costs, and health risks for those performing the process.

[0068] In a fifth embodiment of the present invention, compound IM-1 is a compound having the formula R yis prepared from compound RM-1, where R is hydrogen, followed by converting compound IM-1 to intermediate compound IM-2 by ester cleavage, which is carried out in one combined step in a one-pot reaction. Such a shortened reaction scheme has the advantage of increased efficiency due to fewer intermediate isolation and purification steps. Reaction time and labor can be significantly reduced, and several chromatography steps can be avoided.

[0069] In a sixth aspect of the present invention, compound IM-3 is prepared from compound IM-1 via the in situ formation of intermediate compound IM-2 and the addition of compound RM-2, and the reaction is carried out in a one-pot reaction by a combined (shortened) reaction. Such a shortened reaction scheme has the advantage of increased efficiency due to fewer intermediate isolation and purification steps. Reaction time and labor can be significantly reduced, and several chromatography steps can be avoided.

[0070] In a seventh embodiment of the present invention, compound IM-3 is prepared via a further shortened reaction, in which compound RM-1 is converted to intermediate compound IM-1 similar to that described above, which is subsequently transferred to intermediate compound IM-2 by ester cleavage, followed by conversion to intermediate compound IM-3 by addition of compound RM-2. Such a shortened reaction scheme has the advantage of further increasing efficiency due to further reduced intermediate isolation and purification steps. Reaction time and labor can be further reduced, and chromatography steps can be avoided.

[0071] In an eighth aspect of the present invention, compound (I) is prepared via two shortened reaction steps, wherein the first shortened reaction step corresponds to the preparation of intermediate compound IM-3 as described in the previous seventh aspect, and the second shortened reaction step comprises the in situ conversion of intermediate compound IM-3 into compound (I), followed by its salt formation to achieve the preferred salt of compound (I) of the present invention.

[0072] In a preferred embodiment of the invention, the process for preparing compound (I) is carried out as described elsewhere herein and the resulting free base of compound of formula (I) is isolated by phase separation (solvent extraction) or by direct separation of the resulting oil product phase (oil separation).

[0073] In a preferred embodiment, the present invention relates to a process for preparing a compound of general formula (I) as described herein, wherein the substituent R 5 represents a monocyclic heteroaryl group which may bear 1 to 3 substituents as defined above. 5 may be independently selected from the group consisting of C1-C3-alkyl as defined above, for example, preferably methyl, halogen as defined above, for example, preferably fluorine or bromine, of which fluorine is more preferred, and C1-C3-halogenoalkyl as defined above, for example, preferably trifluoromethyl.

[0074] In a particularly preferred embodiment, the present invention relates to a process for preparing compounds of general formula (I) as described herein, wherein the substituent R 5 teeth,

[0075] [ka] is a group represented by (In the formula, * indicates the bond position, and R y is selected from the group consisting of C1-C3-alkyl as defined above, such as, preferably, methyl, halogen as defined above, such as, preferably, fluorine or bromine (of which fluorine is more preferred), and C1-C3-halogenoalkyl as defined above, such as, preferably, trifluoromethyl. So, R yis particularly preferably fluorine or bromine (of which fluorine is more preferred).

[0076] In a further particular aspect, the present invention provides a novel process for preparing compounds of general formula (I) as defined herein, comprising the following reaction steps: Step 1:

[0077] [ka] Step 2:

[0078] [ka] Step 3:

[0079] [ka] (In the formula, X 1 , X 2 , R 3 , R 4 , R 6 , R y , A, m, n and o have the meanings as defined elsewhere herein).

[0080] Said process steps 1, 2 and 3 are preferably carried out under the process conditions described above.

[0081] Preferably, reaction steps 1 and 2 are carried out in one shortened one-pot reaction step.

[0082] A further preferred embodiment of the present invention relates to a new process for preparing compounds of formula (I), wherein one or more of the following conditions are realized: the substituent "A" represents a CH- group and m represents 1; and / or -o represents 1; and / or -R 1 and R 2 each represent hydrogen; and / or -R 4 represents hydrogen; and / or -R 6 represents hydrogen; and / or -R 3 represents hydrogen; and / or -X 1 is N and X 3 is O or S, and the group

[0083] [ka] Form or X 1 is O or S, and X 2 is N, and the group

[0084] [ka] Form wherein in each case: * indicates the bond position to the carbonyl group, ** indicates the second bonding position, and R 4 and independently have the meaning as defined elsewhere herein; Preferably, X 1 is N and X 3 is O or S, and the group

[0085] [ka] Form wherein in each case: * indicates the bond position to the carbonyl group, ** indicates the second bonding position, and R 4 and independently have the meaning as defined elsewhere herein; More preferably, X 1 is N and X 3 is O, and the group

[0086] [ka] (In the formula, * indicates the bond position to the carbonyl group, ** indicates the second bonding position, and R 4 has the meaning as defined elsewhere in this specification) Form.

[0087] A particularly preferred aspect of the present invention relates to a novel process for preparing compounds of general formula (I) as defined herein, comprising reaction steps 1, 2 and 3 as defined above, wherein: X 1 represents N; X 2 represents O; A represents a CH- group; m represents 1; n represents 2; and o represents 1.

[0088] So, R y represents a halogen atom; R 4 teeth, -hydrogen, halogens as defined above, preferably chlorine, C1-C3-alkyl as defined above, preferably methyl, and C1-C3-halogenoalkyl as defined above, preferably trifluoromethyl selected from the group consisting of It is even more preferable to

[0089] So, R y represents fluorine or bromine, of which fluorine is more preferred; and R 3 , R 4 and R 6 Each represents hydrogen It is even more preferable to

[0090] Thus, a preferred embodiment of the present invention relates to a process as described herein, wherein compound (RM-1) is of formula (RM-1-a):

[0091] [ka] is represented by and / or wherein compound (IM-1) has the formula (IM-1-a):

[0092] [ka] is represented by and / or wherein compound (RM-2) has the formula (RM-2-a) or (RM-2-a′):

[0093] [ka] by, preferably the HCl salt:

[0094] [ka] is expressed in the form and / or wherein compound (RM-3) is represented by formula (RM-3-a):

[0095] [ka] is expressed by

[0096] The process of the present invention comprises the steps of:

[0097] [ka] Or formula (II'):

[0098] [ka] and pharmaceutically acceptable salts thereof, particularly as described herein.

[0099] Thus, a particular aspect of the present invention relates to a process for preparing compounds of formula (II) or (II') and pharmaceutically acceptable salts thereof, comprising the following process steps: Step 1-a:

[0100] [ka] Step 2-a or 2-a', respectively:

[0101] [ka] Step 3-a or 2-a', respectively:

[0102] [ka]

[0103] Preferably, reaction steps 1-a and 2-a are carried out in one shortened one-pot reaction step.

[0104] The preferred process conditions, bases, solvents and catalysts as described above are preferably used in the processes described herein.

[0105] In a further embodiment of the present invention, said particular process is y is chlorine and R 4 is hydrogen, followed by process steps 2-a and 3-a as described above for preparing compounds of formula (II) or (II') and pharmaceutically acceptable salts thereof: Step 1-a':

[0106] [ka]

[0107] In a further embodiment of the present invention, R y is chlorine and R 4 It is particularly preferred to prepare the intermediate compound (IM-1-a) via the following alternative (preferred) process step 1-a″ starting from compound RM-1, where is hydrogen: Step 1-a”:

[0108] [ka]

[0109] As described above, the resulting intermediate compound (IM-1-a) can be used in subsequent process steps described herein for preparing compounds of formula (II) or (II') and pharmaceutically acceptable salts thereof, such as, in particular, by subjecting compound (IM-1-a) to ester cleavage to form compound (IM-2-a), followed by process steps 2-a and 3-a as described above.

[0110] Generally, a wide range of inorganic and organic bases can be used in the process of the present invention as described elsewhere herein, including lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, sodium fluoride, and potassium fluoride. Preferred are sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate. Most preferred are lithium hydroxide and sodium hydroxide.

[0111] Furthermore, in the process of the present invention as described elsewhere herein, a wide range of solvents can generally be used, including, for example, methanol, ethanol, propanol, butanol, ethyl acetate (EtOAc), propyl acetate, isopropyl acetate, acetonitrile, butyronitrile, heptane, cyclohexane, methylcyclohexane, dichloromethane (DCM), toluene, xylenes, chlorobenzene, dichlorobenzenes, 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran, 2,5-dimethyltetrahydrofuran, methyl tert-butyl ether, cyclopentylmethyl ether, N,N-dimethylformamide, water, and mixtures thereof. Preferred are ethanol, ethyl acetate, isopropyl acetate, dichloromethane (DCM), tetrahydrofuran (THF), water, and mixtures thereof. Particularly preferred are the solvents used in the examples described below.

[0112] In a further aspect of the invention, the process for preparing a compound of general formula (I) or (II) or (II') as described anywhere herein comprises the additional step of converting the compound of formula (I) or (II) or (II') into a pharmaceutically acceptable salt or solvate thereof using a corresponding base or acid and / or solvent.

[0113] Preferably, the compound of formula (I) or (II) or (II') is converted to a pharmaceutically acceptable salt using an acid selected from the group consisting of benzoic acid, citric acid, fumaric acid, hydrochloric acid, lactic acid, malic acid, maleic acid, methanesulfonic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid and toluenesulfonic acid. Particularly preferred are acids selected from the group consisting of hydrochloric acid, sulfuric acid and phosphoric acid, of which hydrochloric acid is most preferred.

[0114] More preferably, the compound of formula (I) or (II) or (II') is converted to a pharmaceutically acceptable salt having a ratio of compound (I) or (II) or (II'):acid of 1-2:1-3.

[0115] In principle, crystallization into triple salt (3HCl) or single salt (1HCl) is possible. However, among these, crystallization into single salt is less preferred because it requires additional post-treatment steps of the compound of formula (I) or (II) or (II'), including, for example, solvent exchange and several solvent extraction steps. This is less advantageous in terms of process economics. Therefore, conversion into triple HCl salt (3HCl salt) is most preferred.

[0116] In an alternative embodiment of the invention, the process as described anywhere herein comprises the step of converting the compound of formula (I) or (II) or (II') to a sulfate salt by adding sulfuric acid and crystallizing the sulfate salt.

[0117] The conversion of the compound of formula (I) or (II) or (II') to the hydrochloride salt provides a facile and effective crystallization process that allows for direct crystallization of the decanted product phase without the need for phase separation. Chlorinated solvents can be detrimental to human and environmental safety. However, the preferred process step of converting the compound of formula (I) or (II) or (II') to the hydrochloride salt has the potential for a continuous process, which is also advantageous in terms of process efficiency.

[0118] Generally, the conversion of the compound of formula (I) or (II) or (II') into a salt can be carried out by conventional crystallization methods. Preferably, crystallization is carried out by cooling the reaction mixture containing the compound of formula (I) or (II) or (II') and the reaction product to room temperature, adding a water-miscible solvent, such as preferably ethanol, and adding the selected acid to form the respective acid salt. Preferably, crystallization is carried out at an elevated temperature, preferably below the boiling point of the organic solvent and water. The resulting crystallized salt is cooled below room temperature and isolated by conventional methods, including, for example, filtration, washing, and drying.

[0119] The formation of salts of the compounds of the invention can be carried out in particular by the methods described in international application WO2018 / 192973.

[0120] As described therein, solvents used for crystallization include acetonitrile, dichloromethane (DCM), alcohols, such as, in particular, methanol, ethanol, 2-propanol (isopropanol), aldehydes, ketones, in particular acetone, ethers, such as tetrahydrofuran (THF) or dioxane, esters, such as ethyl acetate, or alkanes, such as, in particular, pentane, hexane, heptane or cyclohexane, and water, and mixtures thereof. Preferred solvents used for crystallization are selected from the group consisting of acetonitrile, dichloromethane, methanol, ethanol, 2-propanol, ethyl acetate, THF, water, and mixtures thereof.

[0121] Particularly preferred solvents used for crystallization are selected from the group consisting of acetonitrile, methanol, ethanol, 2-propanol, ethyl acetate, THF, water, and mixtures thereof. Preferred water / solvent mixtures include mixtures of water and acetone, mixtures of water and ethanol, and mixtures of water and methanol, with mixtures of water and ethanol and mixtures of water and methanol being preferred.

