4h-pyrrolo[3,2-c]pyridin-4-one compounds

Description

Field of application of the invention

[0001] The invention relates to substituted 4H-pyrrolo[3,2-c]pyridin-4-one compounds, a process for their production and uses thereof.BACKGROUND OF THE INVENTION

[0002] The Epidermal Growth Factor Receptor (EGFR or EGF-receptor) receptor tyrosine kinase family consists of 4 members: EGFR (Erbb1, Her1), ERBB2 (Her2), ERBB3 (Her3), and ERBB4 (Her4). EGFR mediates activation of MAPK and PI3K signaling pathways and thereby regulates cell proliferation, differentiation, migration and survival (Pao et al., 2010). EGFR gene amplification, overexpression, and mutations are frequently observed in various cancer indications and are associated with a poor prognosis (Gridelli et al., 2015).

[0003] In lung adenocarcinoma, mutations of EGFR are prevalent in approximately 15% of Western patients and up to 50% of East Asian patients (Paez et al., 2004). These mutations typically occur in one of four exons, exons 18-21, in the kinase domain of EGFR (Paez et al., 2004). The most common activating mutations in EGFR are a point mutation in exon 21, substituting an arginine for a leucine (L858R), and a small in-frame deletion in exon 19 that removes four amino acids (del 19 / del746-750) (Pao et al., 2010). The FDA-approved inhibitors gefitinib, erlotinib, and afatinib, targeting mutations in exons 18, 19, and 21 of EGFR, are effective in patients but the response is often not durable (Mok et al., 2009; Sequist et al., 2013). Resistance frequently occurs in these patients in response to acquisition of a second mutation, T790M (Pao et al., 2005). Second generation inhibitors, e.g. afatinib, irreversibly target this mutation but are still potent inhibitors of wild-type EGFR, leading to dose-limiting toxicity and lack of efficacy in patients. A third-generation irreversible inhibitor, osimertinib, that maximizes activity towards T790M while minimizing activity towards wild-type EGFR, is effective in T790M mutant patients and is currently the standard treatment for T790M positive patients (Mok et al., 2017). Osimertinib is also approved as a front-line therapy for patients with mutations of EGFR exons 19 or 21 (Soria et al., 2018).

[0004] However, patients also develop resistance to irreversible third-generation EGFR inhibitors, such as osimertinib. One of the major osimertinib resistance mechanisms identified is mutation of the cysteine in position 797 to a serine, resulting in loss of the covalently interacting cysteine and loss of sensitivity to irreversible EGFR inhibitors, at which point progressing patients have currently only limited treatment options (Thress et al., 2015; Oxnard et al., 2018). Such C797S mutations can also occur when osimertinib is used as a first-line therapy, in the absence of the T790M mutation (Ramalingham et al., 2018a; Ramalingham et al., 2018b). A novel targeted therapy that is able to specifically address the EGFR-C797S acquired resistance mutation would be highly beneficial for those patients.

[0005] By contrast, and with the exception of A763_Y764insFQEA, small in-frame insertions of EGFR exon20 are resistant to all clinically-approved EGFR inhibitors at doses achievable in lung cancer patients and comprise an unmet medical need (Yasuda et. al., 2013).

[0006] Patients with EGFR exon20 insertions, such as V769_D770insASV, D770_N771insSVD, D770_N771insNPG, N771_P772insH, H773_V774insH, H773_V774insNPH, V774_C775insHV show particular low response rates to all currently approved EGFR-targeted therapies, resulting in significantly reduced progression-free survival as well as overall survival (Chen et al., 2016). This has been shown for the first-generation inhibitors erlotinib and gefitinib as well as for the second-generation inhibitor afatinib (Chen et al., 2016; Yang et al., 2015).

[0007] Therefore, the standard treatment for EGFR exon20 insertion patients is currently chemotherapy.

[0008] The same resistance profile has been observed for exon20 insertion mutations in ERBB2 (e.g. ERBB2 A775_G776insYVMA with the highest prevalence), another member of the EGF-receptor family (Arcila et al., 2012) and some of the uncommon EGFR mutations like L681Q (Chiu et al., 2015).

[0009] Several irreversible inhibitors are currently in clinical trials for the treatment of EGFR exon20 insertion patients: Osimertinib, initially approved for the treatment of T790M mutant NSCLC patients (Floc'h et al., 2018); poziotinib (HM-781-36B), a non-approved pan-Her inhibitor targeting EGFR, Her2 / neu, and Her4 (Robichaux et al., 2018); as well as TAK-788 (AP32788) (Doebele et al., ASCO 2018). Of these, the first clinical data have been published for poziotinib and TAK-788. Both compounds clearly show clinical efficacy in EGFR exon20 insertion patients. However, major adverse events, mediated by inhibition of wild-type EGFR, have been reported for both clinical trials and these adverse events may limit clinical utility.

[0010] More recently, new preclinical data has been published for two additional compounds showing activity on EGFR exon20 insertions: TAS6417 (TCP-064) and compound 1a (Hasako et al., 2018; Jang et al., 2018). No clinical results are yet available for these two compounds.

[0011] International patent application published under number WO 2016 / 120196 A1 relates to 4H-pyrrolo[3,2-c]pyridin-4-one compounds which inhibit Bub1 kinase, processes for their production and to their use as parmaceuticals.

[0012] In summary, mutant EGFR is a promising drug target for cancer therapy. In particular, patients with primary resistance to approved anti-EGFR therapies, due to EGFR exon20 insertions, have only few treatment options to date and there is a great need for novel alternative and / or improved therapeutics to provide these patients with an efficacious, well-tolerable therapy (Oxnard et al., 2013). Therefore, potent inhibitors of mutant EGFR, particularly of mutant EGFR with exon20 insertion mutations that show improved selectivity versus wild-type EGFR, represent valuable compounds that should complement therapeutic options either as single agents or in combination with other drugs.SUMMARY OF THE INVENTION

[0013] The invention provides compounds that inhibit a mutant EGFR; specifically, an EGFR comprising one or more exon 20 insertion mutations, an L858R mutation, or a small in-frame deletion of exon 19, in the presence or absence of a C797S mutation. These compounds furthermore have reduced activity towards the wild-type-EGFR.

[0014] It has now been found that the compounds of the present invention have surprising and advantageous properties.

[0015] In particular, said compounds of the present invention have surprisingly been found to effectively inhibit mutant EGFR with exon 20 insertion mutations, particularly those harboring a D770_N771ins SVD exon 20 insertion with an IC 50 below 5 nM. Furthermore it has been found that these compounds additionally show cellular potency below 1 µM in EGFR V769_D770insASV, D770_N771insSVD, D770_N771insNPG, N771_P772insH, or H773_V774insNPH exon 20 insertion harboring BA / F3 cell lines. Furthermore, the here described compounds are active in BA / F3 cell lines harboring D770_N771insSVD C797S. In addition, the here described compounds potently inhibit proliferation of BA / F3 cell lines carrying EGFR activating mutations with or without C797S acquired resistance mutations (EGFR E746_A750del, L858R, E746_A750del C797S, L858R C797S), uncommon EGFR mutations (EGFR L681Q) or ERBB2 exon20 insertion A775_G776insYVMA.

[0016] Surprisingly, these compounds additionally show at least 5-fold selectivity in an anti proliferative assay of EGFR D770_N771ins SVD exon 20 insertion harboring BA / F3 cell lines versus wild-type EGFR harboring BA / F3 cells and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses or diseases which are accompanied with uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses mediated by mutant EGFR with exon 20 insertion mutations and / or reduce (or block) proliferation in cells harboring EGFR exon 20 insertion mutations, for example, haematological tumours, solid tumours, and / or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and / or metastases thereof.Description of the invention

[0017] The present invention is defined in the appended set of claims.The present text covers methods of preparing compounds of the present invention, said methods comprising the steps as described in the Experimental Section herein. Said methods are not part of the present invention as defined in the appended claims.Definitions

[0018] The term "comprising" when used in the specification includes "consisting of".

[0019] If it is referred to "mentioned above" or "supra" within the description, it is referred to any of the disclosures made within the specification in any of the preceding pages.

[0020] If it is referred to "described herein", "as mentioned in the present text" or "stated herein" within the description, it is referred to any of the disclosures made within the specification in any of the preceding or subsequent pages.

[0021] "Suitable" within the sense of the invention means chemically possible to be made by methods within the knowledge of a skilled person.

[0022] The terms as mentioned in the present text have the following meanings: The term "halogen atom", "halo-" or "Hal-" is to be understood as meaning a fluorine, chlorine, bromine or iodine atom.

[0023] The term "C 1 -C 6 -alkyl" is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl group, or an isomer thereof. Particularly, said group has 1, 2, 3 or 4 carbon atoms ("C 1 -C 4 -alkyl"), e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl group, more particularly 1, 2 or 3 carbon atoms ("C 1 -C 3 -alkyl"), e.g. a methyl, ethyl, n-propyl or iso-propyl group.

[0024] The term "C 1 -C 4 -haloalkyl" is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "C 1 -C 4 -alkyl" is defined supra, and in which one or more hydrogen atoms is replaced by a halogen atom, in identically or differently, i.e. one halogen atom being independent from another. Particularly, said halogen atom is F. Said C 1 -C 4 -haloalkyl group is, for example, -CF 3 , -CHF 2 , -CH 2 F, -CF 2 CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CF 3 , or -CH(CH 2 F) 2 .

[0025] The term "C 2 -C 3 -fluoroalkyl" is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "C 2 -C 3 -alkyl" is defined supra, and in which one or more hydrogen atoms is replaced by a fluoro atom. Said C 2 -C 3 -fluoroalkyl group is, for example, -CF 2 CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CF 3 , or - CH(CH 2 F) 2 .

[0026] The term "C 1 -C 4 -alkoxy" is to be understood as meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula -O-alkyl, in which the term "alkyl" is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy or sec-butoxy group, or an isomer thereof.

[0027] Unless defined otherwise, the term "5- to 6-membered heterocycloalkyl" or "5- to 6-membered heterocyclic ring", is to be understood as meaning a saturated, monovalent, monocyclic hydrocarbon ring which contains 4 or 5 carbon atoms, and one heteroatomcontaining group selected from O and NR, wherein R means a hydrogen atom, a C 1 -C 3 -alkyl or a C 1 -C 3 -haloalkyl group, it being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms.

[0028] Particularly, said heterocycloalkyl is a 5-membered ring, such as tetrahydrofuranyl, pyrazolidinyl, or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, for example.

[0029] The term "C 1 -C 6 ", as used throughout this text, e.g. in the context of the definition of "C 1 -C 6 -alkyl" or "C 1 -C 6 -haloalkyl" is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term "C 1 -C 6 " is to be interpreted as any sub-range comprised therein, e.g. C 1 -C 6 , C 2 -C 6 , C 3 -C 6 , C 1 -C 2 , C 1 -C 3 , particularly C 1 -C 2, C 1 -C 3, C 1 -C 4,

[0030] The term "C 1 -C 4 ", as used throughout this text, e.g. in the context of the definition of "C 1 -C 4 -alkyl", "C 1 -C 4 -haloalkyl", "C 1 -C 4 -alkoxy", or "C 1 -C 4 -haloalkoxy" is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 4, i.e. 1, 2, 3 or 4 carbon atoms. It is to be understood further that said term "C 1 -C 4 " is to be interpreted as any sub-range comprised therein, e.g. C 1 -C 4 , C 2 -C 4 , C 3 -C 4 , C 1 -C 2 , C 1 -C 3 , particularly C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , in the case of "C 1 -C 6 -haloalkyl" or "C 1 -C 4 -haloalkoxy" even more particularly C 1 -C 2 .

[0031] Further, as used herein, the term "C 3 -C 6 ", as used throughout this text, e.g. in the context of the definition of "C 3 -C 6 -cycloalkyl", is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term "C 3 -C 6 " is to be interpreted as any sub-range comprised therein, e.g. C 3 -C 6 , C 4 -C 5 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 5 -C 6; particularly C 3 -C 6 .

[0032] The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0033] The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.

[0034] Ring system substituent means a substituent attached to an aromatic or nonaromatic ring system which, for example, replaces an available hydrogen on the ring system.

[0035] As used herein, the term "one or more", e.g. in the definition of the substituents of the compounds of the general formulae of the present invention as defined in the appended claims, is understood as meaning "one, two, three, four, five, particularly one, two, three or four, more particularly one, two or three, even more particularly one or two".

[0036] Where the plural form of the word compounds or salts is used herein, this is taken to mean also a single compound or salt.

[0037] By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0038] The compounds of this invention may contain one or more asymmetric centre, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (R) or (S) configuration, resulting in racemic mixtures in the case of a single asymmetric centre, and diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.

[0039] Substituents on a ring may also be present in either cis or trans form.

[0040] Preferred compounds are those which produce the more desirable biological activity.

[0041] Separated, pure or partially purified stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also disclosed. The purification and the separation of such materials can be accomplished by standard techniques known in the art.

[0042] The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and / or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.

[0043] In order to limit different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

[0044] The present invention as defined in the appended claims includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. R- or S- isomers, or E- or Z-isomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention as defined in the appended claims may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.

[0045] Further, the compounds of the present invention as defined in the appended claims may exist as tautomers. For example, any compound of the present invention which contains a pyrazole moiety as a heteroaryl group for example can exist as a 1H tautomer, or a 2H tautomer, or even a mixture in any amount of the two tautomers, or a triazole moiety for example can exist as a 1H tautomer, a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said 1H, 2H and 4H tautomers, namely :

[0046] The present invention as defined in the appended claims includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.

[0047] Further, the compounds of the present invention as defined in the appended claims can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N-oxides.

[0048] Further, the compounds of the present invention as defined in the appended claims can exist as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt. Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, customarily used in pharmacy.

[0049] The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.

[0050] A suitable pharmaceutically acceptable salt of the compounds of the present invention is an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric or nitric acid, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic, persulfuric, 3-phenylpropionic, picric, pivalic, 2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic, dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic, methansulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, hemisulfuric or thiocyanic acid.

[0051] Further, another suitably pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic, is an alkali metal salt, which is a sodium or potassium salt, an alkaline earth metal salt, which is a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, which is a salt with N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, dicyclohexylamine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base, or 1-amino-2,3,4-butantriol. Additionally, basic nitrogen containing groups may be quaternised with such agents as lower alkyl halides, which are methyl, ethyl, propyl, and butyl chlorides, bromides or iodides; dialkyl sulfates, which are dimethyl, diethyl, or dibutyl sulfate; and diamyl sulfates, long chain halides, which are decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides, which are benzyl and phenethyl bromides.

[0052] Those skilled in the art will further recognise that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.

[0053] The present invention as defined in the appended claims includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.

[0054] In the present text, in particular in the Experimental Section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and / or purification process, is, in most cases, unknown.

[0055] Unless specified otherwise, suffixes to chemical names or structural formulae, such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HCl", "x CF 3 COOH", "x Na +< ", are to be understood as not a stoichiometric specification, but solely as a salt form.

[0056] This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and / or purification processes described, as solvates, such as hydrates with (if defined) unknown stoichiometric composition.

[0057] The salts include water-insoluble and, particularly, water-soluble salts.

[0058] The term "combination" in the present invention is used as known to persons skilled in the art and may be present as a fixed combination, a non-fixed combination or kit-of-parts.

[0059] A "fixed combination" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity. One example of a "fixed combination" is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical combination wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture.

[0060] A non-fixed combination or "kit-of-parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit. One example of a non-fixed combination or kit-of-parts is a combination wherein the said first active ingredient and the said second active ingredient are present separately. The components of the non-fixed combination or kit-of-parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered. Combinations according to the present invention as as defined in the appended claims.

[0061] The term "(chemotherapeutic) anti-cancer agents" relates to any agent that reduces the survival or proliferation of a cancer cell, which are: 131l-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, Alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, Hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcium folinate, calcium levofolinate, capecitabine, capromab, carboplatin, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, copanlisib, crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (123l), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, lanreotide, lapatinib, lasocholine, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, nedaplatin, nelarabine, neridronic acid, nivolumabpentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, poziotinib, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib, regorafenib, risedronic acid, rhenium-186 etidronate, rituximab, romidepsin, romiplostim, romurtide, roniciclib, samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, or zorubicin.

[0062] By "Epidermal Growth Factor Receptor (EGFR) Polypeptide" is meant a polypeptide having at least about 95% amino acid sequence identity to the sequence provided at UniProt Accession No. P00533-1 or a fragment thereof. In some embodiments, the EGFR fragment binds an EFGR ligand and / or has kinase activity. Mutant EGFR polypeptides include those having an insertion between, for example, amino acids V769 and D770 or between D770 and N771. In other embodiments, the amino acid sequence identity is 96, 97, 98, 99, or 100% to UniProt Accession No. P00533-1.

[0063] An exemplary full length sequence of human EGFR, which indicates V769, D770, and N771 in bold, is provided at UniProt Accession No. P00533-1, which is reproduced below:

[0064] An exemplary polynucleotide encoding EGFR is provided at NCBI Reference Sequence: NM_001346897.1, which is reproduced below:

[0065] The intermediates used for the synthesis of the compounds of claims 1-4 as described below, as well as their use for the synthesis of the compounds of claims 1-4, are one further aspect of the present invention. Preferred intermediates are the Intermediate Examples as disclosed below.General Procedures

[0066] The compounds according to the invention can be prepared according to the following schemes 1 - 4.

[0067] The schemes and procedures described below illustrate synthetic routes to the compounds of general formula (I) of the invention as defined in the appended claims. It is obvious to the person skilled in the art that the order of transformations as exemplified in the schemes can be modified in various ways. In addition, interconversion of any of the substituents R 1< , R 2< , R 3< , R 4< , R 5< , R 6< and PG can be achieved before and / or after the exemplified transformations. These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art. Specific examples are described in the subsequent paragraphs.

[0068] Scheme 1: Route for the preparation of compounds of general formula (I), wherein R 1< , R 2< , R 3< , R 4< , R 5< , R 6< , X, Y, m and n have the meaning as given for general formula (I) and PG can be hydrogen or optionally a suitable protecting group, e.g. tert-butoxycarbonyl (Boc).

[0069] Compound of formula 1, 2, and 4 are either commercially available or can be prepared according to procedures available from the public domain, as understandable to the person skilled in the art. Specific examples are described in the subsequent paragraphs.

[0070] A suitably substituted piperadine-2,4-dione of general formula (Compound of formula 1 ), such as, for example, 2,4-piperadinedione, can be reacted with a suitably substituted isothiocyanate (Compound of formula 2 ), such as, for example, 3-fluorophenylisothiocyanate, in a suitable solvent system, such as, for example, acetonitrile, in the presence of a suitable base, such as, for example, triethylamine or DBU, at temperatures ranging from -78°C to + 100°C, in some embodiments the reaction is carried out at 0°C or +100°C, to furnish general formula (3). Similar reactions have been performed in the literature (D. E. Worrall, J. Am. Chem. Soc., 1940, 62, 675).

[0071] Intermediates of general formula (3) can be converted to Intermediates of general formula (5 ) by reaction with a suitable amine (compounds of general formula 4 ), such as, for example 4-(aminomethyl)pyridine, in a suitable solvent system, such as, for example, ethanol and ethyl acetate, at a temperature between room temperature and the boiling point of the respective solvents, in some embodiments the reaction is carried out at the boiling point of the respective solvents, whereby the water formed in the reaction is removed from the reaction by methods known to those skilled in the art, such as, for example, azeotropic removal of water (Dean-Stark conditions) or with molecular sieves, to furnish general formula (5).

[0072] Intermediates of general formula (3) and intermediates of general formula (5) in which PG represents a protecting group can be converted to Intermediates in which PG represents a hydrogen atom using standard deprotection conditions known to those skilled in the art. When PG is a protecting group such as, for example, tert-butoxycarbonyl (Boc), the deprotection can be carried out using acids, such as, for example, hydrochloric acid and trifluoroacetic acid, in a suitable solvent system, such as, for example, dichloromethane and dioxane, at a temperature between 0°C and the boiling point of the respective solvents, in one embodiment the reaction is carried out at the room temperature, to furnish compounds of general formula (3) and intermediates of general formula (5) whereby PG is hydrogen atom.

[0073] Intermediates of general formula (5) are reacted with a base and / or oxidizing reagent, in one embodiment an oxidizing agent, such as, for example hydrogen peroxide or SIBX (stabilized iodoxybenoic acid, in a suitable solvent system, such as, for example, methanol, in a temperature range from -30°C to the boiling point of the respective solvent, in one embodiment the reaction is carried out at the boiling point of the respective solvent, to furnish compounds of general formula (I). Optionally, these types of reactions can be carried on with an additive, such as, for example, an acid or base, such as, for example, acetic acid or trifluoroacetic acid, and triethylamine or diispropylethylamine.

[0074] Intermediates of general formula (5) could be converted to compounds of general formula (I) by thermal heating them in a suitable solvent at elevated temperatures, which could be above the boiling point of the said solvent, such as, for example, RT to +250°C. These reactions could optionally be carried out in vessel whereby the pressure can be increased, such as, for example, in an autoclave. Intermediates of general formula (5) can also be converted to compounds of general formula (I) by thermal heating in the presence of a metal catalyst, such as, for example, palladium on activated charcoal, in a suitable solvent, such as, for example, DMF, DMA, EtOH, MeOH, NMP, at elevated temperatures, such as, for example, RT to +150°C. Optionally, these types of reactions can be carried on with an additive, such as, for example, an acid or base, such as, for example, acetic acid or trifluoroacetic acid, and triethylamine or diispropylethylamine, to furnish compounds of general formula (I).

[0075] Scheme 2: Process for the preparation of compounds of general formula (4), wherein R 4< , R 5< , R 6< , X, Y, m and n have the meaning as given for general formula (I).

[0076] Compounds of general formula (6) can be converted to compounds of general formula (7) by treatment with a suitable nucleophile, such as for example, amines, alcohols, metal alkoxides, azides, thiols or metal thiolates, under either basic, neutral, acidic, catalytic conditions, in one embodiment basic conditions, in a suitable solvent or using the nucleophile as solvent, such as, for example, DMF, tetrahydrofuran (THF), in a temperature range from -78°C to the boiling point of the respective solvent, in one embodiment the reaction is carried out -10°C to the boiling point of the respective solvent, to furnish general formula (7). Such substitution reactions have been previously reported (Clark et al., J. Med. Chem., 2008, 51, 6631 - 6634; Guo et al., Tetrahedron Letts., 2013, 54, 3233 - 3237; Watterson et al., J. Med. Chem., 2007, 50, 3730 - 3742; Bellale et al., J. Med. Chem., 2014, 57, 6572 - 6582; Klimesova et al., Eur. J. Med. Chem., 1996, 31, 389 - 395; Leroy et al., Synth. Commun., 1997, 27, 2905 - 2916; LaMattina et al., J. Org. Chem., 1981, 46, 4179 - 4182; Beugelmans et al., Tetrahedron, 1983, 39, 4153 - 4162).

[0077] Compounds of general formula (7) can be converted to compounds of general formula (4) by many reducing methods known to those skilled in the art, using numerous different reagents and reaction conditions; such methods and reagents can be carried out with metal hydrides, such as, for example, lithium aluminum hydride in THF (Bullock et al., J. Am. Chem. Soc., 1956, 78, 490, Wang et al., J. Org. Chem., 2006, 71, 4021 - 3160), or using zinc in acetic acid (Rabe, Chem. Ber., 1913, 46, 1024), or using diborane (De Munno et al., Heterocycles, 1996, 43, 1893 - 1900), or using catalytic hydrogenation methods, for example, hydrogen and palladium on carbon under acidic conditions (Stokker et al., J. Med. Chem., 1981, 24, 115 - 117; Bertini et al., J. Med. Chem., 2005, 48, 664 - 670), hydrogen and nickel under basic conditions (Walpole et al., J. Med. Chem., 1993, 36, 2362 - 2372, Kuramochi et al., Bioorg. Med. Chem., 2005, 13, 4022 - 4036.)

[0078] Scheme 3: Process for the preparation of compounds of general formula 2, wherein R 1a< represents methyl or difluoromethyl corresponding to R 1< in the general formula (I) with the meaning of methoxy and difluoromethoxy. The synthesis of compounds 9 and 10 relates to alkoxy substitution of the phenyl ring. However, the isothiocyanate containing product 2 and the synthesis thereof (i.e., 10 → 2 or 11 → 2 ) is general to R 1< groups according to general formula (I).

[0079] Compounds of general formula (8), can be converted to compounds of general formula (9), using various methods which are known to those skilled in the art. Such transformations could be, for example, to alkylate the phenolic alcohol with alkylating reagents, such as, for example, alkyl halides, alkyl sulfonates, in which these alkyl groups can optionally contain fluorides, alkoxyl groups. These alkylation reactions are known to those skilled in the art using a variety of methods: i) K 2 CO 3 in a solvent such as, DMF, acetone, DMFA (see the teachings of Muro et al., J. Med. Chem., 2009, 52, 7974 and WO2009 / 20990 A1); ii) KOH in EtOH (see the teachings of Macias et al., J. Agric. Food Chem., 2006, 54, 9843); iii) Mitsunobu reaction (see the teachings of US2006 / 122168 A1 and EP2151431 A1) to furnish intermediates of general formula (9).

[0080] Compounds of general formula (9) can be converted to compounds of general formula (10) by reduction methods and these methods are known to those skilled in the art. These reductions can be carried using: i) hydrogen gas and a catalyst (for Pd / C as catalyst see the teachings of Chan et al., J. Am. Chem. Soc., 2011, 133, 2989; for platinum see the teachings of Niemann et al., J. Am. Chem Soc., 1941, 63, 2204; for Raney-Nickel see the teachings of US2009 / 253767 A1); ii) iron and ammonium chloride (see the teachings of Sweeney et al., Bioorg. Med. Chem. Lett., 2008, 18, 4348); iii) sodium dithionite (see the teachings of Chong et al., J. Med. Chem., 2012, 55, 10601); iv) zinc and ammonium chloride (see the teachings of WO2010 / 42699 A1) to furnish intermediates of general formula (10).

[0081] Compounds of general formula (10) can be converted to compounds of general formula (2) by using reagents such as, for example, thiophosgene, carbon disulphide, 1,1"-thiocarbonyldi-2(1H)-pyridone or 1,1'-thiocarbonyldiimidazole, in one embodiment thiophosgene, under basic conditions, in a suitable solvent, such as, for example, dichloromethane, chloroform, acetone, or biphasic mixtures, such as, for example, dichloromethane, chloroform with aqueous basic solutions, in another embodiment, dichloromethane with an aqueous saturated solution of sodium hydrogen carbonate or sodium carbonate, in a temperature range from -78°C to the boiling point of the respective solvent, in another embodiment the reaction is carried out 0°C to room temperature, to furnish compounds of general formula (2). Such transformations reactions have been previously reported (Harris et al., J. Med. Chem., 2005, 48, 1610; Degorce et al., Tetrahedron Lett., 2011, 52, 6719; WO2016 / 91845 A1; Fairhurst et al., Org. Lett., 2005, 7, 4697; Chaskar et al., Synth. Commun., 2008, 38, 16940; US2004 / 122237 A1).

[0082] Scheme 4: Route for the preparation of compounds of general formula (I), wherein R 1< , R 2< , R 3< , R 4< , R 5< , R 6< , X, Y, m and n have the meaning as given for general formula (I) and PG represents hydrogen or a suitable protecting group, e.g. tert-butoxycarbonyl (Boc).

[0083] Compounds similar to those of general formula 12 are known to those skilled in the art and their syntheses have been reported in the literature (see the teachings of Voss et al., WO2015 / 22073 A1; Hart et al., WO2016 / 100166 A1; Anderson et al., J. Med. Chem., 2007, 50, 2647; Vanotti et al., J. Med. Chem., 2008, 51, 487).

[0084] Compounds of general formula (12) could be converted to compounds of general formula (13) using standard bromination methods which are known to those skilled in the art (WO2016 / 100166 A1). Such brominations could be carried out using a brominating agent, such as, for example, N-bromosuccinimide, in a suitable solvent, such as, for example, DMF, in a temperature range from -78°C to the boiling point of said solvent, in one embodiment the temperature range is 0°C to RT.

[0085] Intermediates of general formula (13) can be reacted with suitable anilines, such as, for example, 2-difluoromethoxyaniline, in the presence of a base, such as, for example, lithium bis(trimethylsilyl)amide (LHMDS), in the presence of a catalyst, such as, for example a suitable ligand, in one embodiment 2-(di-tert-butylphosphino)-2',4',6'- triisopropyl-3,6-dimethoxy-1,1'-biphenyl (tBuBrettPhos) and in the presence of a pre-catalyst, such as, for example a palladium pre-catalyst, in another embodiment chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos-PreCat MTBE ether adduct) in a suitable solvent system, such as, for example, tetrahydrofuran (THF), at a temperature range of 0°C to 200°C. In one embodiment, the reaction is carried out at 80°C, to furnish compounds of general formula (I). Similar transformations have been carried out and have been reported (WO2015 / 193339 A1).

[0086] Scheme 5: Route for the preparation of compounds of general formula (I), wherein R 1< , R 2< , R 3< , R 4< , R 5< , R 6< , X, Y, m and n have the meaning as given for general formula (I) and PG represents hydrogen or a suitable protecting group, e.g. tert-butoxycarbonyl (Boc).

[0087] Compounds similar to those of general formula (14) can be prepared according to the procedure described by Scheme 1 under the use of 4-(aminomethyl)-3-hydroxypyridine instead of intermediate (4). Intermediates of general formula (14) can be converted to compounds of general formula (I) by reaction with a suitable alcohol under Mitsunobu conditions (the teachings of Oyo Mitsunobu, Synthesis, 1981, 1-28 or Tsunoda et al., Tetrahedron Lett., 1994, 35, 5081) such as, for example oxetan-3-ylmethanol, in the presence of (tributylphosphoranylidene)acetonitrile or triphenylphosphin together with diisopropyl azodicarboxylate in a suitable solvent system, such as, for example, dioxane or THF, at a temperature between room temperature and the boiling point of the respective solvents.

[0088] It is known to the person skilled in the art that, if there are a number of reactive centers on a starting or intermediate compound, it may be necessary to block one or more reactive centers temporarily by protective groups in order to allow a reaction to proceed specifically at the desired reaction center.

[0089] The compounds according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as chromatography on a suitable support material. Furthermore, reverse phase preparative HPLC may be applied. The compounds of the present invention which possess a sufficiently basic or acidic functionality, may result as a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. Salts of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. Additionally, the drying process during the isolation of the compounds of the present invention may not fully remove traces of cosolvents, especially such as formic acid or trifluoroacetic acid, to give solvates or inclusion complexes. The person skilled in the art will recognise which solvates or inclusion complexes are acceptable to be used in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base, free acid, solvate, inclusion complex) of a compound of the present invention as isolated and described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.

[0090] Salts of the compounds of formula (I) according to the invention can be obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, methylethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added. The acid or base can be employed in salt preparation, depending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar ratio or one differing therefrom. The salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts. In this manner, pharmaceutically unacceptable salts, which can be obtained, for example, as process products in the manufacturing on an industrial scale, can be converted into pharmaceutically acceptable salts by processes known to the person skilled in the art. Especially preferred are hydrochlorides and the process used in the example section.

[0091] Pure diastereomers and pure enantiomers of the compounds and salts according to the invention can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis or by splitting up enantiomeric and diasteriomeric mixtures obtained in synthesis.

[0092] Enantiomeric and diastereomeric mixtures can be split up into the pure enantiomers and pure diastereomers by methods known to the person skilled in the art. In one embodiment, diastereomeric mixtures are separated by crystallization, in particular fractional crystallization, or chromatography. Enantiomeric mixtures can be separated e.g. by forming diastereomers with a chiral auxiliary agent, resolving the diastereomers obtained and removing the chiral auxiliary agent. As chiral auxiliary agents, for example, chiral acids can be used to separate enantiomeric bases such as e.g. mandelic acid and chiral bases can be used to separate enantiomeric acids by formation of diastereomeric salts. Furthermore, diastereomeric derivatives such as diastereomeric esters can be formed from enantiomeric mixtures of alcohols or enantiomeric mixtures of acids, respectively, using chiral acids or chiral alcohols, respectively, as chiral auxiliary agents. Additionally, diastereomeric complexes or diastereomeric clathrates may be used for separating enantiomeric mixtures. Alternatively, enantiomeric mixtures can be split up using chiral separating columns in chromatography. Another suitable method for the isolation of enantiomers is the enzymatic separation.

[0093] Optionally, compounds of the formula (I) as defined in the appended claims can be converted into their salts, or, optionally, salts of the compounds of the formula (I) can be converted into the free compounds. Corresponding processes are customary for the skilled person.Commercial utility

[0094] As mentioned supra, the compounds of the present invention as defined in the appended claims have surprisingly been found to effectively inhibit mutant EGFR in a cell (e.g., a cancer cell) contacted with the compound, thereby inducing cell death (e.g., apoptosis) and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by mutant EGFR, such as, for example, benign and malignant neoplasia, more specifically haematological tumours, solid tumours, and / or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and / or metastases thereof, especially haematological tumours, solid tumours, and / or metastases of breast, bladder, bone, brain, central and peripheral nervous system, cervix, colon, endocrine glands (e.g., thyroid and adrenal cortex), endocrine tumours, endometrium, esophagus, gastrointestinal tumours, germ cells, kidney, liver, lung, larynx and hypopharynx, mesothelioma, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, stomach, skin, testis, ureter, vagina and vulva as well as malignant neoplasias including primary tumours in said organs and corresponding secondary tumours in distant organs ("tumour metastases"). Haematological tumours can, e.g., be exemplified by aggressive and indolent forms of leukemia and lymphoma, namely non-Hodgkins disease, chronic and acute myeloid leukemia (CML / AML), acute lymphoblastic leukemia (ALL), Hodgkins disease, multiple myeloma and T-cell lymphoma. Also included are myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes, and cancers of unknown primary site, as well as AIDS related malignancies.

[0095] The compounds of the present invention as defined in the appended claims, are for uses as defined in the appended claims.

[0096] By "hyperproliferative disease" is meant a disease, such as cancer, associated with inappropriately high levels of cell division, inappropriately low levels of apoptosis, or both. The term "inappropriate" within the context of the present invention, in particular in the context of "inappropriate cellular immune responses, or inappropriate cellular inflammatory responses", as used herein, is to be understood as generally meaning a response, which is less than, or greater than normal, and which is associated with, responsible for, or results in, the pathology of said diseases.

[0097] In particular embodiments, the use is in the treatment or prophylaxis of diseases, especially the treatment, wherein the diseases are haematological tumours, solid tumours and / or metastases thereof.

[0098] Hyper-proliferative disorders are psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukaemias.

[0099] Examples of breast cancer are invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

[0100] Examples of cancers of the respiratory tract are small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.

[0101] Examples of brain cancers are brain stem and hypothalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour.

[0102] Tumours of the male reproductive organs are prostate and testicular cancer. Tumours of the female reproductive organs are endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.

[0103] Tumours of the digestive tract are anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.

[0104] Tumours of the urinary tract are bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.

[0105] Eye cancers are intraocular melanoma and retinoblastoma.

[0106] Examples of liver cancers are hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.

[0107] Skin cancers are squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, inverted sinonasal papilloma, inverted sinonasal papilloma-associated sinonasal squamous cell carcinoma, Merkel cell skin cancer, and non-melanoma skin cancer.

[0108] Head-and-neck cancers are laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, inverted sinonasal papilloma, inverted sinonasal papilloma-associated sinonasal squamous cell carcinoma, lip and oral cavity cancer and squamous cell. Lymphomas are AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.

[0109] Sarcomas are sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

[0110] Leukemias are acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

[0111] These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.