[0122] Particularly preferred is the solvent used for crystallization selected from the group consisting of acetonitrile, dichloromethane, ethanol, 2-propanol (isopropanol), acetone and ethyl acetate, and their mixtures with water, for example, in particular the mixture of ethanol and water and the mixture of acetone and water.Particularly preferred is the solvent described in the following examples.

[0123] Particularly preferred mixtures are the following mixtures of solvents and water (ratios of solvent mixtures given elsewhere in this specification always refer to vol:vol): -Acetone:water = 9:1 (vol:vol) -Acetone:water = 95:1 (vol:vol) -Ethanol:water = 4:1 (vol:vol) -Ethanol:water = 3:1 (vol:vol) -Ethanol:water = 8:2 (vol:vol).

[0124] It is particularly preferred to carry out the conversion to a salt of compound (I) or (II) or (II') in a shortened one-pot reaction together with the reaction step of forming compound (I) or (II) or (II') by reacting intermediate compound IM-3 with compound RM-3.

[0125] The salts of the compounds of formula (I) or (II) or (II') can exist in amorphous, polymorphic, crystalline and / or semi-crystalline (partially crystalline) form, as well as in the form of solvates (or hydrates) of the salts. Preferably, the salts of the invention exist in crystalline and / or semi-crystalline (partially crystalline) form and / or in the form of their solvates (hydrates).

[0126] The preferred crystallinity of the salt or salt solvate of the present invention can be determined by conventional analytical methods, for example, by using various X-ray methods, which allow clear and easy analysis of salt compounds.In particular, the crystallinity grade can be determined or confirmed by using the powder X-ray diffraction (reflection) method as described for the examples in the following examples, or by using the powder X-ray diffraction (transmission) method as described for the examples in the following examples (both are hereinafter also abbreviated as PXRD).For crystalline solids with the same chemical composition, different resulting crystal lattices are summarized by the term polymorphism.

[0127] Preferably, the salts of the present invention exhibit a degree of crystallinity, as measured by the PXRD method as described herein, of greater than 30%, more preferably greater than 40%, even more preferably greater than 50%, for example at least 55-60%.

[0128] The salts of the present invention can exist as solvates and / or hydrates, which can be formed by attraction, association, adsorption, adhesion, embedding or complexation of solvent molecules in the crystalline lattice of the salts of the present invention. The solvent molecules that can be embedded in the crystalline lattice can come from the solvent used for crystallization as well as from water resulting from the relative humidity.

[0129] The extent to which the selected solvent or water leads to a solvate or hydrate in a process step or during the crystallization step depends on the combination of process conditions and the various interactions between the selected compound (I) or (II) or (II'), the counteranion from the selected acid, and the selected solvent and humidity conditions. Salt solvates or hydrates may be preferred because the solvent or water molecules in the crystal structure are bound by strong intermolecular forces, thereby representing an element of the structure formation of these crystals that can partially improve the stability of the salt. However, solvent and / or water molecules also exist in certain crystal lattices that are bound by rather weak intermolecular forces. These molecules are more or less integrated in the crystal structure formation, but are integrated toward lower energy effects. The solvent and / or water content of the solvate also depends on drying and environmental conditions (i.e., relative humidity). In the case of stable solvates or hydrates, there is usually a well-defined stoichiometry between the active compound (i.e., salt) and the solvent or water. In many cases, these ratios do not completely satisfy the stoichiometric values, and usually they are lower than theoretical values ​​due to certain crystal defects. The ratio of organic molecules to solvent or water molecules for weaker bound water can vary to a considerable extent, for example, between di-, tri-, or tetrahydrate. On the other hand, in amorphous solids, the molecular structure classification of solvent and / or water is not stoichiometric; however, the classification may be stoichiometric only by chance. In some cases, it is not possible to classify the exact stoichiometry of solvent or water molecules, because the layer structure forms and the embedded solvent or water molecules cannot be determined in a defined form.

[0130] The solvent and / or water content in amorphous solids and in crystalline solvates or hydrates can generally be determined by conventional methods, for example by using the well-known Karl-Fischer titration method, by performing dynamic vapor sorption (DVS) measurements, by performing thermogravimetry (TG-FTIR), etc., as described for the examples in the Examples below. Furthermore, methods for elemental analysis or structural analysis, for example, 1 H NMR spectroscopy or Raman spectroscopy (FT-Raman spectroscopy) can provide information about the extent 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.

[0131] Examples of solvates and / or hydrates according to the present invention include, for example, hemi(0.5), mono, sesqui(1.5), di, tri, tetra, penta, hexa, hepta, octa, nona, deca-, etc. solvates or hydrates, respectively. Further intermediate degrees of solvation are also possible, such as solvates with 2.5, 3.5, 4.5, etc. solvent and / or water molecules.

[0132] Preferred examples of solvates and / or hydrates include those having about 0.5, 1, 1.5, 2.5, 3, 4, and 7 solvates / hydrates per water molecule. Further preferred examples of solvates and / or hydrates include those having about 0.5, 1, 1.5, 2.5, 3, 4, 6, and 7 solvates / hydrates per water molecule. More preferred are hemi- and mono-solvates / hydrates having about 0.5 or 1 solvate / hydrate per water molecule, with hemi- and mono-hydrates being particularly preferred. Anhydrous salts are also preferred. It is further possible that solvent and / or water residues remain in the salt in non-stoichiometric amounts.

[0133] Furthermore, a mixture of water and solvent may remain in the salt, forming so-called mixed hydrate / solvate forms. Examples of such mixed hydrate / solvate forms include, inter alia, acetone / water, preferably in a ratio of 1 to 4:1, e.g., 4:1, in particular; methanol / water, preferably in a ratio of 3 to 9:1, e.g., 3:1, 4:1, and 9:1, in particular; and ethanol / water, preferably in a ratio of 1 to 4:1, e.g., 3:1 and 4:1, in particular.

[0134] Any reference here and hereafter to a salt of a compound of formula (I) or (II) or (II') should be understood to also refer to the corresponding solvates, e.g., hydrates, solvates and mixed hydrate / solvate forms, and polymorphic modifications, and amorphous forms, as appropriate and expedient.

[0135] The new process of the present invention also surprisingly leads to an increase in yield compared to the process as known from the prior art.

[0136] Yields in the range of ≧30%, preferably ≧35%, more preferably ≧40, even more preferably ≧45% are possible here.

[0137] In contrast, prior art processes provided yields of 22% or less. For example, preparation of the 3HCl salt of compound (II) or (II') according to the process of the present invention can provide a yield of >60%, as shown in Example 4 below. In contrast, preparation of the 3HCl salt using the processes as described in WO2017 / 068089 and WO2017 / 068090 provides a yield of only 22%, as shown in the example for preparing Example Compound No. 127.

[0138] In particular, the new shortened process steps of the present invention further provide a more viable cost and labor effective process. Polymer formation in the intermediate formation step can be avoided, which positively impacts process control and yield.

[0139] A further aspect of the present invention relates to compounds of formula (I) or (II) or (II') as described anywhere herein, including salts, hydrates, solvates and mixed hydrate / solvate forms, polymorphic modifications, and amorphous forms obtained by the processes as described herein. The compounds obtained by the new processes described herein are characterized by improved and / or higher purity, as defined by their total impurity content of less than 2.00% relative area, preferably less than 1.50% relative area, and more preferably less than 1.00% relative area, where the impurity content is determined by HPLC as described in the Examples below, and "relative area %" refers to the sum of the relative areas of all impurities in the HPLC spectrum.

[0140] Thus, a further aspect of the invention is a method for producing a cellulose ester comprising at least 97.80% relative area, preferably at least 97.90% relative area, at least 98.00% relative area, at least 98.10% relative area, at least 98.20% relative area, at least 98.30% relative area, at least 98.40% relative area, at least 98.50% relative area, at least 98.60% relative area, at least 98.70% relative area, at least 98.80% relative area, at least 98.90% relative area, at least 99.00% relative area, at least 99.10% relative area, at least 99.20% relative area, at least 99.30% relative area, at least 99.40% relative area, at least 99.50% relative area,

[0023] The present invention relates to compounds of formula (I) and (II) or (II'), as described anywhere herein, including salts, hydrates, solvates and mixed hydrate / solvate forms, polymorphic modifications, and amorphous forms, having a total purity of at least 99.60% relative area, at least 99.70%, at least 99.80%, at least 99.90%, at least 99.95%, at least 99.96%, at least 99.97%, at least 99.98%, at least 99.99% relative area, where purity is determined by HPLC as described in the Examples below, and "relative area %" refers to the relative area of ​​a compound of the invention in the HPLC spectrum.

[0141] In particular, the compounds of formula (I) and (II) or (II') as described anywhere herein, including salts, hydrates, solvates and mixed hydrate / solvate forms, polymorphic modifications, and amorphous forms, are characterized by containing one or more impurities with relative retention times RRT 0.59, 0.65, 0.83 and 1.37 in an amount of less than or equal to 0.20% relative area, preferably less than or equal to 0.15% relative area, more preferably less than or equal to 0.10% relative area, preferably with a lower limit of 0.05% relative area.

[0142] More preferably, the compounds of formula (I) and (II) or (II') as described anywhere herein, including salts, hydrates, solvates and mixed hydrate / solvate forms, polymorphic modifications, and amorphous forms, are characterized by the absence of impurities with the following relative retention times RRT: 0.59, 0.65, 0.83, and 1.37.

[0143] More particularly, the compounds of formula (I) and (II) or (II') as described anywhere herein, including salts, hydrates, solvates and mixed hydrate / solvate forms, polymorphic modifications, and amorphous forms, are characterized by the following relative retention times: RRT 0.27, 0.52, 0.59, 0.65, 0.83, 0.94, 1.19, 1.37, preferably by the absence of impurities with a lower limit of relative area of ​​0.05%.

[0144] More particularly, the compounds of formula (I) and (II) or (II') as described anywhere herein, including salts, hydrates, solvates and mixed hydrate / solvate forms, polymorphic modifications, and amorphous forms, are characterized by an impurity profile comprising one or more impurities at relative retention times: RRT 0.48, 0.70, 1.27, and 1.48.

[0145] Thus, the impurities and their retention times RRT are determined by HPLC as described in the examples below.

[0146] In contrast, using the process for preparing compound (II) in the form of the 3HCl salt as described in WO2017 / 068089 and WO2017 / 068090 (preparation of Example Compound No. 127), it is not possible to achieve such a high degree of purity and improved impurity profile, as can be seen from Figures 6, 7 and 8.

[0147] A particularly preferred embodiment of the present invention relates to a polymorph (PM1) of the triple HCl salt of Compound (II), which is characterized by a powder X-ray diffraction pattern (PXRD pattern) containing characteristic crystalline peaks (major peaks) expressed in degrees 2-theta at about 3.9 and 16.5 ±0.25 degrees, or ±0.20 degrees, or ±0.10 degrees, or ±0.05 degrees.

[0148] Preferably, in such embodiments of the polymorph (PM1) of the triple HCl salt of Compound (II), the PXRD pattern comprises one or more further characteristic (major) peaks, expressed in degrees 2-theta, at about 7.9, 24.1, 19.1, 12.1, and / or 10.0 ±0.25 degrees or ±0.20 degrees or ±0.10 degrees or ±0.05 degrees.

[0149] More preferably, in such embodiments of the polymorph, the PXRD pattern comprises characteristic crystalline (major) peaks expressed in degrees two-theta at 3.9, 16.5, 7.9, 24.1, 19.1, 12.1, and 10.0 ±0.20 degrees or ±0.10 degrees or ±0.05 degrees.

[0150] Preferably, said polymorph (PM1) of the triple HCl salt of Compound (II) exists in the form of a hemihydrate. Preferably, said polymorph (PM1) of the triple HCl salt of Compound (II) is characterized by a water activity of ≦0.5%, preferably ≦0.4%, more preferably ≦0.3%.

[0151] The melting point of said polymorph (PM1) of the triple HCl salt of Compound (II), as determined via DSC as described in the Examples below, is preferably in the range of ≧180° C. and ≦220° C., preferably in the range of ≧185° C. and ≦215° C., more preferably in the range of ≧190 and ≦210° C.

[0152] More preferably, said polymorph (PM1) of the triple HCl salt of Compound (II) exhibits microscopic crystallinity as determined via optical microscopy using polarized light, characterized by spherical polycrystalline particles having low crystallinity, with an average particle size as determined via optical microscopy using polarized light of about 10 to 50 μm.

[0153] The triple HCl salt polymorph (PM1) of Compound (II) is characterized by high flow properties and exists in the form of a free-flowing powder with low electrostatic charge.

[0154] The polymorph (PM1) of the triple HCl salt of Compound (II) is the more thermodynamically stable polymorph at room temperature (23° C.±5° C.).

[0155] A further preferred embodiment of the present invention relates to a polymorph (PM2) of the triple HCl salt of Compound (II) characterized by a powder X-ray diffraction pattern (PXRD pattern) containing characteristic crystalline (major) peaks expressed in degrees 2-theta at about 16.9 and 25.3 ±0.25 degrees, or ±0.20 degrees, or ±0.10 degrees, or ±0.05 degrees.

[0156] Preferably, in such embodiments of the polymorph (PM2) of the triple HCl salt of Compound (II), the PXRD pattern comprises one or more further characteristic (major) peaks, expressed in degrees two-theta, at about 11.7, 28.3, 25.5, 20.1 and / or 26.2 ±0.25 degrees or ±0.20 degrees or ±0.10 degrees or ±0.05 degrees.

[0157] More preferably, in such embodiments of the polymorph (PM2) of the triple HCl salt of Compound (II), the PXRD pattern comprises characteristic crystalline (major) peaks expressed in degrees two-theta at 16.9, 25.3, 11.7, 28.3, 25.5, 20.1, and 26.2 ±0.20 degrees or ±0.10 degrees or ±0.05 degrees.

[0158] Preferably, said polymorph (PM2) of the triple HCl salt of Compound (II) exists in anhydrous form. Preferably, said polymorph (PM2) of the triple HCl salt of Compound (II) is characterized by a water activity of ≦0.8%, preferably ≦0.7%, more preferably ≦0.6%.

[0159] The melting point of said polymorph (PM2) of the triple HCl salt of Compound (II), determined via DSC as described in the Examples below, is preferably in the range of ≧210° C. and ≦240° C., preferably in the range of ≧215° C. and ≦235° C., more preferably in the range of ≧220° C. and ≦230° C.

[0160] More preferably, said polymorph (PM2) of the triple HCl salt of Compound (II) exhibits microscopic crystallinity, as determined via optical microscopy using polarized light, characterized by fine, aggregated needles having a high degree of crystallinity.

[0161] The triple HCl salt polymorph (PM2) of Compound (II) is further characterized by having wool-like solid state properties.

[0162] The polymorph (PM2) of the triple HCl salt of Compound (II) is thermodynamically less stable at room temperature (23° C.±5° C.) than polymorphs PM1 or PM3.

[0163] A further preferred embodiment of the present invention relates to a polymorph (PM3) of the triple HCl salt of Compound (II) characterized by a powder X-ray diffraction pattern (PXRD pattern) containing characteristic crystalline (major) peaks expressed in degrees 2-theta at about 14.7 and 10.3 ±0.25 degrees, or ±0.20 degrees, or ±0.10 degrees, or ±0.05 degrees.

[0164] Preferably, in such embodiments of the polymorph (PM3) of the triple HCl salt of Compound (II), the PXRD pattern comprises one or more further characteristic (major) peaks, expressed in degrees two-theta, at about 17.0, 26.5, 18.1, 22.1 and / or 27.1 ±0.25 degrees or ±0.20 degrees or ±0.10 degrees or ±0.05 degrees.

[0165] More preferably, in such embodiments of the triple HCl salt polymorph (PM3) of Compound (II), the PXRD pattern comprises characteristic crystalline (major) peaks, expressed in degrees two-theta at 14.7, 10.3, 17.0, 26.5, 18.1, 22.1, and 27.1 ±0.20 degrees or ±0.10 degrees or ±0.05 degrees.

[0166] Preferably, said polymorph (PM3) of the triple HCl salt of Compound (II) exists in the form of a monohydrate. Preferably, said polymorph (PM3) of the triple HCl salt of Compound (II) is characterized by a water activity of >0.3%.

[0167] The melting point of said polymorph (PM3) of the triple HCl salt of Compound (II), as determined via DSC as described in the Examples below, is preferably in the range of ≥ 150°C and ≤ 190°C, preferably in the range of ≥ 155°C and ≤ 180°C, more preferably in the range of ≥ 160 and ≤ 175°C.

[0168] More preferably, said polymorph (PM3) of the triple HCl salt of Compound (II) exhibits microscopic crystallinity, as determined via optical microscopy using polarized light, characterized by fine rods having a high degree of crystallinity.

[0169] The triple HCl salt polymorph (PM3) of Compound (II) is further characterized by having bulky, non-flowing powder properties.

[0170] The polymorph (PM3) of the triple HCl salt of Compound (II) is thermodynamically stable at room temperature (23° C.±5° C.).

[0171] Among the above-described polymorphs of the triple salt of Compound (II), PM1 is most preferred due to its thermodynamic stability, especially at room temperature, spherical particle morphology, and its good flow properties with low electrostatic charge, which are advantageous for using said polymorph as a pharmaceutically active ingredient.

[0172] In the embodiments described above, the terms "characteristic peak(s)" or "main peak(s)" refer to those peak(s) in the PXRD pattern that have the highest intensity. The intensities of the peaks in the PXRD pattern decrease in the order of the peaks listed above, and the polymorphs (PM1, PM2, and PM3) are preferably characterized by having two or more characteristic (main) peaks that have the highest intensity.

[0173] The compound (II') described above is not disclosed in the prior art, for example, WO2017 / 068089, WO2017 / 068090, WO2018 / 192973 or WO2011 / 029832, and is a novel compound in itself.

[0174] The compounds of formulas (I), (II), and (II') as described herein are particularly suitable for use as pharmaceuticals that act as ferroportin inhibitors, whereby ferroportin inhibition can be determined as described in any of International Patent Applications WO2018 / 192973, WO2017 / 068089, and WO2017 / 068090.

[0175] The compounds of formula (I), (II) and (II') as described herein, including their preferred salts and polymorphs, are particularly suitable for use in the prevention and / or treatment of disorders of iron metabolism that lead to increased iron levels or increased iron absorption, for example, for use in the prevention and / or treatment of iron overload and / or for use in the prevention and / or treatment of diseases associated with or caused by increased iron levels, increased iron absorption or iron overload, such as thalassemia, hemoglobinopathies, hemoglobin E disorders, hemoglobin H disorders, hemochromatosis, hemolytic anemia, thalassemia, including alpha-thalassemia, beta-thalassemia and delta-thalassemia, sickle cell anemia (sickle cell disease) and congenital dyserythroid anemia.

[0176] The compounds of formula (I) and (II) and (II') as described herein, including preferred salts and polymorphs thereof, are further suitable for use in the prevention and / or treatment of diseases associated with ineffective erythropoiesis, for example myelodysplastic syndromes (MDS, myelodysplasia), polycythemia vera and congenital dyserythropoietic anemia, or for use in adjunctive therapy by limiting the amount of iron available to pathogenic microbial organisms, such as the bacterium Vibrio vulnificus, thereby treating infections caused by said pathogenic microbial organisms, or for use in the prevention and / or treatment of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, by limiting the deposition or increase of iron in tissues or cells, or for use in the prevention and / or treatment of the formation of radicals, reactive oxygen species (ROS) and oxidative stress, or for use in the prevention and / or treatment of cardiac, hepatic and endocrine damage caused by iron overload, or for use in the prevention and / or treatment of inflammation triggered by excess iron.

[0177] Thus, the present invention further relates to medicaments containing one or more of Compounds (I) or (II) or (II'), including their salts, hydrates, solvates and mixed hydrate / solvate forms, polymorphic modifications, and amorphous forms as defined herein, for example, medicaments for use in the prevention or treatment of any of the diseases, conditions, or symptoms as described above. Such medicaments may optionally further contain one or more pharmaceutical carriers and / or adjuvants and / or solvents, and / or at least one additional pharmaceutically active compound, for example, an active compound for the prevention and treatment of iron overload, thalassemia, hemochromatosis, or sickle cell disease, neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease, and related symptoms, or an iron chelating compound.

[0178] The medicaments as described above may be in the form of preparations for oral or parenteral administration.

[0179] Compound (I) or (II) or (II'), including salts, hydrates, solvates and mixed hydrate / solvate forms, polymorphic modifications, and amorphous forms thereof, as defined herein, are further suitable for use in combination therapy comprising the simultaneous administration of a compound of the present invention together with at least one additional pharmaceutically active compound, wherein the simultaneous administration of the combination therapy can be carried out in fixed-dose combination therapy by the simultaneous administration of a compound of the present invention with at least one additional pharmaceutically active compound in a fixed-dose formulation, or wherein the simultaneous administration of the combination therapy can be carried out in free-dose combination therapy by the simultaneous administration of a compound of the present invention and at least one additional pharmaceutically active compound in free doses of each component, either by simultaneous administration of the individual components or by sequential use of the individual components distributed over a period of time, and wherein the combination therapy preferably comprises a compound of the present invention, such as Tmprss6-ASO, an iron chelator, curcumin, SSP-0041, 84, together with one or more other pharmaceutically active compounds for reducing iron overload selected from deferithrine, deferasirox, deferoxamine and / or deferiprone, and / or antioxidants, e.g., n-acetylcysteine; antidiabetic drugs, e.g., GLP-1 receptor agonists; antibiotics, e.g., vancomycin (Van) or tobramycin; drugs for the treatment of malaria; anticancer drugs; antifungal drugs; dopamine agonists such as levodopa; This includes co-administration of the compounds of the present invention with one or more other pharmaceutically active compounds selected from drugs for the treatment of neurodegenerative diseases such as Heimer's disease and Parkinson's disease; antiviral drugs, e.g., interferon-α or ribavirin; immunosuppressants, e.g., cyclosporin A or cyclosporin A derivatives; iron supplements; vitamin supplements; erythropoiesis stimulating drugs (e.g., erythropoietin, Epo); anti-inflammatory biological agents; antithrombolytic drugs; statins; hypertensive drugs; and inotropic compounds.

[0180] A further aspect of the present invention relates to novel intermediate compounds that can be prepared by the novel process steps of the present invention, and the respective processes for preparing them. The process steps for preparing the intermediate compounds can further comprise crystallization, isolation and / or purification steps to isolate the intermediate compounds.

[0181] In particular, the present invention provides a compound represented by the general formula (IM-2-a):

[0182] [ka] The present invention relates to an intermediate compound of the above.

[0183] A further aspect of the present invention relates to a process for preparing said intermediate compound (IM-2-a), comprising the reaction steps as defined anywhere above in context with the description of the preparation of the compound of formula (I), such as in particular the following process, which may further comprise crystallization, isolation and / or purification steps to isolate intermediate compound (IM-1):

[0184] [ka] Thus, the preferred process conditions, bases, solvents and catalysts as described above are preferably used for the preparation and for the crystallization and isolation.

[0185] In a further aspect, the present invention provides an intermediate compound of general formula (IM-3)

[0186] [ka] (In the formula, X 1 , X 2 , R 1 , R 4 , R 5 , A and o have the meanings as defined elsewhere herein) Regarding.

[0187] Preferably, the intermediate compound (IM-3) is represented by the formula

[0188] [ka] (Further, in the formula, o is 1; R 1 is hydrogen; A represents a CH- group. Represented by; The following formula (IM-3-a)

[0189] [ka] (In the formula, X 1 , X 2 , R 4 and R y has the meaning as defined elsewhere in this specification) R represented by 5 It is characterized by having a group.