[0112] The term "treating" or "treatment" as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, of a disease or disorder, such as a carcinoma.

[0113] In various embodiments, the diseases of said method are haematological tumours, solid tumour and / or metastases thereof.

[0114] The compounds of the present invention as defined in the appended claims can be used in therapy and prevention i.e. prophylaxis, especially in therapy of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pretreatment of the tumour growth.Pharmaceutical compositions of the compounds of the invention

[0115] This invention as defined in the appended claims also relates to pharmaceutical compositions containing one or more compounds of the present invention as defined in the appended claims. These compositions can be utilised to achieve the desired pharmacological effect by administration to a patient in need thereof. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition, disorder, or disease.

[0116] Therefore, the present invention includes pharmaceutical compositions as defined in the appended claims

[0117] A pharmaceutically acceptable carrier or auxiliary may be a carrier that is non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. Carriers and auxiliaries are all kinds of additives assisting to the composition to be suitable for administration.

[0118] A pharmaceutically effective amount of compound may be that amount which produces a result or exerts the intended influence on the particular condition being treated.

[0119] The compounds of the present invention as defined in the appended claims can be administered with pharmaceutically-acceptable carriers or auxiliaries well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like.

[0120] For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms can be a capsule that can be of the ordinary hard- or soft-shelled gelatine type containing auxiliaries, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.

[0121] In another embodiment, the compounds of this invention as defined in the appended claims may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatine, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration, such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, colouring agents, and flavouring agents such as peppermint, oil of wintergreen, or cherry flavouring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.

[0122] Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.

[0123] Additional excipients, for example those sweetening, flavouring and colouring agents described above, may also be present.

[0124] The pharmaceutical compositions of this invention as defined in the appended claims may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.

[0125] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more colouring agents; one or more flavouring agents; and one or more sweetening agents such as sucrose or saccharin.

[0126] Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavouring and colouring agents.

[0127] The compounds of this invention as defined in the appended claims may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in, for example, a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methycellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent and other pharmaceutical adjuvants.

[0128] Illustrative of oils which can be used in the parenteral formulations of this invention as defined in the appended claims are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.

[0129] The parenteral compositions of this invention as defined in the appended claims will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimise or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) in one embodiment of from about 12 to about 17. The quantity of surfactant in such formulation in one embodiment ranges from about 5% to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.

[0130] Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.

[0131] The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate.

[0132] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.

[0133] A composition of the invention as defined in the appended claims may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycol.

[0134] Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art.

[0135] It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. Direct techniques for administration, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in US Patent No. 5,011,472, issued April 30, 1991.

[0136] The compositions of the invention as defined in the appended claims can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized.

[0137] Such ingredients and procedures include those described in the following references: Powell, M.F. et al., "Compendium of Excipients for Parenteral Formulations" PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-311; Strickley, R.G "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1" PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S. et al., "Excipients and Their Use in Injectable Products" PDA Journal of Pharmaceutical Science & Technology 1997, 51(4), 166-171.

[0138] Commonly used pharmaceutical ingredients that can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples are acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples are ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples are powdered cellulose and activated charcoal); aerosol propellants (examples are carbon dioxide, CCl 2 F 2 , F 2 ClC-CClF 2 and CClF 3 ); air displacement agents (examples are nitrogen and argon); antifungal preservatives (examples are benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate); antimicrobial preservatives (examples are benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal); antioxidants (examples are ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); binding materials (examples are block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes and styrene-butadiene copolymers); buffering agents (examples are potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate); carrying agents (examples are acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection); chelating agents (examples are edetate disodium and edetic acid); colourants (examples are FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red); clarifying agents (examples are bentonite); emulsifying agents (examples are acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate); encapsulating agents (examples are gelatin and cellulose acetate phthalate); flavourants (examples are anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin); humectants (examples are glycerol, propylene glycol and sorbitol); levigating agents (examples are mineral oil and glycerin); oils (examples are arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil); ointment bases (examples are lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment); penetration enhancers (transdermal delivery) (examples are monohydroxy or polyhydroxy alcohols, mono-or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas); plasticizers (examples are diethyl phthalate and glycerol); solvents (examples are ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation); stiffening agents (examples are cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax); suppository bases (examples are cocoa butter and polyethylene glycols (mixtures)); surfactants (examples are benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan mono-palmitate); suspending agents (examples are agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum); sweetening agents (examples are aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose); tablet anti-adherents (examples are magnesium stearate and talc); tablet binders (examples are acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch); tablet and capsule diluents (examples are dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); tablet coating agents (examples are liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac); tablet direct compression excipients (examples are dibasic calcium phosphate); tablet disintegrants (examples are alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross-linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starch); tablet glidants (examples are colloidal silica, corn starch and talc); tablet lubricants (examples are calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate); tablet / capsule opaquants (examples are titanium dioxide); tablet polishing agents (examples are carnuba wax and white wax); thickening agents (examples are beeswax, cetyl alcohol and paraffin); tonicity agents (examples are dextrose and sodium chloride); viscosity increasing agents (examples are alginic acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth); and wetting agents (examples are heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

[0139] Pharmaceutical compositions according to the present invention as defined in the appended claims can be illustrated as follows: Sterile i.v. solution: A 5 mg / ml solution of the desired compound of this invention can be made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1 - 2 mg / ml with sterile 5% dextrose and is administered as an i.v. infusion over about 60 minutes. Lyophilised powder for i.v. administration: A sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lyophilised powder, (ii) 32- 327 mg / ml sodium citrate, and (iii) 300 - 3000 mg Dextran 40. The formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg / ml, which is further diluted with saline or dextrose 5% to 0.2 - 0.4 mg / ml, and is administered either IV bolus or by IV infusion over 15 - 60 minutes. Intramuscular suspension: The following solution or suspension can be prepared, for intramuscular injection: 50 mg / ml of the desired, water-insoluble compound of this invention 5 mg / ml sodium carboxymethylcellulose 4 mg / ml TWEEN 80 9 mg / ml sodium chloride 9 mg / ml benzyl alcohol Hard Shell Capsules: A large number of unit capsules are prepared by filling standard twopiece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate. Soft Gelatin Capsules: A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix. Tablets: A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption. Immediate Release Tablets / Capsules: These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water. Dose and administration

[0140] Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyper-proliferative disorders and angiogenic disorders, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.

[0141] The total amount of the active ingredient to be administered will generally range from about 0.001 mg / kg to about 200 mg / kg body weight per day, and in particular embodiments from about 0.01 mg / kg to about 20 mg / kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, "drug holidays" in which a patient is not dosed with a drug for a certain period of time, may be beneficial to the overall balance between pharmacological effect and tolerability. A unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will in other embodiments be from 0.01 to 200 mg / kg of total body weight. The average daily rectal dosage regimen will in particular embodiments be from 0.01 to 200 mg / kg of total body weight. The average daily vaginal dosage regimen will in other embodiments be from 0.01 to 200 mg / kg of total body weight. The average daily topical dosage regimen will in still other embodiments be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will in other embodiments be that required to maintain a daily dose of from 0.01 to 200 mg / kg. The average daily inhalation dosage regimen will in other embodiments be from 0.01 to 100 mg / kg of total body weight.

[0142] Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.Combination Therapies

[0143] The compounds of this invention as defined in the appended claims can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. Those combined pharmaceutical agents can be other agents having antiproliferative effects such as for example for the treatment of haematological tumours, solid tumours and / or metastases thereof and / or agents for the treatment of undesired side effects. The present invention relates also to such combinations.

[0144] Other anti-hyper-proliferative agents suitable for use with the composition of the invention are those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 1225-1287, (1996), especially (chemotherapeutic) anti-cancer agents as defined supra. The combination can be a non-fixed combination or a fixed-dose combination as the case may be.

[0145] Methods of testing for a particular pharmacological or pharmaceutical property are well known to persons skilled in the art.

[0146] The example testing experiments described herein serve to illustrate the present invention as defined in the appended claims.

[0147] The following examples illustrate the invention in greater detail. Further compounds according to the invention, of which the preparation is not explicitly described, can be prepared in an analogous way.

[0148] The term "according to" within the experimental section is used in the sense that the procedure referred to is to be used "analogously to".EXPERIMENTAL SECTION

[0149] Chemical names were generated using the ACD / Name software from ACD / Labs. In some cases generally accepted names of commercially available reagents were used in place of ACD / Name generated names.

[0150] The following table 1 lists the abbreviations used in this paragraph and in the Examples section as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person. Table 1: AbbreviationsAbbreviation Meaning ACNAcetonitrileAcOHAcetic acidbrbroad signal (NMR)ddoublet (NMR)DADDiode Array DetectorDASTDiethylaminosulfur trifluorideDBU1,8-Diazabicyclo(5.4.0)undec-7-eneDCMDichloromethanedddoublet of doublet (NMR)DIPEADiisopropylethylamineDMAN,N-dimethylacetamideDMAP4-DimethylaminopyridineDMFN,N-dimethylformamideDMSODimethylsulfoxideEDC.HClN-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride saltESIelectrospray (ES) ionizationEtOAcEthyl acetateEtOHEthanolh, hr (hrs)hour(s)HClhydrogen chloride, hydrochloric acidHPLChigh performance liquid chromatographyLC-MSliquid chromatography-mass spectrometrymmultiplet (NMR)MeCNAcetonitrileMeOHMethanolminminute(s)MSmass spectrometryMTBEMethyl-tert-butyletherMWDMultiple wavelength detectorNMRNuclear Magnetic Resonance spectroscopy : chemical shifts (δ) are given in ppm. The chemical shifts were corrected by setting the DMSO signal to 2.50 ppm using unless otherwise stated.qquartet (NMR)Rt or RTroom temperatureR t , Rtretention timessingulet (NMR)sat.SaturatedSFCSupercritical Fluid Chromatographyttriplet (NMR)tdtriplet of doublet (NMR)TEATriethylamineTFATrifluoroacetic acidTHFTetrahydrofuranδchemical shift

[0151] Other abbreviations have their meanings customary per se to the skilled person.

[0152] The various aspects of the invention described in this application are illustrated by the following examples.

[0153] The example testing experiments described herein serve to illustrate the present invention.EXPERIMENTAL SECTION - GENERAL PART

[0154] All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.

[0155] The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be removed by trituration using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartridges KP-Sil ®< or KP-NH ®< in combination with a Biotage autopurifier system (SP4 ®< or Isolera Four ®< ) and eluents such as gradients of hexane / ethyl acetate or DCM / methanol. In flash column chromatography, unmodified ("regular") silica gel may be used as well as aminophase functionalized silica gel. If reference is made to flash column chromatography or to flash chromatography in the experimental section without specification of a stationary phase, regular silica gel was used.

[0156] In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and / or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.

[0157] In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.Analytical LC-MS Methods: Method 1:

[0158] Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 µm, 50x2.1mm; eluent A: water + 0.1 vol. % formic acid (99 %), eluent B: acetonitrile; gradient: 0-1.6 min. 1-99 % B, 1.6-2.0 min. 99 % B; flow 0.8 ml / min; temperature: 60 °C; DAD scan: 210-400 nm.Method 2:

[0159] Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 µm, 50x2.1mm; eluent A: water + 0.2 vol. % aqueous ammonia (32 %), eluent B: acetonitrile; gradient: 0-1.6 min. 1-99 % B, 1.6-2.0 min. 99 % B; flow 0.8 ml / min; temperature: 60 °C; DAD scan: 210-400 nm.Method 3:

[0160] Instrument: Waters Acquity UPLC H-Class system; Column: Acquity CSH C18 1.7 µm 2.1x50 mm; eluent A: water + 0.1 vol. % formic acid, eluent B: acetonitrile, eluent C: 2 vol. % ammonia (28 %) in water, eluent D: 2 vol. % formic acid in water; gradient: 0-1.2 min 2-95 % B with A and 5 % D throughout, 1.2-1.4 min. 95 % B; flow 0.8 ml / min; temperature: 40 °C; PDA: 215-350 nm.Method 4:

[0161] Instrument: Waters Acquity UPLC H-Class system; Column: XBridge BEH C18 2.5 µm 2.1 x 50 mm; eluent A: water + 0.1 vol % formic acid, eluent B: acetonitrile, eluent C: 2 vol % ammonia (28%) in water, eluent D: 2 vol % formic acid in water; gradient: 0-1.2 min 2-95% B with A and 5% C throughout, 1.2-1.4 min 95% B; flow 0.8 ml / min; temperature: 40 °C; PDA: 215-350 nm.Method 5:

[0162] MS instrument: SHIMADZU LCMS-2020; HPLC instrument: LabSolution Version 5.72; Column: Kinetex@5um EVO C18 30 x 2.1mm; eluent A: 0.0375% TFA in water (v / v), eluent B: 0.01875% TFA in acetonitrile: gradient: 0.0 min 0% B → 3.00 min 60% B → 3.50 min 60% B → 3.51 min 0% B → 4.00 min 0% B; flow rate: 0.8 mL / mix; oven temperature: 50 °C; UV detection: 220 nm & 254 nm.Method 6:

[0163] Instrument: Agilent 1290 UPLCMS 6230 TOF; Säule: BEH C 18 1.7 µm, 50x2.1mm; Eluent A: Wasser + 0.05 % Ameisensäure (99%); Eluent B: Acetonitril + 0.05 % Ameisensäure (99%); Gradient: 0-1.7 2-90% B, 1.7-2.0 90% B; Fluss 1.2 ml / min; Temperatur: 60°C; DAD scan: 190-400 nm.Preparative LC-MS Methods: Method 7:

[0164] Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBrigde C18 5µ 100x30mm; eluent A: water + 0.2 vol. % aqueous ammonia (32 %), eluent B: acetonitrile; gradient: 0-5.5 min. 5-100 % B; flow 70 ml / min; temperature: 25 °C; DAD scan: 210-400 nmMethod 8:

[0165] Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBrigde C18 5µ 50x50mm; eluent A: water + 0.1 vol% formic acid, eluent B: methanol; gradient: 0-0.50 min. 20 % B; flow 50 to 100 ml / min, 0.50-8.00 min. 20 - 60% B; flow 100 ml / min, temperature: 25 °C; DAD scan: 210-400 nmMethod 9:

[0166] Instrument: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 2000, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software. Column: Chromatorex C18 10µM 120x30 mm; Eluent A: water + 0.1% formic acid; Eluent B: acetonitrile; gradient: given for intermediates and examples, rate 150 mL / min, temperature 25°C.; UV 220 nmMethod 10:

[0167] Instrument: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 2000, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software. Column: Chromatorex C18 10µM 120x30 mm; Eluent A: 0.1% ammonia in water; Eluent B: acetonitrile; gradient: given for intermediates and examples, rate 150 mL / min, temperature 25°C.; UV 250 nmMethod 11:

[0168] Instrument: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 2000, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software. Column: Chromatorex C18 10µM 300x50 mm; Eluent A: 0.1% ammonia in water; Eluent B: acetonitrile; gradient: given for intermediates and examples, rate 250 mL / min, temperature 25°C.; UV 250 nmNMR Spectra:

[0169] The multiplicities of proton signals in 1< H NMR spectra given in the following paragraphs reflect the observed signal form and do not take into account any higher-order signal phenomena. As a rule, the chemical shift data refers to the center of the signal in question. In the case of wide multiplets, a range is specified. Signals hidden by solvent or water were either assigned tentatively or are not listed. Strongly broadened signals - e.g. caused by rapid rotation of molecular moieties or by interchanging protons - have also been assigned tentatively (often referred to as a broad multiplet or broad singlet) or are not shown.

[0170] The 1< H-NMR data of selected compounds are listed in the form of 1< H-NMR peaklists. Therein, for each signal peak the δ value in ppm is given, followed by the signal intensity, reported in round brackets. The δ value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: δ 1 (intensity 1 ), δ 2 (intensity 2 ), ... , δ i (intensity i ), ... , δ n (intensity n ).

[0171] The intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spectrum. When compared with other signals, this data can be correlated to the real ratios of the signal intensities. In the case of broad signals, more than one peak, or the center of the signal along with their relative intensity, compared to the most intense signal displayed in the spectrum, are shown. A 1< H-NMR peaklist is similar to a classical 1< H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical 1< H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of the particular target compound, peaks of impurities, 13< C satellite peaks, and / or spinning sidebands. The peaks of stereoisomers, and / or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compound (e.g., with a purity of >90%). Such stereoisomers and / or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify a reproduction of the manufacturing process on the basis of "by-product fingerprints". An expert who calculates the peaks of the target compound by known methods (MestReC, ACD simulation, or by use of empirically evaluated expectation values), can isolate the peaks of the target compound as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical 1< H-NMR interpretation. A detailed description of the reporting of NMR data in the form of peaklists can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (cf. http: / / www.researchdisclosure.com / searching-disclosures, Research Disclosure Database Number 605005, 2014, 01 Aug 2014). In the peak picking routine, as described in the Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be adjusted between 1% and 4%. However, depending on the chemical structure and / or depending on the concentration of the measured compound it may be reasonable to set the parameter "MinimumHeight" <1%.Syntheses of Intermediate 1 Compounds Intermediate 1-1 3-[(1,4-dioxan-2-yl)methoxy]pyridine-4-carbonitrile

[0172]

[0173] 3-chloropyridine-4-carbonitrile (CAS 68325-15-5, 1.40 g, 10.1 mmol) and (1,4-dioxan-2-yl)methanol (CAS 143669-41-4, 1.31 g, 11.1 mmol) were dissolved in THF (45 ml). Potassium tert-butoxide (1.03 g, 9.14 mmol) was added and the mixture was stirred for 1 h at 0°C. The reaction mixture was diluted slowly with sat. ammonium chloride solution and extracted with EtOAc (3x). The organic phase was washed with brine and filtered over a water-repellent filter, concentrated under reduced pressure and purified by flash chromatography (silica, hexane / EtOAc gradient 0-100 %; EtOAc / EtOH gradient 0-35 %) to give 1.18 g of the title compound (53 % yield). 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 8.72 (s, 1H), 8.23 - 8.46 (m, 1H), 7.68 - 7.86 (m, 1H), 4.32 (d, 2H), 3.40 - 3.99 (m, 7H). LC-MS (method 2): R t = 0.77 min; MS (ESlpos): m / z = 221 [M+H] +< Intermediate 1-2 3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridine-4-carbonitrile

[0174]

[0175] To a solution of [(3S)-4-methylmorpholin-3-yl]methanol (CAS 1620510-50-0, 1.00 g, 7.62 mmol) in THF (20 ml) at 0°C was slowly added sodium hydride (366 mg, 9.15 mmol, 60 % purity). The reaction mixture was stirred for 3 hat RT. 3-chloropyridine-4-carbonitrile (CAS 68325-15-5, 1.06 g, 7.62 mmol) in THF (10 ml) was added and the mixture was stirred overnight. The reaction mixture was quenched with 1N HCl until pH = 7. The suspension was filtered through a hydrophobic filter paper and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (basic silica, hexane / EtOAc gradient 0-100 %) to give 355 mg of the title compound (20 % yield). 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 8.75 (s, 1H), 8.40 (d, 1H), 7.78 (d, 1H), 4.44 (dd, 1H), 4.23 (dd, 1H), 3.87 (dd, 1H), 3.71 (dt, 1H), 3.50 (td, 1H), 3.35 - 3.41 (m, 1H), 2.65 - 2.71 (m, 1H), 2.45 - 2.49 (m, 1H), 2.29 - 2.35 (m, 3H), 2.24 (ddd, 1H). LC-MS (method 2): Rt = 0.72 min; MS (ESlpos): m / z = 234.2 [M+H] +< Intermediate 1-3 3-{[4-methylmorpholin-2-yl]methoxy}pyridine-4-carbonitrile

[0176]

[0177] Using an analogous method as described for intermediate 1-1 with 3-chloropyridine-4-carbonitrile (CAS 68325-15-5, 764 mg, 5.51 mmol) and [4-methylmorpholin-2-yl]methanol (CAS 40987-46-0, 940 mg, 7.17 mmol) as the starting materials; 836 mg (90 % purity, 59 % yield) of the title compound were prepared. 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.893 (0.97), 1.920 (1.44), 1.947 (1.07), 1.954 (0.50), 1.962 (0.54), 1.983 (1.01), 1.991 (1.03), 2.011 (0.58), 2.019 (0.52), 2.197 (16.00), 2.518 (0.41), 2.589 (0.80), 2.593 (0.82), 2.617 (0.73), 2.621 (0.74), 2.766 (0.66), 2.770 (0.95), 2.794 (0.63), 2.798 (0.89), 3.513 (0.60), 3.520 (0.73), 3.541 (1.36), 3.547 (1.39), 3.570 (0.80), 3.575 (0.67), 3.793 (0.74), 3.796 (1.10), 3.801 (1.12), 3.805 (0.92), 3.808 (0.85), 3.814 (0.79), 3.821 (1.18), 3.826 (1.18), 3.833 (1.27), 3.839 (0.66), 4.316 (5.03), 4.329 (4.72), 7.772 (2.40), 7.774 (2.63), 7.785 (2.49), 8.381 (3.41), 8.393 (3.28), 8.714 (4.32). LC-MS (method 2): Rt = 0.70 min; MS (ESlpos): m / z = 234.2 [M+H] +< Intermediate 1-4 3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridine-4-carbonitrile

[0178]

[0179] Using an analogous method as described for intermediate 1-2 with 3-chloropyridine-4-carbonitrile (CAS 68325-15-5, 1.00 g, 7.24 mmol) and [(3R)-4-methylmorpholin-3-yl]methanol (1.00 g, 95 % purity, 7.24 mmol; CAS 1620510-51-1) as the starting materials; 823 mg (99 % purity, 48 % yield) of the title compound were prepared. 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 2.211 (0.52), 2.219 (0.64), 2.236 (0.66), 2.240 (0.68), 2.245 (0.68), 2.249 (0.72), 2.266 (0.69), 2.274 (0.63), 2.306 (16.00), 2.472 (0.48), 2.475 (0.50), 2.518 (1.22), 2.522 (0.71), 2.658 (0.56), 2.664 (1.27), 2.671 (0.67), 2.687 (0.47), 2.694 (0.96), 2.701 (0.47), 3.356 (1.17), 3.378 (1.16), 3.384 (1.30), 3.406 (1.20), 3.472 (0.50), 3.478 (0.58), 3.499 (0.80), 3.506 (0.81), 3.525 (0.71), 3.532 (0.61), 3.685 (0.44), 3.692 (0.86), 3.698 (0.45), 3.720 (0.66), 3.856 (0.80), 3.864 (0.81), 3.884 (0.73), 3.892 (0.72), 4.209 (1.03), 4.223 (1.01), 4.234 (1.29), 4.249 (1.23), 4.417 (1.25), 4.429 (1.28), 4.443 (1.03), 4.454 (0.99), 7.778 (2.39), 7.780 (2.38), 7.790 (2.45), 7.792 (2.50), 8.391 (3.23), 8.403 (3.11), 8.745 (3.91). LC-MS (method 2): Rt = 0.70 min; MS (ESlpos): m / z = 234 [M+H] +< Intermediate 1-5 tert-butyl (2S)-2-{[(4-cyanopyridin-3-yl)oxy]methyl}morpholine-4-carboxylate

[0180]

[0181] Using an analogous method as described for intermediate 1-1 with 3-chloropyridine-4-carbonitrile (CAS 68325-15-5, 2.55 g, 18.4 mmol) and tert-butyl (2S)-2-(hydroxymethyl)morpholine-4-carboxylate (CAS 135065-76-8, 4.00 g, 18.4 mmol) as the starting materials; 4.82 g (90 % purity, 74 % yield) of the title compound were prepared. 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 1.41 (s, 9H), 2.72 - 3.05 (m, 2H), 3.46 (br d, 1H), 3.67 - 3.82 (m, 2H), 3.82 - 3.88 (m, 1H), 4.00 (s, 1H), 4.37 (br d, 2H), 7.79 (d, 1H), 8.40 (d, 1H), 8.73 (s, 1H). LC-MS (method 2): Rt = 1.06 min; MS (ESlpos): m / z = 320 [M+H] +< Intermediate 1-6 3-[2-(1,4-dioxan-2-yl)ethoxy]pyridine-4-carbonitrile

[0182]

[0183] Using an analogous method as described for intermediate 1-2 with 3-chloropyridine-4-carbonitrile (CAS 68325-15-5, 2.10 g, 15.1 mmol) and 2-(1,4-dioxan-2-yl)ethan-1-ol (CAS 151720-04-6, 2.00 g, 15.1 mmol) as the starting materials; 2.89 g (99 % purity, 81 % yield) of the title compound were prepared. 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.754 (0.63), 1.768 (1.37), 1.774 (0.82), 1.781 (0.98), 1.790 (2.18), 1.803 (3.39), 1.810 (2.10), 1.817 (1.93), 1.824 (3.23), 1.838 (2.78), 1.855 (2.41), 1.867 (2.45), 1.869 (2.40), 1.874 (2.53), 1.886 (2.23), 1.902 (0.99), 1.910 (0.87), 1.922 (0.67), 2.326 (0.72), 2.668 (0.69), 3.223 (4.26), 3.247 (5.57), 3.250 (5.62), 3.276 (5.26), 3.428 (1.77), 3.434 (1.89), 3.455 (4.59), 3.462 (4.80), 3.483 (3.76), 3.489 (3.97), 3.530 (3.36), 3.535 (3.38), 3.558 (4.71), 3.564 (5.40), 3.585 (1.93), 3.592 (3.08), 3.626 (4.58), 3.631 (4.33), 3.654 (3.70), 3.659 (4.02), 3.668 (1.98), 3.673 (1.97), 3.680 (2.77), 3.687 (2.85), 3.693 (2.89), 3.706 (6.98), 3.712 (6.06), 3.724 (1.75), 3.735 (3.40), 3.759 (4.77), 3.766 (4.02), 3.788 (4.04), 3.794 (3.73), 4.315 (0.93), 4.329 (1.18), 4.339 (3.54), 4.354 (6.92), 4.359 (5.21), 4.370 (6.49), 4.384 (3.79), 4.392 (1.47), 4.408 (0.68), 7.778 (9.22), 7.790 (9.58), 8.380 (10.88), 8.392 (10.45), 8.698 (16.00). LC-MS (method 6): Rt = 0.64 min; MS (ESlpos): m / z = 235 [M+H] +< Intermediate 1-7 3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridine-4-carbonitrile

[0184]

[0185] Using an analogous method as described for intermediate 1-2 with 3-chloropyridine-4-carbonitrile (CAS 68325-15-5, 948 mg, 6.84 mmol) and (5,5-dimethyl-1,4-dioxan-2-yl)methanol (1.00 g, 6.84 mmol; CAS 54321-57-2) as the starting materials; 1.31 g (95 % purity, 73 % yield) of the title compound were prepared. 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.014 (0.69), 1.048 (16.00), 1.172 (0.55), 1.200 (0.51), 1.263 (13.01), 1.987 (0.92), 2.518 (0.62), 2.523 (0.43), 3.313 (1.67), 3.340 (2.27), 3.342 (2.21), 3.542 (2.95), 3.570 (2.39), 3.604 (1.50), 3.627 (1.97), 3.734 (1.24), 3.760 (3.08), 3.781 (2.25), 3.787 (2.73), 3.791 (1.58), 3.796 (0.77), 3.802 (0.63), 4.356 (3.63), 4.365 (4.41), 7.780 (3.42), 7.792 (3.63), 8.387 (4.49), 8.399 (4.29), 8.715 (5.54). LC-MS (method 6): Rt = 0.75 min; MS (ESlpos): m / z = 249 [M+H] +< Intermediate 1-8 3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridine-4-carbonitrile

[0186]

[0187] Using an analogous method as described for intermediate 1-1 with 3-chloropyridine-4-carbonitrile (CAS 68325-15-5, 1.00 g, 7.22 mmol) and [(2R)-1,4-dioxan-2-yl]methanol (CAS406913-88-0, 938 mg, 7.94 mmol) as the starting materials; 490 mg (95% purity, 29% yield) of the title compound were prepared. Optical rotation:[α] D = - 1.68° + / - 0.35° (c = 7 mg / ml, methanol) 1< H-NMR (400 MHz, DMSO-d 6 ): δ ppm= 3.41 - 3.53 (m, 2 H), 3.59 - 3.72 (m, 2 H), 3.75 - 3.81 (m, 1 H), 3.82 - 3.87 (m, 1 H), 3.87 - 3.95 (m, 1 H), 4.27 - 4.37 (m, 2 H), 7.77 - 7.80 (m, 1 H), 8.38 - 8.41 (m, 1 H), 8.71 - 8.73 (m, 1 H). Intermediate 1-9 tert-butyl (3R)-3-{[(4-cyanopyridin-3-yl)oxy]methyl}morpholine-4-carboxylate

[0188]

[0189] To a solution of tert-butyl (3S)-3-(hydroxymethyl)morpholine-4-carboxylate (4.30 g, 19.8 mmol) in THF (28 ml) at 0°C was slowly added sodium hydride (1.55 g, 55% purity, 35.6 mmol). The reaction mixture was stirred for 1 h. 3-fluoropyridine-4-carbonitrile (CAS 113770-88-0, 2.42 g, 19.8 mmol) in THF (14 ml) was added and the mixture was stirred for 4 h at 0°C. The reaction mixture was quenched with 2N HCl until pH = 6 - 7 and was extracted with EE. The organic layer was filtered through a water repellent filter paper and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, DCM / EtOH gradient 0-7%) to give 4 g of the title compound (70% yield). LC-MS (method 6): Rt = 0.95 min; MS (ESlpos): m / z = 264 [M+H] +< Intermediate 1-10 tert-butyl (2R)-2-{[(4-cyanopyridin-3-yl)oxy]methyl}morpholine-4-carboxylate

[0190]

[0191] Using an analogous method as described for intermediate 1-1 with 3-chloropyridine-4-carbonitrile (CAS 68325-15-5, 3.25 g, 23.5 mmol) and tert-butyl (2R)-2-(hydroxymethyl)morpholine-4-carboxylate (CAS 135065-71-3, 5.10 g, 23.5 mmol) as the starting materials; 6.92 g (90% purity, 83% yield) of the title compound were prepared. 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 1.41 (s, 9H), 2.73 - 3.00 (m, 2H), 3.39 - 3.50 (m, 1H), 3.75 (m, 2H), 3.82 - 3.89 (m, 1H), 3.95 - 4.00 (m, 1H), 4.37 (br d, 2H), 7.79 (d, 1H), 8.40 (d, 1H), 8.73 (s, 1H). LC-MS (method 2): Rt = 1.04 min; MS (ESlpos): m / z = 320 [M+H] +< Intermediate 1-11 3-[(1S)-1-(1,4-dioxan-2-yl)ethoxy]pyridine-4-carbonitrile

[0192]

[0193] Using an analogous method as described for intermediate 1-9 with 3-fluoropyridine-4-carbonitrile (878 mg, 7.19 mmol) and (1S)-1-[1,4-dioxan-2-yl]ethan-1-ol (CAS 1372875-59-6, 950 mg, 7.19 mmol) as the starting materials; 1.68 g (95 % purity, 95 % yield) of the title compound were prepared. 1< H-NMR (400 MHz, DMSO- d 6 ): δ ppm= 0.988 (0.85), 1.004 (0.92), 1.056 (0.59), 1.071 (0.60), 1.154 (4.47), 1.166 (0.63), 1.172 (9.29), 1.189 (4.59), 1.276 (12.44), 1.292 (12.55), 1.325 (11.08), 1.341 (11.16), 1.987 (16.00), 2.518 (1.63), 2.522 (1.05), 3.300 (0.46), 3.396 (1.81), 3.421 (2.99), 3.424 (2.99), 3.429 (1.78), 3.450 (5.06), 3.457 (3.42), 3.472 (1.97), 3.478 (1.62), 3.485 (2.38), 3.497 (2.19), 3.500 (1.91), 3.525 (2.26), 3.552 (1.16), 3.559 (1.31), 3.582 (2.48), 3.588 (2.91), 3.611 (1.70), 3.616 (2.62), 3.638 (4.15), 3.642 (3.63), 3.664 (3.89), 3.671 (4.01), 3.676 (1.93), 3.683 (1.76), 3.685 (1.80), 3.689 (1.79), 3.695 (1.76), 3.701 (1.17), 3.704 (1.27), 3.707 (1.26), 3.710 (1.28), 3.744 (1.82), 3.750 (3.32), 3.757 (1.01), 3.778 (3.94), 3.784 (2.19), 3.807 (1.47), 3.813 (1.33), 3.906 (1.40), 3.912 (1.35), 3.935 (1.24), 3.941 (1.18), 3.999 (1.24), 4.016 (3.72), 4.034 (3.66), 4.052 (1.20), 4.804 (0.41), 4.821 (1.95), 4.836 (3.43), 4.852 (2.64), 4.864 (1.34), 7.755 (3.58), 7.757 (3.60), 7.769 (4.33), 7.771 (3.80), 7.783 (3.28), 7.785 (3.20), 8.351 (4.95), 8.363 (4.90), 8.368 (4.48), 8.380 (4.17), 8.749 (6.40), 8.772 (5.46). LC-MS (method 6): Rt = 0.64 min; MS (ESlpos): m / z = 235 [M+H] +< Intermediate 1-12 3-{(1R)-1-[1,4-dioxan-2-yl]ethoxy}pyridine-4-carbonitrile

[0194]

[0195] Using an analogous method as described for intermediate 1-9 with 3-fluoropyridine-4-carbonitrile (905 mg, 7.42 mmol) and (1R)-1-[1,4-dioxan-2-yl]ethan-1-ol (CAS 1372881-98-5, 980 mg, 7.42 mmol) as the starting materials; 1.39 g (95 % purity, 76 % yield) of the title compound were prepared. 1< H-NMR (400 MHz, DMSO- d 6 ): δ ppm= 1.274 (0.82), 1.289 (0.87), 1.322 (16.00), 1.337 (15.97), 1.984 (0.48), 2.331 (0.56), 2.673 (0.57), 3.427 (2.95), 3.448 (3.45), 3.455 (3.30), 3.471 (3.27), 3.482 (2.59), 3.496 (3.79), 3.499 (3.36), 3.524 (3.41), 3.580 (1.59), 3.586 (1.80), 3.609 (2.32), 3.615 (2.92), 3.636 (5.12), 3.662 (3.60), 3.668 (3.70), 3.680 (2.08), 3.687 (1.49), 3.693 (1.53), 3.698 (1.52), 3.704 (1.41), 3.746 (3.19), 3.754 (1.74), 3.775 (2.26), 3.903 (2.52), 3.909 (2.44), 3.932 (2.24), 3.937 (2.13), 4.818 (0.65), 4.833 (2.08), 4.845 (2.30), 4.849 (2.22), 4.861 (2.00), 4.876 (0.57), 7.766 (5.15), 7.778 (5.29), 8.348 (0.42), 8.365 (6.23), 8.377 (6.01), 8.743 (0.51), 8.765 (9.13). LC-MS (method 6): Rt = 0.67 min; MS (ESlpos): m / z = 235 [M+H] +< Intermediate 1-71 3-[1-(4-methylmorpholin-2-yl)ethoxy]isonicotinonitrile

[0196]

[0197] Using an analogous method as described for intermediate 1-9 with 3-fluoropyridine-4-carbonitrile (824 mg, 6.75 mmol) and 1-(4-methylmorpholin-2-yl)ethanol (980 mg, 6.75 mmol, CAS 1540922-49-3) as the starting materials; 817 mg (99 % purity, 48 % yield) of the title compound were prepared after column chromatography using the Biotage Isolera. 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.285 (4.44), 1.300 (4.47), 1.318 (5.38), 1.333 (5.31), 1.848 (0.57), 1.874 (0.94), 1.901 (0.63), 1.927 (0.93), 1.933 (0.66), 1.953 (2.04), 1.961 (1.23), 1.981 (1.32), 1.990 (0.60), 2.188 (16.00), 2.518 (1.33), 2.522 (0.90), 2.572 (0.89), 2.600 (0.79), 2.718 (0.54), 2.746 (0.52), 2.839 (0.64), 2.867 (0.60), 3.485 (0.78), 3.488 (0.66), 3.491 (0.85), 3.516 (1.00), 3.522 (0.92), 3.544 (0.48), 3.550 (0.42), 3.562 (0.44), 3.568 (0.54), 3.573 (0.73), 3.578 (0.77), 3.587 (0.81), 3.593 (0.83), 3.598 (0.85), 3.604 (0.71), 3.772 (0.51), 3.777 (0.56), 3.781 (0.78), 3.786 (0.61), 3.789 (0.59), 3.794 (0.56), 3.800 (0.46), 3.805 (0.46), 3.809 (0.64), 3.814 (0.50), 3.817 (0.45), 4.818 (0.60), 4.833 (0.97), 4.848 (0.79), 4.858 (0.65), 4.862 (0.67), 4.874 (0.57), 7.746 (1.41), 7.760 (2.88), 7.772 (1.71), 8.341 (1.93), 8.355 (2.69), 8.368 (2.12), 8.745 (2.34), 8.766 (2.68). LC-MS (method 6): Rt = 0.32 min; MS (ESlpos): m / z = 248 [M+H] +< Syntheses of Intermediate 2 Compounds Intermediate 2-1 1-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine

[0198]

[0199] An autoclave was charged with 3-[(1,4-dioxan-2-yl)methoxy]pyridine-4-carbonitrile (intermediate 1-1, 1.17 g, 5.34 mmol), ammonia (19 ml, 7.0 M in methanol, 850 mmol) and Raney-Nickel (CAS 7440-02-0, 783 mg, 50 % wetted) and the mixture was stirred under 25 bar hydrogen atmosphere at RT for 22 h. The mixture was filtered through a pad of celite, eluted with methanol and the combined filtrates were concentrated under reduced pressure. The residue was used directly in the next step without further purification (1.13 g, 94 % yield). 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 8.24 (s, 1H), 8.17 (d, 1H), 7.38 (d, 1H), 4.09 (d, 2H), 3.73 - 3.91 (m, 3H), 3.59 - 3.73 (m, 4H), 3.46 - 3.52 (m, 2H), 3.39 - 3.45 (m, 2H). 2.06 (br., 2H). LC-MS (method 2): Rt = 0.54 min; MS (ESlpos): m / z = 225 [M+H] +< Intermediate 2-2 1-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methanamine

[0200]

[0201] Using an analogous method as described for intermediate 2-1 with 3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridine-4-carbonitrile (intermediate 1-2, 355 mg, 1.52 mmol) as the starting material; 350 mg of the title compound were prepared (89 % yield).