[0190] More preferably, the intermediate compound (IM-3) is X 1 represents N; X 2 represents O; A represents a CH- group; o represents 1; R 4 represents hydrogen; and R y represents fluorine or bromine (fluorine is preferred) It is characterized in that; This is represented by the following formula (IM-3-b) or (IM-3-b'):

[0191] [ka] is expressed by

[0192] A further aspect of the present invention relates to a process for preparing intermediate compounds (IM-3), (IM-3-a) or (IM-3-b) or (IM-3-b') as defined above, comprising the reaction steps as defined anywhere above in the context of the description of the preparation of compounds of formula (I). Thus, the preferred process conditions, bases, solvents and catalysts as described above are preferably used for the preparation and for crystallization and isolation.

[0193] A further aspect of the present invention relates to a new process for preparing intermediate compound (IM-1) or (IM-1-a) as defined anywhere above, said process comprising the reaction steps as described above in the fourth aspect of the invention or in the process according to process step 1-a′ and more preferably process step 1-a″, both as described above. Thus, the preferred process conditions, bases, solvents and catalysts as described above are preferably used for the preparation as well as for crystallization and isolation.

[0194] The present invention is illustrated in more detail by the following examples, which are merely illustrative and will enable those skilled in the art to extend the specific examples to further suitable variations, which are covered below. [Example]

[0195] Abbreviation DCM dichloromethane DSC Differential Scanning Calorimetry IPC HPLC High Pressure Liquid Chromatography PXRD Powder X-ray Diffraction THF tetrahydrofuran Mw Molecular weight

[0196] 1a. Process for preparing intermediate compound (IM-2-a) by crystallization from HCl Chemicals:

[0197] [Table 1]

[0198] reaction:

[0199] [ka]

[0200] procedure: The vessel is purged with N2 for ≥ 15 minutes.

[0201] Charge LitOBu, add 70 ml of THF, and stir at 20-25°C for ≥10 minutes.

[0202] Heat the mixture to 55-60°C and stir for ≥ 5 minutes.

[0203] A solution of 1,2-dibromoethane in 15 ml of THF is added at 55-60°C.

[0204] The mixture is stirred for ≥30 minutes at this temperature.

[0205] Cool the mixture to 45-50°C.

[0206] Add Pd(PPh3)4, purge with several ml of THF and stir at this temperature for ≥ 5 min.

[0207] The mixture is heated to 60-65° C. and a solution of ethyl 4-oxazolecarboxylate in 15 ml of THF is added at 60-65° C. (exothermic).

[0208] The mixture is stirred at this temperature for ≥ 30 minutes.

[0209] Cool the mixture to 20-25°C.

[0210] A solution of LiOH in 35 ml of water is added at 20-25° C. and stirred overnight (exothermic). IPC via HPLC: ≥ 95% conversion

[0211] The mixture is extracted three times with isopropyl acetate. The organic phase is discarded.

[0212] The aqueous phase is cooled to 0-5°C and the pH is measured.

[0213] The pH is adjusted to 0.9-1.1 with HCl 20% by keeping the temperature at ≦10°C.

[0214] The suspension is stirred at -5°C to 0°C for ≥ 45 minutes.

[0215] The suspension is filtered, washed with 50 ml of cold (≦5° C.) HCl at pH 0, 20 ml of cold (≦5° C.) water and dried to dryness in vacuo at 45° C.

[0216] yield:

[0217] [Table 2]

[0218] 1b. Alternative process steps for preparing intermediate compound (IM-1-a) In an alternative (but less preferred) process according to Example 1a above, the process steps of Step 1 and Step 2 described therein can alternatively be carried out by starting with compound RM-1, where R y is chlorine and R 4 is hydrogen, which is designated herein as RM-1-a', leading to the intermediate compound IM-1-a.

[0219] Chemicals:

[0220] [Table 3]

[0221] reaction:

[0222] [ka]

[0223] procedure: Ethyl 2-chlorooxazole-4-carboxylate, tributyl(vinyl)tin, and Pd(PhP)Cl are placed in dioxane under nitrogen. The mixture is heated to reflux (OT 100-110°C) for ≥ 4 hours. The mixture is cooled to OT 20-25°C, filtered over Celite, and the filter cake is washed with 200 ml of dioxane. The filtrate is evaporated to dryness in vacuo, and the crude product is purified by chromatography. Column: Kp-Sil 1500g Eluent: EtOAc / heptane 20:80 Method: duration 7CV, no gradient, threshold 20mAU; The crude material is dissolved in 20:80 EtOAc / heptane and two columns are used at this scale.

[0224] yield:

[0225] [Table 4]

[0226] NMR is consistent with the structure

[0227] 1c. Alternative process steps for preparing intermediate compound (IM-1-a) In a further alternative (preferred) process according to Example 1a above, the process steps of stage 1 and stage 2 described therein can alternatively be carried out by starting with compound RM-1, wherein R y is chlorine and R 4 is hydrogen, which is designated herein as RM-1-a', leading to the intermediate compound IM-1-a.

[0228] reaction:

[0229] [ka]

[0230] procedure: Ethyl 2-chlorooxazole-4-carboxylate (RM-1-a' / 1.0 equiv.) was charged to a RBF, and 2-MeTHF (9 V) and water (1 V) were added under a nitrogen atmosphere at 25–30 °C. To this mixture, vinylboronic acid pinacol ester (1.2 equiv.) and potassium carbonate (2.5 equiv.) were added at 25–30 °C, and the resulting mixture was degassed with nitrogen for 15 min. Pd(PPh3)4 (0.05 equiv.) was added under a nitrogen atmosphere, and the reaction mixture was warmed to 80 °C. The reaction mixture was stirred at 80–85 °C for 8–12 h, and completion of the reaction was monitored by TLC / HPLC. After completion of the reaction, the reaction mixture was cooled to 25–30 °C and diluted with water (5 V). The phases were separated, and the aqueous phase was extracted with 2-MeTHF (5 V). The combined organic phase was washed with water (5V) followed by brine solution (5V) and then dried over sodium sulfate. The organic phase was filtered and concentrated under vacuum below 50°C to give the crude product as a brown liquid. The crude product was purified using silica gel (60-120 mesh) column chromatography eluting with ethyl acetate and n-heptane to give the pure product. NMR is consistent with the structure.

[0231] yield: 55-60%

[0232] purity: The purity of the obtained materials ranged from 96 to 99%.

[0233] Further purification using n-heptane crystallization at lower temperatures below 0° C. gave a purity of >98%. When this highly purified material was tested for palladium content using ICP-MS, amounts in the range of 10-250 ppm were found, which was further reduced to a content of less than 25 ppm by treatment with Siliabond thiol scavenger (heterogeneous Pd scavenger treatment).

[0234] 2. Process for preparing intermediate compound (IM-2-a) by crystallization from water Chemicals:

[0235] [Table 5]

[0236] reaction: The starting compound IM-1-a can be prepared according to the process steps "Step 1" and "Step 2" of Example 1a or (less preferably) as described in Example 1b.

[0237] [ka]

[0238] procedure: IM-1-a is charged into a reactor and dissolved in THF.

[0239] Cool the solution to 3-7 °C.

[0240] A solution of LiOH (15.76 g in 500 ml water) is added over ≥15 min (slightly exothermic) at 3-7° C. The mixture is stirred for ≥3 h at 3-7° C.

[0241] IPC via LC / MS, ≥97% conversion.

[0242] The mixture is extracted twice with DCM. DCM phase extraction and separation is performed with the aqueous phase at 5° C., but with DCM having room temperature and without active cooling.

[0243] The phase is allowed to stand for ≥ 30 minutes.

[0244] The organic layer is discarded.

[0245] The vessel is cleaned with HCl 20% and ethanol.

[0246] Add HCl 20% to the aqueous phase at 3-7°C to a pH of 0.5-1.0 (slightly exothermic, HCl should not rinse the vessel walls). Towards the end of the HCl addition during crystallization, increase the agitator speed from 80 rpm to 300 rpm for good mixing of the suspension.

[0247] The suspension is stirred for ≥30 min at 3-7°C.

[0248] The suspension is filtered and the reactor is rinsed once with the mother liquor.

[0249] The wet cake is washed with water at 5-10°C and dried to dryness at 45°C / vacuum <50mbar. Transfer of the fine suspension onto the filter leaves some residue in the vessel, but these are easily removed with a single rinse with the mother liquor.

[0250] yield:

[0251] [Table 6]

[0252] 3a. Process for preparing intermediate compound (IM-3-b) by crystallization from water Chemicals:

[0253] [Table 7]

[0254] reaction:

[0255] [ka]

[0256] procedure: The starting compound IM-2-a can be prepared as described in Example 1 or 2.

[0257] Under an inert atmosphere, compound IM-2-a is suspended in DCM and 4-methylmorpholine is added at -5 to 0°C.

[0258] Ethyl chloroformate is then added (exothermic addition) while maintaining the temperature at ≦0° C. Compound RM-2-a (ground) is added portionwise while maintaining the temperature at ≦0° C.

[0259] The suspension is stirred for ≥ 2 hours at -5°C to 0°C.

[0260] IPC control by LC / MS, conversion ≥ 93% area.

[0261] The mixture is heated to 15-25°C and extracted twice with a 10% NaCl solution.

[0262] The organic phase is extracted three times with 450 ml of HCl 10% w / w.

[0263] While maintaining the temperature at ≦10° C., the combined aqueous phases are adjusted to pH 2 with 30% NaOH and then to pH 7-8 with 5% NaOH.

[0264] The suspension is filtered, washed twice with 400 ml of water and dried to dryness in vacuo at 45°C.

[0265] yield:

[0266] [Table 8]

[0267] 3b. Short synthesis via process IM-2-a for preparing intermediate compound (IM-3-b) reaction:

[0268] [ka]

[0269] Process Variant 1: Chemicals:

[0270] [Table 9]

[0271] procedure: The starting compound IM-1-a can be prepared as described in Example 1 or 2.

[0272] The starting compound IM-1-a is dissolved in THF. A solution of 1.72 g of LiOH in 20 ml of water is added at 0-5° C. The mixture is stirred at 3-7° C. for ≥ 3 hours.

[0273] IPC via HPLC-MS, ≥97% conversion.

[0274] The mixture is adjusted to an IT of 15-20°C and the pH is set to 0.8-1.2 by adding 20% ​​HCl in this temperature range. The mixture is extracted three times with DCM. The combined organic phases are dried via azeotropic solvent removal by distilling off a volume of 50 ml at OT 30°C / 600 mbar and then adding 50 ml of DCM.

[0275] This procedure is repeated until the water content, as determined by Karl Fischer, is 0.13%.

[0276] The solution is filled to a volume of 160 ml with DCM and cooled to an IT of -5 to 0°C. 4-Methylmorpholine is added in this temperature range. Ethyl chloroformate is added in this temperature range (exothermic). RM-2-a (ground) is added portionwise at an IT of ≦0°C. The mixture is stirred at -5 to 0°C for ≧3 hours. IPC via HPLC-MS, ≥93% conversion.

[0277] The mixture is extracted twice with a NaCl 10% solution. The aqueous phase is discarded. The organic phase is extracted three times with 75 ml of HCl 10%. The organic phase is discarded. The combined aqueous phases are adjusted at an IT ≦10°C first to pH 2 with NaOH 30% and then to pH 7-8 with NaOH 5%. After stirring for ≧15 min at ≦10°C, the suspension is filtered and washed twice with 60 ml of water. The filter cake is dried to dryness at OT 45°C / <100 mbar.

[0278] yield:

[0279] [Table 10]

[0280] In experiments using a DCM water content of 0.04% by azeotroping, the yield was even up to 85%.

[0281] Process Variant 2: Chemicals:

[0282] [Table 11]

[0283] procedure: The starting compound IM-1-a can be prepared as described in Example 1 or 2.

[0284] The starting compound IM-1-a is charged into a reactor and filled with THF. The solution is cooled to 0-5°C and the LiOH solution is added at an IT ≤ 5°C. The solution is stirred at an IT ≤ 0-5°C for ≥ 60 min. IPC via HPLC:

[0285] If IPC IM-1-a<0.2% a / a, adjust the pH to 0.5-1.0 with HCl 20% at 15-20°C.

[0286] The mixture is extracted 3x with DCM. The combined organic phases are dried over MgSO4, filtered, and the filter cake is washed with DCM. DCM is evaporated at OT 32-37°C / 400 mbar. 8.5 equivalents of DMF are added. THF is evaporated at 32-37°C / 35 mbar. (End point of distillation when no further solvent condenses.) IPC via KF, ≤0.2% water:

[0287] If the IPC is out of specification, add 10 equivalents of DCM and distill again at 32-37°C, followed by IPC KF.

[0288] 4-Methylmorpholine is added to the DMF solution at an IT of -5°C to 0°C. Ethyl chloroformate is added at an IT of -5°C to 0°C. RM-2-a (ground) is added at an IT of -5°C to 0°C. The mixture is stirred for ≥ 5 hours at an IT of -5°C to 0°C. IPC via HPLC:

[0289] If IPC IM-3-a > 85% a / a, water is added slowly at an IT < 10°C. The pH of the reaction mixture is adjusted to pH 6-8 with NaOH 30% if necessary. The product suspension is stirred for ≥ 60 min at an IT 0-5°C, filtered, washed twice with water and dried in vacuo at 45°C.

[0290] yield: Yield = 448.42g = 75.6% HPLC assay = 98.2% HPLC purity=99.7%

[0291] 3c. Short synthesis via process IM-2-a to prepare intermediate compound (IM-3-b)

[0292] reaction:

[0293] [ka]

[0294] Process Variant 1: Chemicals:

[0295] [Table 12]

[0296] procedure: The vessel is purged with N2 for ≥ 15 min. LitOBu is charged to the vessel, 70 ml of THF is added, and the mixture is stirred at 20-25°C for ≥ 10 min.

[0297] Heat the mixture to IT 53-57°C and stir for ≥ 5 min.

[0298] A solution of 1,2-dibromoethane in 15 ml of THF is added at an IT of 55-60°C (exothermic) and the mixture is stirred for ≥30 min at an IT of 58-62°C.

[0299] The mixture is cooled to an IT of 43-47°C.

[0300] Add Pd(PPh3)4 and stir for ≥ 5 minutes.

[0301] The mixture is heated to an IT of 58-62°C and a solution of ethyl 4-oxazolecarboxylate in 15 ml of THF is added at an IT of 60-65°C.

[0302] The mixture is stirred for ≥30 min at 58-62 °C.

[0303] Information about IPC via HPLC: -Ethyl 4-oxazolecarboxylate -Ethyl ester product 72% - tert-butyl ester product 23% -Intermediate product IM-1-a 5%

[0304] Cool the mixture to IT 20-25°C.

[0305] A solution of 35 ml of LiOH in water is added at an IT of 20-27° C. and the mixture is stirred at an IT of 23-27° C. for ≧16 hours. IPC via HPLC, ≥93%

[0306] 35 ml of water is added and the mixture is extracted twice with 70 ml of TBME.

[0307] Add 50 ml of THF and adjust the pH to 0.5-1.0 with HCl 20% at 15-20°C.

[0308] The mixture is extracted with 3 x 50 ml of DCM.

[0309] The combined organic phase is dried over Na2SO4 (15-20 g), filtered, and the filter cake is washed with 10 ml of DCM. DCM phase = 0.51% water via Karl Fischer.

[0310] Set the OT to -20°C.

[0311] 4-Methylmorpholine is added at -5°C to 0°C.

[0312] Ethyl chloroformate is added at IT -5 to 0°C.

[0313] RM-2-a (ground) is added portionwise at IT ≦0° C. and the mixture is stirred at IT −5° C. to 0° C. for ≧3 hours. IPC via HPLC, ≥90%.

[0314] The mixture is extracted twice with 100 ml of NaCl 10%.

[0315] The middle layer is retained with the organic phase.

[0316] The organic phase is extracted 3 times with 80 ml of HCl 10%.

[0317] The aqueous solution is filtered and the pH is adjusted first with NaOH 30% to 2-5 and then with NaOH 5% to pH 7-8. The IT is kept at ≦10° C. during the pH addition.

[0318] The suspension is filtered and washed twice with 60 ml of water.

[0319] The product is dried to dryness at 45° C. / <100 mbar. exterior: HPLC purity: 99.0%

[0320] yield:

[0321] [Table 13]

[0322] In experiments using a DCM water content of 0.04% by azeotroping, the yield was up to 85%.

[0323] Process Variant 2: Chemicals:

[0324] [Table 14]

[0325] procedure: The reactor is purged with nitrogen for 15 minutes and the condenser is cooled to -30°C.

[0326] Charge tBuOLi to the reactor and add THF. Heat the mixture to TI=55°C (TM=58°C) and stir for 5 minutes. Add a solution of 1,2-dibromomethane in THF at TI ≦60°C. Stir the mixture at TI=60°C (TM=63°C) for 60 minutes. Cool the mixture to TI=45°C.

[0327] Pd(PPh3)4 is added and the mixture is heated to TI=60°C (TM=63°C).

[0328] A solution of ethyl 4-oxazolecarboxylate in THF is added at a TI ≦ 65°C. The mixture is stirred for 30 min at TI = 60°C (TM = 63°C). The mixture is cooled to TI = 20-25°C (TM = 20°C).

[0329] IPC via HPLC-MS.

[0330] A solution of LiOH in water is added at TI≦25° C. The mixture is stirred at TI=25° C. for ≧16 h.

[0331] IPC via HPLC-MS

[0332] Water is added and the mixture is extracted 2x with MTBE. The MTBE phase is discarded. THF is added and the pH is adjusted to 0.5-1.0 with HCl 20% at 15-20°C. The mixture is extracted 3x with DCM. The combined organic extracts are dried over MgSO4, filtered and the filter cake is washed with DCM. DCM is evaporated at 35°C / 400 mbar. 8.5 equivalents of DMF are added and THF is evaporated at 35°C / 35 mbar. The distillation end point is when no further solvent is condensed.

[0333] IPC via KF, ≤0.2% water, otherwise additional azeotrope.

[0334] For further azeotroping, 10 equivalents of DCM are added and evaporated at 35° C. / 400 mbar. The IPC via KF is repeated.

[0335] This procedure is repeated until the IPC via KF is within specifications. 4-Methylmorpholine is added to the DMF solution at TI = -5°C to 0°C. Ethyl chloroformate is added at TI = -5°C to 0°C. RM-2-a (ground) is added at TI = -5°C to 0°C. The mixture is stirred for >5 hours at TI = -3°C.

[0336] IPC via HPLC-MS

[0337] If IPC IM2>85% a / a, add water at IT<10°C.

[0338] The pH of the reaction mixture is adjusted to pH 6-8 with NaOH 30% if necessary. The product suspension is stirred for ≥ 60 min at IT 0-5°C, filtered, washed twice with water and dried in vacuo at 45°C.

[0339] yield: Yield = 5.5g = 62.4% HPLC assay = 99.6% m / m HPLC purity=99.7%a / a

[0340] 4.3 Process for preparing compound (II) in the form of the HCl salt - a shortened synthesis using solvent exchange Process variant 1 (solvent extraction): Chemicals:

[0341] [Table 15]

[0342] reaction:

[0343] [ka]

[0344] procedure: The intermediate compound IM-3-b can be prepared as described in Example 3.

[0345] Compound RM-3-a (ground) is charged into a reactor and suspended in water at 20-25°C.

[0346] Add NaOH 30% and stir the suspension at 20-25°C until a solution is formed (approximately 15 minutes).

[0347] Intermediate compound IM-3-b (ground) is added and the mixture is heated to 60-65° C. for 72 hours.

[0348] IPC via LC / MS, conversion ≥ 93% area.

[0349] The mixture is cooled to 20-25° C. and DCM is added.

[0350] Adjust the pH to 3.9-4.1 with HCl 10%.

[0351] The mixture is stirred for 5 minutes and the phases are allowed to settle for 1 hour. The lower phase is discarded. The DCM extraction is repeated three times.

[0352] The aqueous phase is adjusted to pH 9.9-10.1 with NaOH 15% and EtOAc is added.

[0353] The mixture is stirred for 5 minutes and the phases are allowed to settle for 1 hour. The lower phase is discarded. The EtOAc extraction is repeated twice.

[0354] The organic phases are combined (volume=8.5 l) and concentrated under vacuum / OT 40° C. to a volume of 1.7 l (1 / 5 of the volume).

[0355] 3.2 l EtOH is added and the solution is concentrated under vacuum / OT 40° C. to a volume of 1.7 l (1 / 2 of the volume).

[0356] 3.2 l EtOH is added and the solution is concentrated under vacuum / OT 40° C. to a volume of 1.05 l (1 / 3 of the volume).

[0357] Add 4.55 L EtOH (5.6 L - 1.05 L), filter the solution and heat to 55-60°C. HCl 32% is added at 55-60°C within ≥20 min and the suspension is slowly cooled to 0-5°C within ≥3 h.

[0358] The suspension is stirred at 0-5°C for ≥ 1 hour and filtered.

[0359] The filter cake is washed with 0.8 l EtOH and dried to dryness at 45° C. / vacuum <50 mbar.

[0360] yield:

[0361] [Table 16]

[0362] Process variant 2 (oil separation): reaction:

[0363] [ka]

[0364] Chemicals:

[0365] [Table 17]

[0366] procedure: RM-3-a is charged to a reactor and suspended in water. NaOH 30% is added. IM-3-b is added and the mixture is heated to an IT of 58-62°C for ≥ 72 hours. IPC via LC / MS, product ≥ 75% area (all compounds pooled).

[0367] The mixture is cooled to 5-25°C and allowed to settle for ≥16 hours. The lower oil phase is separated by draining from the reactor, decanting, or suction from the aqueous phase using vacuum. The separated oil phase is dissolved in 560 ml of EtOH. The solution is filtered and heated to an IT of 60-65°C. 0.7 mg of seed crystals are added. HCl 32% is added within 20 minutes at an IT of 60-65°C using a stirrer speed of 100 rpm. After the HCl addition, the stirrer speed is reduced to 60 rpm and the suspension is slowly cooled to an IT of 0-5°C within ≥4 hours. The suspension is stirred at 0-5°C for ≥1 hour and filtered. The filter cake is washed with 105 ml of EtOH and dried to dryness at 45°C / vacuum <50 mbar.

[0368] yield:

[0369] [Table 18]

[0370] Preparation of Polymorph PM2 of Compound (II) in the Form of the 3HCl Salt Polymorphic form PM2 is obtained by thermal recrystallization of a solution of compound (II) as the 3HCl salt in the form of polymorph PM1 as obtained in Example 4 described above.

[0371] Thermal recrystallization was carried out in a solvent mixture of toluene:methanol in a 1:1 ratio.

[0372] Polymorph PM2 1 The 1 H NMR spectrum is essentially unchanged compared to that of polymorph PM1, but shows a sharp singlet at about δ 3.16 ppm assigned to methanol, suggesting a methanol content of about 2 mole percent.

[0373] Elemental analysis of polymorph PM2 to determine the amount of chloride provided an average value of 20.0% (m / m), which is in good agreement with the predicted value of 20.5% for the 3:1 HCl:free base salt. DSC: 226℃ PXRD analysis: Polymorphic form PM2 (PXRD pattern according to Figure 2)

[0374] Preparation of Polymorph PM3 of Compound (II) in the Form of the 3HCl Salt Polymorphic form PM3 is obtained by preparing a saturated solution of compound (II) as the 3HCl salt in the form of polymorph PM1 as obtained in Example 4 described above in a solvent mixture of acetone:water in a ratio of 9:1 (v / v) at 50°C, cooling to 5°C, and then precipitating a white solid by adding acetone.

[0375] Polymorph PM3 1 The 1 H NMR spectrum exhibits only slight differences compared to that of polymorph PM1 with a slight shift in the broad resonance.

[0376] Elemental analysis of polymorph PM3 to determine the amount of chloride provided an average value of 19.3% (m / m), which is in good agreement with the expected value of 20.5% for the 3:1 HCl:free base salt. DSC: 169℃ PXRD analysis: Polymorphic form PM3 (PXRD pattern according to Figure 3)

[0377] 5. Process for preparing compound (II) in the form of HCl salt (simple salt) - abbreviated synthesis Chemicals:

[0378] [Table 19]

[0379] reaction:

[0380] [ka]

[0381] procedure: The intermediate compound IM-3-b can be prepared as described in Example 3.