[0202] 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 8.24 - 8.31 (m, 1H), 8.17 (d, 1H), 7.39 (d, 1H), 4.18 - 4.27 (m, 1H), 4.00 (dd, 1H), 3.86 (dd, 1H), 3.63 - 3.75 (m, 3H), 3.42 - 3.55 (m, 1H), 3.36 - 3.41 (m, 1H), 2.67 (dq, 1H), 2.40 - 2.47 (m, 1H), 2.19 - 2.31 (m, 4H), 1.63 - 2.19 (m, 2H).Intermediate 2-3 1-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)methanamine

[0203]

[0204] Using an analogous method as described for intermediate 2-1 with 3-{[4-methylmorpholin-2-yl]methoxy}pyridine-4-carbonitrile (interemediate 1-3, 836 mg, 3.58 mmol) as the starting material; 860 mg (90 % purity, 91 % yield) of the title compound were prepared. 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 1.68 - 1.84 (br s, 2H), 1.85 - 1.94 (t, 1H), 1.94 - 2.05 (td, 1H), 2.19 (s, 3H), 2.57 - 2.64 (d, 1H), 2.73 - 2.83 (d, 1H), 3.46 - 3.63 (t, 1H), 3.63 - 3.73 (s, 2H), 3.73 - 3.86 (m, 3H), 4.10 (br d, 2H), 7.34 - 7.44 (d, 1H), 8.10 - 8.20 (d, 1H), 8.21 - 8.30 (s, 1H). LC-MS (method 2): Rt = 0.56 min; MS (ESlpos): m / z = 238 [M+H] +< Intermediate 2-4 1-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methanamine

[0205]

[0206] Using an analogous method as described for intermediate 2-1 with 3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridine-4-carbonitrile (intermediate 1-4, 823 mg, 3.53 mmol) as the starting material; 798 mg (90 % purity, 86 % yield) of the title compound were prepared.

[0207] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.865 (0.49), 2.199 (0.64), 2.210 (1.08), 2.228 (0.99), 2.233 (0.96), 2.236 (0.96), 2.254 (0.85), 2.263 (0.81), 2.269 (0.55), 2.284 (16.00), 2.327 (0.53), 2.430 (0.78), 2.439 (0.81), 2.447 (0.65), 2.518 (2.11), 2.523 (1.42), 2.649 (0.75), 2.654 (1.38), 2.660 (0.91), 2.669 (0.65), 2.674 (0.60), 2.678 (0.83), 2.684 (1.22), 2.690 (0.66), 3.361 (1.52), 3.365 (1.53), 3.388 (1.10), 3.469 (0.59), 3.474 (0.65), 3.496 (1.15), 3.502 (1.16), 3.523 (0.75), 3.528 (0.68), 3.683 (2.49), 3.690 (2.42), 3.712 (0.79), 3.719 (1.11), 3.846 (1.01), 3.853 (1.04), 3.873 (0.94), 3.880 (0.91), 3.982 (0.79), 3.997 (0.86), 4.007 (1.03), 4.021 (0.96), 4.215 (1.01), 4.226 (1.09), 4.240 (0.86), 4.250 (0.84), 7.379 (0.99), 7.389 (1.01), 8.168 (1.06), 8.179 (1.11), 8.259 (1.53).Intermediate 2-5 tert-butyl (2S)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylate

[0208]

[0209] Using an analogous method as described for intermediate 2-1 with tert-butyl (2S)-2-{[(4-cyanopyridin-3-yl)oxy]methyl}morpholine-4-carboxylate (intermediate 1-5, 5.75 g, 18.0 mmol) as the starting material; 6.00 g (95 % purity, 98 % yield) of the title compound were prepared. 1H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 1.41 (s, 9H), 3.16 (s, 2H), 3.39 - 3.49 (m, 2H), 3.66 - 3.79 (m, 5H), 3.79 - 3.98 (m, 3H), 4.07 - 4.20 (m, 3H), 7.39 (d, 1H), 8.19 (d, 1H), 8.27 (s, 1H). LC-MS (method 2): Rt = 0.84 min; MS (ESlpos): m / z = 324 [M+H] +< Intermediate 2-6 1-{3-[2-(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methanamine

[0210]

[0211] Using an analogous method as described for intermediate 2-1 with 3-[2-(1,4-dioxan-2-yl)ethoxy]pyridine-4-carbonitrile (intermediate 1-6, 2.89 g, 12.3 mmol) as the starting material; 2.22 g (90 % purity, 68 % yield) of the title compound were prepared.

[0212] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.536 (0.40), 1.729 (1.99), 1.751 (3.41), 1.765 (5.01), 1.785 (6.00), 1.804 (5.59), 1.817 (5.34), 1.834 (4.06), 1.852 (2.92), 1.870 (2.15), 2.326 (1.02), 2.669 (1.04), 3.159 (0.53), 3.208 (5.54), 3.235 (8.67), 3.261 (7.11), 3.424 (3.46), 3.430 (3.63), 3.451 (7.09), 3.457 (7.51), 3.479 (5.43), 3.485 (5.78), 3.528 (4.90), 3.534 (5.03), 3.557 (6.69), 3.563 (7.65), 3.584 (3.06), 3.590 (4.57), 3.622 (8.16), 3.653 (8.66), 3.688 (14.98), 3.697 (16.00), 3.731 (13.03), 3.759 (6.36), 4.136 (7.05), 4.152 (13.01), 4.167 (8.38), 7.385 (5.36), 7.394 (5.58), 8.163 (5.21), 8.172 (5.56), 8.224 (7.44).Intermediate 2-7 1-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine

[0213]

[0214] Using an analogous method as described for intermediate 2-1 with 3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridine-4-carbonitrile (intermediate 1-7, 1.30 g, 5.24 mmol) as the starting material; 1.26 g (90 % purity, 86 % yield) of the title compound were prepared.

[0215] 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.014 (0.96), 1.049 (16.00), 1.201 (0.72), 1.262 (13.58), 1.751 (0.48), 2.518 (2.17), 2.523 (1.47), 3.308 (2.76), 3.539 (2.43), 3.567 (1.99), 3.601 (1.13), 3.623 (1.75), 3.694 (1.97), 3.720 (2.07), 3.746 (2.38), 3.783 (0.46), 4.128 (3.01), 4.136 (2.80), 7.386 (0.85), 8.181 (0.83), 8.237 (0.96).Intermediate 2-8 1-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methanamine

[0216]

[0217] Using an analogous method as described for intermediate 2-1 with 3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridine-4-carbonitrile (intermediate 1-8, 1.24 g, 5.63 mmol) as the starting material; 1.56 g (80% purity, 99% yield) of the title compound were prepared.

[0218] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.232 (0.52), 1.845 (1.06), 2.518 (2.37), 2.523 (1.54), 3.159 (14.24), 3.171 (14.33), 3.376 (0.69), 3.379 (0.65), 3.404 (2.41), 3.419 (0.41), 3.428 (3.79), 3.431 (3.86), 3.439 (0.59), 3.447 (0.69), 3.455 (2.71), 3.465 (1.97), 3.474 (0.57), 3.486 (2.71), 3.493 (2.97), 3.508 (1.01), 3.520 (2.61), 3.592 (0.45), 3.601 (1.92), 3.608 (2.10), 3.630 (2.77), 3.636 (3.65), 3.659 (5.73), 3.661 (5.45), 3.683 (16.00), 3.700 (1.95), 3.754 (3.49), 3.762 (2.18), 3.784 (2.51), 3.794 (0.57), 3.812 (0.61), 3.823 (2.48), 3.829 (3.16), 3.842 (0.81), 3.849 (2.07), 3.856 (6.45), 3.868 (1.93), 3.874 (1.37), 3.880 (1.69), 3.887 (1.30), 3.892 (1.13), 3.899 (0.89), 4.087 (11.44), 4.099 (10.46), 4.111 (2.62), 4.125 (1.15), 7.380 (4.02), 7.391 (4.11), 7.411 (0.67), 7.423 (0.67), 8.168 (6.28), 8.179 (6.26), 8.184 (1.58), 8.196 (1.02), 8.230 (10.21), 8.274 (1.76).Intermediate 2-9 tert-butyl (3R)-3-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylate

[0219]

[0220] Using an analogous method as described for intermediate 2-1 with tert-butyl (3R)-3-{[(4-cyanopyridin-3-yl)oxy]methyl}morpholine-4-carboxylate (intermediate 1-9, 4.00 g, 12.5 mmol) as the starting material; 3.65 g of the title compound were prepared (86% yield). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.038 (0.41), 1.055 (0.77), 1.073 (0.44), 1.363 (10.92), 1.754 (6.47), 2.200 (1.02), 2.325 (1.05), 2.330 (1.42), 2.334 (1.05), 2.521 (5.72), 2.526 (3.72), 2.667 (0.88), 2.672 (1.22), 2.676 (0.89), 3.057 (1.02), 3.068 (1.10), 3.087 (1.65), 3.090 (1.62), 3.097 (1.89), 3.101 (1.73), 3.120 (2.21), 3.130 (2.39), 3.168 (16.00), 3.210 (1.86), 3.235 (0.59), 3.240 (1.07), 3.258 (1.25), 3.265 (1.40), 3.286 (1.75), 3.294 (2.07), 3.316 (3.15), 3.365 (3.67), 3.372 (3.73), 3.395 (1.88), 3.402 (1.68), 3.462 (1.41), 3.470 (1.43), 3.503 (3.53), 3.534 (2.78), 3.682 (7.14), 3.764 (1.68), 3.774 (1.81), 3.792 (3.17), 3.802 (2.81), 3.820 (1.93), 3.855 (0.89), 3.859 (1.19), 3.865 (1.80), 3.869 (2.32), 3.873 (3.62), 3.882 (2.64), 3.886 (3.02), 3.889 (2.79), 3.893 (4.31), 3.899 (3.39), 3.902 (2.87), 3.927 (2.09), 4.111 (1.76), 4.227 (3.64), 4.303 (0.96), 4.315 (1.37), 4.329 (3.71), 4.331 (3.43), 4.338 (1.95), 4.345 (2.50), 7.401 (2.60), 8.192 (2.81), 8.337 (2.91). LC-MS (method 1): Rt = 0.49 min; MS (ESlpos): m / z = 324 [M+H] +< Intermediate 2-10 tert-butyl (2R)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylate

[0221]

[0222] Using an analogous method as described for intermediate 2-1 with tert-butyl (2R)-2-{[(4-cyanopyridin-3-yl)oxy]methyl}morpholine-4-carboxylate (intermediate 1-10, 6.92 g, 21.7 mmol) as the starting material; 6.95 g of the title compound were prepared (90% purity, 89% yield). 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 1.41 (s, 9H), 2.70 - 3.01 (m, 2H), 3.17 (d, 3H), 3.41 - 3.52 (m, 1H), 3.63 - 3.70 (m, 2H), 3.70 - 3.81 (m, 2H), 3.82 - 4.00 (m, 2H), 4.08 - 4.18 (m, 3H), 7.39 (d, 1H), 8.18 (d, 1H), 8.25 (s, 1H). LC-MS (method 2): Rt = 0.84 min; MS (ESlpos): m / z = 324 [M+H] +< Intermediate 2-11 1-{3-[(1S)-1-(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methanamine

[0223]

[0224] Using an analogous method as described for intermediate 2-1 with 3-[(1S)-1-(1,4-dioxan-2-yl)ethoxy]pyridine-4-carbonitrile (intermediate 1-11, 1.68 g, 7.17 mmol) as the starting material; 1.49 g (90% purity, 78% yield) of the title compound were prepared. LC-MS (method 6): Rt = 0.2 min; MS (ESlpos): m / z = 239 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.990 (0.87), 1.006 (0.89), 1.058 (0.73), 1.073 (0.73), 1.165 (0.76), 1.216 (15.68), 1.232 (16.00), 1.256 (14.15), 1.272 (13.96), 1.755 (9.46), 1.917 (0.88), 3.240 (0.43), 3.265 (0.46), 3.276 (0.41), 3.293 (0.54), 3.302 (0.81), 3.325 (0.68), 3.338 (0.50), 3.350 (0.56), 3.371 (0.56), 3.378 (0.58), 3.400 (2.78), 3.412 (2.79), 3.426 (5.84), 3.438 (5.24), 3.453 (6.52), 3.459 (6.28), 3.466 (5.96), 3.479 (2.46), 3.486 (3.26), 3.493 (2.78), 3.521 (0.49), 3.529 (0.67), 3.535 (0.58), 3.564 (2.05), 3.572 (2.72), 3.580 (2.41), 3.600 (6.11), 3.609 (5.52), 3.617 (4.09), 3.634 (11.25), 3.637 (11.05), 3.756 (8.08), 3.785 (6.75), 3.889 (2.49), 3.894 (2.48), 3.917 (2.26), 3.922 (2.16), 4.540 (1.04), 4.555 (3.05), 4.569 (4.27), 4.580 (2.83), 4.584 (2.84), 7.369 (3.21), 7.379 (4.91), 8.135 (3.33), 8.146 (5.23), 8.157 (3.20), 8.261 (4.69), 8.275 (4.23). Intermediate 2-12 1-{3-[(1R)-1-(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methanamine

[0225]

[0226] Using an analogous method as described for intermediate 2-1 with 3-{(1R)-1-[1,4-dioxan-2-yl]ethoxy}pyridine-4-carbonitrile (intermediate 1-12, 1.39 g, 5.93 mmol) as the starting material; 1.36 g (95 % purity, 91 % yield) of the title compound were prepared. 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.216 (0.81), 1.232 (0.99), 1.255 (15.91), 1.271 (16.00), 1.753 (0.71), 3.290 (0.44), 3.399 (0.54), 3.412 (2.42), 3.424 (0.71), 3.437 (3.81), 3.440 (3.42), 3.453 (0.77), 3.459 (2.72), 3.465 (5.00), 3.485 (1.48), 3.494 (2.02), 3.573 (1.45), 3.580 (1.70), 3.598 (2.00), 3.603 (3.43), 3.609 (3.84), 3.616 (2.24), 3.622 (2.04), 3.628 (1.97), 3.634 (4.41), 3.638 (4.68), 3.645 (2.04), 3.662 (5.32), 3.672 (6.05), 3.713 (0.63), 3.757 (2.28), 3.764 (2.39), 3.787 (1.75), 3.790 (1.84), 3.887 (2.14), 3.894 (2.12), 3.916 (1.94), 3.922 (1.85), 4.535 (0.53), 4.550 (1.85), 4.564 (2.15), 4.566 (2.17), 4.579 (1.80), 4.595 (0.50), 7.381 (3.18), 7.393 (3.14), 8.144 (4.36), 8.156 (4.13), 8.257 (0.50), 8.272 (6.58). LC-MS (method 6): Rt = 0.21 min; MS (ESlpos): m / z = 239 [M+H] +< Intermediate 2-71 1-{3-[1-(4-methylmorpholin-2-yl)ethoxy]pyridin-4-yl}methanamine

[0227]

[0228] Using an analogous method as described for intermediate 2-1 with 3-({1-[4-methylmorpholin-2-yl]ethyl}oxy)pyridine-4-carbonitrile (intermediate 1-71, 815 mg, 3.30 mmol) as the starting material; 810 mg (99 % purity, 97 % yield) of the title compound were prepared. 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.227 (3.82), 1.242 (3.97), 1.254 (4.80), 1.270 (4.60), 1.850 (1.08), 1.862 (1.12), 1.876 (1.43), 1.888 (1.42), 1.903 (0.90), 1.915 (1.07), 1.928 (0.67), 1.937 (0.65), 1.945 (0.81), 1.957 (1.14), 1.965 (0.95), 1.973 (0.53), 1.985 (0.64), 1.993 (0.48), 2.152 (0.51), 2.183 (16.00), 2.332 (0.45), 2.518 (2.14), 2.522 (1.29), 2.575 (1.38), 2.602 (1.24), 2.673 (0.44), 2.692 (0.68), 2.720 (0.63), 2.834 (0.79), 2.862 (0.75), 3.475 (0.48), 3.480 (0.56), 3.487 (0.60), 3.504 (1.27), 3.508 (1.56), 3.514 (1.44), 3.536 (1.04), 3.542 (1.01), 3.563 (0.49), 3.568 (0.50), 3.575 (0.48), 3.588 (0.47), 3.667 (1.61), 3.793 (1.27), 3.821 (1.05), 4.561 (0.97), 7.374 (1.24), 8.138 (1.27), 8.267 (1.31). LC-MS (method 6): Rt = 0.11 min; MS (ESlpos): m / z = 252 [M+H] +< Syntheses of Intermediate 3 Compounds Intermediate 3-1 1-chloro-3-isothiocyanato-2-methoxybenzene

[0229]

[0230] 3-chloro-2-methoxyaniline (CAS 51114-68-2, 8.4 ml, 63 mmol) was solved in DCM (100 ml) and sat. sodium bicarbonate solution (100 ml) was added. To the ice cooled mixture was slowly added thiophosgene (5.4 ml, 70 mmol). The reaction was stirred at 0°C for 2 h. At RT the DCM layer was separated and washed with sat. sodium bicarbonate solution, filtered through a hydrophobic filter and concentrated under reduced pressure to give the title compound (12.97 g, 100 % yield) which was used directly in the next step.

[0231] 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 7.51 (dd, 1H), 7.35 (dd, 1H), 7.20 (t, 1H), 3.85 - 3.91 (m, 3H).Intermediate 3-4 1-fluoro-3-isothiocyanato-2-methoxybenzene

[0232]

[0233] Using an analogous method as described for intermediate 3-1; 3-fluoro-2-methoxyaniline (CAS 437-83-2, 5.00 g, 35.4 mmol) as the starting material; 6.24 g of the title compound were prepared (96 % yield).

[0234] 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 7.32 (m, 1H), 7.10 - 7.19 (m, 2H), 3.96 (d, 3H).Intermediate 3-18 1-chloro-5-fluoro-3-isothiocyanato-2-methoxybenzene

[0235]

[0236] Using an analogous method as described for intermediate 3-1 with 3-chloro-5-fluoro-2-methoxyaniline (1.00 g, 5.70 mmol) as the starting material; 1.17 g of the title compound were prepared (95 % purity, 90 % yield).

[0237] 1H NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 3.86 (s, 3 H) 7.38 (dd, 1H) 7.58 (dd, 1H).Intermediate 3-29 1-chloro-2-ethyl-3-isothiocyanatobenzene

[0238]

[0239] Using an analogous method as described for intermediate 3-1; 3-chloro-2-ethylaniline (5.00 g, 85 % purity, 27.3 mmol) as the starting material, the title compound was prepared 6.29 g (85 % purity, 99 % yield).

[0240] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.009 (7.50), 1.027 (16.00), 1.046 (7.55), 1.090 (0.44), 1.109 (0.89), 1.128 (0.44), 2.590 (2.26), 2.608 (6.71), 2.627 (6.58), 2.646 (2.00), 5.199 (6.39), 6.533 (4.44), 6.539 (4.27), 6.553 (5.20), 6.559 (4.97), 6.821 (3.47), 6.841 (5.70), 6.861 (2.75), 7.056 (0.43), 7.060 (0.52).Intermediate 3-65 2-ethyl-1-fluoro-3-isothiocyanatobenzene

[0241]

[0242] Using an analogous method as described for intermediate 3-1; 2-ethyl-3-fluoroaniline (2.50 g, 18.0 mmol, CAS 1139437-61-8) as the starting material, the title compound was prepared 3.0 g (90 % purity, 83 % yield).

[0243] 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.108 (7.13), 1.127 (16.00), 1.146 (7.13), 2.462 (0.95), 2.483 (1.27), 2.517 (0.79), 2.522 (0.48), 2.637 (0.95), 2.641 (1.11), 2.655 (3.17), 2.659 (3.17), 2.674 (3.17), 2.678 (3.17), 2.693 (0.95), 2.697 (0.95), 3.461 (0.48), 3.477 (0.63), 3.484 (0.63), 3.506 (1.11), 3.528 (2.06), 3.537 (2.69), 3.625 (3.01), 3.648 (1.11), 3.663 (0.63), 3.669 (0.63), 7.185 (1.11), 7.189 (1.11), 7.205 (1.58), 7.209 (2.53), 7.212 (1.27), 7.229 (1.43), 7.233 (1.74), 7.243 (1.27), 7.246 (1.43), 7.263 (3.80), 7.266 (2.38), 7.282 (2.53), 7.296 (2.38), 7.301 (2.38), 7.317 (2.53), 7.322 (0.79), 7.337 (0.79).Syntheses of Intermediate 4 Compounds Intermediate 4-1 tert-butyl 5-[(3-chloro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

[0244]

[0245] To an ice-cooled solution of 1-chloro-3-isothiocyanato-2-methoxybenzene (intermediate 3-1, 4.00 g, 20.0 mmol) and tert-butyl 2,4-dioxopiperidine-1-carboxylate (CAS 845267-78-9, 4.27 g, 20.0 mmol) in acetonitrile (92 ml) was added dropwise DBU (4.5 ml, 30 mmol). The reaction was stirred at RT overnight. To the reaction mixture was added ice-water (200 mL) and conc. HCl (2 mL). The mixture was stirred for 20 min. and extracted with DCM. The organic phase was filtered over a water-repellent filter, conentrated under reduced pressure and purified by flash chromatography (silica, hexane / EtOAc gradient 0-50 %) to give 6.54 g of the title compound (71 % yield). 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 13.36 (br s, 1H), 7.73 (d, 1H), 7.47 (dd, 1H), 7.22 (t, 1H), 3.76 - 3.82 (m, 5H), 2.88 (t, 2H), 1.48 (s, 9H). LC-MS (method 1): Rt = 1.49 min; MS (ESlpos): m / z = 413.1 [M+H] +< Intermediate 4-4 tert-butyl 5-[(3-fluoro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

[0246]

[0247] Using an analogous method as described for Intermediate 4-1 with tert-butyl 2,4-dioxopiperidine-1-carboxylate (CAS 845267-78-9, 7.26 g, 34.1 mmol) and 1-fluoro-3-isothiocyanato-2-methoxybenzene (intermediate 3-4, 6.24 g, 34.1 mmol) as the starting materials; 9.49 g of the title compound were prepared (67 % yield) after stirring the product in MeOH, filtration and drying of the precipitate in vacuo. 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 13.37 (br s, 1H), 7.58 (br d, 1H), 7.23 - 7.30 (m, 1H), 7.09 - 7.21 (m, 1H), 4.10 (br s, 1H), 3.78 (t, 2H), 3.17 (s, 3H), 2.88 (br t, 2H), 1.48 (s, 9H). LC-MS (method 2): Rt = 0.66 min; MS (ESlpos): m / z = 397.3 [M+H] +< Intermediate 4-7 tert-butyl 5-[(2,3-dichlorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

[0248]

[0249] 1,2-Dichloro-3-isothiocyanatobenzene (CAS 6590-97-2, 5.00 g, 24.5 mmol) and tert-butyl 2,4-dioxopiperidine-1-carboxylate (CAS 845267-78-9, 5.22 g, 24.5 mmol) were solubilised in acetonitrile (55 ml), DBU (5.5 ml, 37 mmol) was added carefully at 0°C under argon atmosphere and the mixture was stirred overnight at RT. The reaction mixture was diluted with HCl (200 ml, 1N in water) and stirred for 30 min. at RT. The resulting solid was filtered off, the filter cake was washed with water and dried at 50°C in vacuo oven overnight to give 9.40 g of the title compound (92 % yield). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.467 (16.00), 1.484 (0.56), 1.622 (0.34), 1.644 (0.25), 1.661 (0.20), 1.674 (0.17), 1.898 (0.19), 1.913 (0.31), 1.927 (0.19), 2.075 (0.20), 2.327 (0.18), 2.518 (0.60), 2.523 (0.39), 2.621 (0.30), 2.647 (0.32), 2.665 (0.24), 2.669 (0.29), 2.673 (0.25), 3.249 (0.25), 3.459 (0.23), 3.473 (0.39), 3.487 (0.22), 3.538 (0.28), 3.561 (0.29), 3.727 (0.50), 7.357 (0.17), 7.377 (0.36), 7.383 (0.28), 7.397 (0.28), 7.544 (0.27), 7.547 (0.33), 7.560 (0.29), 7.564 (0.31), 7.568 (0.25), 7.580 (0.18). LC-MS (method 2): Rt = 0.70 min; MS (ESlpos): m / z = 416 [M-H] -< Intermediate 4-10 tert-butyl 5-[(3-chloro-2-methylphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1 (2H)-carboxylate

[0250]

[0251] According to the method described for intermediate 4-1; 1-chloro-3-isothiocyanato-2-methylbenzene (CAS 19241-35-1; 2.50 g, 13.6 mmol) and tert-butyl 2,4-dioxopiperidine-1-carboxylate (CAS 845267-78-9, 2.9 g, 13.6 mmol) as the starting materials; 4.68 g of the title compound were prepared (78 % yield), after addition of HCl ,filtration ,and drying of the precipitate in vacuo. 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 15.73 (s, 1H), 12.77 (br s, 1H), 7.45 (d, 1H), 7.30 (t, 1H), 7.19 (d, 1H), 3.78 (t, 2H), 2.85 (t, 2H), 2.20 (s, 3H), 1.48 (s, 9H). LC-MS (method 2): Rt = 0.72 min; MS (ESlpos): m / z = 397.3 [M+H] +< Intermediate 4-18 tert-butyl 5-[(3-chloro-5-fluoro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

[0252]

[0253] Using an analogous method as described for Intermediate 4-1 with tert-butyl 2,4-dioxopiperidine-1-carboxylate (CAS 845267-78-9, 1.15 g, 5.38 mmol) and 1-chloro-5-fluoro-3-isothiocyanato-2-methoxybenzene (intermediate 3-18, 1.17 g, 5.38 mmol) as the starting materials; 1.42 g of the title compound were prepared (75 % purity, 46 % yield). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.154 (0.88), 1.172 (1.70), 1.189 (0.80), 1.484 (16.00), 1.987 (3.28), 2.518 (0.89), 2.522 (0.61), 2.883 (0.73), 2.899 (0.40), 3.359 (0.69), 3.644 (4.46), 3.760 (7.94), 3.774 (0.44), 3.782 (1.03), 3.798 (0.53), 4.017 (0.69), 4.035 (0.69), 6.400 (0.60), 6.405 (0.53), 6.427 (1.00), 7.498 (0.41). LC-MS (method 2): Rt = 0.73 min; MS (ESlpos): m / z = 431 [M+H] +< Intermediate 4-29 tert-butyl 5-[(3-chloro-2-ethylphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1 (2H)-carboxylate

[0254]

[0255] Using an analogous method as described for Intermediate 4-1 with tert-butyl 2,4-dioxopiperidine-1-carboxylate (CAS 845267-78-9, 5.77 g, 27.0 mmol) and 2-chloro-1-ethyl-3-isothiocyanatobenzene (intermediate 3-29, 6.29 g, 85 % purity, 27.0 mmol) as the starting materials; 6.35 g of the title compound were prepared (85 % purity, 49 % yield).

[0256] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.063 (0.89), 1.082 (2.14), 1.100 (0.95), 1.362 (0.65), 1.478 (16.00), 1.486 (1.29), 2.518 (0.64), 2.523 (0.44), 2.631 (0.70), 2.650 (0.69), 2.850 (0.41), 2.866 (0.78), 2.883 (0.43), 3.775 (0.51), 3.791 (0.90), 3.807 (0.46), 7.212 (0.46), 7.214 (0.44), 7.232 (0.62), 7.234 (0.61), 7.293 (0.62), 7.313 (1.08), 7.332 (0.53), 7.440 (0.61), 7.443 (0.62), 7.460 (0.49), 7.463 (0.45).Intermediate 4-38 tert-butyl 5-[(3-fluoro-2-methylphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1 (2H)-carboxylate

[0257]

[0258] Using an analogous method as described for Intermediate 4-1 with tert-butyl 2,4-dioxopiperidine-1-carboxylate (CAS 845267-78-9, 8.19 g, 38.4 mmol) and 1-fluoro-3-isothiocyanato-2-methylbenzene (CAS 363179-58-2, 6.42 g, 38.4 mmol) as the starting materials; 11.1 g of the title compound were prepared (95% purity, 72% yield) after stirring the product in MeOH, filtration and drying of the precipitate in vacuo.

[0259] 1< H-NMR (400 MHz, DMSO- d 6 ): δ [ppm]= 1.479 (16.00), 2.084 (2.80), 2.088 (2.74), 2.834 (0.58), 2.850 (1.12), 2.866 (0.61), 3.768 (0.64), 3.784 (1.16), 3.800 (0.59), 7.073 (0.61), 7.093 (0.71), 7.186 (0.59), 7.299 (0.45), 7.316 (0.42).Intermediate 4-40 tert-butyl 5-{[2-(2,2-difluoroethyl)-3-fluorophenyl]carbamothioyl}-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

[0260]

[0261] Using an analogous method as described for Intermediate 4-1 with tert-butyl 2,4-dioxopiperidine-1-carboxylate (CAS 845267-78-9, 7.85 g, 36.8 mmol) and 2-(2,2-difluoroethyl)-1-fluoro-3-isothiocyanatobenzene (CAS 2311902-79-9, 8.00 g, 36.8 mmol) as the starting materials; 12.1 g of the title compound were prepared (95% purity, 72% yield).

[0262] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.471 (16.00), 2.518 (0.65), 2.523 (0.43), 2.788 (0.47), 2.804 (0.87), 2.820 (0.50), 3.166 (3.72), 3.754 (0.60), 3.770 (1.08), 3.786 (0.57), 7.149 (0.62), 7.169 (0.70), 7.271 (0.58), 7.446 (0.46), 7.462 (0.43).Intermediate 4-65 tert-butyl 5-[(2-ethyl-3-fluorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

[0263]

[0264] Using an analogous method as described for Intermediate 4-1 with tert-butyl 2,4-dioxopiperidine-1-carboxylate (CAS 845267-78-9, 7.85 g, 36.8 mmol) and 2-ethyl-1-fluoro-3-isothiocyanatobenzene (intermediate 3-65, 3.00 g, 16.6 mmol) as the starting materials; 5.46 g of the title compound were prepared (95% purity, 79% yield). 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.066 (1.02), 1.085 (2.41), 1.104 (1.06), 1.477 (16.00), 1.486 (1.04), 2.074 (0.65), 2.518 (1.12), 2.522 (0.92), 2.538 (0.61), 2.858 (0.69), 3.771 (0.55), 3.787 (0.98), 3.803 (0.50), 7.092 (0.50), 7.112 (0.55), 7.186 (0.45), 7.311 (0.44), 7.327 (0.41).LC-MS (method 2): Rt = 0.72 min; MS (ESlpos): m / z = 395 [M+H] +< Syntheses of Intermediate 5 Compounds Intermediate 5-1 N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0265]

[0266] To a solution of tert-butyl 5-[(3-chloro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (intermediate 4-1, 6.54 g, 15.8 mmol) in dichloromethane (94 ml) was added TFA (12 ml, 160 mmol) and the mixture was stirred 1.5 h at RT. The reaction mixture was concentrated under reduced pressure and the residue was solved in EtOAc and washed with sat. sodium bicarbonate solution and brine. The organic layer was filtered through a hydrophobic filter and the filtrate was dried to dryness. The residue was purified by flash chromatography (silica, hexane / EtOAc gradient 20-100 %) to give 4.06 g of the title compound (78 % yield). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 16.45 (d, 1H), 14.69 (s, 1H), 14.33 (s, 1H), 9.37 (br s, 1H), 8.18 (br s, 1H), 7.76 - 7.87 (m, 1H), 7.37 - 7.45 (m, 1H), 7.15 - 7.23 (m, 1H), 3.73 - 3.76 (m, 3H), 3.43 (td, 1H), 3.27 - 3.32 (m, 1H), 2.79 (t, 1H), 2.59 - 2.69 (m, 1H). LC-MS (method 1): Rt = 1.19 min; MS (ESlpos): m / z = 313 [M+H] +< Intermediate 5-4 N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0267]

[0268] Using an analogous method as described for intermediate 5-1 with tert-butyl 5-[(3-fluoro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (intermediate 4-4, 9.49 g, 23.9 mmol) as the starting material, 6.98 g of the title compound was prepared (89 % yield) after 15 min of stirring and used in the next steps without further purification. 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 16.48 (d, 1H), 14.63 (s, 0.5H), 14.28 (s, 0.5H), 9.34 (br s, 0.5H), 8.16 (br s, 0.5H), 7.65 (t, 1H), 6.97 - 7.37 (m, 2H), 3.79 - 3.85 (m, 3H), 3.35 - 3.46 (m, 1H), 3.26 - 3.32 (m, 1H), 2.78 (t, 1H), 2.63 (t, 1H). LC-MS (method 2): Rt = 0.46 min; MS (ESlpos): m / z = 297.1 [M+H] +< Intermediate 5-7 N-(2,3-dichlorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0269]

[0270] Using an analogous method as described for intermediate 5-1 with tert-butyl 5-[(2,3-dichlorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (intermediate 4-7, 9.40 g, 22.5 mmol) as the starting material; 5.71 g of the title compound were prepared (62 % yield) after stirring overnight.

[0271] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.018 (1.18), 1.050 (1.33), 1.072 (0.81), 1.102 (0.59), 1.132 (0.81), 1.154 (1.84), 1.172 (3.17), 1.189 (1.84), 1.199 (0.88), 1.231 (1.92), 1.259 (1.40), 1.486 (0.66), 1.593 (1.33), 1.626 (1.18), 1.695 (1.25), 1.727 (1.18), 1.907 (2.14), 1.987 (5.97), 2.322 (3.17), 2.326 (4.28), 2.331 (3.17), 2.518 (15.85), 2.522 (9.44), 2.638 (11.06), 2.664 (7.82), 2.669 (7.52), 2.673 (5.53), 2.798 (8.11), 3.436 (9.81), 4.017 (1.18), 4.035 (1.11), 5.560 (1.33), 5.579 (1.25), 7.392 (4.42), 7.410 (10.03), 7.430 (9.22), 7.565 (12.24), 7.585 (16.00), 7.605 (9.51), 8.134 (0.74), 8.197 (4.35), 9.418 (3.91), 14.273 (6.93), 14.665 (6.64), 16.114 (1.03), 16.295 (9.95), 16.352 (5.82), 16.503 (1.11).

[0272] LC-MS (method 2): Rt = 0.55 min; MS (ESlpos): m / z = 316 [M-H] -< .Intermediate 5-10 N-(3-chloro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0273]

[0274] Using an analogous method as described for intermediate 5-1 with tert-butyl 5-[(3-chloro-2-methylphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (intermediate 4-10, 4.67 g, 11.8 mmol) as the starting material, 3.54 g of the title compound were prepared (91 % yield) after 3 h and used in the next steps without further purification.

[0275] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 16.42 (d, 1H), 14.01 - 14.37 (m, 1H), 8.14 - 9.40 (m, 1H), 7.43 (br t, 1H), 7.16 - 7.32 (m, 2H), 3.42 - 3.48 (m, 1H), 3.26 - 3.34 (m, 1H), 2.78 (t, 1H), 2.60 - 2.68 (m, 1H), 2.12 - 2.21 (m, 3H).

[0276] LC-MS (method 2): Rt = 0.60 min; MS (ESlpos): m / z = 297.4 [M+H] +< .Intermediate 5-18 N-(3-chloro-5-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0277]

[0278] Using an analogous method as described for intermediate 5-1 with tert-butyl 5-[(3-chloro-5-fluoro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (intermediate 4-18, 1.42 g, 3.30 mmol) as the starting material; 690 mg of the title compound were prepared (95 % purity, 60 % yield).

[0279] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 2.61 - 2.70 (m, 1H), 2.80 (m, 1H), 3.25 - 3.32 (m, 1H), 3.38 - 3.47 (m, 1H), 3.74 (s, 3H), 7.39 - 7.62 (m, 1H), 7.83 - 8.02 (m, 1H), 8.20 - 8.33 (s, 0,5H), 9.33 - 9.57 (s, 0,5H), 14.53 (s, 0,5H), 14.93 (s, 0,5H), 16.29 (s, 0,5H), 16.36 (s, 0,5H).

[0280] LC-MS (method 2): Rt = 0.57 min; MS (ESlneg): m / z = 329 [M-H] -< .Intermediate 5-29 N-(3-chloro-2-ethylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0281]

[0282] Using an analogous method as described for intermediate 5-1 with tert-butyl 5-[(3-chloro-2-ethylphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (intermediate 4-29, 2.35 g, 75 % purity, 4.29 mmol) as the starting material; 1.22 g of the title compound were prepared (95 % purity, 87 % yield).

[0283] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.048 (7.06), 1.067 (16.00), 1.086 (7.43), 1.107 (1.58), 1.124 (1.32), 1.143 (0.50), 1.154 (1.34), 1.172 (2.43), 1.190 (1.24), 1.232 (0.50), 1.988 (4.56), 2.318 (0.47), 2.323 (1.05), 2.327 (1.56), 2.332 (1.11), 2.336 (0.47), 2.518 (5.61), 2.523 (4.03), 2.581 (2.03), 2.600 (6.41), 2.619 (6.62), 2.642 (4.59), 2.661 (2.69), 2.669 (1.90), 2.673 (1.27), 2.678 (0.58), 2.771 (2.35), 2.789 (4.82), 2.807 (2.58), 3.287 (1.61), 3.294 (1.79), 3.305 (3.11), 3.312 (3.14), 3.323 (2.06), 3.330 (2.35), 3.415 (1.53), 3.422 (1.66), 3.433 (2.56), 3.441 (2.45), 3.452 (1.40), 3.459 (1.24), 4.017 (1.03), 4.035 (1.00), 7.166 (0.95), 7.176 (0.58), 7.179 (0.58), 7.248 (0.71), 7.259 (6.30), 7.268 (3.58), 7.275 (4.43), 7.287 (7.20), 7.294 (3.90), 7.303 (3.56), 7.324 (0.87), 7.392 (1.85), 7.400 (1.37), 7.407 (1.85), 7.415 (1.74), 7.419 (2.40), 7.426 (1.77), 7.436 (1.77), 7.443 (1.45), 8.174 (1.77), 9.335 (1.42), 14.111 (2.98), 14.452 (2.74), 16.428 (7.88), 16.441 (7.38).

[0284] LC-MS (method 6): Rt = 1.28 min; MS (ESlpos): m / z = 311 [M+H] +< .Intermediate 5-38 N-(3-fluoro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0285]

[0286] Using an analogous method as described for intermediate 5-1 with tert-butyl 5-[(3-fluoro-2-methylphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (intermediate 4-38, 11.1 g, 29.1 mmol) as the starting material, 7.25 g of the title compound was prepared (84% yield) after 15 min of stirring and used in the next steps without further purification.

[0287] 1< H-NMR (400 MHz, DMSO- d 6 ): δ [ppm]= 1.172 (0.55), 1.987 (1.05), 2.063 (16.00), 2.518 (1.49), 2.523 (1.01), 2.612 (1.94), 2.631 (3.67), 2.649 (2.11), 2.761 (1.99), 2.779 (4.22), 2.798 (2.26), 3.280 (1.36), 3.287 (1.47), 3.298 (2.58), 3.305 (2.57), 3.315 (1.39), 3.322 (1.33), 3.410 (1.40), 3.417 (1.48), 3.428 (2.27), 3.435 (2.22), 3.446 (1.27), 3.454 (1.15), 7.112 (1.56), 7.119 (0.96), 7.132 (2.25), 7.141 (3.30), 7.161 (2.66), 7.168 (2.15), 7.192 (1.12), 7.243 (0.73), 7.262 (1.15), 7.272 (0.99), 7.279 (1.25), 7.292 (1.27), 7.308 (1.21), 7.328 (0.45), 8.150 (1.43), 9.317 (1.16), 14.003 (2.32), 14.321 (2.05), 16.439 (5.35), 16.468 (4.62).

[0288] LC-MS (method 2): Rt = 0.47 min; MS (ESlpos): m / z = 281 [M+H] +< .Intermediate 5-40 N-[2-(2,2-difluoroethyl)-3-fluorophenyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0289]

[0290] Using an analogous method as described for intermediate 5-1 with tert-butyl 5-{[2-(2,2-difluoroethyl)-3-fluorophenyl]carbamothioyl}-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (intermediate 4-40, 12.1 g, 28.0 mmol) as the starting material; 8.81 g of the title compound were prepared (95% purity, 90% yield).

[0291] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.145 (0.50), 1.154 (1.98), 1.172 (3.87), 1.190 (1.88), 1.441 (0.60), 1.987 (7.01), 2.323 (1.39), 2.327 (1.98), 2.332 (1.39), 2.518 (8.20), 2.523 (5.52), 2.617 (6.21), 2.635 (11.74), 2.653 (7.04), 2.665 (3.21), 2.669 (3.14), 2.673 (2.21), 2.769 (5.92), 2.786 (10.81), 2.803 (6.18), 3.059 (7.57), 3.067 (7.93), 3.104 (15.40), 3.111 (15.40), 3.148 (7.93), 3.307 (9.36), 3.434 (8.96), 4.000 (0.56), 4.017 (1.65), 4.035 (1.65), 4.053 (0.53), 6.057 (3.27), 6.067 (6.55), 6.077 (2.98), 6.198 (6.18), 6.208 (13.09), 6.217 (6.12), 6.339 (2.81), 6.348 (6.12), 6.358 (3.01), 7.165 (5.62), 7.185 (7.24), 7.207 (6.64), 7.227 (8.53), 7.242 (9.39), 7.265 (9.26), 7.288 (3.31), 7.393 (2.38), 7.413 (5.55), 7.430 (6.51), 7.459 (4.53), 7.479 (1.45), 8.152 (5.29), 9.352 (4.96), 14.013 (9.02), 14.389 (7.90), 16.346 (15.47), 16.353 (16.00).

[0292] LC-MS (method 2): Rt = 0.48 min; MS (ESlpos): m / z = 331.1 [M+H] +< .Intermediate 5-65 N-(2-ethyl-3-fluorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0293]

[0294] Using an analogous method as described for intermediate 5-1 with tert-butyl 5-[(2-ethyl-3-fluorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (intermediate 4-65, 5.46 g, 71 % purity, 9.83 mmol) as the starting material; 4.0 g of the title compound were prepared (70% purity, 97% yield).

[0295] 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.052 (6.61), 1.071 (16.00), 1.089 (6.75), 1.116 (0.56), 1.224 (4.60), 1.734 (1.58), 2.326 (0.43), 2.472 (1.56), 2.518 (2.10), 2.523 (1.69), 2.647 (0.85), 2.659 (0.85), 2.664 (0.98), 2.668 (1.03), 2.673 (0.80), 2.782 (0.89), 3.423 (0.82), 4.037 (0.62), 7.160 (2.35), 7.288 (0.98), 8.170 (0.48), 14.073 (0.46), 14.414 (0.52).

[0296] LC-MS (method 6): Rt = 1.18 min; MS (ESlpos): m / z = 295 [M+H] +< .Syntheses of Intermediate 6 Compounds Intermediate 6-1 N-(3-chloro-2-methoxyphenyl)-4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0297]

[0298] A mixture of N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-1, 498 mg, 1.59 mmol) and 1-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (intermediate 2-1, 0.5 g, 2.23 mmol) was stirred for 4 h at 120°C. The reaction mixture was purified by flash chromatography (silica, DCM / EtOH gradient 0-30 %) to give 325 mg of the title compound (39 % yield).

[0299] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 14.79 (s, 1H), 13.69 (t, 1H), 8.39 (s, 1H), 8.24 (d, 1H), 7.81 (dd, 1H), 7.73 (s, 1H), 7.26 - 7.33 (m, 2H), 7.11 (t, 1H), 4.67 (d, 2H), 4.16 (t, 2H), 3.84 - 3.95 (m, 2H), 3.74 - 3.79 (m, 1H), 3.71 (s, 3H), 3.59 - 3.70 (m, 2H), 3.45 - 3.54 (m, 2H), 3.11 - 3.20 (m, 2H), 2.78 (t, 2H).

[0300] LC-MS (method 2): Rt = 1.07 min; MS (ESlpos): m / z = 519.2 [M+H] +< .Intermediate 6-2 N-(3-chloro-2-methoxyphenyl)-4-{[(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0301]

[0302] A mixture of N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-1, 866 mg, 2.77 mmol) and 1-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methanamine (intermediate 2-8, 776 mg, 80% purity, 2.77 mmol) in ACN (22 ml) was treated with N,O-bis(trimethylsilyl)acetamide (2.05 ml, 8.6 mmol, CAS 10416-59-8) and stirred at 80°C for 4 h. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography (silica, DCM / EtOH gradient 0-20%) to give 1.23 g (95% purity, 81 % yield) of the title compound. 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 2.78 (t, 2H), 3.16 (td, 2H), 3.40 - 3.54 (m, 3H), 3.59 - 3.69 (m, 2H), 3.71 (s, 3H), 3.73 - 3.79 (m, 1H), 3.83 - 3.95 (m, 2H), 4.16 (t, 2H), 4.67 (d, 2H), 7.11 (t, 1H), 7.27 - 7.33 (m, 2H), 7.73 (br s, 1H), 7.81 (dd, 1H), 8.24 (d, 1H), 8.39 (s, 1H), 13.69 (s, 1H), 14.79 (s, 1H). LC-MS (method 2): Rt = 1.09 min; MS (ESlpos): m / z = 519 [M+H] +< Intermediate 6-4 4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-N-(3-fluoro-2-methoxyphenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0303]

[0304] Using an analogous method as described for intermediate 6-1 with N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-4, 179 mg, 604 µmol) and 1-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (intermediate 2-1, 190 mg, 845 µmol) as the starting materials; 120 mg of the title compound were prepared (34 % yield) after heating for 2 h and purification by flash chromatography (amino phase silica, DCM / EtOH gradient 0-10 %).

[0305] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 14.74 (s, 1H), 13.70 (br t, 1H), 8.39 (s, 1H), 8.24 (d, 1H), 7.64 - 7.73 (m, 2H), 7.30 (d, 1H), 7.02 - 7.14 (m, 2H), 4.67 (d, 2H), 4.13 - 4.21 (m, 2H), 3.84 - 3.95 (m, 2H), 3.59 - 3.77 (m, 4H), 3.40 - 3.53 (m, 2H), 3.13 - 3.22 (m, 2H), 2.68 - 2.80 (m, 2H), 1.59 (br s, 1H), 0.93 - 1.39 (m, 1H).

[0306] LC-MS (method 2): Rt = 1.01 min; MS (ESlpos): m / z = 503 [M+H] +< .Intermediate 6-7 N-(2,3-dichlorophenyl)-4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino)]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0307]

[0308] Using an analogous method as described for intermediate 6-1 with N-(2,3-dichlorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-7, 160 mg, 504 µmol) and 1-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (intermediate 2-1, 158 mg, 706 µmol) as the starting materials; 110 mg of the title compound were prepared (35 % yield) after and heating for 2 h and purification by flash chromatography (amino phase silica, DCM / EtOH gradient 0-10 %).

[0309] 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 14.90 (s, 1H), 13.66 (t, 1H), 8.39 (s, 1H), 8.24 (d, 1H), 7.75 (br s, 1H), 7.55 (dd, 1H), 7.51 (dd, 1H), 7.28 - 7.38 (m, 3H), 4.68 (d, 3H), 4.14 - 4.21 (m, 2H), 3.87 - 3.90 (m, 1H), 3.72 - 3.76 (m, 1H), 3.64 - 3.67 (m, 1H), 3.58 - 3.63 (m, 1H), 3.35 - 3.53 (m, 3H), 2.79 (t, 2H).

[0310] LC-MS (method 2): Rt = 1.08 min; MS (ESlpos): m / z = 523 [M+H] +< .Intermediate 6-10 N-(3-chloro-2-methylphenyl)-4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0311]

[0312] Using an analogous method as described for intermediate 6-1; N-(3-chloro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-10, 189 mg, 637 µmol) and 1-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (intermediate 2-1, 200 mg, 892 µmol) as the starting materials; 180 mg of the title compound were prepared (56 % yield) after heating for 2 h and purification by flash chromatography (amino phase silica, DCM / EtOH gradient 0-10 %).

[0313] 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 14.54 (s, 1H), 13.64 (br t, 1H), 8.38 (s, 1H), 8.24 (d, 1H), 7.69 (br s, 1H), 7.28 - 7.37 (m, 2H), 7.13 - 7.26 (m, 2H), 4.65 (d, 2H), 4.14 - 4.20 (m, 2H), 3.74 - 3.88 (m, 3H), 3.63 - 3.71 (m, 2H), 3.42 - 3.53 (m, 2H), 3.14 - 3.31 (m, 2H), 2.77 (t, 2H), 2.16 (s, 3H).

[0314] LC-MS (method 2): Rt = 1.09 min; MS (ESlpos): m / z = 501 [M+H] +< .Intermediate 6-11 N-(3-chloro-2-methoxyphenyl)-4-{[(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0315]

[0316] Using an analogous method as described for intermediate 6-1 with N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-1, 142 mg, 407 µmol) and 1-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methanamine (intermediate 2-2, 116 mg, 489 µmol) as the starting materials; 85.6 mg of the title compound were prepared (36 % yield) after heating for 3 h and purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 30% B, 0.50 - 6.00 min 30 - 70% B). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 14.79 (s, 1H), 13.67 (br t, 1H), 8.41 (s, 1H), 8.24 (d, 1H), 7.81 (dd, 1H), 7.73 (br s, 1H), 7.28 - 7.33 (m, 2H), 7.11 (t, 1H), 4.67 (br d, 2H), 4.31 (dd, 1H), 4.05 (dd, 1H), 3.90 (dd, 1H), 3.67 - 3.73 (m, 4H), 3.50 (td, 1H), 3.34 - 3.40 (m, 1H), 3.13 - 3.21 (m, 2H), 2.79 (t, 2H), 2.63 - 2.70 (m, 1H), 2.19 - 2.33 (m, 4H), 1.46 - 1.76 (m, 1H). LC-MS (method 2): Rt = 1.08 min; MS (ESlpos): m / z = 532.5 [M+H] +< Intermediate 6-12 N-(3-fluoro-2-methoxyphenyl)-4-(((3-hydroxypyridin-4-yl)methyl)amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0317]

[0318] A mixture of 4-(aminomethyl)pyridin-3-ol (CAS 20485-35-2, 75 g, 0.604 mol) and N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-4, 150 g, 0.506 mol) in DMA (1.2 L) was stirrred at 120°C for 2.5 h under nitrogen. The mixture was concentrated in vacuum to remove most of the solvent. The dark brown solution was slowly added to EtOAc (8 L) with stirring. The resulting mixture was washed with water (2.5 L) and brine (2.5 L x 2). The organic phase was dried over sodium sulphate, filtered and concentrated in vacuum. The residue was slurried with EtOAc (300 mL) and filtered. The filter cake was dried in vacuum to afford the title compound (87 g, 47 % yield) as a yellow solid.

[0319] 1< H NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 14.73 (s, 1H), 13.69 (t, 1H), 10.28 (s, 1H), 8.21-8.13 (m, 2H), 7.67-7.66 (m, 2H), 7.10 (br.s, 1H), 7.09-7.04 (m, 2H), 4.61 (d, 2H), 3.79 (s, 3H), 3.16 (t, 2H), 2.77 (t, 2H).Intermediate 6-15 N-(3-chloro-2-methoxyphenyl)-4-[({3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0320]

[0321] Using an analogous method as described for intermediate 6-1 with N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-4, 100 mg, 320 µmol) and 1-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)methanamine (intermediate 2-3, 114 mg, 480 µmol) as the starting materials; 74.3 mg (80 % purity, 35 % yield) of the title compound were prepared after heating for 4 h and purification by flash chromatography (amino phase silica, DCM / EtOH gradient 0-10 %). 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.880 (0.45), 2.176 (4.07), 2.186 (0.73), 2.191 (0.45), 2.518 (1.66), 2.523 (1.13), 2.787 (0.65), 2.799 (0.61), 3.162 (0.56), 3.169 (0.54), 3.533 (0.46), 3.539 (0.45), 3.711 (9.24), 3.819 (0.47), 3.823 (0.40), 4.149 (0.65), 4.161 (1.12), 4.176 (0.61), 4.655 (0.80), 4.670 (0.82), 5.759 (16.00), 7.086 (0.63), 7.107 (1.27), 7.127 (0.73), 7.283 (0.77), 7.287 (0.81), 7.302 (0.77), 7.306 (1.39), 7.318 (0.80), 7.723 (0.53), 7.803 (0.59), 7.806 (0.60), 7.823 (0.57), 7.827 (0.53), 8.234 (1.27), 8.246 (1.26), 8.392 (1.87), 14.791 (1.01). LC-MS (method 2): Rt = 0.84 min; MS (ESlpos): m / z = 532 [M+H] +< Intermediate 6-18 N-(3-chloro-5-fluoro-2-methoxyphenyl)-4-[({3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0322]

[0323] Using an analogous method as described for intermediate 6-1 with N-(3-chloro-5-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-18, 100 mg, 302 µmol) and 1-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)methanamine (intermediate 2-3, 108 mg, 453 µmol) as the starting materials; 166 mg (70 % purity, 70 % yield) of the title compound were prepared after purification by flash chromatography (amino phase silica, DCM / EtOH gradient 0-10 %). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.881 (0.59), 1.908 (0.51), 1.984 (0.51), 1.991 (0.55), 2.174 (5.75), 2.185 (0.88), 2.191 (2.53), 2.518 (2.46), 2.523 (1.65), 2.581 (0.55), 2.609 (0.49), 2.785 (0.52), 2.798 (0.96), 2.815 (0.60), 3.096 (0.44), 3.161 (0.55), 3.168 (0.51), 3.387 (0.97), 3.535 (0.57), 3.542 (0.68), 3.700 (7.75), 3.786 (0.69), 3.791 (0.73), 3.795 (0.71), 3.810 (0.63), 3.815 (0.70), 3.823 (0.75), 4.115 (0.52), 4.119 (0.55), 4.128 (0.53), 4.154 (0.77), 4.166 (0.94), 4.181 (0.60), 4.672 (0.76), 4.687 (0.77), 5.759 (16.00), 7.267 (0.58), 7.275 (0.65), 7.287 (0.58), 7.295 (0.63), 7.313 (0.77), 7.325 (0.74), 7.792 (0.49), 8.046 (0.50), 8.053 (0.50), 8.073 (0.47), 8.080 (0.47), 8.238 (1.20), 8.250 (1.12), 8.267 (0.55), 8.279 (0.66), 8.399 (1.72), 15.080 (0.94). LC-MS (method 2): Rt = 1.11 min; MS (ESlpos): m / z = 550 [M+H] +< Intermediate 6-19 N-(3-chloro-5-fluoro-2-methoxyphenyl)-4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0324]

[0325] Using an analogous method as described for intermediate 6-1 with N-(3-chloro-5-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-18, 100 mg, 302 µmol) and 1-(3-{[1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methanamine (intermediate 2-1, 94.9 mg, 423 µmol) as the starting materials, 160 mg (90 % purity, 89 % yield) of the title compound were prepared after purification by flash chromatography (silica, DCM / EtOH gradient 0-30 %). 1< H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 0.821 (0.41), 0.904 (0.45), 1.035 (8.84), 1.052 (16.00), 1.070 (9.56), 1.154 (1.90), 1.172 (3.66), 1.189 (1.72), 1.987 (6.85), 2.518 (1.36), 2.522 (0.92), 2.790 (0.61), 3.157 (0.42), 3.404 (1.39), 3.417 (1.49), 3.421 (4.01), 3.434 (4.35), 3.439 (4.40), 3.452 (4.43), 3.457 (1.21), 3.461 (0.53), 3.469 (1.28), 3.501 (0.40), 3.652 (0.66), 3.655 (0.65), 3.702 (7.42), 3.750 (0.43), 3.785 (0.67), 3.788 (0.43), 3.890 (0.58), 3.999 (0.46), 4.017 (1.36), 4.035 (1.39), 4.053 (0.47), 4.156 (0.56), 4.165 (0.77), 4.179 (0.54), 4.343 (2.52), 4.356 (4.91), 4.368 (2.35), 4.683 (0.68), 4.697 (0.68), 7.272 (0.48), 7.280 (0.60), 7.293 (0.51), 7.300 (0.64), 7.305 (0.63), 7.317 (0.62), 7.800 (0.42), 8.032 (0.40), 8.040 (0.42), 8.059 (0.41), 8.066 (0.40), 8.242 (0.98), 8.254 (0.94), 8.394 (1.43), 15.078 (0.82). LC-MS (method 2): Rt = 1.14 min; MS (ESlpos): m / z = 537 [M+H] +< Intermediate 6-20 N-(3-fluoro-2-methoxyphenyl)-4-{[(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0326]

[0327] Using an analogous method as described for intermediate 6-1 with N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-4, 200 mg, 675 µmol) and 1-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methanamine (intermediate 2-4, 208 mg, 877 µmol) as the starting materials, 105 mg (99 % purity, 30 % yield) of the title compound were prepared after heating for 3 h and purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 15% B, 0.50 - 6.00 min 15 - 55% B). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 2.195 (0.50), 2.203 (0.62), 2.221 (0.73), 2.224 (0.80), 2.229 (0.79), 2.232 (0.77), 2.250 (0.69), 2.258 (0.63), 2.287 (16.00), 2.322 (0.48), 2.326 (0.65), 2.331 (0.46), 2.518 (2.86), 2.522 (1.80), 2.645 (0.60), 2.651 (1.24), 2.658 (0.75), 2.664 (0.58), 2.668 (0.75), 2.673 (0.96), 2.680 (1.16), 2.687 (0.56), 2.760 (1.14), 2.776 (2.31), 2.793 (1.34), 3.134 (0.86), 3.142 (0.98), 3.152 (1.59), 3.158 (1.51), 3.167 (0.87), 3.175 (0.73), 3.347 (1.31), 3.371 (1.26), 3.375 (1.37), 3.398 (1.19), 3.473 (0.50), 3.480 (0.60), 3.501 (0.98), 3.507 (0.98), 3.527 (0.72), 3.533 (0.60), 3.677 (0.56), 3.683 (1.07), 3.690 (0.58), 3.704 (0.46), 3.711 (0.82), 3.718 (0.41), 3.780 (13.85), 3.783 (13.72), 3.884 (0.99), 3.892 (0.99), 3.912 (0.89), 3.920 (0.88), 4.029 (0.98), 4.044 (1.01), 4.054 (1.17), 4.070 (1.12), 4.291 (1.18), 4.302 (1.21), 4.317 (1.03), 4.327 (0.97), 4.658 (1.87), 4.674 (1.89), 7.044 (0.58), 7.049 (1.31), 7.065 (1.59), 7.069 (2.63), 7.075 (1.64), 7.085 (1.41), 7.090 (0.58), 7.096 (1.44), 7.101 (1.44), 7.117 (0.56), 7.122 (0.41), 7.296 (2.20), 7.308 (2.24), 7.653 (1.44), 7.658 (0.89), 7.670 (1.15), 7.676 (0.86), 7.704 (1.58), 8.236 (3.27), 8.247 (3.17), 8.411 (4.92), 13.661 (0.56), 13.676 (1.10), 13.690 (0.53), 14.736 (2.92). LC-MS (method 6): Rt = 0.62 min; MS (ESlpos): m / z = 516 [M+H] +< Intermediate 6-21 N-(3-chloro-2-methoxyphenyl)-4-{[(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0328]

[0329] Using an analogous method as described for intermediate 6-1 with N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-1, 200 mg, 639 µmol) and 1-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methanamine (intermediate 2-4, 197 mg, 831 µmol) as the starting materials 102 mg (99 % purity, 30 % yield) of the title compound were prepared after heating for 3h at 120°C and purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 15% B, 0.50 - 6.00 min 15 - 55% B). 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.288 (3.78), 2.327 (0.47), 2.518 (1.87), 2.523 (1.27), 2.651 (0.43), 2.665 (0.45), 2.669 (0.59), 2.673 (0.55), 2.679 (0.47), 2.769 (0.69), 2.786 (1.40), 2.803 (0.81), 3.141 (0.53), 3.148 (0.61), 3.157 (0.97), 3.164 (0.93), 3.174 (0.53), 3.181 (0.44), 3.346 (0.55), 3.372 (0.52), 3.506 (0.45), 3.684 (0.50), 3.712 (16.00), 3.883 (0.44), 3.891 (0.53), 3.912 (0.42), 4.293 (0.54), 4.304 (0.56), 4.319 (0.47), 4.329 (0.44), 4.663 (1.08), 4.679 (1.10), 7.088 (1.04), 7.108 (2.24), 7.128 (1.28), 7.285 (1.42), 7.289 (1.49), 7.301 (1.47), 7.305 (1.46), 7.309 (1.44), 7.312 (1.47), 7.726 (0.92), 7.794 (1.07), 7.797 (1.08), 7.814 (1.02), 7.818 (0.96), 8.238 (1.81), 8.250 (1.65), 8.413 (3.11), 13.667 (0.68), 14.787 (1.82). LC-MS (method 6): Rt = 0.68 min; MS (ESlpos): m / z = 532 [M+H] +< Intermediate 6-22 tert-butyl (2S)-2-[({4-[({5-[(3-fluoro-2-methoxyphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate

[0330]

[0331] Using an analogous method as described for intermediate 6-1 with N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-4, 1.00 g, 3.37 mmol) and tert-butyl (2S)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylate (intermediate 2-5, 1.53 g, 4.72 mmol) as the starting materials; 1.43 g (70 % purity, 49 % yield) of the title compound were prepared after heating for 6 h and purification by flash chromatography (silica, DCM / EtOH gradient 0-20 %). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.035 (6.69), 1.052 (16.00), 1.070 (7.70), 1.394 (4.63), 1.401 (2.39), 1.405 (3.46), 2.331 (0.41), 2.518 (1.92), 2.523 (1.41), 2.673 (0.42), 3.404 (1.10), 3.417 (1.21), 3.422 (3.66), 3.435 (3.78), 3.440 (3.26), 3.452 (3.33), 3.457 (1.19), 3.469 (1.18), 3.780 (2.11), 3.782 (2.08), 3.797 (0.42), 3.857 (0.84), 3.860 (0.83), 4.219 (0.41), 4.231 (0.42), 4.344 (2.52), 4.356 (4.87), 4.369 (2.35), 8.241 (0.54), 8.253 (0.53), 8.402 (0.81), 14.735 (0.40). LC-MS (method 2): Rt = 1.19 min; MS (ESlpos): m / z = 602 [M+H] +< Intermediate 6-24 N-(3-chloro-2-methoxyphenyl)-4-[({3-[2-(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0332]

[0333] Using an analogous method as described for intermediate 6-1 with N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-1, 200 mg, 639 µmol) and 1-(3-{2-[1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)methanamine (intermediate 2-6, 198 mg, 831 µmol) as the starting materials, 110 mg (96 % purity, 31 % yield) of the title compound were prepared after heating for 3h at 130°C and purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 15% B, 0.50 - 6.00 min 15 - 55% B). 1< H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 1.792 (0.45), 1.812 (0.43), 1.838 (0.40), 1.850 (0.42), 2.518 (1.13), 2.523 (0.78), 2.763 (0.87), 2.771 (0.86), 2.780 (0.52), 2.786 (0.47), 3.140 (0.51), 3.148 (0.57), 3.156 (0.97), 3.164 (0.96), 3.173 (0.50), 3.181 (0.43), 3.197 (0.60), 3.224 (0.94), 3.227 (0.95), 3.253 (0.64), 3.445 (0.75), 3.452 (0.83), 3.471 (0.48), 3.480 (0.60), 3.545 (0.45), 3.551 (0.53), 3.573 (0.70), 3.580 (0.81), 3.605 (0.86), 3.611 (1.14), 3.617 (0.53), 3.638 (0.55), 3.644 (0.47), 3.689 (0.92), 3.697 (1.10), 3.712 (16.00), 3.718 (2.12), 3.744 (0.88), 3.749 (0.65), 4.203 (0.84), 4.219 (1.35), 4.232 (0.58), 4.238 (0.56), 4.656 (1.44), 4.670 (1.43), 7.089 (1.01), 7.110 (2.16), 7.130 (1.25), 7.286 (1.37), 7.289 (1.46), 7.306 (2.13), 7.310 (1.42), 7.317 (1.10), 7.726 (0.93), 7.802 (1.03), 7.806 (1.05), 7.823 (0.99), 7.826 (0.93), 8.225 (1.23), 8.237 (1.18), 8.373 (1.98), 13.695 (0.65), 14.792 (1.75). LC-MS (method 6): Rt = 0.90 min; MS (ESlpos): m / z = 533 [M+H] +< Intermediate 6-27 tert-butyl (2S)-2-[({4-[({5-[(3-chloro-5-fluoro-2-methoxyphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate

[0334]

[0335] Using an analogous method as described for intermediate 6-1 with N-(3-chloro-5-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-18, 225 mg, 680 µmol) and tert-butyl (2S)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylate (intermediate 2-5, 308 mg, 952 µmol) as the starting materials; 150 mg (80 % purity, 28 % yield) of the title compound were prepared after heating for 6 h and purification by flash chromatography (silica, DCM / EtOH gradient 0-20 %). 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.035 (2.70), 1.052 (5.86), 1.070 (3.02), 1.232 (0.46), 1.389 (16.00), 1.405 (6.16), 1.419 (1.21), 2.331 (0.75), 2.430 (0.47), 2.447 (0.51), 2.518 (3.46), 2.523 (2.53), 2.673 (0.75), 2.772 (0.61), 2.789 (1.14), 2.805 (0.74), 3.137 (0.46), 3.145 (0.53), 3.154 (0.79), 3.161 (0.75), 3.405 (0.58), 3.417 (0.72), 3.422 (1.54), 3.435 (1.70), 3.440 (1.70), 3.445 (0.63), 3.452 (1.56), 3.457 (0.61), 3.469 (0.63), 3.655 (0.79), 3.699 (12.68), 3.719 (0.53), 3.732 (0.75), 3.738 (0.84), 3.757 (0.49), 3.764 (0.44), 3.787 (2.07), 3.821 (0.49), 3.842 (0.93), 3.870 (0.40), 4.225 (1.58), 4.237 (1.60), 4.344 (0.84), 4.357 (1.63), 4.370 (0.82), 4.681 (1.14), 4.696 (1.11), 5.759 (0.75), 7.267 (0.93), 7.275 (1.12), 7.287 (0.96), 7.295 (1.05), 7.311 (0.79), 7.323 (0.79), 7.799 (0.77), 8.031 (0.67), 8.038 (0.68), 8.057 (0.67), 8.065 (0.63), 8.245 (1.81), 8.257 (1.63), 8.290 (0.54), 8.410 (2.60), 13.671 (0.58), 15.074 (1.58). LC-MS (method 2): Rt = 1.30 min; MS (ESlpos): m / z = 636 [M+H] +< Intermediate 6-29 N-(3-chloro-2-ethylphenyl)-4-[({3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0336]

[0337] Using an analogous method as described for intermediate 6-1 with N-(3-chloro-2-ethylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-29, 300 mg, 965 µmol) and 1-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)methanamine (intermediate 2-3, 321 mg, 1.35 mmol) as the starting materials; 300 mg (80 % purity, 47 % yield) of the title compound were prepared after heating for 6 h and purification by flash chromatography (silica, DCM / EtOH gradient 0-20 %). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 0.798 (0.84), 0.814 (0.93), 0.821 (0.93), 0.840 (0.43), 0.886 (0.53), 0.904 (1.07), 0.922 (0.50), 1.035 (9.51), 1.052 (16.00), 1.066 (1.09), 1.070 (9.08), 1.073 (1.50), 1.232 (0.45), 1.874 (0.59), 1.901 (0.47), 1.907 (0.59), 1.983 (0.41), 1.990 (0.52), 2.178 (5.56), 2.195 (1.38), 2.202 (0.47), 2.331 (0.74), 2.518 (3.86), 2.522 (2.50), 2.580 (0.57), 2.591 (1.05), 2.610 (1.21), 2.673 (0.95), 2.784 (0.95), 2.817 (0.50), 3.162 (0.41), 3.172 (0.69), 3.179 (0.65), 3.404 (1.33), 3.417 (1.38), 3.421 (3.41), 3.434 (3.43), 3.439 (3.91), 3.452 (4.01), 3.457 (1.15), 3.469 (1.19), 3.529 (0.57), 3.535 (0.57), 3.735 (0.55), 3.784 (0.47), 3.788 (0.47), 3.792 (0.47), 3.812 (0.64), 3.816 (0.62), 4.111 (0.41), 4.123 (0.48), 4.138 (0.83), 4.149 (0.83), 4.154 (0.88), 4.168 (0.74), 4.343 (2.64), 4.356 (5.06), 4.368 (2.39), 4.636 (0.93), 4.651 (0.93), 7.205 (1.50), 7.208 (1.38), 7.218 (2.69), 7.296 (1.02), 7.305 (1.02), 7.308 (1.05), 7.315 (1.17), 7.327 (0.55), 7.701 (0.64), 8.228 (1.50), 8.240 (1.38), 8.282 (0.47), 8.385 (2.07), 13.654 (0.43), 14.636 (1.17). LC-MS (method 2): Rt = 1.14 min; MS (ESlpos): m / z = 530 [M+H] +< Intermediate 6-30 N-(3-chloro-2-methoxyphenyl)-4-[({3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0338]