[0382] Compound RM-3-a (ground) is suspended in water at 20-25°C and NaOH 30% is added.

[0383] The suspension is stirred for ≥15 minutes at 20-25°C to form a solution.

[0384] Intermediate compound IM-3-b (ground) is added and the suspension is heated to 60-65° C. for ≧72 hours.

[0385] IPC control via HPLC, ≥93% conversion.

[0386] The emulsion is cooled to 20-25°C and 650 ml of DCM is added.

[0387] The mixture is stirred for ≥ 10 minutes and the phases are allowed to settle for ≥ 1 hour. The aqueous phase is discarded.

[0388] Add 650 ml water to the DCM phase and adjust the pH to 5.4-5.6 with HCl 20%. Stir the mixture vigorously for ≥10 minutes and allow the phases to settle for ≥1 hour. Discard the DCM phase.

[0389] The aqueous phase is stirred for ≧16 hours and the resulting suspension is filtered.

[0390] The wet cake is washed with 80 ml of EtOH.

[0391] The filtered cake is dried to dryness at 50° C. / <100 mbar.

[0392] yield:

[0393] [Table 20]

[0394] 6. Process for preparing compound (II) in the form of the H2SO4 salt - abbreviated synthesis Chemicals:

[0395] [Table 21]

[0396] reaction:

[0397] [ka]

[0398] procedure: The intermediate compound IM-3-b can be prepared as described in Example 3.

[0399] Compound RM-3-a (ground) is suspended in water at 20-25° C. 30% NaOH is added and the mixture is stirred for ≥15 minutes at 20-25° C.

[0400] Intermediate compound IM-3-b (ground) is added and the mixture is heated to 60-65° C. for ≧72 hours.

[0401] IPC conversion via HPLC, ≥93%.

[0402] Cool the mixture to 20-25°C.

[0403] Add 640 ml of DCM, stir and let the phases settle for ≥ 1 hour. Discard the aqueous phase.

[0404] Add 640 ml of water to the DCM phase and adjust the pH to 3.4-3.6 with 20% H2SO4. Allow the phases to settle for ≥ 1 hour and discard the DCM phase.

[0405] The aqueous phase is stirred and cooled to 0-5°C within ≥2 hours.

[0406] The suspension is heated to 40° C. and stirred at this temperature for ≧16 hours. The suspension is cooled to 0-5° C. within ≧4 hours and stirred at 0-5° C. for ≧1 hour.

[0407] The suspension is filtered and the filter cake is washed with 160 ml of ethanol.

[0408] The filtered cake is dried to dryness at 50° C. / <100 mbar vacuum.

[0409] yield:

[0410] [Table 22]

[0411] 7. Process for preparing compound (II) in the form of its 0.5H3PO4 salt - abbreviated synthesis Chemicals:

[0412] [Table 23]

[0413] reaction:

[0414] [ka]

[0415] procedure: The intermediate compound IM-3-b can be prepared as described in Example 3.

[0416] Compound RM-3-a (ground) is suspended in water at 20-25°C and NaOH 30% is added. The suspension is stirred for ≥15 minutes at 20-25°C to form a solution. Intermediate compound IM-3-b (ground) is added and the suspension is heated to 60-65°C for ≥72 hours. IPC control via HPLC, ≥93% conversion.

[0417] The emulsion is cooled to 20-25°C and 320 ml of DCM is added.

[0418] Adjust the pH to 3.9-4.1 with HCl 20%.

[0419] The mixture is vigorously stirred for ≥10 minutes and the phases are allowed to settle for ≥1 hour. The organic phase is discarded.

[0420] This DCM extraction is repeated three more times.

[0421] The aqueous phase is adjusted to pH 9.9-10.1 with NaOH 30%.

[0422] 320 ml of EtOAc is added and the mixture is stirred vigorously for ≥ 10 minutes. The phases are allowed to settle for ≥ 1 hour. The aqueous phase is discarded.

[0423] This EtOAc extraction is repeated two more times.

[0424] The combined organic phases are concentrated in vacuo at 40° C. to 13 ml.

[0425] 320 ml of ethanol is added and the solution is concentrated to a volume of 18 ml.

[0426] Add 110 ml of ethanol and 5 × 6.5 ml of H3PO4 30% at 20-25 °C. Stir the mixture for ≥ 24 h at 28-32 °C. Cool the suspension to 20-25 °C within ≥ 1 h and filter. Wash the filter cake with 40 ml of EtOH.

[0427] The filtered cake is dried to dryness at 45° C. / <100 mbar.

[0428] yield:

[0429] [Table 24]

[0430] 8. Process for preparing compound (II) in the form of H3PO4 salt - conversion to 1:1 salt Chemicals:

[0431] [Table 25]

[0432] reaction:

[0433] [ka]

[0434] procedure: The 0.5H3PO4 salt of Compound (II) can be prepared as described in Example 7.

[0435] Compound (II) 0.5H3PO4 salt is suspended in ethanol at 20-25°C and stirred at this temperature for 4 days.

[0436] The suspension is filtered and the wet cake is dried to dryness at 45° C. / <100 mbar.

[0437] yield:

[0438] [Table 26]

[0439] 9a. Process for preparing intermediate compound (IM-3-b') Chemicals:

[0440] [Table 27]

[0441] reaction:

[0442] [ka]

[0443] procedure: The reaction is carried out under a stream of N2.

[0444] 2-Vinyloxazole-4-carboxylate (IM-2-a) is suspended in dichloromethane and cooled to -5°C.

[0445] Add 4-methylmorpholine dropwise in such a way that the temperature does not exceed 0° C. (exothermic).

[0446] Ethyl chloroformate is added dropwise in such a way that the temperature does not exceed 0° C. (exothermic).

[0447] After a stirring time of 20 minutes, 2-(aminomethyl)-3-bromopyridine (RM-2-a') is added in such a way that the temperature does not exceed 0°C.

[0448] The mixture is stirred overnight at 0-5°C.

[0449] The mixture is washed three times with 10% NaCl solution.

[0450] The organic phase is concentrated on a rotary evaporator at 45°C.

[0451] EtOAc / heptane 20:80 (1.7 ml / g) is added to the crude product, stirred at room temperature for 4 hours, filtered off, washed twice with EtOAc / heptane and dried at 50° C. to constant weight.

[0452] yield:

[0453] [Table 28]

[0454] 9b. Process for preparing compound (II') Chemicals:

[0455] [Table 29]

[0456] reaction:

[0457] [ka]

[0458] procedure: Benzimidazole-ethylamine (RM-3) is ground in a mortar and suspended in water.

[0459] Add 30% sodium hydroxide solution dropwise and stir for 10 minutes at room temperature.

[0460] Intermediate compound IM-3-b' is added to the mixture and stirred at an internal temperature of 63° C. for 72 hours.

[0461] The mixture is cooled to room temperature.

[0462] Add 110 ml of DCM and stir for 10 minutes.

[0463] The pH value is set to 4 with HCl 20%.

[0464] The aqueous phase is extracted 4 times with 110 ml of DCM, left for 1 hour for phase separation and the DCM phase is discarded.

[0465] The aqueous phase is adjusted to pH 10 with NaOH 30%, extracted 3 times with EtOAc, left for 1 hour for phase separation and the aqueous phase is discarded.

[0466] The EtOAc phase is dried over magnesium sulfate, filtered and concentrated to dryness on a rotary evaporator.

[0467] yield:

[0468] [Table 30]

[0469] 9c. Process for preparing the 3HCl salt of compound (II') Chemicals:

[0470] [Table 31]

[0471] reaction:

[0472] [ka]

[0473] procedure: Compound (II') is dissolved in ethanol and heated to an internal temperature of 40°C.

[0474] HCl 32% is added dropwise.

[0475] The suspension is slowly cooled to 0°C.

[0476] The suspension is stirred at 0° C. for 1 hour.

[0477] The suspension is filtered and the wet cake is washed with ethanol and dried to dryness at 40°C.

[0478] yield:

[0479] [Table 32]

[0480] 10. Intermediates and Example Compounds 1 H-NMR, PXRD and DSC analysis 10.1 NMR analysis NMR analysis of intermediate compounds IM-1-a, IM-2-a and IM-3-b, prepared by the processes as described in Examples 1b, 1a and 3a, respectively, was carried out to provide the following NMR-data:

[0481] [Table 33]

[0482] NMR analysis of example compound (II) in the form of 3HCl salt (polymorphic forms PM1, PM2 and PM2), 1HCl salt, H2SO4 salt, 0.5H3PO4 salt and 1H3PO4 salt prepared by the process as described in Examples 4, 5, 6, 7 and 8 respectively was carried out and provided the following NMR-data:

[0483] [Table 34]

[0484] NMR analysis of intermediate compound IM-3-b', compound (II') and the 3HCl salt of compound (II'), prepared by the processes as described in Examples 9a, 9b and 9c, respectively, was carried out to provide the following NMR-data:

[0485] [Table 35]

[0486] 10.2 PXRD analysis Further PXRD analysis of Example Compound (II) in the form of the 3HCl salt (PM1, PM2 and PM3), HSO salt and 1HPO salt prepared by the processes as described in Examples 4, 6 and 8, respectively, was carried out to provide the PXRD spectra as shown in Figures 1 to 5.

[0487] method Sample preparation and measurement: - Sample preparation: 10 mg to 20 mg of sample was placed between two acetate foils in a Stoe transmission sample holder; the sample was rotated during the measurement -Stoe Stadi P (G.52.SYS.S072); Mythen 1K detector; Cu-Ka1 radiation; standard measurement conditions: transmission; tube power of 40 kV and 40 mA; curved Ge monochromator; -0.02° 2-theta step size, 48 seconds step time, 1.5~50.5° 2-theta scan range; detector mode: step scan; 1° 2-theta detector step;

[0488] Data Evaluation: d-value analysis was performed with the software EVA, version 14,0,0,0 from Bruker. -Background subtracted Only lines up to -35°2 theta are listed -Calculating relative potency using formulas in Excel

[0489] PXRD conditions—Compound (II) 3HCl salt (PM1, PM2, and PM3 in Figures 1, 2, and 3)

[0490] [Table 36]

[0491] Polymorph PM1:

[0492] [Table 37]

[0493] Polymorph PM2:

[0494] [Table 38]

[0495] Polymorph PM3:

[0496] [Table 39]

[0497] [Table 40]

[0498] PXRD conditions - Compound (II) H2SO4 salt (Figure 4)

[0499] [Table 41]

[0500] [Table 42]

[0501] PXRD conditions - Compound (II) H3PO4 salt (Figure 5)

[0502] [Table 43]

[0503] [Table 44]

[0504] 10.3 DSC measurement Differential scanning calorimetry is performed in a sealed gold pan at a heating rate of 10°C / min.

[0505] 10.4 HPLC Determination of Identity, Impurity Profile and Degree of Purity The identity and assay of the compounds of the present invention, bases and their impurities are determined by qualitative and quantitative analysis by high performance liquid chromatography (HPLC) with diode array detection using in-house methods based on Ph.Eur.2.2.29.

[0506] The identity of the synthesized compounds is confirmed by comparison with the retention times and spectra of the corresponding reference materials. The assay is calculated based on an external calibration curve of the test compound in its base form, both in salt form and its impurities.

[0507] procedure Equipment HPLC equipped with pump, autosampler, column oven, and diode array detector, as well as analytical balance (category 1), pipettes (e.g., Gilson, Rainin), volumetric flasks (10 ml, 25 ml, and 50 ml), and membrane filters (0.2 μm)

[0508] reagent -Methanol (HPLC grade), Sigma (or equivalent) - 100% Trifluoroacetic Acid (TFA) for HPLC, Sigma (or equivalent) Mobile phase: A: Water / methanol (95+5 V / V; 0.1% TFA) B: Methanol / water (95+5 V / V; 0.1% TFA)

[0509] Mobile phase A: Water / methanol (95+5 V / V; 0.1% TFA) Dilute 100 ml of methanol to 2 liters with water R. Add 2.0 ml of TFA, then mix thoroughly and degas in an ultrasonic bath.

[0510] Mobile phase B: methanol / water (95+5 V / V; 0.1% TFA) Dilute 50 ml of water R to 1 liter with methanol. Add 1.0 ml of TFA, then mix thoroughly and degas in an ultrasonic bath.

[0511] Stock solutions A and B (1000 mg / L): Prepare two stock solutions of 1,000 mg / L each of the compound to be tested by dissolving 50 mg in 50 mL of mobile phase A.

[0512] Standard solutions A and B (40 mg / l): Each of the stock solutions is diluted 1:25 with mobile phase A. The samples are filtered through a 0.2 μm filter into HPLC glass vials.

[0513] SST stock solution 10 mg of a reference impurity, for example an intermediate compound expected from the process, is weighed into a 10 ml volumetric flask, 5 ml of methanol is added and diluted with water.

[0514] Impurity solution C (1 mg / l) Pipette 100 μl of stock solution A into a 100 ml volumetric flask and dilute with mobile phase A. Filter the sample through a 0.2 μm filter into an HPLC glass vial.

[0515] Impurity solution D / SST standard solution (10 mg / l) Pipette 1000 μl of stock solution B and 1000 μl of SST stock solution into a 100 ml volumetric flask and dilute with mobile phase A. Filter the sample through a 0.2 μm filter into an HPLC glass vial.

[0516] Chromatography Systems The liquid chromatograph is equipped with a column compartment maintained at a controlled temperature of 40°C ± 5°C, a diode array detector (200-400 nm), and a 4.6 mm × 150 mm C18 column (e.g., Ascentis Express C18, 2.7 μm). The flow rate is 1.0 ml / min.

[0517] LC gradient:

[0518] [Table 45]

[0519] System Suitability Testing (SST) and Quality Control Checks (QC) Appropriate injection of SST standard solution proves the suitability of the chromatographic system if the RSD of the test compound peak area and retention time are ≤2%, respectively, the resolution of the test compound is ≥1.5, and the tailing factor of the test compound peak is in the range 0.8-1.5.

[0520] Standard solution A is injected six times at the beginning of the sequence (SST) and twice at the end of the sequence (QC). The sequence can only be used if the above requirements are met.

[0521] standard curve A standard curve for a test compound (assay) can be obtained, for example, by injecting 5.0 μL, 7.5 μL and 10.0 μL of standard solution A and 12.5 μL and 15.0 μL of standard solution B.

[0522] A standard curve for a test compound impurity can be obtained, for example, by injecting 5.0 μL and 10.0 μL of Impurity Solution C and 5.0 μL, 10.0 μL, and 15.0 μL of Impurity Solution D.

[0523] The regression coefficient for both standard curves should be ≧0.9990.

[0524] Sample preparation Procedure - Impurities Approximately 50 mg of the compound to be tested in its salt form is accurately weighed into a 50 ml flask and made up to the mark with mobile phase A. Prepare the sample solution in duplicate. Filter the solution through a 0.2 μm membrane filter and inject 10 μl.

[0525] Procedure - Assay Use both solutions prepared for "impurities" and dilute 1:25 with mobile phase A. Filter the solutions through a 0.2 μm membrane filter and inject 10 μl.

[0526] calculation qualitative decision The retention time of the test compound should not deviate more than 0.3 minutes from the peak of the standard A solution. The spectrum obtained for the test compound in the sample is correlated with the reference spectrum of the test compound in the standard A solution. The library match factor is determined. The latter should be ≥ 990.

[0527] The retention time of any impurity in the test compound should not deviate by more than 0.1 minutes from the corresponding reference substance. The spectrum obtained for the impurity in the sample is correlated with the reference spectrum of the corresponding impurity in SST solution. The library match factor is determined. The latter should be ≥ 990.

[0528] Quantitative determination - assay The peak area versus the concentration of the standard solution, expressed as the amount of test compound in the form of its base (μg), is plotted and the intercept (a) and slope (b) are extracted. The obtained correlation coefficient should not be less than 0.999. The amount of test compound base is calculated using the following formula:

[0529]

number

[0530] Quantitative determination of impurities Quantitative determination of impurities as % area All peaks in the sample chromatogram at 254 nm are accumulated. Peaks associated with the blank are not considered. The percentage of area of ​​total impurities and each single impurity ≧0.05% is determined and reported.

[0531] Quantitative determination of impurities as %m / m The concentration of the standard solution, expressed as the amount of test compound in the form of its base (µg), is plotted against the peak area and the intercept (a) and slope (b) are extracted. The correlation coefficient obtained should not be less than 0.999. The amount of each impurity is calculated, taking into account the response factor, using the following formula:

[0532]

number

[0533] The above method is used to determine the identity and assay of Compound (II) in the form of the 3HCl salt (polymorph PM1) prepared by the process according to Example 4 (process variants 1 and 2).

[0534] [Table 46]

[0535] [Table 47]

[0536] [Table 48]

[0537] [Table 49]

[0538] result:

[0539] [Table 50]

[0540] FIG. 6 shows an HPLC chromatogram of the impurity profile of Compound (II) 3HCl salt (polymorph PM1 / VIT-2763) prepared by the process according to Example 4, followed by solvent extraction (Process Variant 1).

[0541] [Table 51]

[0542] FIG. 7 shows an HPLC chromatogram of the impurity profile of Compound (II) 3HCl salt (polymorph PM1 / VIT-2763) prepared by the process according to Example 4, followed by oil separation (Process Variant 2).

[0543] [Table 52]

[0544] Comparative Example - Example Compound 127 according to WO2017068090A1: FIG. 8 shows an HPLC chromatogram of the impurity profile of Compound (II) 3HCl salt (polymorph PM1 / VIT-2763) obtained by the process described in WO2017068090A1 (preparation of Example Compound No. 127).

[0545] [Table 53]

[0546] Conversion of Compound (II) base to Compound (II) in 3HCl VIT-2763-3HCl[%(m / m)]=VIT-2763 base[%(m / m)]×517.81[g / mol] / 408.44[g / mol]

[0547] This corresponds to a conversion factor of 1.27.

[0548] 11. Pharmacological Assays for Evaluating the Activity of Compounds (II) and (II') The following table summarizes the activity of compounds (II) and (II') as ferroportin inhibitors compared to hepcidin:

[0549] [Table 54]

[0550] Compounds (II) and (II') were tested in the form of their 3HCl salts.

[0551] 11.1 Hepcidin Internalization Assay (J774) This cellular assay allows for quantification of hepcidin binding to ferroportin (Fpn) via microscopic detection of the internalization of fluorescently labeled hepcidin into J774 cells. J774 is a murine macrophage cell line that has been shown to endogenously express Fpn upon incubation with iron (Knutson et al., 2005). Binding of hepcidin to Fpn triggers the internalization and degradation of both hepcidin and Fpn. However, the TMR (6-carboxytetramethylrhodamine) fluorophore attached to hepcidin remains associated with cells after degradation of the hepcidin peptide backbone. Therefore, microscopic detection of cell-associated TMR fluorescence is a measure of hepcidin binding to Fpn and the internalization of hepcidin and Fpn. If TMR-hepcidin is prevented from binding to Fpn, cellular TMR fluorescence remains low (Durrenberger et al., 2013). The effect of low molecular weight Fpn inhibitor compounds in this assay was evaluated in vitro as described below.

[0552] J774 cells harvested from approximately 80% confluent cultures were plated at 8 × 10 in complete medium (DMEM, 10% FBS, 1% penicillin-streptomycin) containing 200 μM Fe(III)NTA (nitrilotriacetic acid), 100 μl per well in 96-well MicroClear plates (Greiner; Cat. 655090). 5Cells were plated at 1000 cells / ml and grown at 37°C in 5% CO2. After overnight incubation, cells were washed three times with prewarmed DMEM with phenol red. After the final wash, 30 μl / well of DMEM with phenol red was added, and 10 μl / well of a dilution series of test compounds was added in triplicate. J774 cells were preincubated with test compounds at 37°C in 5% CO2 for 15 minutes, after which TMR-hepcidin was added at a final concentration of 25 nM. Cells were incubated in a total volume of 50 μl at 37°C in 5% CO2 for 2 hours. Hoechst 33342 dye was then added to a final concentration of 0.5 μg / ml to stain the nuclei, followed by further incubation for 10 minutes at 37°C in 5% CO2. Cells were washed three times with PBS and fixed in 100 μl of 4% paraformaldehyde in PBS at room temperature for 15 minutes. After removing the paraformaldehyde solution, cells were washed three times with PBS, leaving 100 μl per well, and the plate was sealed with a foil plate seal. Using a ScanR plate imager (Olympus) with a 20x high-NA objective, TMR (530-550 nm excitation / 575-625 nm emission / 400 ms exposure time) and Hoechst 33342 (360-370 nm excitation / 420-460 nm emission / 10 ms exposure time) fluorescence images were acquired. Four photographs per well, covering approximately 1500 cells per well, were acquired for each fluorescence channel. The acquired image data were analyzed using ScanR image analysis software. Image analysis included detection of nuclei (Hoechst 33342 fluorescence), identification of cell-associated regions, application of virtual channels, and thresholding for rolling-ball background reduction, followed by application of a summation (average) algorithm to measure cell-associated TMR fluorescence as a quantitative measure of internalized TMR-hepcidin. IC values ​​were calculated using the summation (average) raw data using "log(inhibitor) vs. response" curve fitting in Prism 5 software (GraphPad Software Inc., version 5.02). 50For each data set, the fit of the "log(inhibitor) vs. response (three parameters)" model was compared to the fit of the "log(inhibitor) vs. response - variable slope (four parameters)" model, and the IC value of the preferred model was calculated. 50 Data were used. IC of compounds according to formula (II) and (II') tested in the hepcidin internalization assay 50 The data are shown in Table 1. The IC of unlabeled hepcidin in this assay 50 is 0.015±0.011 μM.

[0553] [Table 55]

[0554] 11.2 Biophysical Ferroportin-Hepcidin Binding Assay This biophysical assay was developed to more directly confirm the inhibition of hepcidin binding to ferroportin (Fpn). Incubation of TMR-hepcidin with purified human Fpn isolated from Pichia pastoris yeast cells expressing human Fpn with a C-terminal FLAG affinity tag (Bonaccorsi di Patti, 2014) leads to an increase in the fluorescence polarization (FP) of the TMR-hepcidin ligand. Compounds (II) and (IF) were tested for inhibition of TMR-hepcidin binding to Fpn, as detected by a dose-dependent decrease in the TMR FP signal, as described in detail below.

[0555] A mixture of 1.3 mM human Fpn and 30 nM TMR-hepcidin in FP assay buffer containing 50 mM Tris-HCl pH 7.3, 200 mM NaCl, 0.02% DDM, and 0.1% BSA was plated at 16 ml per well into a 384-well black, low-volume, round-bottom plate (Corning, Cat. 3677). Eight ml of serial dilutions of test compound were added in duplicate to reach final Fpn and TMR-hepcidin concentrations of 1 mM and 20 nM, respectively. The plate was incubated for 90 minutes at room temperature, and parallel (S) and perpendicular (P) fluorescence were measured in a Synergy H1 fluorescence reader (BioTek). FP values ​​in mP were calculated according to the following formula:

[0556]

number

[0557] The calculated mP values ​​were used to calculate IC as described for the hepcidin internalization assay. 50 The IC values ​​were determined and are listed in Table 2. The IC of unlabeled hepcidin in this assay 50 is 0.37±0.067 μM.

[0558] [Table 56]

[0559] 11.3 Inhibition of ferroportin-mediated iron transport activity in iron response assays In this assay, intracellular iron levels are indirectly measured by monitoring the activity of a beta-lactamase (BLA) reporter gene fused to the human ferritin promoter and associated iron regulatory element (IRE) contained within the 5' untranslated region of ferritin mRNA. Expression of ferroportin (Fpn) in these cell lines leads to iron efflux and lower iron levels, as reflected by lower reporter gene activity. On the other hand, inhibition of Fpn-mediated iron efflux leads to elevated cellular iron levels, detected as increased reporter gene activity. Low-molecular-weight Fpn inhibitor compounds were tested for dose-dependent effects in this in vitro iron response assay, as described below.