[0339] Using an analogous method as described for intermediate 6-1 with N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-1, 200 mg, 639 µmol) and 1-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (intermediate 2-7, 210 mg, 831 µmol) as the starting materials; 55.0 mg (98 % purity, 15 % yield) of the title compound were prepared after heating for 3h at 130°C and purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 15% B, 0.50 - 6.00 min 15 - 55% B). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.042 (9.29), 1.249 (8.31), 2.518 (2.85), 2.523 (1.83), 2.752 (0.79), 2.768 (1.57), 2.785 (0.95), 3.147 (0.74), 3.156 (1.18), 3.164 (1.13), 3.299 (1.11), 3.533 (1.90), 3.562 (1.50), 3.628 (0.50), 3.648 (1.21), 3.658 (1.28), 3.667 (1.26), 3.691 (1.55), 3.713 (16.00), 3.720 (1.14), 3.795 (0.51), 3.806 (0.64), 3.817 (0.52), 4.154 (0.42), 4.164 (0.43), 4.180 (1.25), 4.191 (1.23), 4.198 (1.31), 4.212 (1.18), 4.225 (0.43), 4.663 (1.86), 4.678 (1.86), 7.088 (1.13), 7.108 (2.42), 7.128 (1.39), 7.286 (1.58), 7.290 (1.68), 7.305 (2.17), 7.310 (1.58), 7.316 (1.59), 7.729 (1.16), 7.799 (1.26), 7.803 (1.27), 7.819 (1.18), 7.823 (1.14), 8.241 (1.91), 8.253 (1.81), 8.397 (3.02), 13.669 (0.43), 13.683 (0.81), 14.792 (2.17). LC-MS (method 6): Rt = 1.04 min; MS (ESlpos): m / z = 547 [M+H] +< Intermediate 6-33 4-[({3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-N-(3-fluoro-2-methoxyphenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0340]

[0341] Using an analogous method as described for intermediate 6-1; N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-1, 200 mg, 675 µmol) and 1-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (intermediate 2-7, 221 mg, 877 µmol) as the starting materials, 130 mg (96 % purity, 35 % yield) of the title compound were prepared after heating for 2 h at 130°C and purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 15% B, 0.50 - 6.00 min 15 - 55% B). 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.043 (15.59), 1.251 (13.74), 2.518 (2.60), 2.523 (1.78), 2.742 (1.25), 2.759 (2.52), 2.775 (1.52), 3.134 (1.00), 3.142 (1.15), 3.152 (1.86), 3.158 (1.79), 3.167 (1.02), 3.175 (0.86), 3.300 (1.91), 3.535 (3.14), 3.563 (2.56), 3.622 (0.60), 3.630 (0.81), 3.650 (1.97), 3.659 (2.07), 3.668 (2.14), 3.692 (2.45), 3.722 (1.19), 3.782 (15.81), 3.785 (16.00), 3.796 (0.91), 3.808 (1.03), 3.819 (0.82), 3.832 (0.62), 4.155 (0.57), 4.165 (0.61), 4.181 (1.80), 4.192 (1.83), 4.198 (1.91), 4.212 (1.68), 4.225 (0.61), 4.238 (0.55), 4.658 (2.20), 4.672 (2.17), 7.029 (0.54), 7.045 (0.69), 7.050 (1.65), 7.065 (1.84), 7.069 (2.29), 7.071 (2.14), 7.077 (2.06), 7.085 (1.65), 7.093 (0.69), 7.098 (1.72), 7.103 (1.74), 7.119 (0.69), 7.124 (0.54), 7.307 (0.94), 7.317 (0.99), 7.657 (1.74), 7.662 (1.08), 7.676 (1.36), 7.681 (1.03), 7.708 (1.84), 8.254 (0.72), 8.404 (0.81), 13.678 (0.65), 13.693 (1.25), 13.707 (0.60), 14.741 (3.47). LC-MS (method 6): Rt = 0.94 min; MS (ESlpos): m / z = 531 [M+H] +< Intermediate 6-35 4-{[(3-{2-[1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)methyl]amino}-N-(3-fluoro-2-methoxyphenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0342]

[0343] Using an analogous method as described for intermediate 6-1; N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-4, 200 mg, 675 µmol) and 1-(3-{2-[1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)methanamine (intermediate 2-6, 209 mg, 877 µmol) as the starting materials, 137 mg (96 % purity, 38 % yield) of the title compound were prepared. LC-MS (method 6): Rt = 0.83 min; MS (ESlpos): m / z = 517 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.757 (0.42), 1.778 (0.61), 1.793 (0.89), 1.813 (0.86), 1.822 (0.55), 1.826 (0.49), 1.833 (0.54), 1.840 (0.80), 1.852 (0.85), 1.857 (0.64), 1.868 (0.60), 2.518 (2.52), 2.523 (1.61), 2.674 (0.45), 2.735 (0.74), 2.752 (1.68), 2.761 (1.69), 2.769 (1.02), 2.777 (0.89), 3.134 (1.00), 3.142 (1.11), 3.151 (1.92), 3.159 (1.89), 3.168 (0.98), 3.175 (0.85), 3.198 (1.19), 3.224 (1.91), 3.228 (1.91), 3.254 (1.24), 3.421 (0.47), 3.425 (0.68), 3.446 (1.52), 3.453 (1.67), 3.472 (0.99), 3.481 (1.19), 3.545 (0.92), 3.552 (1.09), 3.574 (1.39), 3.580 (1.60), 3.606 (1.73), 3.612 (2.26), 3.618 (1.04), 3.639 (1.07), 3.645 (0.93), 3.690 (1.77), 3.697 (2.11), 3.709 (0.79), 3.719 (3.54), 3.728 (1.41), 3.735 (0.73), 3.744 (1.71), 3.751 (1.33), 3.782 (15.79), 3.784 (16.00), 4.203 (1.78), 4.219 (2.73), 4.232 (1.20), 4.237 (1.18), 4.653 (2.89), 4.667 (2.88), 7.030 (0.49), 7.046 (0.68), 7.051 (1.63), 7.067 (1.82), 7.070 (3.31), 7.077 (2.11), 7.086 (1.65), 7.092 (0.71), 7.098 (1.72), 7.103 (1.73), 7.119 (0.68), 7.124 (0.52), 7.303 (1.99), 7.314 (2.03), 7.660 (1.68), 7.665 (1.06), 7.677 (1.35), 7.683 (1.07), 7.703 (1.84), 8.226 (1.84), 8.237 (1.79), 8.373 (2.98), 13.689 (0.64), 13.704 (1.28), 13.718 (0.60), 14.740 (3.42). Intermediate 6-37 N-(3-fluoro-2-methoxyphenyl)-4-{[(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0344]

[0345] Using an analogous method as described for intermediate 6-1 with N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-4, 200 mg, 675 µmol) and 1-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methanamine (intermediate 2-2, 224 mg, 945 µmol) as the starting materials; 134 mg of the title compound were prepared (38% yield) after heating for 1 h at 124 °C and purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 15% B, 0.50 - 6.00 min 15 - 55% B). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 2.205 (0.86), 2.226 (1.57), 2.254 (1.23), 2.290 (15.27), 2.327 (1.28), 2.654 (2.07), 2.681 (1.95), 2.762 (2.11), 2.779 (3.81), 2.795 (2.41), 3.155 (3.13), 3.374 (3.80), 3.401 (2.16), 3.482 (0.97), 3.504 (1.80), 3.531 (1.16), 3.686 (1.75), 3.714 (1.51), 3.784 (16.00), 3.888 (1.65), 3.916 (1.59), 4.031 (1.27), 4.047 (1.48), 4.057 (1.61), 4.073 (1.47), 4.294 (1.53), 4.304 (1.57), 4.320 (1.45), 4.328 (1.29), 4.661 (3.52), 4.675 (3.54), 7.031 (0.48), 7.052 (1.50), 7.070 (3.26), 7.087 (1.82), 7.099 (1.95), 7.122 (0.79), 7.299 (2.83), 7.311 (2.84), 7.655 (2.12), 7.672 (2.11), 7.706 (2.52), 8.239 (3.08), 8.250 (2.98), 8.414 (5.21), 13.678 (1.85), 14.738 (3.80). LC-MS (method 6): Rt = 0.64 min; MS (ESlpos): m / z = 516 [M+H] +< Intermediate 6-38 4-[[3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]-4-pyridyl]methylamino]-N-(3-fluoro-2-methylphenyl)-6-oxo-2,3-dihydro-1H-pyridine-5-carbothioamide

[0346]

[0347] Using an analogous method as described for intermediate 6-1 with N-(3-fluoro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-38, 350 mg, 1.25 mmol) and 1-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (intermediate 2-7, 315 mg, 1.25 mmol) as the starting materials; 192 mg of the title compound were prepared (27% yield) after heating for 3 h at 120 °C and purification by preparative HPLC (method 11, gradient: 0.00 - 2.00 min 30% B, 2.00 - 14.00 min 30 - 70% B). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.046 (16.00), 1.253 (14.02), 2.045 (8.35), 2.050 (8.21), 2.063 (1.09), 2.521 (2.37), 2.525 (1.62), 2.741 (1.29), 2.757 (2.61), 2.774 (1.60), 3.145 (1.01), 3.152 (1.15), 3.161 (1.90), 3.168 (1.80), 3.178 (0.99), 3.185 (0.85), 3.298 (1.92), 3.534 (3.17), 3.562 (2.60), 3.617 (0.65), 3.626 (0.83), 3.647 (2.00), 3.656 (2.10), 3.666 (2.13), 3.690 (2.57), 3.719 (1.29), 3.780 (0.43), 3.793 (0.82), 3.803 (1.04), 3.814 (0.83), 3.828 (0.60), 4.148 (0.72), 4.159 (0.78), 4.174 (2.17), 4.186 (2.01), 4.194 (2.14), 4.208 (2.03), 4.220 (0.76), 4.234 (0.69), 4.647 (3.08), 4.662 (3.06), 7.040 (0.87), 7.061 (1.78), 7.074 (1.74), 7.085 (1.37), 7.094 (2.40), 7.189 (0.89), 7.208 (1.38), 7.225 (1.30), 7.244 (0.54), 7.295 (2.49), 7.307 (2.52), 7.686 (1.77), 8.237 (2.54), 8.249 (2.42), 8.393 (3.97), 13.662 (1.07), 14.520 (2.54). LC-MS (method 6): Rt = 0.98 min; MS (ESlpos): m / z = 515 [M+H] +< Intermediate 6-40 N-[2-(2,2-difluoroethyl)-3-fluoro-phenyl]-4-[[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]methylamino]-6-oxo-2,3-dihydro-1H-pyridine-5-carbothioamide

[0348]

[0349] Using an analogous method as described for intermediate 6-1 with N-[2-(2,2-difluoroethyl)-3-fluorophenyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-40, 100 mg, 303 µmol) and 1-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (intermediate 2-1, 95.0 mg, 424 µmol) as the starting materials; 19.5 mg of the title compound were prepared (10% yield) after purification by flash chromatography (silica, DCM / EtOH gradient 0-10%). LC-MS (method 2): Rt = 1.07 min; MS (ESlpos): m / z = 537 [M+H] +< Intermediate 6-41 tert-butyl (2S)-2-{[(4-{[(5-{[2-(2,2-difluoroethyl)-3-fluorophenyl]carbamothioyl}-6-oxo-1,2,3,6-tetrahydropyridin-4-yl)amino]methyl}pyridin-3-yl)oxy]methyl}morpholine-4-carboxylate

[0350]

[0351] A mixture of N-[2-(2,2-difluoroethyl)-3-fluorophenyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-40, 200 mg, 605 µmol) and tert-butyl (2S)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylate (intermediate 2-5, 274 mg, 848 µmol) in ACN (2.5 ml) was treatet with N,O-bis-(trimethylsiliyl)acetamide (111 µl, 0.6 mmol, CAS 10416-59-8) and stirred at 80°C for 5 h. The reaction was treated with another equivalent (111 µl, 0.6 mmol) of N,O-bis-(trimethylsiliyl)acetamide and stirred at 80°C overnight. The reaction mixture was diluted in DCM and purified by flash chromatography (silica, DCM / EtOH gradient 0-20%) to give 255 mg (45% yield) of the title compound. LC-MS (method 2): Rt = 1.25 min; MS (ESlpos): m / z = 636 [M+H] +< Intermediate 6-42 tert-butyl (2S)-2-[({4-[({5-[(3-chloro-2-methylphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate

[0352]

[0353] Using an analogous method as described for intermediate 6-1 with N-(3-chloro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-10, 350 mg, 1.18 mmol) and tert-butyl (2S)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylate (intermediate 2-5, 381 mg, 1.18 mmol) as the starting materials; 208 mg of the title compound were prepared (99% purity, 29% yield) after heating for 3 h and purification by preparative HPLC (method 11, 0.00-1.00 min 30% B, 1.00-12.74 min 30-68.9% B, 12.74 - 14.19 min 68.9 B, 14.19 - 14.45 min 68.9 - 70% B) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.396 (16.00), 2.077 (0.96), 2.158 (7.73), 2.520 (2.53), 2.525 (1.63), 2.542 (0.50), 2.747 (0.68), 2.763 (1.35), 2.780 (0.85), 3.146 (0.53), 3.153 (0.62), 3.162 (0.99), 3.169 (0.96), 3.434 (0.57), 3.441 (0.60), 3.710 (0.46), 3.723 (0.54), 3.730 (0.70), 3.737 (0.68), 3.749 (0.56), 3.756 (0.45), 3.837 (0.42), 4.213 (1.89), 4.225 (1.86), 4.648 (1.39), 4.663 (1.40), 7.153 (0.57), 7.170 (1.15), 7.196 (0.92), 7.216 (1.36), 7.236 (0.59), 7.294 (0.89), 7.306 (0.92), 7.326 (1.13), 7.329 (1.10), 7.346 (0.85), 7.349 (0.79), 7.691 (0.91), 8.237 (2.11), 8.249 (1.94), 8.399 (3.05), 13.653 (0.59), 14.540 (1.38). LC-MS (method 6): Rt = 1.17 min; MS (ESlpos): m / z = 602 [M+H] +< Intermediate 6-43 tert-butyl (3R)-3-[({4-[({5-[(3-chloro-2-methylphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate

[0354]

[0355] Using an analogous method as described for intermediate 6-1 with N-(3-chloro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-10, 350 mg, 1.18 mmol) and tert-butyl (3R)-3-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylate (intermediate 2-9, 381 mg, 1.18 mmol) as the starting materials; 184 mg of the title compound were prepared (99% purity, 26% yield) after heating for 3 h and by preparative HPLC (method 11, 0.00-1.00 min 30% B, 1.00-12.74 min 30-68.9% B, 12.74 - 14.19 min 68.9 B, 14.19 - 14.45 min 68.9 - 70% B) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.339 (2.92), 2.087 (1.31), 2.161 (16.00), 2.521 (1.63), 2.525 (1.08), 2.676 (0.52), 2.708 (0.66), 2.725 (1.74), 2.742 (1.82), 2.757 (0.75), 3.140 (1.42), 3.147 (1.59), 3.156 (2.44), 3.163 (2.41), 3.319 (0.58), 3.365 (1.06), 3.372 (1.25), 3.395 (0.56), 3.402 (0.54), 3.478 (0.92), 3.507 (1.00), 3.651 (0.51), 3.797 (0.72), 3.821 (0.64), 3.957 (0.67), 3.985 (0.59), 4.236 (1.53), 4.415 (0.46), 4.441 (0.83), 4.625 (2.12), 4.639 (2.15), 7.160 (1.07), 7.178 (2.26), 7.200 (2.08), 7.220 (3.03), 7.239 (1.27), 7.291 (1.19), 7.301 (1.19), 7.329 (2.50), 7.332 (2.34), 7.349 (1.83), 7.352 (1.71), 7.691 (1.99), 8.240 (3.22), 8.252 (3.11), 8.489 (2.72), 13.669 (0.94), 14.536 (3.05). LC-MS (method 6): Rt = 1.17 min; MS (ESlpos): m / z = 602 [M+H] +< Intermediate 6-44 N-(3-chloro-2-methyl-phenyl)-4-[[3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]-4-pyridyl]methylamino]-6-oxo-2,3-dihydro-1H-pyridine-5-carbothioamide

[0356]

[0357] Using an analogous method as described for intermediate 6-41 with N-(3-chloro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-10, 200 mg, 674 µmol) and 1-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (intermediate 2-7, 200 mg, 85% purity, 674 µmol) as the starting materials; 328 mg of the title compound were prepared (97% purity, 89% yield). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.047 (14.25), 1.253 (12.85), 2.077 (16.00), 2.162 (14.45), 2.520 (1.87), 2.525 (1.19), 2.742 (1.21), 2.759 (2.44), 2.775 (1.45), 3.147 (0.98), 3.154 (1.11), 3.163 (1.80), 3.170 (1.74), 3.180 (0.98), 3.186 (0.82), 3.297 (1.66), 3.327 (2.92), 3.533 (2.87), 3.561 (2.30), 3.617 (0.55), 3.626 (0.77), 3.646 (1.84), 3.655 (1.96), 3.664 (1.91), 3.689 (2.20), 3.718 (1.12), 3.791 (0.79), 3.802 (0.97), 3.812 (0.78), 3.826 (0.56), 4.147 (0.62), 4.158 (0.66), 4.173 (1.85), 4.184 (1.77), 4.193 (1.88), 4.206 (1.73), 4.220 (0.66), 4.233 (0.60), 4.644 (2.79), 4.659 (2.74), 7.158 (1.13), 7.175 (2.37), 7.200 (1.72), 7.220 (2.58), 7.239 (1.09), 7.298 (1.31), 7.310 (1.39), 7.328 (2.08), 7.332 (2.01), 7.348 (1.56), 7.351 (1.42), 7.689 (1.69), 8.245 (0.80), 8.399 (1.03), 13.621 (0.57), 13.635 (1.07), 14.542 (2.54). LC-MS (method 6): Rt = 1.06 min; MS (ESlpos): m / z = 531 [M+H] +< Intermediate 6-47 4-[[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]methylamino]-N-(3-fluoro-2-methyl-phenyl)-6-oxo-2,3-dihydro-1H-pyridine-5-carbothioamide

[0358]

[0359] Using an analogous method as described for intermediate 6-41 with N-(3-fluoro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-38, 300 mg, 1.07 mmol) and 1-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (intermediate 2-1, 240 mg, 1.07 mmol) as the starting materials; 156.3 mg of the title compound were prepared (93% purity, 71% yield). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 0.000 (0.70), 1.998 (0.55), 2.033 (16.00), 2.038 (15.45), 2.064 (3.23), 2.508 (3.78), 2.513 (2.36), 2.737 (2.61), 2.754 (5.23), 2.771 (2.96), 3.142 (2.39), 3.151 (3.71), 3.158 (3.53), 3.168 (2.07), 3.393 (2.34), 3.418 (3.51), 3.421 (3.41), 3.446 (3.16), 3.461 (1.34), 3.482 (2.56), 3.488 (2.76), 3.506 (1.42), 3.516 (2.71), 3.579 (1.64), 3.585 (1.94), 3.608 (2.49), 3.614 (2.79), 3.641 (5.03), 3.670 (1.97), 3.735 (2.71), 3.744 (2.66), 3.769 (2.09), 3.837 (2.39), 3.844 (2.81), 3.871 (4.35), 3.883 (1.72), 3.890 (1.32), 3.895 (1.57), 3.902 (1.32), 3.907 (1.44), 3.914 (1.14), 3.926 (0.62), 4.108 (0.85), 4.120 (0.95), 4.134 (3.73), 4.145 (6.69), 4.158 (3.48), 4.171 (0.87), 4.184 (0.75), 4.624 (4.75), 4.639 (4.68), 7.028 (1.64), 7.050 (3.46), 7.062 (3.48), 7.073 (2.79), 7.081 (4.60), 7.179 (1.62), 7.198 (2.71), 7.215 (2.51), 7.235 (1.00), 7.333 (1.12), 7.676 (3.41), 8.321 (0.42), 13.651 (2.04), 14.509 (4.80). LC-MS (method 6): Rt = 0.85 min; MS (ESlpos): m / z = 487 [M+H] +< Intermediate 6-50 N-(3-chloro-2-methyl-phenyl)-4-[[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]methylamino]-6-oxo-2,3-dihydro-1H-pyridine-5-carbothioamide

[0360]

[0361] Using an analogous method as described for intermediate 6-41 with N-(3-chloro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-10, 200 mg, 674 µmol) and 1-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (intermediate 2-1, 151 mg, 674 µmol) as the starting materials; 150.0 mg of the title compound were prepared (96% purity, 42% yield). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 2.077 (1.64), 2.162 (16.00), 2.520 (2.60), 2.525 (1.64), 2.751 (1.41), 2.768 (2.82), 2.784 (1.63), 3.156 (1.22), 3.165 (1.94), 3.172 (1.87), 3.404 (1.32), 3.429 (1.94), 3.432 (1.93), 3.457 (1.81), 3.472 (0.72), 3.493 (1.40), 3.500 (1.50), 3.518 (0.79), 3.528 (1.45), 3.591 (0.91), 3.597 (1.05), 3.619 (1.35), 3.626 (1.54), 3.650 (2.14), 3.653 (2.65), 3.660 (0.95), 3.682 (1.04), 3.748 (1.44), 3.756 (1.54), 3.781 (1.16), 3.849 (1.30), 3.855 (1.59), 3.883 (2.54), 3.894 (0.99), 3.901 (0.68), 3.906 (0.89), 3.913 (0.76), 3.918 (0.79), 3.925 (0.62), 3.930 (0.51), 4.118 (0.55), 4.129 (0.59), 4.144 (2.26), 4.155 (4.42), 4.168 (2.30), 4.181 (0.52), 4.194 (0.48), 4.648 (3.19), 4.663 (3.19), 7.159 (1.24), 7.176 (2.55), 7.203 (1.84), 7.222 (2.83), 7.242 (1.22), 7.290 (2.72), 7.302 (2.78), 7.330 (2.22), 7.333 (2.19), 7.349 (1.69), 7.353 (1.54), 7.691 (1.83), 8.233 (4.07), 8.245 (3.96), 8.383 (6.40), 13.623 (0.61), 13.637 (1.14), 14.544 (2.74). LC-MS (method 6): Rt = 0.94 min; MS (ESlpos): m / z = 503 [M+H] +< Intermediate 6-52 N-(3-chloro-2-ethyl-phenyl)-4-[[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]methylamino]-6-oxo-2,3-dihydro-1H-pyridine-5-carbothioamide

[0362]

[0363] Using an analogous method as described for intermediate 6-41 with N-(3-chloro-2-ethylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-29, 150 mg, 483 µmol) and 1-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methanamine (intermediate 2-1, 108 mg, 483 µmol) as the starting materials; 150.0 mg of the title compound were prepared (90% purity, 54% yield) by using flash chromatography (silica, DCM / EtOH gradient 1-13%). 1< H-NMR (400 MHz, DMSO-d 6 ): δ ppm= 1.01 - 1.11 (m, 4 H), 2.56 - 2.65 (m, 2 H), 2.73 - 2.81 (m, 2 H), 3.12 - 3.22 (m, 2 H), 3.39 - 3.54 (m, 3 H), 3.58 - 3.69 (m, 2 H), 3.73 - 3.80 (m, 1 H), 3.88 (s, 2 H), 4.09 - 4.23 (m, 2 H), 4.11 - 4.15 (m, 1 H), 4.57 - 4.71 (m, 2 H), 7.16 - 7.25 (m, 2 H), 7.28 - 7.36 (m, 2 H), 7.32 (s, 1 H), 7.66 - 7.75 (m, 1 H), 8.07 - 8.11 (m, 1 H), 8.21 - 8.26 (m, 1 H), 8.33 - 8.43 (m, 1 H), 13.60 - 13.70 (m, 1 H), 14.59 - 14.67 (m, 1 H). LC-MS (method 2): Rt = 1.15 min; MS (ESlpos): m / z = 517 [M+H] +< Intermediate 6-53 N-(3-chloro-2-ethylphenyl)-4-{[(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0364]

[0365] Using an analogous method as described for intermediate 6-41 with N-(3-chloro-2-ethylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-29, 210 mg, 676 µmol) and 1-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methanamine (intermediate 2-8, 185 mg, 90% purity, 743 µmol) as the starting materials; 320.0 mg of the title compound were prepared (86% yield) by using flash chromatography (silica, DCM / EtOH gradient 1-15%). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.036 (8.39), 1.040 (4.03), 1.053 (16.00), 1.059 (9.01), 1.071 (8.71), 1.078 (3.84), 2.066 (0.41), 2.518 (1.19), 2.523 (0.81), 2.577 (0.95), 2.596 (2.98), 2.614 (2.87), 2.632 (0.86), 2.757 (1.69), 2.774 (3.38), 2.790 (1.92), 3.152 (1.31), 3.159 (1.49), 3.169 (2.36), 3.174 (2.23), 3.185 (1.26), 3.403 (1.67), 3.405 (1.77), 3.418 (1.45), 3.423 (4.19), 3.427 (2.48), 3.430 (2.54), 3.435 (4.26), 3.440 (3.60), 3.453 (4.76), 3.457 (2.12), 3.470 (1.96), 3.492 (1.59), 3.498 (1.73), 3.516 (0.85), 3.526 (1.70), 3.589 (1.03), 3.594 (1.21), 3.617 (1.57), 3.623 (1.85), 3.651 (3.24), 3.679 (1.31), 3.745 (1.75), 3.754 (1.70), 3.779 (2.03), 3.847 (1.59), 3.853 (1.84), 3.880 (2.81), 3.893 (1.13), 3.900 (0.84), 3.905 (1.04), 3.912 (0.89), 3.917 (0.95), 3.924 (0.75), 3.929 (0.59), 3.936 (0.44), 4.116 (0.64), 4.127 (0.69), 4.142 (2.65), 4.154 (5.01), 4.167 (2.53), 4.180 (0.60), 4.193 (0.55), 4.343 (2.64), 4.356 (5.10), 4.369 (2.52), 4.647 (3.70), 4.662 (3.66), 7.209 (5.05), 7.211 (4.85), 7.222 (8.23), 7.231 (0.55), 7.293 (2.86), 7.307 (4.24), 7.319 (3.43), 7.331 (1.67), 7.706 (2.31), 8.234 (3.16), 8.246 (3.01), 8.383 (5.19), 13.642 (0.84), 13.657 (1.55), 13.672 (0.72), 14.639 (4.11). LC-MS (method 2): Rt = 1.17 min; MS (ESlpos): m / z = 517 [M+H] +< Intermediate 6-55 tert-butyl (2R)-2-[({4-[({5-[(3-chloro-2-ethylphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate

[0366]

[0367] Using an analogous method as described for intermediate 6-41 with N-(3-chloro-2-ethylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-29, 300 mg, 965 µmol) and tert-butyl (2R)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)morpholine-4-carboxylate (intermediate 2-10, 312 mg, 965 µmol) as the starting materials; 476.0 mg of the title compound were prepared (95% purity, 76% yield) by using flash chromatography (silica, DCM / EtOH gradient 1-10%). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.036 (1.51), 1.055 (3.57), 1.073 (1.55), 1.393 (16.00), 2.518 (1.71), 2.523 (1.10), 2.590 (1.19), 2.609 (1.16), 2.751 (0.68), 2.769 (1.33), 2.785 (0.84), 3.165 (0.96), 3.171 (0.92), 3.431 (0.55), 3.438 (0.59), 3.729 (0.71), 3.749 (0.48), 3.756 (0.41), 3.835 (0.41), 4.210 (1.81), 4.222 (1.76), 4.646 (1.35), 4.662 (1.35), 5.758 (7.84), 7.202 (2.06), 7.214 (2.99), 7.296 (1.00), 7.304 (1.58), 7.316 (1.60), 7.328 (0.75), 7.703 (0.94), 8.236 (1.90), 8.248 (1.81), 8.398 (2.84), 13.671 (0.64), 14.632 (1.67). LC-MS (method 2): Rt = 1.32 min; MS (ESlpos): m / z = 616 [M+H] +< Intermediate 6-56 tert-butyl (2S)-2-[({4-[({5-[(3-chloro-2-ethylphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate

[0368]

[0369] Using an analogous method as described for intermediate 6-41 with N-(3-chloro-2-ethylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-29, 300 mg, 965 µmol) and tert-butyl(2S)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl) morpholine-4-carboxylate (intermediate 2-5, 312 mg, 965 µmol) as the starting materials; 479.0 mg of the title compound were prepared (95% purity, 77% yield) after purification by flash chromatography (silica, DCM / EtOH gradient 1-10%). 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 14.55 - 14.67 (m, 1H), 13.60 - 13.72 (m, 1H), 8.40 (s, 1H), 8.24 (d, 1H), 7.70 (br s, 1H), 7.16 - 7.36 (m, 4H), 5.70 - 5.80 (m, 1H), 5.66 - 5.81 (m, 1H), 4.59 - 4.73 (m, 2H), 4.12 - 4.27 (m, 2H), 3.80 - 3.99 (m, 2H), 3.65 - 3.78 (m, 2H), 3.37 - 3.50 (m, 1H), 3.10 - 3.22 (m, 2H), 2.70 - 2.99 (m, 4H), 2.55 - 2.64 (m, 2H), 1.30 - 1.46 (m, 9H), 1.01 - 1.12 (m, 3H). LC-MS (method 2): Rt = 1.32 min; MS (ESlpos): m / z = 616 [M+H] +< Intermediate 6-57 N-(3-chloro-2-methoxyphenyl)-4-([{3-[(1S)-1-(1 ,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0370]

[0371] Using an analogous method as described for intermediate 6-41 with N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-1, 300 mg, 959 µmol) and 1-{3-[(1S)-1-(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methanamine (intermediate 2-11, 251 mg, 1.06 mmol) as the starting materials; 384 mg of the title compound were prepared (99% purity, 74% yield) as mixture of diastereomers. 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 0.064 (0.95), 1.239 (2.82), 1.255 (2.83), 1.279 (2.06), 1.295 (2.09), 2.518 (1.11), 2.523 (0.82), 2.761 (0.76), 2.777 (0.86), 3.141 (0.52), 3.148 (0.60), 3.157 (1.00), 3.164 (0.99), 3.181 (0.43), 3.417 (0.87), 3.443 (0.88), 3.455 (0.44), 3.462 (0.47), 3.470 (0.68), 3.476 (0.41), 3.591 (0.40), 3.597 (0.65), 3.620 (0.88), 3.632 (0.76), 3.639 (0.41), 3.647 (0.54), 3.653 (0.56), 3.672 (0.40), 3.678 (0.44), 3.711 (16.00), 3.732 (0.56), 3.766 (0.89), 3.772 (0.52), 3.794 (0.57), 4.651 (1.27), 4.665 (1.31), 4.682 (0.58), 7.090 (0.70), 7.110 (1.53), 7.131 (0.88), 7.287 (1.67), 7.289 (1.87), 7.300 (1.26), 7.305 (1.12), 7.309 (1.02), 7.314 (0.67), 7.726 (0.98), 7.791 (0.95), 7.794 (0.96), 7.811 (0.90), 7.815 (0.85), 8.198 (1.34), 8.211 (1.99), 8.223 (0.91), 8.416 (1.88), 8.432 (1.35), 13.666 (0.43), 13.675 (0.50), 14.790 (1.61). LC-MS (method 6): Rt = 0.96 min and Rt = 0.98 min; MS (ESlpos): m / z = 533.2 [M+H] +< Intermediate 6-60 N-(3-chloro-2-methoxyphenyl)-4-{[(3-{(1R)-1-[1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0372]

[0373] Using an analogous method as described for intermediate 6-41 with N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-1, 300 mg, 959 µmol) and 1-{3-[(1R)-1-(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methanamine (intermediate 2-12, 251 mg, 1.06 mmol) as the starting materials; 346 mg (99% purity, 67% yield) of the title compound were prepared. 1< H-NMR (400 MHz, DMSO- d 6 ): δ [ppm]= 1.278 (5.25), 1.294 (5.21), 2.073 (0.98), 2.331 (0.40), 2.518 (2.02), 2.522 (1.36), 2.673 (0.42), 2.749 (0.74), 2.765 (0.56), 2.775 (0.83), 2.792 (0.42), 3.140 (0.62), 3.147 (0.73), 3.156 (1.17), 3.164 (1.16), 3.417 (0.81), 3.441 (1.16), 3.445 (1.15), 3.469 (1.68), 3.475 (0.85), 3.503 (0.74), 3.570 (0.47), 3.576 (0.55), 3.598 (0.72), 3.604 (0.82), 3.631 (1.87), 3.638 (0.97), 3.646 (0.63), 3.652 (0.78), 3.657 (1.02), 3.663 (0.93), 3.670 (0.52), 3.677 (0.47), 3.710 (16.00), 3.758 (0.87), 3.767 (0.74), 3.790 (0.67), 3.920 (0.78), 3.926 (0.76), 3.949 (0.72), 3.955 (0.66), 4.646 (1.57), 4.653 (1.48), 4.662 (1.63), 4.682 (0.73), 7.092 (1.08), 7.112 (2.33), 7.133 (1.33), 7.287 (1.60), 7.290 (1.60), 7.302 (1.73), 7.306 (1.61), 7.310 (1.69), 7.314 (1.68), 7.725 (1.16), 7.791 (1.23), 7.794 (1.22), 7.811 (1.17), 7.814 (1.08), 8.210 (2.42), 8.222 (2.24), 8.430 (3.36), 13.651 (0.41), 13.665 (0.79), 14.786 (2.12). LC-MS (method 6): Rt = 0.96 min; MS (ESlpos): m / z = 533 [M+H] +< Intermediate 6-62 N-(3-fluoro-2-methylphenyl)-4-{[(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0374]

[0375] Using an analogous method as described for intermediate 6-41 with N-(3-fluoro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-38, 197 mg, 704 µmol) and 1-(3-{[-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)methanamine (intermediate 2-3, 167 mg, 704 µmol) as the starting materials; 170 mg of the title compound were prepared (93% purity, 45% yield) after purification by reversed phase HPLC (basic). 1< H-NMR (400 MHz, DMSO- d 6 ): δ [ppm]= 1.035 (0.65), 1.053 (1.08), 1.070 (0.68), 1.848 (1.00), 1.876 (1.47), 1.901 (1.11), 1.953 (0.45), 1.962 (0.59), 1.982 (1.04), 1.990 (1.08), 2.010 (0.69), 2.019 (0.57), 2.040 (7.36), 2.044 (6.91), 2.177 (16.00), 2.518 (1.64), 2.522 (1.10), 2.578 (0.88), 2.607 (0.81), 2.756 (0.84), 2.770 (1.72), 2.789 (2.10), 2.817 (1.02), 3.149 (0.83), 3.156 (0.97), 3.166 (1.67), 3.173 (1.63), 3.182 (0.94), 3.318 (0.50), 3.501 (0.55), 3.507 (0.70), 3.529 (1.25), 3.535 (1.29), 3.557 (0.76), 3.563 (0.62), 3.784 (0.93), 3.788 (0.90), 3.791 (0.76), 3.812 (1.29), 3.815 (1.26), 3.829 (0.63), 3.837 (0.57), 4.112 (0.53), 4.124 (0.56), 4.138 (1.82), 4.150 (1.97), 4.154 (2.08), 4.168 (1.68), 4.180 (0.56), 4.194 (0.52), 4.636 (2.30), 4.651 (2.34), 7.034 (0.71), 7.055 (1.49), 7.070 (1.47), 7.079 (1.12), 7.089 (1.98), 7.185 (0.72), 7.204 (1.19), 7.221 (1.13), 7.241 (0.44), 7.295 (2.26), 7.306 (2.30), 7.679 (1.46), 8.227 (3.76), 8.239 (3.55), 8.383 (5.45), 13.662 (0.88), 14.516 (2.06). LC-MS (method 6): Rt = 0.62 min; MS (ESlpos): m / z = 500 [M+H] +< Intermediate 6-65 4-{[(3-{[1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methyl]amino}-N-(2-ethyl-3-fluorophenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0376]