[0560] 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, Cat. 631068) and (ii) a human ferritin promoter-BLA reporter gene into a derivative of the HEK-293 Tet-ON Advanced cell line (Clontech). To generate the ferritin-BLA reporter gene construct, a 1.4 kb fragment of the human ferritin H promoter was amplified by PCR from human genomic DNA (forward primer 5'-CAGGTTTGTGAGCATCCTGAA-3'; reverse primer 5'-GGCGGCGACTAAGGAGAGG-3') and inserted in front of the BLA gene present in the pcDNA™6.2 / cGeneBLAzer™-DEST plasmid (Invitrogen, Cat. 12578-043), thereby replacing the original CMV promoter and placing an IRE regulating ferritin gene translation approximately 170 bp upstream of the start codon of the reporter gene. #354 cells were harvested from approximately 80% confluent cultures and plated at 1.8 x 10 cells / well in DMEM / F12 GlutaMAX™ medium (Invitrogen, Cat. 31331-028) containing 10% FBS (Clontech, Cat. 631106), 1% penicillin-streptomycin, 200 μg / ml hygromycin B (Invitrogen, Cat. 10687-010), 5 μg / ml blasticidin (Invitrogen, Cat. R210-01), 4 μg / ml doxycycline (Clontech, Cat. 631311), 50 μl per well of a 384-well PDL-coated plate. 5Cells were seeded at 1000 cells / ml and grown at 37°C and 5% CO2. After overnight incubation, 10 μl / well of a quadruplicate dilution series of test compounds was added, and the plate was further incubated overnight at 37°C and 5% CO2. Cells were washed three times with HBSS, leaving 25 μl per well. BLA activity was detected by adding 5 μl / well of Gene Blazer Reagent CCF4-AM (Invitrogen, Cat. K1085) to the cells. After incubation of the plate in the dark at 18°C ​​for 60 minutes, blue and green fluorescent signals were measured in a Safire2 fluorescent plate reader (Tecan) with excitation at 410 nm and emission at 458 nm (blue) and 522 nm (green). The blue / green fluorescence ratio was calculated as a measure of BLA activity, and the calculated blue / green fluorescence ratio was used to determine EC as described for the hepcidin internalization assay. 50 The EC values ​​of the test compounds (II) and (II') were determined. 50 The data are listed in Table 3. EC of hepcidin in this assay 50 is 0.096±0.063 μM (n=37).

[0561] [Table 57]

[0562] 11.4 Ferroportin Internalization and Degradation Assays 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 11.3). Growing HEK-293 #354 cells in doxycycline-containing medium induced expression of a human Fpn-GFP fusion protein on the cell surface. Data from 10 independent experiments showed that culturing HEK #354 cells in the presence of 4 μg / ml doxycycline for 48 hours induced an average of 42.6% ± 6.4% of Fpn-GFP-positive cells. Small molecular weight Fpn inhibitor compounds were tested for their dose-dependent effects on Fpn-GFP mean fluorescence intensity (MFI) on HEK-293 cell line #354, as described below.

[0563] HEK#354 cells were harvested from approximately 80% confluent cultures and plated at 0.6 × 10 cells per well in DMEM / F12 GlutaMAX™ medium (Invitrogen, Cat. 31331-028) containing 10% FBS (Clontech, Cat. 631106), 1% penicillin-streptomycin (Invitrogen, Cat. 15140-122), 200 μg / ml hygromycin B (Invitrogen, Cat. 10687-010), 5 μg / ml blasticidin (Invitrogen, Cat. R210-01), 4 μg / ml doxycycline (Clontech, Cat. 631311), 50 μl per well of a 384-well plate (Greiner; Cat. 781091). 6Cells were seeded at 1000 cells / ml and grown at 37°C and 5% CO2. After overnight incubation, 10 μl / well of a quadruplicate dilution series of test compounds was added, and the plate was further incubated overnight at 37°C and 5% CO2. Cells were washed once with FACS buffer (PBS containing 1% FBS, 2 mM EDTA, and 0.05% NaN3), collected in FACS buffer with 0.5 μg / ml propidium iodide (Sigma, Cat. P4864), and analyzed on a flow cytometer (CANTO™ II, BD Biosciences) equipped with a high-throughput sampler. Live HEK#354 cells were gated as a propidium iodide-negative population and analyzed for Fpn-GFP expression. FlowJo (Tree Star's, Oregon) was used to calculate the MFI of Fpn-GFP in >2000 living cells for each compound dilution, and the potency of Fpn-inhibitors to induce internalization and degradation of Fpn-GFP was calculated as described for the hepcidin internalization assay. EC values ​​of compounds (II) and (II') tested in the ferroportin internalization and degradation assay by FACS were calculated. 50 The data are listed in Table 4. The mean EC 50 The value is 0.004±0.002 μM.

[0564] [Table 58]

Claims

1. Compounds of formula (I) and pharmaceutically acceptable salts thereof 【Chemistry 1】 1. A process for preparing The compound of formula (IM-3) is reacted with the compound of formula (RM-3) 【Chemistry 2】 to provide a compound of formula (I) Processes including (In the formula, X １ is N, S or O; and X ２ is N, S or O; However, X １ and X ２ One of the is N and the other is X １ and X ２ are different; m is an integer of 1, 2, or 3; n is an integer of 1, 2, 3, or 4; o is an integer of 1, 2, 3, or 4; A is a CH- group, CH ２ -CH- group or CH ２ -CH ２ represents a —CH— group; R １ and R ２ teeth, -hydrogen and -C optionally substituted with 1 or 2 substituents １ ~C ４ -Alkyl are independently selected from the group consisting of: R ３ teeth, -halogen, -Cyano, -C １ ~C ４ - alkyl, -C １ ~C ３ -halogenoalkyl; -C １ ~C ４ -alkoxy, and - carboxyl group represents one, two, or three optional substituents which may be independently selected from the group consisting of: R ４ teeth, -hydrogen, -halogen, -C １ ~C ３ -alkyl, and -C １ ~C ３ -halogenoalkyl selected from the group consisting of: R ５ teeth, - aryl, which may carry 1 to 3 substituents, and - monocyclic or bicyclic heteroaryl, which may bear 1 to 3 substituents; selected from the group consisting of: R ６ teeth, -hydrogen, -halogen, -C optionally substituted with 1 or 2 substituents １ ~C ４ - alkyl; -C １ ~C ３ -halogenoalkyl (selected from the group consisting of:

2. The compound of formula (IM-2) is reacted with a compound of formula (RM-2) to give the form (IM-3): 【Transformation 3】 (In the formula, X １ , X ２ ,o,A,R １ , R ４ and R ５ has the meaning as defined in claim 1) 2. A process for preparing a compound of general formula (I) as claimed in claim 1 and its pharmaceutically acceptable salts, further comprising the step of forming a compound of formula (I):

3. Preparing a compound of formula (IM-2) by converting compound (RM-1) to compound (IM-1), followed by ester cleavage: 【Chemistry 4】 (In the formula, R ｙ teeth, -hydrogen or -halogen represents; and X １ , X ２ , A and R ４ have the meaning as defined in claims 1 and 2) The process of claim 2 further comprising:

4. The compound of formula (IM-1) can be prepared by the following reaction scheme: 【Transformation 5】 (In the formula, X １ , X ２ , A and R ４ has the meaning as defined in any one of claims 1 to 3) 4. The process of claim 3, wherein the compound is prepared according to one of the following methods:

5. The preparation of compound (IM-2) from compound (RM-1) via intermediate compound (IM-1) is carried out in one process step in a one-pot reaction; 5. The process of claim 3 or 4.

6. R ５ but, -C １ ~C ３ - alkyl, - halogen and -C １ ~C ３ -halogenoalkyl represents a monocyclic heteroaryl group which may bear 1 to 3 substituents which may be independently selected from Preferably, R ５ but, 【Transformation 6】 (In the formula, ＊ indicates the bond position, R ｙ teeth, -C １ ~C ３ - alkyl, - halogen and -C １ ~C ３ -halogenoalkyl Selected from: Preferably, R ｙ is fluorine or bromine) The process of claim 1 , wherein the group is represented by

7. The following reaction steps: Step 1: 【Transformation 7】 Step 2: 【Transformation 8】 Step 3: 【Chemistry 9】 (In the formula, X １ , X ２ , R ３ , R ４ , R ６ , R ｙ , A, m, n and o have the meanings as defined in any one of claims 1 to 6).

7. The process of claim 1, comprising:

8. The following conditions: A represents a CH- group; and / or m represents 1; and / or o represents 1; and / or R １ and R ２ each represent hydrogen; and / or R ４ represents hydrogen; and / or R ６ represents hydrogen; and / or R ３ represents hydrogen; and / or X １ is N and X ３ is O or S, and the group 【Chemistry 10】 Form or X １ is O or S, and X ２ is N, and the group 【Chemistry 11】 Form wherein in each case: ＊ indicates the bond position to the carbonyl group, ＊＊ indicates the second binding site; R ５ has the meaning as defined in any one of claims 1 to 7), The process of claim 1 , wherein one or more of the following conditions are met:

9. The following process steps: Step 1-a: 【Chemistry 12】 Step 2-a: 【Chemistry 13】 Step 3-a: 【Chemistry 14】 Formula (II) 【Chemistry 15】 9. A process according to any one of claims 1 to 8 for preparing a compound of formula (I) and its pharmaceutically acceptable salts.

10. The following process steps: Step 1-a: 【Chemistry 16】 Step 2-a: 【Chemistry 17】 Step 3-a: [Chemistry 18] Including, Formula (II') 【Chemistry 19】 10. The process according to any one of claims 1 to 9 for preparing a compound of formula (I) and its pharmaceutically acceptable salts.

11. The process comprises the steps of converting the compound of formula (I) or (II) or (II') into its pharmaceutically acceptable salt or solvate using a corresponding base or acid and / or solvent, preferably using an acid selected from the group consisting of benzoic acid, citric acid, fumaric acid, hydrochloric acid, lactic acid, malic acid, maleic acid, methanesulfonic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid and toluenesulfonic acid; preferably converting the compound of formula (I) or (II) or (II') into its pharmaceutically acceptable salt or solvate using a single HCl salt (1HCl), a triple HCl salt (3HCl), H ２ SO ４ Salt, 0.5H ３ P.O. ４ Salt and 1H ３ P.O. ４ 11. The process of claim 1, further comprising converting to a salt selected from the group consisting of:

12. 12. The process of any one of claims 1 to 11, wherein steps 1 and 2 or 1-a and 2-a, respectively, are carried out in one shortened one-pot reaction, and / or the step of converting intermediate compound IM-3, if present, to a salt of compound (I) or (II) or (II'), is carried out in one shortened one-pot reaction.

13. General formula (IM-3) 【Chemistry 20】 (In the formula, X １ and X ２ are different and independently represent O or S; R １ , R ４ , R ５ , A and o have the meanings as defined in any one of claims 1 to 12); or General formula (IM-3-a) 【Chemistry 21】 (In the formula, X １ and X ２ are different and independently represent O or S; R ４ and R ｙ has the meaning as defined in any one of claims 1 to 12) or General formula (IM-3-b) 【Chemistry 22】 or General formula (IM-3-b') 【Chemistry 23】 An intermediate compound.

14. A process for preparing intermediate compound (IM-1) as defined in claim 3 or 4, comprising the reaction step of claim 5; or intermediate compound (IM-3), (IM-3-a), (IM-3-b) or (IM-3-b') as defined in claim 13, comprising the reaction step as defined in one or more of the preceding claims 2 to 10.

15. Compounds according to formula (II'), including salts, hydrates, solvates and mixed hydrate / solvate forms, polymorphic modifications, and amorphous forms.

16. Purity standards as follows: a total impurity content of less than 2.00% relative area; and / or a purity of ≧97.80% relative area, ≧98.00% relative area, ≧98.50% relative area, or ≧99.00% relative area; and / or containing one or more of the impurities at relative retention times RRT 0.59, 0.65, 0.83, and 1.37 in an amount of less than or equal to 0.20% relative area; and / or Absence of the following impurities at relative retention times RRT: 0.59, 0.65, 0.83, and 1.37; characterized by one or more of: wherein the degree of purity, impurity content, retention time RRT and relative area value are determined by HPLC. 3HCl salt of the compound according to formula (II) or (II') 【Chemistry 24】 or a solvate, hydrate or polymorph thereof.

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