[0377] Using an analogous method as described for intermediate 6-41 with N-(2-ethyl-3-fluorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (300 mg, 1.02 mmol) and 1-(3-{[1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methanamine (229 mg, 1.02 mmol) as the starting materials; 218 mg of the title compound were prepared (90% purity, 38% yield) after evaporation of the solvent, filtration and washing of the solid with ACN. 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.057 (1.12), 1.042 (7.32), 1.061 (16.00), 1.080 (7.29), 1.231 (0.88), 1.751 (0.58), 2.074 (6.86), 2.522 (5.66), 2.753 (3.09), 2.770 (6.11), 2.787 (3.52), 3.156 (2.86), 3.166 (4.42), 3.172 (4.30), 3.181 (2.51), 3.402 (2.65), 3.427 (3.92), 3.430 (3.92), 3.455 (3.70), 3.471 (1.62), 3.491 (2.84), 3.498 (3.08), 3.516 (1.51), 3.526 (2.87), 3.589 (1.80), 3.594 (1.99), 3.617 (2.79), 3.623 (3.19), 3.650 (5.74), 3.679 (2.35), 3.745 (3.17), 3.754 (3.06), 3.778 (2.46), 3.846 (2.80), 3.853 (3.24), 3.881 (4.78), 3.893 (1.98), 3.900 (1.58), 3.905 (1.80), 3.911 (1.59), 3.918 (1.69), 3.925 (1.36), 3.936 (0.73), 4.117 (1.01), 4.129 (1.14), 4.143 (4.20), 4.155 (7.71), 4.168 (3.95), 4.181 (1.08), 4.194 (0.91), 4.632 (5.48), 4.646 (5.40), 7.029 (2.23), 7.051 (3.97), 7.074 (2.84), 7.091 (3.92), 7.110 (5.33), 7.191 (2.31), 7.207 (2.86), 7.211 (3.55), 7.228 (3.42), 7.248 (1.35), 7.351 (1.30), 7.701 (4.14), 8.329 (0.48), 8.476 (0.42), 13.662 (1.51), 13.676 (2.76), 13.691 (1.37), 14.588 (6.37). LC-MS (method 6): Rt = 0.92 min; MS (ESlpos): m / z = 501 [M+H] +< Intermediate 6-68 4-{[(3-{[5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methyl]amino}-N-(2-ethyl-3-fluorophenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0378]

[0379] Using an analogous method as described for intermediate 6-41 with N-(2-ethyl-3-fluorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (300 mg, 1.02 mmol) and 1-(3-{[5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methanamine (257 mg, 1.02 mmol) as the starting materials; 360 mg of the title compound were prepared (93% purity, 62% yield) after purification by column chromatography. 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.014 (0.69), 1.044 (16.00), 1.061 (7.08), 1.080 (3.30), 1.172 (0.52), 1.200 (0.60), 1.251 (13.22), 1.987 (0.87), 2.745 (1.36), 2.761 (2.65), 2.779 (1.61), 3.164 (2.11), 3.170 (2.09), 3.295 (1.79), 3.532 (2.73), 3.560 (2.19), 3.615 (0.59), 3.624 (0.79), 3.644 (1.91), 3.653 (2.05), 3.664 (1.79), 3.688 (2.07), 3.718 (1.01), 3.778 (0.45), 3.789 (0.91), 3.801 (1.07), 3.812 (0.86), 3.824 (0.63), 4.145 (0.65), 4.156 (0.71), 4.172 (1.96), 4.182 (1.95), 4.191 (2.02), 4.205 (1.76), 4.218 (0.69), 4.231 (0.59), 4.644 (3.11), 4.658 (3.10), 7.029 (0.86), 7.050 (1.63), 7.074 (1.12), 7.091 (1.71), 7.111 (2.37), 7.189 (0.89), 7.208 (1.52), 7.225 (1.39), 7.245 (0.52), 7.295 (2.40), 7.306 (2.41), 7.700 (1.92), 8.235 (3.11), 8.247 (2.98), 8.389 (5.24), 13.661 (0.71), 13.675 (1.32), 13.688 (0.68), 14.587 (3.04). LC-MS (method 6): Rt = 1.03 min; MS (ESlpos): m / z = 529 [M+H] +< Intermediate 6-71 N-(3-chloro-2-methoxyphenyl)-4-({[3-({1-[4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

[0380]

[0381] Using an analogous method as described for intermediate 6-41 with N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 5-1, 300 mg, 959 µmol) and 1-[3-({1-[4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl]methanamine (intermediate 2-71, 265 mg, 1.06 mmol) as the starting materials; 360 mg of the title compound were prepared (93% purity, 62% yield) after purification by column chromatography. 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.014 (0.69), 1.044 (16.00), 1.061 (7.08), 1.080 (3.30), 1.172 (0.52), 1.200 (0.60), 1.251 (13.22), 1.987 (0.87), 2.745 (1.36), 2.761 (2.65), 2.779 (1.61), 3.164 (2.11), 3.170 (2.09), 3.295 (1.79), 3.532 (2.73), 3.560 (2.19), 3.615 (0.59), 3.624 (0.79), 3.644 (1.91), 3.653 (2.05), 3.664 (1.79), 3.688 (2.07), 3.718 (1.01), 3.778 (0.45), 3.789 (0.91), 3.801 (1.07), 3.812 (0.86), 3.824 (0.63), 4.145 (0.65), 4.156 (0.71), 4.172 (1.96), 4.182 (1.95), 4.191 (2.02), 4.205 (1.76), 4.218 (0.69), 4.231 (0.59), 4.644 (3.11), 4.658 (3.10), 7.029 (0.86), 7.050 (1.63), 7.074 (1.12), 7.091 (1.71), 7.111 (2.37), 7.189 (0.89), 7.208 (1.52), 7.225 (1.39), 7.245 (0.52), 7.295 (2.40), 7.306 (2.41), 7.700 (1.92), 8.235 (3.11), 8.247 (2.98), 8.389 (5.24), 13.661 (0.71), 13.675 (1.32), 13.688 (0.68), 14.587 (3.04). LC-MS (method 6): Rt = 1.03 min; MS (ESlpos): m / z = 529 [M+H] +< Intermediate 12 3-((3-fluoro-2-methoxyphenyl)amino)-2-(3-hydroxypyridin-4-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

[0382]

[0383] To a suspension of N-(3-fluoro-2-methoxyphenyl)-4-(((3-hydroxypyridin-4-yl)methyl)amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-12, 41 g, 101.88 mmol) in MeOH (410 mL) was added TFA (0.75 mL, 10.13 mmol), followed by hydrogen peroxide (18 mL, 30 % in water). The mixture was heated to 60°C and stirred for 16 h. Additional TFA (6.8 mL, 91.84 mmol) and hydrogen peroxide (1.5 mL, 30 % in water) were added. The suspension was stirred at 60°C for further 3 h. The mixture was cooled to room temperature and stand overnight. The suspension was combined with a second batch that was generated identically. The comined suspension was filtered and the cake was washed with water (250 mL) and MeOH (150 mL), and then slurried in MeOH (150 mL). The suspension was filtered. The cake was washed with MeOH (75 mL) and dried in vacuum to afford the title compound (25.4 g, 33.8 % yield) as a yellow solid. 1< H NMR (400 MHz, DMSO-d 6 ): δ = 11.45 (s, 1H), 8.18 (s, 1H), 7.98 (d, 1H), 7.39 (d, 1H), 7.18 (s, 1H), 6.67 (t, 1H), 6.54 (t, 1H), 6.04 (d, 1H), 3.92 (s, 3H), 3.40 (t, 2H), 2.90 (t, 2H). LC-MS (method 5): Rt = 1.851 min; m / z = 369.0 (M +H) +< Intermediate 22-1 tert-butyl (2S)-2-[({4-[3-(3-fluoro-2-methoxyanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate

[0384]

[0385] Using an analogous method as described for example 1 with tert-butyl (2S)-2-[({4-[({5-[(3-fluoro-2-methoxyphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (intermediate 6-22, 1.43 g, 2.38 mmol) as the starting material; 572 mg (80 % purity, 34 % yield) of the title compound were prepared after purification by flash chromatography (silica, DCM / EtOH gradient 0-10 %). 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.035 (0.86), 1.053 (1.99), 1.071 (0.88), 1.380 (0.83), 1.401 (6.79), 1.409 (16.00), 2.518 (1.63), 2.523 (1.18), 2.842 (0.65), 2.859 (1.16), 2.877 (0.76), 3.178 (0.95), 3.301 (0.60), 3.398 (0.50), 3.404 (0.61), 3.415 (0.94), 3.418 (0.82), 3.422 (1.10), 3.435 (0.77), 3.440 (0.72), 3.452 (0.50), 3.553 (0.42), 3.560 (0.43), 3.750 (0.64), 3.760 (0.40), 3.851 (0.50), 3.858 (0.40), 3.873 (0.46), 3.906 (6.63), 3.936 (0.57), 3.939 (0.59), 3.950 (0.46), 4.343 (0.56), 4.356 (0.65), 5.759 (1.09), 5.993 (0.75), 6.013 (0.76), 6.485 (0.50), 6.489 (0.49), 6.492 (0.42), 6.513 (0.45), 6.516 (0.42), 6.627 (0.54), 6.642 (0.52), 7.147 (0.86), 7.280 (1.09), 7.293 (1.13), 7.509 (0.98), 8.025 (1.38), 8.038 (1.27), 8.401 (2.10), 11.020 (0.61). LC-MS (method 2): Rt = 1.12 min; MS (ESlpos): m / z = 568 [M+H] +< Intermediate 22-2 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0386]

[0387] Tert-butyl (2S)-2-[({4-[3-(3-fluoro-2-methoxyanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (intermediate 22-1, 572 mg, 1.01 mmol) was solubilised in dichloromethane (7.2 ml) and TFA (780 µl, 10 mmol) was added. The mixture was stirred for 2h at RT. The mixture was evaporated and purified by flash chromatography (amino phase silica, DCM / EtOH gradient 0-20 %) to give 352 mg (95 % purity, 71 % yield) of the title compound. 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 2.53 - 2.78 (m, 4H), 2.80 - 2.90 (m, 3H), 3.38 - 3.47 (m, 3H), 3.55 - 3.66 (m, 1H), 3.83 - 3.90 (m, 1H), 3.91 - 3.95 (s, 3H), 4.07 - 4.16 (m, 1H), 4.29 - 4.39 (m, 1H), 6.01 (d, 1H), 6.44 - 6.56 (m, 1H), 6.65 (dt, 1H), 7.17 (s, 1H), 7.29 (d, 1H), 7.53 (s, 1H), 8.01 (d, 1H), 8.39 (s, 1H), 11.10 (s, 1H). LC-MS (method 2): Rt = 0.84 min; MS (ESlpos): m / z = 468 [M+H] +< Intermediate 27-1 tert-butyl (2S)-2-[({4-[3-(3-chloro-5-fluoro-2-methoxyanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate

[0388]

[0389] Using an analogous method as described for example 1 with tert-butyl (2S)-2-[({4-[({5-[(3-chloro-5-fluoro-2-methoxyphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (intermediate 6-27, 150 mg, 236 µmol) as the starting material, 73.5 mg (90 % purity, 47 % yield) of the title compound were prepared. 1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.40 (s, 9H), 2.52 - 2.53 (m, 2H), 2.70 - 3.03 (m, 1H), 2.87 (br t, 2H), 3.42 (td, 2H), 3.46 - 3.61 (m, 1H), 3.71 - 3.79 (m, 1H), 3.82 (s, 4H), 3.93 (br d, 1H), 4.20 (m, 1H), 4.27 - 4.33 (dd, 1H), 5.85 (dd, 1H), 6.55 (dd, 1H), 7.11 (s, 1H), 7.32 (d, 1H), 7.60 (s, 1H), 8.10 (d, 1H), 8.44 (s, 1H), 11.17 (s, 1H). LC-MS (method 2): Rt = 1.19 min; MS (ESlpos): m / z = 602 [M+H] +< Intermediate 27-2 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0390]

[0391] Using an analogous method as described for intermediate 22-2 with tert-butyl (2S)-2-[({4-[3-(3-chloro-5-fluoro-2-methoxyanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (intermediate 27-1, 73.0 mg, 121 µmol) as the starting material; 56.3 mg (95 % purity, 88 % yield) of the title compound were prepared after purification by flash chromatography (amino phase silica, DCM / EtOH gradient 0-15 %). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 2.51 - 2.58 (m, 2H), 2.61 - 2.75 (m, 2H), 2.77 - 2.94 (m, 3H), 3.38 - 3.48 (m, 1H), 3.56 (td, 1H), 3.76 - 3.92 (m, 2H), 3.84 (s, 3H), 4.10 (dd, 1H), 4.29 (dd, 1H), 5.85 (dd, 1H), 6.57 (dd, 1H), 7.13 (s, 1H), 7.32 (d, 1H), 7.64 (d, 1H), 8.09 (d, 1H), 8.43 (s, 1H), 11.22 (s, 1H). LC-MS (method 2): Rt = 0.93 min; MS (ESlpos): m / z = 502 [M+H] +< . Intermediate 41-1 tert-butyl (2S)-2-{[(4-{3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl}pyridin-3-yl)oxy]methyl}morpholine-4-carboxylate

[0392]

[0393] Using an analogous method as described for example 1 with tert-butyl (2S)-2-{[(4-{[(5-{[2-(2,2-difluoroethyl)-3-fluorophenyl]carbamothioyl}-6-oxo-1,2,3,6-tetrahydropyridin-4-yl)amino]methyl}pyridin-3-yl)oxy]methyl}morpholine-4-carboxylate (intermediate 6-41, 266 mg, 418 µmol) as the starting material; 33.0 mg (65% purity, 9% yield) of the title compound were prepared after purification by preparative HPLC (method 10, gradient: 0.00-0.50 min 30% B, 0.50-6.00 min 30-70% B). LC-MS (method 2): Rt = 1.16 min; MS (ESlneg): m / z = 600 [M-H] -< Intermediate 41-2 3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0394]

[0395] Using an analogous method as described for intermediate 22-2 with tert-butyl (2S)-2-{[(4-{3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl}pyridin-3-yl)oxy]methyl}morpholine-4-carboxylate (intermediate 41-1, 33.0 mg, 54.9 µmol) as the starting material; 22.0 mg (65% purity, 52% yield) of the title compound were prepared after purification by flash chromatography (amino phase silica, DCM / EtOH gradient 0-10%). LC-MS (method 2): Rt = 0.92 min; MS (ESlneg): m / z = 500 [M-H] -< Intermediate 42-1 tert-butyl (2S)-2-[({4-[3-(3-chloro-2-methylanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate

[0396]

[0397] Using an analogous method as described for example 1 with tert-butyl (2S)-2-[({4-[({5-[(3-chloro-2-methylphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (intermediate 6-42, 207 mg, 344 µmol) as the starting material; 27.8 mg (90% purity, 13% yield) of the title compound were prepared after purification by preparative HPLC (method 9, gradient: 0.00-0.50 min 15% B, 0.50-4.65 min 15-44.9% B, 4.65 - 5.94 min 44.9% B, 5.94 - 7.29 min 44.9 - 55% B). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.414 (16.00), 2.349 (5.99), 2.520 (0.82), 2.525 (0.50), 2.853 (0.68), 2.870 (1.29), 2.887 (0.75), 3.405 (0.49), 3.410 (0.53), 3.422 (0.95), 3.428 (0.93), 3.439 (0.48), 3.445 (0.43), 3.554 (0.43), 3.560 (0.45), 4.294 (0.43), 4.304 (0.45), 6.191 (0.69), 6.195 (0.66), 6.211 (0.71), 6.214 (0.69), 6.719 (0.48), 6.735 (1.31), 6.738 (1.11), 6.747 (0.85), 6.767 (0.82), 7.175 (0.83), 7.232 (0.92), 7.245 (0.92), 7.351 (0.48), 7.998 (1.24), 8.010 (1.16), 8.378 (1.84), 11.016 (0.78). LC-MS (method 6): Rt = 0.92 min; MS (ESlpos): m / z = 568 [M+H] +< Intermediate 42-2 3-(3-chloro-2-methylanilino)-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0398]

[0399] Using an analogous method as described for intermediate 22-2 with tert-butyl (2S)-2-[({4-[3-(3-chloro-2-methylanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (intermediate 42-1, 30.0 mg, 52.8 µmol) as the starting material, 19.0 mg (92% purity, 71% yield) of the title compound were prepared after filtration through a SCX-2 column (MeOH wash followed by eluation with 1M ammonia in MeOH). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.235 (1.09), 2.334 (1.58), 2.338 (0.84), 2.362 (16.00), 2.520 (7.24), 2.525 (4.55), 2.545 (1.21), 2.570 (1.33), 2.575 (1.40), 2.601 (1.20), 2.676 (1.83), 2.680 (1.06), 2.705 (1.02), 2.713 (0.99), 2.732 (1.01), 2.740 (0.93), 2.758 (1.50), 2.787 (0.62), 2.846 (1.74), 2.863 (4.52), 2.880 (2.07), 2.894 (1.12), 3.300 (4.30), 3.410 (1.44), 3.416 (1.55), 3.427 (2.54), 3.433 (2.52), 3.445 (1.29), 3.585 (0.65), 3.593 (0.77), 3.612 (1.20), 3.620 (1.22), 3.640 (0.69), 3.646 (0.62), 3.851 (0.59), 3.868 (0.92), 3.875 (0.91), 3.902 (1.40), 3.930 (1.00), 4.073 (1.20), 4.090 (1.18), 4.098 (1.63), 4.116 (1.39), 4.274 (1.41), 4.282 (1.45), 4.299 (1.18), 4.307 (1.08), 5.528 (0.41), 6.196 (1.85), 6.200 (1.81), 6.215 (2.00), 6.219 (1.86), 6.726 (1.04), 6.730 (1.33), 6.746 (3.44), 6.750 (2.92), 6.761 (2.53), 6.780 (2.58), 6.800 (0.88), 7.192 (2.31), 7.231 (3.82), 7.244 (3.92), 7.364 (4.42), 7.980 (4.81), 7.993 (4.51), 8.370 (6.73), 8.397 (0.45), 11.102 (2.40). LC-MS (method 6): Rt = 0.52 min; MS (ESlpos): m / z = 468 [M+H] +< Intermediate 43-1 tert-butyl (3R)-3-[({4-[3-(3-chloro-2-methylanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate

[0400]

[0401] Using an analogous method as described for example 1 with tert-butyl (3R)-3-[({4-[({5-[(3-chloro-2-methylphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (180 mg, 299 µmol) as the starting material; 35.1 mg (90% purity, 19% yield) of the title compound were prepared after purification by preparative HPLC (method 9, gradient: 0.00-0.50 min 15% B, 0.50-4.23 min 15-41.9% B, 4.23 - 5.60 min 41.9% B, 5.60 - 7.37 min 41.9 - 55% B). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.344 (16.00), 2.357 (14.22), 2.520 (2.49), 2.525 (1.70), 2.891 (0.42), 2.923 (1.43), 3.384 (1.03), 3.405 (2.12), 3.412 (2.73), 3.417 (2.74), 3.435 (1.48), 3.555 (0.76), 3.577 (0.85), 3.680 (1.24), 3.709 (1.06), 3.840 (1.02), 3.860 (0.92), 3.952 (1.42), 3.982 (1.23), 4.301 (0.62), 6.161 (1.64), 6.165 (1.44), 6.179 (1.77), 6.184 (1.67), 6.725 (0.94), 6.740 (3.11), 6.745 (3.77), 6.765 (1.40), 6.785 (0.46), 7.187 (1.94), 7.309 (2.75), 7.322 (2.75), 7.351 (4.78), 7.971 (1.97), 7.983 (1.88), 8.445 (5.01), 11.063 (1.60). LC-MS (method 6): Rt = 0.92 min; MS (ESlpos): m / z = 568 [M+H] +< Intermediate 43-2 3-(3-chloro-2-methylanilino)-2-(3-{[(3R)-morpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0402]

[0403] Using an analogous method as described for intermediate 22-2 with tert-butyl (3R)-3-[({4-[3-(3-chloro-2-methylanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (intermediate 43-1, 30.0 mg, 52.8 µmol) as the starting material 25.3 mg (97% purity, 99% yield) of the title compound were prepared after filtration through a SCX-2 column (MeOH wash followed by eluation with 1M ammonia in MeOH). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.235 (0.47), 2.334 (1.10), 2.338 (0.53), 2.367 (16.00), 2.383 (0.45), 2.520 (5.15), 2.525 (3.36), 2.676 (1.09), 2.680 (0.50), 2.825 (1.81), 2.842 (3.79), 2.860 (2.41), 2.888 (0.56), 2.945 (0.90), 2.976 (0.54), 3.155 (0.67), 3.371 (1.08), 3.398 (1.36), 3.416 (2.04), 3.426 (3.16), 3.433 (2.75), 3.444 (2.06), 3.450 (1.95), 3.471 (0.57), 3.720 (1.01), 3.747 (0.86), 3.794 (1.03), 3.816 (0.90), 4.192 (0.59), 4.208 (0.66), 4.218 (1.25), 4.232 (1.21), 4.252 (1.38), 4.261 (1.46), 4.277 (0.69), 4.286 (0.59), 6.222 (1.82), 6.225 (1.83), 6.241 (1.98), 6.245 (1.89), 6.731 (1.15), 6.735 (1.43), 6.751 (3.26), 6.754 (2.74), 6.769 (2.24), 6.790 (2.51), 6.809 (0.87), 7.172 (2.36), 7.217 (2.75), 7.230 (2.77), 7.391 (4.55), 7.941 (1.75), 7.953 (1.66), 8.359 (2.93), 12.612 (0.40). LC-MS (method 6): Rt = 0.53 min; MS (ESlpos): m / z = 468 [M+H] +< Intermediate 55-1 tert-butyl (2R)-2-[({4-[3-(3-chloro-2-ethylanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate

[0404]

[0405] Using an analogous method as described for example 1 with tert-butyl (2R)-2-[({4-[({5-[(3-chloro-2-ethylphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (intermediate 6-55, 473 mg, 768 µmol) as the starting material; 57.0 mg (95% purity, 12% yield) of the title compound were prepared after purification by preparative HPLC (method 10, gradient: 0.00-0.50 min 10% B, 0.50-11.05 min 10-34.4% B, 11.05 - 12.46 min 34.4% B, 12.46 - 24.12 min 34.4 - 60% B) followed by flash chromatography (silica, DCM / EtOH gradient 0-12%). LC-MS (method 2): Rt = 1.26 min; MS (ESlpos): m / z = 582 [M+H] +< Intermediate 55-2 3-(3-chloro-2-ethylanilino)-2-(3-{[(2R)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0406]

[0407] Using an analogous method as described for intermediate 22-2 with tert-butyl (2R)-2-[({4-[3-(3-chloro-2-ethylanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (intermediate 55-1, 70.4 mg, 121 µmol) as the starting material; 58.0 mg (95% purity, 95% yield) of the title compound were prepared after purification by flash chromatography (silica, DCM / EtOH + triethylamine gradient 1-40%). 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 10.96 - 11.17 (m, 1H), 8.36 (s, 1H), 7.69 - 8.02 (m, 1H), 7.37 - 7.51 (m, 1H), 7.19 (s, 2H), 6.65 - 6.86 (m, 2H), 6.15 - 6.24 (m, 1H), 6.12 - 6.31 (m, 1H), 4.26 - 4.36 (m, 1H), 4.06 - 4.14 (m, 1H), 3.85 - 3.96 (m, 2H), 3.58 - 3.67 (m, 1H), 3.40 - 3.46 (m, 2H), 3.35 - 3.39 (m, 1H), 2.69 - 2.96 (m, 7H), 2.56 - 2.64 (m, 1H), 1.19 - 1.27 (m, 6H). LC-MS (method 2): Rt = 0.99 min; MS (ESlneg): m / z = 480 [M-H] -< Intermediate 56-1 tert-butyl (2S)-2-[({4-[3-(3-chloro-2-ethylanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate

[0408]

[0409] Using an analogous method as described for example 1 with tert-butyl (2S)-2-[({4-[({5-[(3-chloro-2-ethylphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (intermediate 6-56, 476 mg, 772 µmol) as the starting material; 68.0 mg (95% purity, 14% yield) of the title compound were prepared after purification by preparative HPLC (method 10, gradient: 0.00-0.50 min 20% B, 0.50-12.99 min 20-40% B, 12.99 - 15.46 min 40% B, 15.46 - 24.12 min 40 - 55% B) followed by flash chromatography (silica, DCM / EtOH gradient 0-12%). LC-MS (method 2): Rt = 1.26 min; MS (ESlpos): m / z = 582 [M+H] +< Intermediate 56-2 3-(3-chloro-2-ethylanilino)-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0410]

[0411] Using an analogous method as described for intermediate 22-2 with tert-butyl (2S)-2-[({4-[3-(3-chloro-2-ethylanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]morpholine-4-carboxylate (intermediate 56-1, 70.4 mg, 121 µmol) as the starting material; 46.9 mg (95% purity, 78% yield) of the title compound were prepared after purification by flash chromatography (amino phase silica, DCM / EtOH gradient 1-35%). 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 11.09 (s, 1H), 8.36 (s, 1H), 7.96 (d, 1H), 7.46 (s, 1H), 7.19 (d, 2H), 6.68 - 6.84 (m, 2H), 6.23 (dd, 1H), 4.24 - 4.34 (m, 1H), 4.03 - 4.16 (m, 1H), 3.82 - 3.96 (m, 2H), 3.57 - 3.65 (m, 1H), 3.39 - 3.48 (m, 2H), 2.82 - 2.94 (m, 5H), 2.64 - 2.79 (m, 2H), 2.54 - 2.60 (m, 1H), 1.23 (t, 3H). LC-MS (method 2): Rt = 0.99 min; MS (ESlneg): m / z = 480 [M-H] -< Examples Example 1 3-(3-chloro-2-methoxyanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0412]

[0413] To a suspension of N-(3-chloro-2-methoxyphenyl)-4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-1, 140 mg, 240 µmol) in MeOH (2.7 ml) was added TFA (42 µl, 540 µmol) followed by aqueous hydrogen peroxide (94 µl, 35 % purity, 1.08 mmol) and the mixture was heated at 50°C for 17 h. The reaction mixture was allowed to cool down to RT and concentrated under reduced pressure. The residue was purified by preparative HPLC (method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B) to give 70 mg of the title compound (51 % yield). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 2.86 (t, 2H), 3.37 - 3.57 (m, 4H), 3.70 - 3.90 (m, 4H), 3.88 (s, 3H), 3.92 - 4.08 (m, 1H), 4.10 - 4.20 (m, 1H), 4.28 (dd, 1H), 6.15 (t, 1H), 6.68 (d, 2H), 7.16 (br s, 1H), 7.28 (d, 1H), 7.52 (s, 1H), 8.04 (d, 1H), 8.39 (s, 1H), 11.07 (s, 1H). LC-MS (method 2): Rt = 0.98 min; MS (ESlpos): m / z = 485 [M+H] +< Example 2 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (Stereoisomer 1)

[0414]

[0415] The title compound from example 1 (140 mg) was separated into enantiomers by preparative chiral HPLC to give title compound (enantiomer 1, 27 mg at Rt = 14.0 - 17.0 min) and enantiomer 2 (25 mg at Rt = 20.0 - 24.8 min, see example 3).Preparative chiral HPLC method:

[0416] Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000; column: Cellulose SB 5µ, 250x30 mm; eluent A: hexane + 0.1 vol. % diethylamine (99 %); eluent B: 2-propanol; isocratic: 50 % A + 50 % B; flow 50 ml / min; UV: 254 nm.Analytical chiral HPLC method:

[0417] Instrument: Agilent HPLC 1260; column: Cellulose SB 3µ, 100x4.6 mm; eluent A: hexane + 0.1 vol. % diethylamine (99 %); eluent B: 2-propanol; isocratic: 50 % A + 50 % B, flow 1.4 ml / min; temperature: 25°C; UV: 254 nm

[0418] Analytical chiral HPLC: Rt = 4.49 min.

[0419] Optical rotation: α D = 1.7 ° + / − 0.98 ° c = 3.6 mg / 2 ml , methanol

[0420] Enantioselective synthesis confirmed the title compound as 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. 872 mg (95% purity, 72% yield) of the title compound were prepared in analogy to example 1 using N-(3-chloro-2-methoxyphenyl)-4-{[(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-2, 1.23 g, 2.36 mmol) as starting material, followed by purification with preparative HPLC (method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B).

[0421] 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 2.86 (t, 2H), 3.38 - 3.47 (m, 3H), 3.53 (td, 1H), 3.69 - 3.78 (m, 2H), 3.83 (dd, 1H), 3.88 (s, 3H), 3.90 (m, 1H), 3.98 - 4.08 (m, 1H), 4.12 - 4.18 (m, 1H), 4.28 (dd, 1H), 6.12 - 6.17 (quin, 1H), 6.66 - 6.71 (m, 2H), 7.16 (s, 1H), 7.28 (d, 1H), 7.52 (s, 1H), 8.04 (d, 1H), 8.39 (s, 1H), 11.07 (s, 1H).

[0422] Analytical chiral HPLC: Rt = 4.46 min.

[0423] Optical rotation: α D = − 12.5 ° + / − 0.52 ° c = 5.6 mg / ml , chloroform Example 3 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (Stereoisomer 2)

[0424]

[0425] For the preparation of the racemic title compound see example 1. Separation of enantiomers by preparative chiral HPLC (method see example 2) gave 25 mg of the title compound (at Rt = 20.0 - 24.8 min).

[0426] Analytical chiral HPLC (method see example 2): R t = 6.56 min.

[0427] Optical rotation: α D = − 3.0 ° + / − 1.03 ° c = 3.2 mg / 2 ml , methanol

[0428] Optical rotation: α D = 22.8 ° + / − 6.1 ° c = 6.3 mg / ml , chloroform Example 4 2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0429]

[0430] In analogy to example 1 4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-N-(3-fluoro-2-methoxyphenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-4, 120 mg, 239 µmol) was used to prepare 25.7 mg of the title compound (21 % yield) after heating for 25 hours and purification by preparative HPLC (method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 2.86 (t, 2H), 3.37 - 3.57 (m, 4H), 3.66 - 3.89 (m, 4H), 3.91 (s, 3H), 3.98 - 4.09 (m, 1H), 4.09 - 4.20 (m, 1H), 4.28 (dd, 1H), 6.00 (d, 1H), 6.45 - 6.54 (m, 1H), 6.64 (m, 1H), 7.16 (br s, 1H), 7.29 (d, 1H), 7.53 (s, 1H), 8.04 (d, 1H), 8.39 (s, 1H), 11.05 (s, 1H). LC-MS (method 2): Rt = 0.92 min; MS (ESlpos): m / z = 469 [M+H] +< Example 5 2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 1)

[0431]

[0432] The title compound from example 4 (26 mg) was separated into enantiomers by preparative chiral HPLC to give title compound (enantiomer 1, 11 mg, at R t = 8.2 - 9.1 min, 10 % yield) and enantiomer 2 (12 mg, at R t = 9.7 - 10.7 min, see example 6).Preparative chiral HPLC method:

[0433] Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000; column: Cellulose SB 5µ, 250x30 mm; eluent A: MTBE + 0.1 vol. % diethylamine (99 %); eluent B: acetonitrile; gradient: 2-60 % B in 20 min; flow 50 ml / min; UV: 280 nmAnalytical chiral HPLC method:

[0434] Instrument: Agilent HPLC 1260; column: Cellulose SB 3µ, 100x4.6 mm; eluent A: MTBE + 0.1 vol. % diethylamine (99 %); eluent B: acetonitrile; gradient: 2-60 % B in 7 min, flow 1.4 ml / min; temperature: 25°C; UV: 280 nm

[0435] Analytical chiral HPLC: Rt = 4.34 min.

[0436] Optical rotation: α D = − 0.5 ° + / − 0.87 ° c = 7.5 mg / 2 ml , methanol Example 6 2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 2)

[0437]

[0438] For the preparation of the racemic title compound see example 4. Separation of enantiomers by preparative chiral HPLC (method see example 5) to give 12 mg of the title compound (at Rt = 9.7 - 10.7 min, 11 % yield).

[0439] Analytical chiral HPLC (method see example 5): R t = 5.11 min.

[0440] Optical rotation: α D = − 0.1 ° + / − 0.89 ° c = 6.3 mg / 3 ml , methanol Example 7 3-(2,3-dichloroanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0441]

[0442] In analogy to example 1 N-(2,3-dichlorophenyl)-4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-7, 110 mg, 210 µmol) was used to prepare 34.6 mg of the title compound (32 % yield) after heating for 25 hours and purification by preparative HPLC (method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 2.86 (br t, 2H), 3.35 - 3.45 (m, 3H), 3.47 - 3.56 (m, 1H), 3.65 - 3.75 (m, 2H), 3.75 - 3.88 (m, 2H), 3.93 - 4.04 (m, 1H), 4.06 - 4.20 (m, 2H), 6.27 (dd, 1H), 6.83 - 6.91 (m, 2H), 7.17 (br s, 1H), 7.26 (d, 1H), 7.66 (s, 1H), 8.08 (d, 1H), 8.38 (s, 1H), 11.21 (s, 1H). LC-MS (method 2): Rt = 1.01 min; MS (ESlpos): m / z = 489 [M+H] +< Example 8 3-(2,3-dichloroanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 1)

[0443]

[0444] The title compound from example 7 (27 mg) was separated into enantiomers by preparative chiral HPLC to give title compound (enantiomer 1, 10 mg) and enantiomer 2 (12 mg, see example 9).Preparative chiral HPLC method:

[0445] Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000; column: Cellulose SB 5µ, 250x30 mm; eluent A: MTBE + 0.1 vol. % diethylamine (99 %); eluent B: acetonitrile; gradient: 2-60 % B in 20 min; flow 50 ml / min; UV: 280 nmAnalytical chiral HPLC method:

[0446] Instrument: Agilent HPLC 1260; column: Cellulose SB 3µ, 100x4.6 mm; eluent A: MTBE + 0.1 vol. % diethylamine (99 %); eluent B: acetonitrile; gradient: 2-60 % B in 7 min, flow 1.4 ml / min; temperature: 25°C; UV: 280 nm

[0447] Analytical chiral HPLC : Rt = 5.11 min.

[0448] Optical rotation: α D = 1.4 ° + / − 0.69 ° c = 5.8 mg / 2 ml , methanol Example 9 3-(2,3-Dichloroanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 2)

[0449]

[0450] For the preparation of the racemic title compound see example 7. Separation of enantiomers by preparative chiral HPLC (method see example 8) to gave 12 mg of the title compound.

[0451] Analytical chiral HPLC (method see example 8): R t = 6.74 min.

[0452] Optical rotation: α D = − 14.9 ° + / − 3.16 ° c = 5.6 mg / ml , methanol Example 10 3-(3-chloro-2-methylanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0453]

[0454] In analogy to example 1 N-(3-chloro-2-methylphenyl)-4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-10, 180 mg, 358 µmol) was used to prepare 12.1 mg of the title compound (7 % yield) after heating for 25 hours and purification by preparative HPLC (method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 2.35 (s, 3H), 2.86 (br t, 2H), 3.37 - 3.47 (m, 3H), 3.55 (br dd, 1H), 3.67 - 3.85 (m, 3H), 3.89 (br d, 1H), 4.01 (br dd, 1H), 4.08 - 4.18 (m, 1H), 4.24 (dd, 1H), 6.20 (d, 1H), 6.71 - 6.80 (m, 2H), 7.19 (br s, 1H), 7.24 (d, 1H), 7.37 (s, 1H), 8.01 (d, 1H), 8.37 (s, 1H), 11.05 (s, 1H). LC-MS (method 2): Rt = 1.02 min; MS (ESlpos): m / z = 469 [M+H] +< Example 11 3-(3-chloro-2-methoxyanilino)-2-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0455]

[0456] In analogy to example 1 N-(3-chloro-2-methoxyphenyl)-4-{[(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-11, 82 mg, 139 µmol) was used to prepare 11 mg of the title compound (15 % yield) after heating for 17 hours and purification by preparative HPLC (method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 11.51 - 12.57 (m, 1H), 8.40 (br s, 1H), 8.04 (br s, 1H), 7.62 (br s, 1H), 7.32 (d, 1H), 7.19 (br s, 1H), 6.71 (br d, 2H), 6.15 (dd, 1H), 4.40 (br s, 2H), 3.90 (s, 4H), 3.85 (br s, 1H), 3.60 (br d, 3H), 3.40 - 3.51 (m, 3H), 3.01 (br s, 1H), 2.74 - 2.96 (m, 3H), 2.22 - 2.43 (m, 2H). LC-MS (method 6): Rt = 0.55 min; MS (ESlpos): m / z = 498.2 [M+H] +<

[0457] Optical rotation: α D = − 82.0 ° + / − 0.41 ° c = 5.8 mg / ml , methanol Example 12 3-(3-fluoro-2-methoxyanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0458]

[0459] 3-(3-Fluoro-2-methoxyanilino)-2-(3-hydroxypyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (intermediate 12, 150 mg, 407 µmol) was solved in dioxane (4.8 ml). The reaction mixture was degassed with argon. Then (tributylphosphanylidene)acetonitrile (384 µl, 1.5 mmol, CAS 157141-27-0) and (4-methylmorpholin-2-yl)methanol (CAS 40987-46-0, 80.0 mg, 610 µmol) were added and the mixture was stirred at 50°C for 30 h. The mixture was concentrated under reduced pressure and sat. sodium bicarbonate solution was added. The mixture was extracted with DCM. The organic phase was filtered over a water-repellent filter, concentrated under reduced pressure and purified by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 1% B, 0.50 - 27.40 min 1 - 50% B) to give 16.2 mg of the title compound (8 % yield). 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 11.05 (s, 1H), 8.40 (s, 1H), 8.02 (d, 1H), 7.52 (s, 1H), 7.29 (d, 1H), 7.16 (s, 1H), 6.64 (td, 1H), 6.50 (ddd, 1H), 6.01 (d, 1H), 4.34 (dd, 1H), 4.15 (dd, 1H), 3.88 - 4.00 (m, 5H), 3.67 (td, 1H), 3.37 - 3.47 (m, 2H), 2.85 (t, 2H), 2.77 (br d, 1H), 2.66 - 2.70 (m, 1H), 2.20 (s, 3H), 2.04 (td, 1H), 1.91 (t, 1H). LC-MS (method 2): Rt = 0.92 min; MS (ESlpos): m / z = 482.3 [M+H] +< Example 13 3-(3-fluoro-2-methoxyanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 1)

[0460]

[0461] The title compound from example 12 (19 mg) was separated into enantiomers by preparative chiral HPLC to give title compound (enantiomer 1, 6 mg, at R t = 6.7 - 8.7 min, 3 % yield) and enantiomer 2 (7 mg, at Rt = 8.9 - 11.9 min, see example 14).Preparative chiral HPLC method:

[0462] Instrument: PrepCon Labomatic HPLC; column: Chiralcel OD-H 5µ, 250x20; eluent A: acetonitrile + 0.1 vol. % diethylamine (99 %); eluent B: ethanol; isocratic: 93 % A + 7 % B; flow 20 ml / min; temperature: 25°C; UV: 254 nmAnalytical chiral HPLC method:

[0463] Instrument: Waters Alliance 2695; column: Chiralcel OD-H 5µ, 100x4.6; eluent A: ethanol + 0.1 vol. % diethylamine (99 %); eluent B: ethanol; isocratic: 90 % A + 10 % B, flow 1.4 ml / min; temperature: 25°C; UV: 254 nm

[0464] Analytical chiral HPLC : Rt = 2.91 min.

[0465] 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 11.05 (s, 1H), 8.40 (s, 1H), 8.02 (d, 1H), 7.53 (s, 1H), 7.29 (d, 1H), 7.16 (s, 1H), 6.64 (td, 1H), 6.50 (t, 1H), 6.01 (d, 1H), 4.34 (dd, 1H), 4.15 (dd, 1H), 3.89 - 3.99 (m, 5H), 3.67 (td, 1H), 3.38 - 3.46 (m, 2H), 2.85 (t, 2H), 2.77 (br d, 1H), 2.61 - 2.71 (m, 1H), 2.20 (s, 3H), 1.98 - 2.16 (m, 1H), 1.91 (t, 1H).Example 14 3-(3-fluoro-2-methoxyanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 2)

[0466]

[0467] For the preparation of the racemic title compound see example 12. Separation of enantiomers by preparative chiral HPLC (method see example 13) to give 7 mg of the title compound (at Rt = 8.9 - 11.9 min , 3 % yield).

[0468] Analytical chiral HPLC (method see example 13): R t = 3.70 min.

[0469] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 11.05 (s, 1H), 8.40 (s, 1H), 8.02 (br d, 1H), 7.53 (s, 1H), 7.29 (d, 1H), 7.16 (br s, 1H), 6.59 - 6.70 (m, 1H), 6.50 (br t, 1H), 6.01 (br d, 1H), 4.34 (br dd, 1H), 4.15 (br dd, 1H), 3.86 - 4.00 (m, 5H), 3.60 - 3.74 (m, 1H), 3.40 - 3.48 (m, 2H), 2.85 (br t, 2H), 2.77 (br d, 1H), 2.63 - 2.70 (m, 1H), 2.20 (s, 3H), 1.99 - 2.09 (m, 1H), 1.91 (br t, 1H).Example 15 3-(3-chloro-2-methoxyanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0470]

[0471] In analogy to example 1 N-(3-chloro-2-methoxyphenyl)-4-[({3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-15, 74.0 mg, 139 µmol) was used to prepare 24.1 mg (90 % purity, 31 % yield) of the title compound after heating for 18 hours and purification by preparative HPLC (method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.86 - 1.95 (t, 1H), 2.00 - 2.09 (td, 1H), 2.20 (s, 3H), 2.66 (br d, 1H), 2.73 - 2.81 (br d, 1H), 2.86 (t, 2H), 3.42 (td, 2H), 3.61 - 3.73 (td, 1H), 3.88 (s, 3H), 3.91 - 4.02 (m, 2H), 4.16 (dd, 1H), 4.33 (dd, 1H), 6.15 (t, 1H), 6.69 (d, 2H), 7.16 (s, 1H), 7.28 (d, 1H), 7.53 (s, 1H), 8.03 (d, 1H), 8.40 (s, 1H), 11.07 (s, 1H). LC-MS (method 2): Rt = 0.97 min; MS (ESlpos): m / z = 498 [M+H] +< Example 16 3-(3-chloro-2-methoxyanilino)-2-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 1)

[0472]

[0473] The title compound from example 15 (24.1 mg) was separated into enantiomers by preparative chiral HPLC to give title compound (enantiomer 1, 8 mg, at R t = 17.4 - 21.8, 11 % yield) and enantiomer 2 (7 mg, at Rt = 12.5 - 14.5 min, see example 17).Preparative chiral HPLC method:

[0474] Instrument: PrepCon Labomatic HPLC; Column: Chiralpak IF 5µ, 250x30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 50%A+50%B; flow: 40 ml / min; temperature: 25°C; UV: 280 nmAnalytical chiral HPLC method:

[0475] Instrument: Waters Alliance 2695; Column: Chiralpak IF 3µ, 100x4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 50%A+50%B; flow: 1.4 ml / min; temperature: 25°C; UV: 280 nm

[0476] Analytical chiral HPLC : Rt = 4.55 min.

[0477] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.232 (1.95), 1.259 (0.49), 1.888 (0.59), 1.914 (1.04), 1.941 (0.65), 2.016 (0.40), 2.037 (0.73), 2.045 (0.70), 2.065 (0.49), 2.206 (9.36), 2.327 (0.42), 2.518 (1.60), 2.523 (1.15), 2.540 (16.00), 2.646 (0.75), 2.670 (0.96), 2.673 (0.98), 2.758 (0.81), 2.787 (0.77), 2.841 (1.13), 2.858 (2.36), 2.876 (1.27), 3.405 (0.89), 3.410 (0.98), 3.422 (1.69), 3.428 (1.67), 3.439 (0.85), 3.445 (0.77), 3.638 (0.41), 3.644 (0.49), 3.666 (0.89), 3.672 (0.89), 3.694 (0.54), 3.700 (0.52), 3.883 (15.90), 3.933 (0.86), 3.952 (0.89), 3.960 (1.15), 3.976 (0.47), 3.983 (0.40), 4.137 (0.82), 4.154 (0.74), 4.163 (1.02), 4.179 (0.84), 4.315 (0.97), 4.324 (1.01), 4.341 (0.80), 4.349 (0.72), 6.139 (1.35), 6.151 (2.23), 6.163 (1.38), 6.681 (4.49), 6.692 (3.40), 6.694 (3.35), 7.163 (1.58), 7.274 (1.81), 7.287 (1.83), 7.533 (3.41), 8.021 (1.20), 8.034 (1.14), 8.402 (1.87), 11.066 (1.70).Example 17 3-(3-chloro-2-methoxyanilino)-2-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 2)

[0478]

[0479] For the preparation of the racemic title compound see example 15. Separation of enantiomers by preparative chiral HPLC (method see example 16) to give 7 mg of the title compound (at Rt = 12.5 - 14.5 min).

[0480] Analytical chiral HPLC (method see example 16): R t = 2.93 min.Example 18 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0481]

[0482] Using an analogous method as described for example 1 with N-(3-chloro-5-fluoro-2-methoxyphenyl)-4-[({3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-18, 166 mg, 302 µmol) as the starting material; 13.0 mg (95 % purity, 8 % yield) of the title compound were prepared after purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 15% B, 0.50 - 6.00 min 15 - 55% B). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.88 (t, 1H), 1.93 - 2.05 (dt, 1H), 2.19 (s, 3H), 2.60 - 2.66 (d, 1H), 2.70 - 2.77 (d, 1H), 2.86 (t, 2H), 3.37 - 3.48 (m, 2H), 3.56 - 3.68 (m, 1H), 3.83 (s, 3H), 3.90 (br d, 2H), 4.15 (m, 1H), 4.27 (dd, 1H), 5.85 (dd, 1H), 6.56 (dd, 1H), 7.13 (s, 1H), 7.33 (d, 1H), 7.64 (s, 1H), 8.10 (d, 1H), 8.43 (s, 1H), 11.18 (s, 1H). LC-MS (method 2): Rt = 1.00 min; MS (ESlpos): m / z = 516 [M+H] +< Example 19 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0483]

[0484] Using an analogous method as described for example 1 with N-(3-chloro-5-fluoro-2-methoxyphenyl)-4-[({3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-19, 160 mg, 298 µmol) as the starting material; 3.90 mg (90 % purity, 2 % yield) of the title compound were prepared after purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 15% B, 0.50 - 6.00 min 15 - 55% B). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 2.86 (t, 2H), 3.37 - 3.45 (m, 3H), 3.47 - 3.61 (m, 1H), 3.62 - 3.77 (m, 3H), 3.77 - 3.87 (m, 6H), 3.94 - 4.01 (m, 1H), 4.07 - 4.20 (m, 1H), 4.24 (dd, 1H), 5.85 (dd, 1H), 6.56 (dd, 1H), 7.13 (s, 1H), 7.33 (d, 1H), 7.60 - 7.66 (d, 1H), 8.11 (br d, 1H), 8.42 (s, 1H), 11.19 (s, 1H). LC-MS (method 2): Rt = 1.01 min; MS (ESlpos): m / z = 503 [M+H] +< Example 20 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0485]

[0486] Using an analogous method as described for example 1 with N-(3-fluoro-2-methoxyphenyl)-4-{[(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-20, 102 mg, 197 µmol) as the starting material; 27.9 mg (90 % purity, 26 % yield) of the title compound were prepared after purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 10% B, 0.50 - 6.00 min 10 - 50% B). LC-MS (method 6): Rt = 0.51 min; MS (ESlpos): m / z = 482 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.274 (13.29), 2.304 (1.76), 2.318 (0.55), 2.404 (0.46), 2.426 (0.88), 2.434 (0.91), 2.449 (0.43), 2.454 (0.88), 2.458 (1.03), 2.463 (1.43), 2.468 (1.37), 2.473 (1.55), 2.518 (5.99), 2.523 (4.32), 2.775 (0.40), 2.798 (0.70), 2.815 (1.49), 2.822 (0.88), 2.832 (0.91), 2.841 (1.16), 2.858 (0.79), 2.908 (1.13), 2.938 (1.00), 3.294 (0.43), 3.406 (0.64), 3.423 (1.46), 3.429 (1.19), 3.438 (1.37), 3.453 (0.58), 3.459 (0.55), 3.546 (1.13), 3.573 (1.76), 3.589 (1.13), 3.594 (1.22), 3.600 (1.28), 3.618 (0.61), 3.816 (0.94), 3.840 (1.83), 3.847 (1.95), 3.868 (1.06), 3.875 (0.97), 3.938 (16.00), 3.951 (2.07), 4.374 (1.67), 4.386 (2.71), 4.414 (0.46), 6.011 (1.89), 6.031 (1.89), 6.514 (1.03), 6.518 (0.97), 6.535 (1.28), 6.539 (1.34), 6.541 (1.19), 6.545 (0.94), 6.562 (1.19), 6.565 (1.06), 6.655 (0.97), 6.670 (1.03), 6.675 (1.70), 6.691 (1.55), 6.696 (0.82), 6.711 (0.67), 7.176 (2.07), 7.310 (3.71), 7.323 (3.68), 7.514 (0.43), 7.527 (0.52), 7.533 (0.58), 7.601 (4.56), 7.977 (5.29), 7.990 (4.50), 8.067 (0.61), 8.080 (0.55), 8.358 (6.27), 8.439 (0.73), 12.011 (2.13). Example 21 3-(3-chloro-2-methoxyanilino)-2-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0487]

[0488] Using an analogous method as described for example 1 with N-(3-chloro-2-methoxyphenyl)-4-{[(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-21, 99.5 mg, 187 µmol) as the starting material; 4.70 mg (98 % purity, 5 % yield) of the title compound were prepared after purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 10% B, 0.50 - 6.00 min 10 - 50% B). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.232 (0.45), 2.276 (9.36), 2.426 (0.63), 2.434 (0.67), 2.456 (0.51), 2.464 (0.76), 2.472 (0.79), 2.518 (1.95), 2.523 (1.26), 2.539 (9.95), 2.806 (0.54), 2.823 (1.37), 2.841 (1.19), 2.860 (0.60), 2.910 (0.85), 2.940 (0.76), 3.408 (0.49), 3.425 (1.12), 3.431 (0.95), 3.441 (1.04), 3.454 (0.49), 3.460 (0.44), 3.544 (0.71), 3.572 (1.31), 3.588 (0.84), 3.594 (0.92), 3.599 (0.96), 3.617 (0.47), 3.817 (0.72), 3.841 (1.23), 3.847 (1.34), 3.868 (0.69), 3.875 (0.63), 3.912 (16.00), 3.924 (0.49), 4.376 (1.24), 4.387 (2.11), 6.151 (1.35), 6.162 (2.22), 6.175 (1.39), 6.718 (3.50), 6.720 (3.93), 6.731 (4.23), 7.179 (1.54), 7.299 (2.18), 7.312 (2.21), 7.614 (3.34), 7.983 (1.76), 7.995 (1.68), 8.362 (2.68), 12.027 (1.61). LC-MS (method 6): Rt = 0.54 min; MS (ESlpos): m / z = 498 [M+H] +< Example 22 2-(3-{[(2S)-4-(2,2-difluoroethyl)morpholin-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0489]

[0490] 3-(3-Fluoro-2-methoxyanilino)-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7- tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (intermediate 22, 50.0 mg, 107 µmol) was solubilized in DMF (1.6 ml), triethylamine (89 µl, 640 µmol) and 2,2-difluoroethyl trifluoromethanesulfonate (64 µl, 480 µmol) were added and the mxiture was stirred for 1h at RT. The mixture was purified by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 15% B, 0.50 - 6.00 min 15 - 55% B) to give 11.3 mg (90 % purity, 18 % yield) of the target compound. 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 2.24 (t, 1H), 2.34 - 2.40 (dd, 1H), 2.78 (m, 1H), 2.78 - 2.81 (m, 1H), 2.83 (m, 1H), 2.85 - 2.90 (t, 2H), 2.90 - 2.97 (d, 1H), 3.38 - 3.47 (m, 2H), 3.68 (dt, 1H), 3.89 - 3.92 (s, 3H), 3.92 - 4.03 (m, 2H), 4.17 (dd, 1H), 4.29 (dd, 1H), 5.97 - 6.02 (d, 1H), 6.02 - 6.34 (tt, 1H), 6.47 - 6.54 (m, 1H), 6.64 (td, 1H), 7.16 (s, 1H), 7.29 (d, 1H), 7.54 (s, 1H), 8.02 (d, 1H), 8.40 (s, 1H), 11.03 (s, 1H). LC-MS (method 2): Rt = 1.04 min; MS (ESlpos): m / z = 532 [M+H] +< Example 23 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(2S)-4-(2,2,2-trifluoroethyl)morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0491]

[0492] Using an analogous method as described for example 22 with 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (intermediate 22, 35.0 mg, 74.9 µmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (CAS 6226-25-1, 16 µl, 110 µmol) as the starting materials; 11.9 mg (95 % purity, 27 % yield) of the title compound were prepared after preparative HPLC (method 10, gradient: 0.00 - 0.50 min 30% B, 0.50 - 6.00 min 30 - 70% B). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.231 (0.47), 1.264 (0.47), 2.326 (2.22), 2.331 (1.58), 2.359 (0.93), 2.387 (1.69), 2.414 (1.15), 2.518 (7.61), 2.522 (5.31), 2.668 (2.30), 2.673 (1.58), 2.805 (1.18), 2.836 (2.55), 2.853 (3.44), 2.870 (1.79), 2.936 (1.26), 2.964 (1.11), 3.196 (0.54), 3.205 (0.61), 3.221 (1.54), 3.230 (1.58), 3.247 (1.51), 3.255 (1.47), 3.271 (0.61), 3.281 (0.54), 3.400 (1.26), 3.406 (1.33), 3.417 (2.37), 3.423 (2.26), 3.434 (1.15), 3.440 (1.08), 3.654 (0.54), 3.660 (0.65), 3.674 (0.72), 3.683 (1.18), 3.688 (1.15), 3.711 (0.68), 3.912 (16.00), 3.934 (1.11), 3.966 (1.11), 3.983 (0.72), 3.999 (0.75), 4.008 (0.65), 4.157 (1.04), 4.174 (1.00), 4.183 (1.51), 4.199 (1.22), 4.277 (1.40), 4.286 (1.36), 4.303 (1.04), 4.312 (0.86), 5.989 (1.94), 6.010 (1.97), 6.472 (0.86), 6.475 (0.86), 6.493 (1.26), 6.497 (1.26), 6.502 (0.93), 6.520 (1.18), 6.523 (1.04), 6.611 (0.90), 6.626 (1.04), 6.632 (1.54), 6.647 (1.51), 6.652 (0.75), 6.668 (0.65), 7.161 (2.22), 7.278 (3.52), 7.291 (3.55), 7.535 (4.77), 8.018 (4.38), 8.030 (4.02), 8.391 (6.17), 11.018 (2.48). LC-MS (method 2): Rt = 1.09 min; MS (ESlpos): m / z = 550 [M+H] +< Example 24 3-(3-chloro-2-methoxyanilino)-2-{3-[2-(4-dioxan-2-yl)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0493]

[0494] Using an analogous method as described for example 1 with N-(3-chloro-2-methoxyphenyl)-4-[({3-[2-(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide(intermediate 6-24, 105 mg, 197 µmol) as the starting material; 43.5 mg (95 % purity, 42 % yield) of the title compound were prepared after preparative HPLC (method 7). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.817 (0.39), 1.834 (1.18), 1.849 (1.57), 1.861 (1.08), 1.876 (0.49), 2.518 (3.04), 2.522 (2.06), 2.673 (0.59), 2.833 (0.88), 2.846 (1.87), 2.863 (0.98), 3.204 (0.88), 3.231 (1.47), 3.260 (1.08), 3.312 (1.28), 3.396 (1.67), 3.408 (2.16), 3.413 (2.16), 3.426 (1.28), 3.456 (1.18), 3.462 (1.08), 3.484 (0.98), 3.490 (0.98), 3.521 (0.79), 3.525 (0.88), 3.549 (1.08), 3.554 (1.18), 3.582 (0.69), 3.625 (1.28), 3.648 (1.37), 3.668 (2.45), 3.678 (0.98), 3.693 (1.37), 3.716 (1.28), 3.745 (0.98), 3.858 (16.00), 4.226 (1.37), 4.241 (2.94), 4.257 (1.37), 6.103 (1.47), 6.115 (2.06), 6.127 (1.47), 6.640 (5.60), 6.650 (3.63), 7.108 (1.77), 7.287 (2.65), 7.299 (2.75), 7.458 (3.93), 8.020 (3.04), 8.033 (2.85), 8.350 (4.32), 11.191 (1.96). LC-MS (method 6): Rt = 0.68 min; MS (ESlpos): m / z = 499 [M+H] +< Example 25 3-(3-chloro-2-methoxyanilino)-2-{3-[2-(4-dioxan-2-yl)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 1)

[0495]

[0496] The title compound from example 24 (40 mg) was separated into enantiomers by preparative chiral HPLC to give title compound (enantiomer 1, 18.0 mg, at R t = 18.8 - 21.3 min, 96 % purity) and enantiomer 2 (17 mg, at Rt = 21.7 - 24.5 min, see example 26).Preparative chiral HPLC method:

[0497] Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5µ, 250x30; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile + 0.1 vol % diethylamine; gradient: 0-20 min 2-60% B; flow: 40 ml / min; temperature: 25°C; UV: 280 nm

[0498] Analytical chiral HPLC method:

[0499] Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3µ, 100x4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; gradient: 0-7 min 2-60% B; flow: 1.4 ml / min; temperature: 25°C; UV: 280 nm

[0500] Analytical chiral HPLC: Rt = 4.94 min.

[0501] Optical rotation: α D = − 1.6 ° + / − 1.63 ° c = 2 , 8 mg / ml in methanol

[0502] 1< H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]= 1.835 (1.01), 1.851 (1.31), 1.862 (0.93), 1.877 (0.41), 2.518 (1.52), 2.522 (0.99), 2.834 (0.77), 2.846 (1.61), 2.852 (1.47), 2.864 (0.82), 2.869 (0.80), 3.205 (0.76), 3.231 (1.30), 3.235 (1.27), 3.261 (0.85), 3.391 (0.83), 3.397 (0.91), 3.408 (1.57), 3.415 (1.62), 3.430 (0.98), 3.457 (0.99), 3.463 (1.01), 3.485 (0.84), 3.491 (0.79), 3.522 (0.72), 3.527 (0.76), 3.551 (0.96), 3.556 (1.07), 3.584 (0.57), 3.624 (1.00), 3.649 (1.11), 3.654 (1.11), 3.671 (1.96), 3.680 (0.81), 3.687 (0.53), 3.695 (1.23), 3.718 (1.09), 3.723 (1.01), 3.747 (0.79), 3.859 (16.00), 4.227 (1.22), 4.242 (2.58), 4.258 (1.21), 6.105 (1.40), 6.118 (1.81), 6.129 (1.46), 6.641 (5.45), 6.651 (3.33), 6.654 (3.12), 7.110 (1.60), 7.288 (2.35), 7.300 (2.36), 7.306 (0.49), 7.462 (3.57), 8.023 (2.38), 8.035 (2.27), 8.353 (3.43), 11.186 (1.77).Example 26 3-(3-chloro-2-methoxyanilino)-2-{3-[2-(4-dioxan-2-yl)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (Stereoisomer 2)

[0503]

[0504] For the preparation of the racemic title compound see example 24. Separation of enantiomers by preparative chiral HPLC (method see example 25) to give 25 mg of the title compound (at Rt = 21.7 - 24.5 min, 19 % yield).

[0505] Analytical chiral HPLC (method see example 25): R t = 5.49 min.

[0506] Optical rotation: α D = 2.5 ° + / − 1.93 ° c = 2 , 7 mg / ml in methanol Example 27 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0507]

[0508] 3-(3-Chloro-5-fluoro-2-methoxyanilino)-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (intermediate 27, 24.0 mg, 47.8 µmol) was solubilized in methanol (650 µl), formaldehyde (7.2 µl, 37 % purity, 96 µmol) and acetic acid (2.7 µl, 48 µmol) were added and the mixture was stirred for 15 min at RT. Sodium triacetoxyborohydride (15.2 mg, 71.7 µmol) was added and the mixture was stirred for 1h at RT. The mixture was diluted with methanol, filtered through a SCX column and washed with methanol and ammonia (7 M in methanol). The filtrate was evaporated and purified by preparative HPLC (method 9, gradient: 0.00 - 0.50 min 15% B, 0.50 - 6.00 min 15 - 55% B) to yield 17.3 mg (95 % purity, 61 % yield) of the title compound as its formate salt. LC-MS (method 2): Rt = 1.01 min; MS (ESlpos): m / z = 516 [M+H] +<

[0509] 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.189 (13.49), 2.330 (5.06), 2.729 (5.60), 2.861 (7.86), 3.348 (16.00), 3.419 (15.57), 3.624 (4.81), 3.830 (14.46), 3.908 (6.49), 7.633 (4.30), 8.098 (4.59), 8.146 (8.39).

[0510] 3-(3-chloro-5-fluoro-2-methoxy-anilino)-2-[3-[[(2S)-4-methylmorpholin-4-ium-2-yl]methoxy]-4-pyridyl]-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one;formate were solubilized in DCM and whashed saturated aqueous NaHCO 3 and brine to yield 9.00 mg (90 % purity, 33 % yield) of the target compound as its free base.

[0511] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.79 - 1.96 (t, 1H), 1.97 - 2.05 (td, 1H), 2.19 (s, 3H), 2.63 (br d, 1H), 2.71 - 2.82 (br d, 1H), 2.86 (t, 2H), 3.43 (td, 2H), 3.58 - 3.67 (m, 1H), 3.83 (s, 3H), 3.87 - 4.01 (m, 2H), 4.14 (dd, 1H), 4.29 (dd, 1H), 5.85 (dd, 1H), 6.56 (dd, 1H), 7.13 (s, 1H), 7.33 (d, 1H), 7.64 (d, 1H), 8.07 - 8.12 (d, 1H), 8.43 (s, 1H), 11.18 (s, 1H).Example 28 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[(2S)-4-(2,2,2-trifluoroethyl)morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0512]

[0513] Using an analogous method as described for example 22 with 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (intermediate 27, 25.0 mg, 49.8 µmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (CAS 6226-25-1, 11 µl, 75 µmol) as the starting materials; 15.1 mg (95 % purity, 49 % yield) of the title compound were prepared after preparative HPLC (method 10, gradient: 0.00 - 0.50 min 30% B, 0.50 - 6.00 min 30 - 70% B). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 2.35 (t, 1H), 2.77 - 2.95 (m, 4H), 3.21 (dd, 2H), 3.42 (td, 2H), 3.60 - 3.69 (m, 1H), 3.83 (s, 3H), 3.88 - 4.01 (m, 2H), 4.14 - 4.28 (m, 2H), 5.84 (dd, 1H), 6.56 (dd, 1H), 7.13 (s, 1H), 7.32 (d, 1H), 7.62 - 7.66 (m, 1H), 8.10 (d, 1H), 8.43 (s, 1H), 11.16 (s, 1H). LC-MS (method 2): Rt = 1.19 min; MS (ESlpos): m / z = 584 [M+H] +< Example 29 3-(3-chloro-2-ethylanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0514]

[0515] Using an analogous method as described for example 1 with N-(3-chloro-2-ethylphenyl)-4-[({3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-29, 300 mg, 566 µmol) as the starting material; 3.00 mg (85 % purity, 1 % yield) of the title compound were prepared after preparative HPLC (method 10, gradient: 0.00 - 0.50 min 30% B, 0.50 - 6.00 min 30 - 70% B). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 0.851 (0.47), 1.210 (0.41), 1.230 (2.24), 1.352 (0.41), 2.206 (1.49), 2.331 (2.92), 2.336 (1.36), 2.518 (16.00), 2.522 (10.31), 2.539 (1.02), 2.673 (3.05), 2.678 (1.42), 2.864 (0.41), 6.728 (0.41), 6.735 (0.47), 7.188 (0.47), 7.201 (0.47), 7.962 (0.54), 7.975 (0.47), 8.365 (0.68). LC-MS (method 2): Rt = 1.07 min; MS (ESlpos): m / z = 496 [M+H] +< Example 30 3-(3-chloro-2-methoxyanilino)-2-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0516]

[0517] Using an analogous method as described for example 1 with N-(3-chloro-2-methoxyphenyl)-4-[({3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-30, 55.0 mg, 101 µmol) as the starting material; 28.00 mg (98 % purity, 53 % yield) of the title compound were prepared after purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 30% B, 0.50 - 6.00 min 30 - 70% B). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.066 (9.57), 1.234 (8.81), 2.074 (0.42), 2.326 (1.06), 2.331 (0.74), 2.518 (3.90), 2.522 (2.65), 2.668 (1.04), 2.673 (0.76), 2.819 (1.08), 2.837 (2.21), 2.853 (1.18), 3.398 (1.96), 3.409 (1.62), 3.416 (1.61), 3.427 (2.05), 3.580 (0.57), 3.588 (0.65), 3.609 (1.17), 3.618 (1.13), 3.629 (1.85), 3.654 (1.43), 3.657 (1.70), 3.679 (1.32), 3.709 (0.74), 3.868 (16.00), 3.894 (0.49), 3.902 (0.53), 3.910 (0.64), 3.918 (0.58), 3.927 (0.42), 4.155 (0.76), 4.171 (0.72), 4.181 (1.01), 4.198 (0.88), 4.295 (0.97), 4.304 (0.99), 4.322 (0.76), 4.330 (0.67), 6.143 (1.40), 6.155 (1.71), 6.167 (1.40), 6.653 (0.46), 6.663 (5.26), 6.673 (3.14), 6.676 (2.88), 7.138 (1.48), 7.270 (2.51), 7.283 (2.51), 7.475 (3.39), 8.033 (3.36), 8.045 (2.98), 8.404 (4.26), 11.073 (1.66). LC-MS (method 6): Rt = 0.80 min; MS (ESlpos): m / z = 513 [M+H] +< Example 31 3-(3-chloro-2-methoxyanilino)-2-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (Stereoisomer 1)

[0518]

[0519] The title compound from example 30 (26.3 mg) was separated into enantiomers by preparative chiral HPLC to give title compound (enantiomer 1, 11.00 mg, at R t = 10.7 - 13.4 min) and enantiomer 2 (10 mg, at Rt = 14.0 - 19.9 min, see example 32).Preparative chiral HPLC method:

[0520] Instrument: PrepCon Labomatic HPLC; Column: Chiralcel OD-H 5µ, 250x20; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 70%A+30%B; flow: 20 ml / min; temperature: 25°C; UV: 280 nmAnalytical chiral HPLC method:

[0521] Instrument: Waters Alliance 2695; Column: Chiralcel OD-H 5µ, 100x4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 70%A+30%B; flow: 1.4 ml / min; temperature: 25°C; UV: 280 nm

[0522] Analytical chiral HPLC: Rt = 6.72 min.Example 32 3-(3-chloro-2-methoxyanilino)-2-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (Stereoisomer 2)

[0523]

[0524] For the preparation of the racemic title compound see example 30. Separation of enantiomers by preparative chiral HPLC (method see example 31) to give 10 mg of the title compound (at Rt = 14.0 - 19.9 min).

[0525] Analytical chiral HPLC (method see example 31): R t = 10.04 min.Example 332-(3-{[5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0526]

[0527] Using an analogous method as described for example 1; 4-{[(3-{[5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methyl]amino}-N-(3-fluoro-2-methoxyphenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-33, 125 mg, 236 µmol) as the starting material, 15.00 mg (80 % purity, 10 % yield) of the title compound were prepared after preparative HPLC (method 7). 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.068 (15.53), 1.236 (15.37), 2.517 (2.98), 2.522 (2.00), 2.817 (1.52), 2.834 (3.10), 2.851 (1.65), 2.903 (0.47), 2.921 (0.89), 2.936 (0.48), 3.402 (2.87), 3.408 (2.55), 3.415 (2.29), 3.431 (3.39), 3.580 (0.97), 3.588 (1.12), 3.609 (2.52), 3.618 (2.17), 3.633 (3.03), 3.651 (2.10), 3.661 (2.34), 3.677 (2.32), 3.706 (1.26), 3.900 (16.00), 3.917 (5.39), 3.933 (0.80), 3.942 (0.71), 4.147 (1.18), 4.163 (1.12), 4.173 (1.56), 4.189 (1.34), 4.294 (1.63), 4.302 (1.37), 4.320 (1.26), 4.329 (0.93), 4.769 (0.55), 4.780 (0.55), 4.787 (0.58), 4.797 (0.52), 5.696 (0.85), 5.759 (1.92), 5.985 (0.55), 6.000 (1.88), 6.020 (1.84), 6.455 (0.97), 6.476 (1.43), 6.479 (1.49), 6.503 (1.30), 6.597 (0.86), 6.612 (1.11), 6.618 (1.49), 6.625 (0.60), 6.633 (1.47), 6.638 (0.71), 6.653 (0.62), 7.141 (2.11), 7.277 (3.15), 7.289 (3.21), 7.297 (1.00), 7.479 (4.43), 7.531 (1.26), 8.030 (3.74), 8.042 (3.54), 8.399 (6.35), 11.053 (2.30), 11.085 (0.73). LC-MS (method 6): Rt = 0.71 min; MS (ESlpos): m / z = 497 [M+H] +< 2-(3-{[5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (Stereoisomer 1)

[0528]

[0529] The title compound from example 33 (15.0 mg) was separated into enantiomers by preparative chiral HPLC to give title compound (enantiomer 1, 5.00 mg, at Rt = 10.9 - 13.1 min, 32 % yield) and enantiomer 2 (4 mg, at R t = 13.5 - 18.3 min, see example 34).Preparative chiral HPLC method:

[0530] Instrument: PrepCon Labomatic HPLC; Column: Chiralcel OD-H 5µ, 250x20; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 70%A+30%B; flow: 20 ml / min; temperature: 25°C; UV: 280 nm

[0531] Analytical chiral HPLC method:

[0532] Instrument: Waters Alliance 2695; Column: Chiralcel OD-H 5µ, 100x4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 70%A+30%B; flow: 1.4 ml / min; temperature: 25°C; UV: 280 nm

[0533] Analytical chiral HPLC: Rt = 6.58 min.

[0534] Optical rotation: α D = 2.6 ° + / − 1.66 ° c = 2 , 3 mg / ml in methanol Example 34 2-(3-{[5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 2)

[0535]

[0536] For the preparation of the racemic title compound see example 33. Separation of enantiomers by preparative chiral HPLC (method see example 33) to give 4 mg of the title compound (at Rt = 13.5 - 18.3 min, 24 % yield).

[0537] Analytical chiral HPLC (method see example 33): R t = 9.21 min.

[0538] 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.046 (0.67), 1.068 (13.52), 1.108 (0.86), 1.185 (0.55), 1.236 (13.07), 1.259 (0.64), 2.084 (0.44), 2.331 (0.49), 2.518 (2.88), 2.523 (1.93), 2.673 (0.47), 2.817 (1.52), 2.834 (3.11), 2.851 (1.67), 3.403 (2.57), 3.409 (2.57), 3.416 (2.39), 3.431 (2.89), 3.581 (0.83), 3.589 (0.95), 3.611 (1.68), 3.618 (1.66), 3.633 (2.61), 3.652 (1.72), 3.661 (2.23), 3.678 (1.86), 3.707 (1.00), 3.901 (16.00), 3.917 (1.07), 3.926 (0.91), 3.934 (0.65), 3.943 (0.58), 4.148 (1.01), 4.165 (0.96), 4.174 (1.36), 4.190 (1.18), 4.294 (1.36), 4.303 (1.36), 4.320 (1.03), 4.329 (0.91), 6.000 (1.83), 6.021 (1.91), 6.455 (0.83), 6.459 (0.87), 6.476 (1.19), 6.480 (1.27), 6.486 (0.94), 6.503 (1.10), 6.506 (1.01), 6.597 (0.86), 6.612 (1.01), 6.618 (1.47), 6.633 (1.44), 6.638 (0.75), 6.654 (0.61), 7.141 (2.15), 7.277 (2.70), 7.290 (2.68), 7.479 (4.53), 8.030 (2.67), 8.043 (2.48), 8.400 (4.07), 11.054 (2.33).Example 35 2-(3-{2-[1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (stereoisomer 1)

[0539]

[0540] Using an analogous method as described for example 1 with 4-{[(3-{2-[1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)methyl]amino}-N-(3-fluoro-2-methoxyphenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-35, 130 mg, 252 µmol) as the starting material, 30.0 mg (90 % purity, 22 % yield) of the racemic title compound were prepared after preparative HPLC (method 7). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.229 (0.48), 1.827 (0.71), 1.843 (1.74), 1.859 (2.06), 1.869 (1.50), 1.885 (0.63), 2.331 (0.40), 2.517 (2.30), 2.522 (1.50), 2.539 (4.51), 2.669 (0.55), 2.673 (0.48), 2.831 (1.19), 2.842 (2.22), 2.848 (2.06), 2.858 (1.19), 2.865 (1.11), 3.162 (1.27), 3.174 (0.71), 3.207 (1.35), 3.233 (2.14), 3.236 (2.14), 3.262 (1.58), 3.406 (4.44), 3.412 (3.88), 3.428 (2.22), 3.456 (1.90), 3.462 (1.82), 3.484 (1.50), 3.490 (1.50), 3.522 (1.27), 3.527 (1.35), 3.550 (1.66), 3.556 (1.90), 3.578 (0.95), 3.583 (1.27), 3.624 (2.22), 3.651 (2.14), 3.671 (3.25), 3.681 (1.50), 3.695 (2.22), 3.700 (1.98), 3.716 (2.06), 3.721 (1.98), 3.728 (1.35), 3.745 (1.50), 3.780 (0.71), 3.862 (0.95), 3.889 (16.00), 3.906 (1.19), 4.074 (0.71), 4.222 (2.14), 4.238 (3.96), 4.253 (1.82), 4.754 (0.55), 5.960 (1.98), 5.981 (1.98), 6.430 (0.95), 6.433 (0.95), 6.451 (1.43), 6.455 (1.43), 6.461 (0.95), 6.478 (1.19), 6.482 (1.11), 6.572 (0.95), 6.587 (1.11), 6.593 (1.58), 6.608 (1.58), 6.613 (0.79), 6.628 (0.63), 7.108 (2.30), 7.292 (2.77), 7.305 (2.77), 7.455 (4.67), 8.017 (2.61), 8.030 (2.46), 8.344 (4.04), 11.175 (2.46). LC-MS (method 6): Rt = 0.63 min; MS (ESlpos): m / z = 483 [M+H] +<

[0541] Racemic 2-(3-{2-[1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (25.0 mg) was separated into enantiomers by preparative chiral HPLC to give title compound (enantiomer 1, 12.00 mg, at Rt = 15.1 - 17.0 min, ) and enantiomer 2 (4 mg, at Rt = 19.8 - 26.8 min, see example 36).Preparative chiral HPLC method:

[0542] Instrument: PrepCon Labomatic HPLC; Column: Chiralpak IF 5µ, 250x30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 70%A+30%B; flow: 50 ml / min; temperature: 25°C; UV: 280 nm

[0543] Analytical chiral HPLC method:

[0544] Instrument: Waters Alliance 2695; Column: Chiralpak IF 3µ, 100x4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 70%A+30%B; flow: 1.4 ml / min; temperature: 25°C; UV: 280 nm

[0545] Analytical chiral HPLC: Rt = 4.68 min.

[0546] Optical rotation: α D = − 12.9 ° + / − 1.72 ° c = 1 , 4 mg / ml in methanol Example 36 2-(3-{2-[1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (Stereoisomer 2)

[0547]

[0548] For the preparation of the racemic title compound see example 35. Separation of enantiomers by preparative chiral HPLC (method see example 35) gave 4 mg of the title compound (at Rt = 19.8 - 26.8 min).

[0549] Analytical chiral HPLC (method see example 35): Rt = 6.58 min.

[0550] Optical rotation: α D = − 21.4 ° + / − 1.94 ° c = 1 , 3 mg / ml in methanol Example 37 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0551]

[0552] Using an analogous method as described for example 1; N-(3-fluoro-2-methoxyphenyl)-4-{[(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-37, 130 mg, 252 µmol) as the starting material, 35.00 mg (92% purity, 27% yield) of the title compound were prepared after preparative HPLC (method 7). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 2.277 (13.00), 2.292 (1.54), 2.307 (0.96), 2.324 (0.70), 2.329 (0.89), 2.334 (0.66), 2.407 (0.69), 2.428 (1.27), 2.435 (1.36), 2.520 (2.98), 2.525 (1.88), 2.667 (0.63), 2.671 (0.83), 2.676 (0.62), 2.777 (0.67), 2.801 (0.82), 2.818 (1.61), 2.825 (0.99), 2.835 (1.02), 2.844 (1.23), 2.860 (0.82), 2.911 (1.23), 2.940 (1.09), 3.388 (0.53), 3.408 (0.96), 3.425 (1.66), 3.431 (1.41), 3.441 (1.54), 3.455 (0.69), 3.548 (1.12), 3.576 (1.89), 3.592 (1.35), 3.597 (1.35), 3.602 (1.33), 3.621 (0.70), 3.626 (0.70), 3.783 (1.37), 3.785 (1.33), 3.818 (1.11), 3.843 (1.97), 3.849 (2.06), 3.870 (1.11), 3.878 (0.99), 3.941 (16.00), 3.954 (1.12), 4.078 (0.56), 4.349 (0.43), 4.358 (0.42), 4.376 (1.85), 4.388 (2.91), 4.416 (0.47), 6.013 (1.90), 6.034 (1.91), 6.516 (0.95), 6.520 (0.92), 6.537 (1.27), 6.541 (1.33), 6.547 (0.95), 6.564 (1.12), 6.568 (1.03), 6.657 (0.94), 6.672 (1.04), 6.678 (1.61), 6.693 (1.51), 6.698 (0.80), 6.714 (0.65), 7.180 (2.21), 7.313 (3.72), 7.325 (3.57), 7.605 (4.51), 7.980 (4.40), 7.993 (4.17), 8.360 (6.21), 8.414 (0.59), 12.014 (2.24). LC-MS (method 6): Rt = 0.51 min; MS (ESlpos): m / z = 482 [M+H] +< Example 38 2-[3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]-4-pyridyl]-3-(3-fluoro-2-methyl-anilino)-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one

[0553]

[0554] Using an analogous method as described for example 1; 4-[[3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]-4-pyridyl]methylamino]-N-(3-fluoro-2-methyl-phenyl)-6-oxo-2,3-dihydro-1H-pyridine-5-carbothioamide (intermediate 6-38, 190 mg, 369 µmol) as the starting material, 30.2 mg (98% purity, 17% yield) of the title compound were prepared after preparative HPLC (method 10, gradient: 0.00 - 0.50 min 15% B, 0.50 - 5.59 min 15 - 51.7% B, 5.59 - 5.88 min 51.7% B, 5.88 - 5.93 min 51.7 - 52.1% B, 5.93 - 5.95 min 52.1% B, 5.95 - 6.32 min 52.1-55% B) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.073 (16.00), 1.243 (14.37), 2.177 (9.43), 2.180 (9.37), 2.520 (3.20), 2.525 (2.30), 2.542 (0.63), 2.826 (1.74), 2.843 (3.73), 2.861 (2.01), 3.406 (3.15), 3.417 (2.63), 3.424 (2.71), 3.434 (3.36), 3.569 (0.91), 3.577 (1.10), 3.598 (1.87), 3.607 (1.84), 3.643 (4.40), 3.671 (4.37), 3.699 (1.24), 3.881 (0.69), 3.890 (0.81), 3.898 (1.03), 3.907 (0.94), 3.915 (0.67), 3.923 (0.65), 4.121 (1.26), 4.137 (1.17), 4.147 (1.71), 4.163 (1.45), 4.265 (1.62), 4.274 (1.65), 4.291 (1.24), 4.300 (1.11), 6.059 (2.34), 6.080 (2.42), 6.427 (1.06), 6.449 (1.94), 6.470 (1.21), 6.721 (0.73), 6.742 (1.51), 6.759 (1.47), 6.779 (0.63), 7.168 (2.42), 7.232 (4.19), 7.244 (4.24), 7.308 (4.82), 7.997 (5.22), 8.009 (4.80), 8.373 (6.80), 11.029 (2.61). LC-MS (method 6): Rt = 0.74 min; MS (ESlpos): m / z = 481 [M+H] +< Example 39 2-[3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]-4-pyridyl]-3-(3-fluoro-2-methyl-anilino)-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one (stereoisomer 1)

[0555]

[0556] The title compound from example 38 (30.2 mg) was separated into enantiomers by preparative chiral HPLC to give title compound (enantiomer 1, 10.00 mg, Rt = 30.4 - 36.0 min, 5% yield) and enantiomer 2 (9 mg, Rt = 45.9 - 51.7 min).Preparative chiral HPLC method: NPB

[0557] Instrument: PrepCon Labomatic HPLC; Column: Chiralpak IF 5µ, 250x30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 90%A+10%B; flow: 50 ml / min; temperature: 25°C; UV: 254 nmAnalytical chiral HPLC method: NPB

[0558] Instrument: Waters Alliance 2695; Column: Chiralpak IF 3µ, 100x4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 90%A+10%B; flow: 1.4 ml / min; temperature: 25°C; UV: 254 nm

[0559] Analytical chiral HPLC: Rt = 11.60 min.

[0560] Optical rotation: α D = − 6.4 ° + / − 0.47 ° c = 6 , 2 mg / ml in DMSO

[0561] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 0.700 (5.10), 0.744 (1.84), 0.764 (1.85), 0.836 (0.93), 0.854 (1.20), 1.073 (15.11), 1.152 (5.69), 1.235 (8.54), 1.243 (16.00), 1.296 (2.78), 1.350 (0.95), 1.378 (0.62), 1.672 (0.88), 2.179 (9.59), 2.525 (2.28), 2.827 (1.75), 2.844 (3.61), 2.861 (1.95), 3.407 (3.22), 3.418 (2.68), 3.424 (2.72), 3.434 (3.38), 3.570 (0.86), 3.578 (1.00), 3.599 (1.76), 3.607 (1.71), 3.644 (4.10), 3.671 (4.05), 3.700 (1.09), 3.882 (0.67), 3.890 (0.80), 3.899 (1.00), 3.907 (0.92), 3.915 (0.66), 3.924 (0.61), 4.121 (1.09), 4.138 (1.06), 4.147 (1.50), 4.164 (1.30), 4.267 (1.44), 4.275 (1.48), 4.292 (1.11), 4.301 (1.01), 6.060 (2.24), 6.080 (2.31), 6.428 (1.04), 6.450 (1.90), 6.472 (1.17), 6.722 (0.70), 6.742 (1.49), 6.759 (1.45), 6.780 (0.58), 6.959 (0.44), 7.170 (2.40), 7.201 (0.51), 7.222 (0.55), 7.234 (1.95), 7.246 (1.95), 7.309 (4.47), 7.999 (1.12), 8.010 (1.08), 8.375 (1.57), 11.031 (2.61).Example 40 3-[2-(2,2-difluoroethyl)-3-fluoro-anilino]-2-[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one

[0562]

[0563] Using an analogous method as described for example 1 with N-[2-(2,2-difluoroethyl)-3-fluorophenyl]-4-{[(3-{[1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-40, 19.5 mg, 36.3 µmol) as the starting material; 3.80 mg (92% purity, 19% yield) of the title compound were prepared after purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 30% B, 0.50 - 6.00 min 30 - 70% B). 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 2.86 (t, 2H), 3.22 - 3.30 (m, 1H), 3.39 - 3.48 (m, 3H), 3.50 - 3.58 (td, 1H), 3.67 - 3.93 (m, 5H), 3.97 - 4.06 (m, 1H), 4.09 - 4.18 (m, 1H), 4.25 - 4.31 (dd, 1H), 6.07 - 6.17 (d, 1H), 6.29 - 6.63 (q, 2H), 6.83 - 6.94 (m, 1H), 7.10 (s, 1H), 7.34 (s, 1H), 7.37 (d, 2H), 8.00 (d, 1H), 8.38 (s, 1H), 11.07 (s, 1H). LC-MS (method 2): Rt = 0.99 min; MS (ESlpos): m / z = 503 [M+H] +< Example 41 3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0564]

[0565] 3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (intermediate 41, 22.0 mg, 43.9 µmol) was suspended in MeOH, formaldehyde (6.6 µl, 37% purity in water, 88 µmol) and acetic acid (2.5 µl, 44 µmol) were added. The reaction mixture was stirred for 15 min at room temperature. Sodium triacetoxyborohydride (13.9 mg, 65.8 µmol) was added the the mixture was stirred for 1h at room temperature. The mixture was filtered through a SCX column and washed with MeOH and ammonia (7M in MeOH). The ammonia filtrate was evaporated and purified by preparative HPLC (method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B) to give 8.8 mg (90% purity, 35% yield) of the title compound. 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 2.07 (m, 3H), 2.22 (s, 3H), 2.63 - 2.83 (m, 2H), 2.86 (t, 2H), 3.27 - 3.31 (m, 1H), 3.35 - 3.38 (m, 1H), 3.42 (td, 2H), 3.68 (td, 1H), 3.91 - 4.00 (m, 2H), 4.12 - 4.19 (dd, 1H), 4.33 (dd, 1H), 6.13 (d, 1H), 6.29 - 6.64 (m, 1H), 6.89 (q, 1H), 7.07 - 7.14 (m, 1H), 7.33 - 7.40 (t, 2H), 7.99 (d, 1H), 8.39 (s, 1H), 11.07 (s, 1H). LC-MS (method 2): Rt = 0.98 min; MS (ESlpos): m / z = 516 [M+H] +< Example 42 3-(3-chloro-2-methylanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0566]

[0567] Using an analogous method as described for example 41 with 3-(3-chloro-2-methylanilino)-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (intermediate 42, 18.0 mg, 38.5 µmol) as the starting material; 10.9 mg (94% purity, 55% yield) of the title compound were prepared after purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 15% B, 0.50 - 6.00 min 15 - 55% B). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.234 (0.45), 1.874 (1.12), 1.901 (1.88), 1.928 (1.19), 2.006 (0.51), 2.015 (0.63), 2.035 (1.18), 2.043 (1.18), 2.064 (0.68), 2.072 (0.56), 2.207 (15.79), 2.324 (0.67), 2.329 (0.91), 2.334 (0.71), 2.338 (0.45), 2.357 (16.00), 2.374 (1.16), 2.520 (2.98), 2.525 (1.85), 2.647 (1.22), 2.671 (1.61), 2.676 (1.69), 2.736 (1.32), 2.764 (1.23), 2.847 (1.67), 2.865 (3.57), 2.882 (1.86), 3.411 (1.24), 3.417 (1.33), 3.428 (2.40), 3.434 (2.36), 3.445 (1.17), 3.451 (1.06), 3.639 (0.62), 3.645 (0.95), 3.667 (1.35), 3.672 (1.38), 3.695 (0.78), 3.701 (0.66), 3.937 (1.97), 3.960 (1.51), 4.111 (1.22), 4.128 (1.10), 4.137 (1.63), 4.153 (1.36), 4.253 (1.46), 4.262 (1.52), 4.279 (1.14), 4.287 (1.03), 6.190 (1.81), 6.194 (1.78), 6.209 (1.99), 6.213 (1.81), 6.722 (0.90), 6.726 (1.25), 6.742 (3.67), 6.746 (2.96), 6.753 (2.81), 6.773 (2.59), 6.792 (0.84), 7.190 (2.30), 7.232 (3.39), 7.244 (3.38), 7.377 (4.48), 7.990 (3.43), 8.003 (3.19), 8.370 (5.23), 11.051 (2.53). LC-MS (method 6): Rt = 0.52 min; MS (ESlpos): m / z = 482 [M+H] +< Example 43 3-(3-chloro-2-methylanilino)-2-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0568]

[0569] Using an analogous method as described for example 41 with 3-(3-chloro-2-methylanilino)-2-(3-{[(3R)-morpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (30.0 mg, 64.1 µmol) as the starting material; 7.0 mg (94% purity, 21% yield) of the title compound were prepared after purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 15% B, 0.50 - 6.00 min 15 - 55% B). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= -0.002 (3.00), 0.879 (0.57), 2.085 (5.27), 2.272 (14.21), 2.318 (0.47), 2.382 (16.00), 2.397 (1.43), 2.423 (1.05), 2.431 (1.10), 2.460 (1.63), 2.518 (5.17), 2.523 (3.38), 2.660 (0.46), 2.810 (0.81), 2.828 (2.27), 2.845 (1.96), 2.864 (0.87), 2.909 (1.32), 2.938 (1.16), 3.411 (0.70), 3.428 (1.64), 3.435 (1.37), 3.444 (1.50), 3.464 (0.63), 3.540 (1.08), 3.568 (2.41), 3.595 (2.18), 3.620 (0.70), 3.818 (1.11), 3.844 (2.09), 3.864 (1.06), 3.872 (0.93), 4.357 (1.94), 4.368 (3.51), 4.395 (0.46), 6.209 (1.79), 6.212 (1.85), 6.228 (1.98), 6.232 (1.91), 6.756 (1.10), 6.760 (1.40), 6.776 (3.46), 6.779 (2.93), 6.793 (2.52), 6.813 (2.75), 6.833 (0.95), 7.200 (2.25), 7.250 (3.55), 7.263 (3.70), 7.431 (4.31), 7.946 (3.93), 7.958 (3.66), 8.338 (5.51), 12.003 (2.32). LC-MS (method 6): Rt = 0.57 min; MS (ESlpos): m / z = 512 [M+H] +< Example 44 3-(3-chloro-2-methyl-anilino)-2-[3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]-4-pyridyl]-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one

[0570]

[0571] In analogy to example 1 N-(3-chloro-2-methyl-phenyl)-4-[[3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]-4-pyridyl]methylamino]-6-oxo-2,3-dihydro-1H-pyridine-5-carbothioamide (intermediate 6-44, 320 mg, 603 µmol) was used to prepare 32 mg of the title compound (98% purity, 10% yield) after stirring for 2 h at room temperature and purification by preparative HPLC (method 10, gradient: 0.00-0.50 min 15% B, 0.50-5.92 min 15-54.2% B, 5.92 - 7.34 min 54.2% B, 7.34 - 7.42 min 54.2 - 55% B). 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.072 (14.59), 1.241 (13.05), 2.325 (0.47), 2.329 (0.73), 2.344 (16.00), 2.520 (1.82), 2.525 (1.27), 2.671 (0.54), 2.828 (1.59), 2.845 (3.40), 2.862 (1.80), 3.402 (2.68), 3.417 (2.39), 3.423 (2.57), 3.431 (2.75), 3.565 (0.87), 3.574 (1.01), 3.595 (1.70), 3.603 (1.65), 3.640 (3.45), 3.668 (4.15), 3.697 (1.17), 3.872 (0.64), 3.880 (0.75), 3.888 (0.95), 3.897 (0.88), 3.905 (0.63), 3.914 (0.58), 4.122 (1.12), 4.139 (1.05), 4.149 (1.54), 4.165 (1.34), 4.254 (1.47), 4.263 (1.52), 4.281 (1.10), 4.289 (0.98), 6.196 (1.81), 6.199 (1.76), 6.215 (1.97), 6.218 (1.81), 6.705 (0.97), 6.709 (1.30), 6.725 (3.57), 6.729 (2.82), 6.738 (2.56), 6.757 (2.50), 6.778 (0.82), 7.165 (2.26), 7.230 (3.85), 7.243 (3.87), 7.323 (4.45), 8.004 (5.13), 8.016 (4.69), 8.374 (6.56), 11.049 (2.45). LC-MS (method 6): Rt = 0.79 min; MS (ESlpos): m / z = 497 [M+H] +< Example 45 3-(3-chloro-2-methyl-anilino)-2-[3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]-4-pyridyl]-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one (stereoisomer 1)

[0572]

[0573] The title compound from example 44 (32.0 mg) was separated into enantiomers by preparative chiral HPLC to give title compound (enantiomer 1, 15.50 mg, R t = 12.1 - 14.2 min) and enantiomer 2 (12.6 mg, Rt = 14.5 - 19.0 min, see example 46).Preparative chiral HPLC method: POB

[0574] Instrument: PrepCon Labomatic HPLC; Column: Chiralcel OD-H 5µ, 250x20; eluent A: ethanol + 0.1 vol % diethylamine; eluent B: methanol; isocratic: 70%A+30%B; flow: 10 ml / min; temperature: 25°C; UV: 280 nmAnalytical chiral HPLC method: POB

[0575] Instrument: Waters Alliance 2695; Column: Chiralcel OD-H 5µ, 100x4.6; eluent A: ethanol + 0.1 vol % diethylamine; eluent B: methanol; isocratic: 70%A+30%B; flow: 1.4 ml / min; temperature: 25°C; UV: 280 nm

[0576] Analytical chiral HPLC: Rt = 3.52 min.

[0577] Optical rotation: α D = 30.31 ° + / − 1.05 ° c = 2 , 7 mg / ml in Chloroform

[0578] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.050 (0.51), 1.070 (14.54), 1.119 (0.40), 1.137 (0.77), 1.155 (0.80), 1.190 (0.47), 1.239 (13.63), 2.085 (0.73), 2.318 (0.77), 2.323 (1.71), 2.327 (2.48), 2.332 (2.11), 2.342 (16.00), 2.518 (7.25), 2.523 (5.03), 2.660 (0.73), 2.665 (1.64), 2.669 (2.30), 2.673 (1.60), 2.679 (0.73), 2.825 (1.60), 2.842 (3.43), 2.859 (1.86), 3.306 (0.95), 3.399 (2.77), 3.415 (2.44), 3.421 (2.59), 3.429 (2.84), 3.563 (0.87), 3.572 (1.02), 3.592 (1.71), 3.601 (1.68), 3.638 (3.46), 3.665 (4.15), 3.695 (1.17), 3.869 (0.77), 3.878 (0.77), 3.886 (0.95), 3.894 (0.87), 3.903 (0.62), 3.911 (0.58), 4.120 (1.13), 4.137 (1.06), 4.147 (1.53), 4.163 (1.31), 4.252 (1.46), 4.261 (1.53), 4.278 (1.09), 4.287 (0.98), 6.193 (1.82), 6.197 (1.75), 6.212 (1.93), 6.216 (1.82), 6.703 (0.98), 6.707 (1.28), 6.723 (3.50), 6.727 (2.81), 6.736 (2.59), 6.756 (2.51), 6.775 (0.84), 7.162 (2.22), 7.228 (3.64), 7.241 (3.64), 7.321 (4.48), 8.002 (4.30), 8.014 (4.01), 8.372 (5.94), 11.046 (2.48). LC-MS (method 6): Rt = 0.80 min; MS (ESlpos): m / z = 497 [M+H] +< Example 46 3-(3-chloro-2-methyl-anilino)-2-[3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]-4-pyridyl]-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one (stereoisomer 2)

[0579]

[0580] For the preparation of the racemic title compound see example 44. Separation of enantiomers by preparative chiral HPLC (method see example 45) to give 12.6 mg of the title compound (Rt = 14.5 - 19.0 min).

[0581] Analytical chiral HPLC (method see example 45): Rt = 4.43 min.

[0582] Optical rotation: α D = − 26.44 ° + / − 1.41 ° c = 2 , 9 mg / ml in Chloroform

[0583] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 0.748 (0.44), 0.764 (0.44), 1.053 (0.52), 1.070 (14.81), 1.154 (1.45), 1.239 (13.86), 2.085 (1.85), 2.318 (0.46), 2.323 (0.99), 2.327 (1.45), 2.332 (1.39), 2.342 (16.00), 2.518 (4.03), 2.523 (2.82), 2.540 (0.54), 2.665 (0.89), 2.669 (1.25), 2.673 (0.85), 2.825 (1.61), 2.843 (3.39), 2.859 (1.81), 3.399 (2.78), 3.415 (2.48), 3.421 (2.64), 3.429 (2.88), 3.563 (0.83), 3.572 (0.99), 3.593 (1.69), 3.601 (1.67), 3.638 (3.49), 3.665 (4.15), 3.695 (1.15), 3.869 (0.83), 3.878 (0.77), 3.886 (0.95), 3.895 (0.89), 3.903 (0.64), 3.912 (0.58), 4.120 (1.09), 4.137 (1.03), 4.147 (1.53), 4.163 (1.33), 4.252 (1.45), 4.261 (1.51), 4.278 (1.09), 4.287 (0.97), 6.193 (1.77), 6.197 (1.75), 6.212 (1.97), 6.216 (1.85), 6.703 (0.95), 6.707 (1.27), 6.723 (3.51), 6.727 (2.82), 6.736 (2.58), 6.756 (2.54), 6.775 (0.85), 7.162 (2.26), 7.228 (3.10), 7.241 (3.12), 7.321 (4.45), 8.002 (2.54), 8.015 (2.36), 8.372 (3.89), 11.046 (2.46). LC-MS (method 6): Rt = 0.80 min; MS (ESlpos): m / z = 497 [M+H] +< Example 47 2-[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]-3-(3-fluoro-2-methyl-anilino)-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one

[0584]

[0585] In analogy to example 1 4-[[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]methylamino]-N-(3-fluoro-2-methyl-phenyl)-6-oxo-2,3-dihydro-1H-pyridine-5-carbothioamide (intermediate 6-47, 399 mg, 820 µmol) was used to prepare 135 mg of the title compound (97% purity, 35% yield) after stirring for overnight at 60 °C and purification by preparative HPLC (method 9, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B). 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (4.20), 1.172 (8.22), 1.189 (3.94), 1.987 (16.00), 2.185 (2.36), 2.189 (2.36), 2.518 (0.75), 2.522 (0.47), 2.843 (0.44), 2.860 (0.94), 2.877 (0.50), 3.398 (0.42), 3.425 (1.01), 3.451 (0.56), 3.709 (0.44), 3.740 (0.57), 3.999 (1.26), 4.017 (3.61), 4.035 (3.57), 4.053 (1.15), 4.125 (0.48), 4.230 (0.43), 4.239 (0.42), 5.758 (0.88), 6.052 (0.58), 6.072 (0.60), 6.459 (0.48), 7.186 (0.59), 7.234 (1.00), 7.247 (1.01), 7.345 (1.17), 7.990 (1.32), 8.002 (1.20), 8.361 (1.76), 11.030 (0.60). LC-MS (method 6): Rt = 0.65 min; MS (ESlpos): m / z = 453 [M+H] +< Example 48 2-[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]-3-(3-fluoro-2-methyl-anilino)-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one (stereoisomer 1)

[0586]

[0587] The title compound from example 47 (15.0 mg) was separated into enantiomers by preparative chiral HPLC to give title compound (enantiomer 1, 3.0 mg, R t = 5.5 - 6.2 min) and enantiomer 2 (2.0 mg, Rt = 9.0 - 9.9 min, see example 49).Preparative chiral HPLC method: MTBE

[0588] Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5µ, 250x30; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 55%B+45%A; flow: 80 ml / min; temperature: 25°C; UV: 280 nm;Analytical chiral HPLC method: MTBE

[0589] Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3µ, 100x4.6; eluent A: methyl tert-butyl ether + 0.2 vol % diethylamine; eluent B: acetonitrile; isocratic: 50%A+50%B; flow: 1.4 ml / min; temperature: 25°C; UV: 280 nm;

[0590] Analytical chiral HPLC: Rt = 2.90 min.

[0591] Optical rotation: α D = − 19.1 ° + / − 1.65 ° c = 2 , 19 mg / ml in Chloroform

[0592] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= -0.008 (0.55), 0.000 (16.00), 0.008 (0.53), 0.700 (0.57), 0.752 (0.76), 0.770 (0.76), 1.140 (1.18), 1.160 (2.36), 1.234 (1.64), 1.296 (0.42), 2.189 (11.55), 2.191 (11.53), 2.521 (2.85), 2.525 (1.90), 2.846 (2.15), 2.863 (4.59), 2.880 (2.42), 3.401 (1.96), 3.410 (1.71), 3.417 (1.88), 3.428 (4.95), 3.444 (1.64), 3.454 (2.68), 3.505 (0.67), 3.510 (0.82), 3.532 (1.56), 3.539 (1.58), 3.560 (1.14), 3.569 (1.03), 3.712 (2.13), 3.721 (1.35), 3.743 (2.76), 3.750 (1.24), 3.771 (1.14), 3.778 (0.84), 3.800 (1.69), 3.806 (1.85), 3.829 (1.52), 3.835 (1.54), 3.885 (1.66), 3.912 (1.22), 3.992 (0.42), 4.001 (0.68), 4.008 (1.01), 4.017 (1.14), 4.025 (1.10), 4.033 (0.93), 4.042 (0.78), 4.049 (0.53), 4.103 (1.71), 4.119 (1.24), 4.129 (2.26), 4.145 (1.73), 4.233 (2.09), 4.243 (2.05), 4.259 (1.54), 4.269 (1.33), 6.056 (2.82), 6.076 (2.91), 6.440 (1.29), 6.463 (2.36), 6.484 (1.46), 6.734 (0.89), 6.754 (1.85), 6.771 (1.77), 6.792 (0.72), 7.187 (2.91), 7.237 (3.80), 7.250 (3.82), 7.348 (5.65), 7.994 (2.64), 8.006 (2.47), 8.365 (4.17), 11.029 (3.12). LC-MS (method 6): Rt = 0.66 min; MS (ESlpos): m / z = 453 [M+H] +< Example 49 2-[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]-3-(3-fluoro-2-methyl-anilino)-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one (stereoisomer 2)

[0593]

[0594] For the preparation of the racemic title compound see example 47. Separation of enantiomers by preparative chiral HPLC (method see example 48) to give 2.0 mg of the title compound (Rt = 9.0 - 9.9 min).

[0595] Analytical chiral HPLC (method see example 48): R t = 4.67 min.

[0596] Optical rotation: α D = 24.3 ° + / − 7.66 ° c = 1 , 29 mg / ml in Chloroform

[0597] 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.54), 0.000 (16.00), 0.008 (0.54), 0.700 (0.74), 0.752 (0.54), 0.771 (0.57), 0.854 (0.52), 1.139 (0.91), 1.160 (1.70), 1.234 (2.19), 1.296 (0.52), 2.087 (0.66), 2.189 (11.26), 2.191 (11.28), 2.521 (4.55), 2.525 (3.00), 2.846 (2.09), 2.863 (4.47), 2.880 (2.36), 3.401 (1.99), 3.410 (1.67), 3.417 (1.87), 3.428 (4.87), 3.444 (1.65), 3.454 (2.65), 3.505 (0.69), 3.510 (0.84), 3.532 (1.52), 3.539 (1.55), 3.560 (1.13), 3.569 (1.03), 3.712 (2.09), 3.721 (1.35), 3.744 (2.70), 3.750 (1.23), 3.771 (1.16), 3.778 (0.81), 3.800 (1.67), 3.806 (1.77), 3.829 (1.50), 3.835 (1.52), 3.885 (1.62), 3.912 (1.20), 3.992 (0.42), 4.001 (0.66), 4.009 (0.98), 4.017 (1.11), 4.025 (1.08), 4.033 (0.91), 4.042 (0.76), 4.049 (0.54), 4.103 (1.70), 4.119 (1.20), 4.129 (2.19), 4.145 (1.72), 4.233 (2.04), 4.243 (2.04), 4.259 (1.52), 4.269 (1.33), 6.055 (2.75), 6.076 (2.85), 6.440 (1.25), 6.463 (2.31), 6.484 (1.45), 6.734 (0.86), 6.754 (1.79), 6.772 (1.72), 6.792 (0.74), 7.187 (2.83), 7.237 (3.37), 7.250 (3.42), 7.349 (5.43), 7.994 (2.24), 8.007 (2.14), 8.365 (3.56), 11.030 (3.02).Example 50 3-(3-chloro-2-methylanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0598]

[0599] Using an analogous method as described for example 1 with N-(3-chloro-2-methyl-phenyl)-4-[[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]methylamino]-6-oxo-2,3-dihydro-1H-pyridine-5-carbothioamide (intermediate 6-50, 150 mg, 298 µmol) as the starting material, 35.0 mg (25% yield) of the racemic title compound were prepared after preparative HPLC (method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B). LC-MS (method 6): Rt = 0.71 min; MS (ESlpos): m / z = 469 [M+H] +<

[0600] Racemic 3-(3-chloro-2-methyl-anilino)-2-[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one (35.0 mg) was separated into enantiomers by preparative chiral HPLC to give title compound (enantiomer 1, 12.5 mg, R t = 14.3 - 16.6 min, ) and enantiomer 2 (13.4 mg, Rt = 21.1 -25.3 min, see example 51).Preparative chiral HPLC method: MTBE

[0601] Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5µ, 250x30; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: ethanol; gradient:; flow: 40 ml / min; temperature: 25°C; UV: 254 nmAnalytical chiral HPLC method: MTBE

[0602] Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3µ, 100x4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: ethanol; gradient:; flow: 1.4 ml / min; temperature: 25°C; UV: 254 nm

[0603] Analytical chiral HPLC: Rt = 3.23 min.

[0604] Optical rotation: α D = − 20.5 ° + / − 1.23 ° c = 2 , 7 mg / ml in Chloroform

[0605] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.234 (0.41), 2.338 (0.44), 2.355 (16.00), 2.520 (2.76), 2.524 (1.87), 2.847 (1.60), 2.864 (3.40), 2.882 (1.80), 3.398 (1.50), 3.410 (1.20), 3.416 (1.35), 3.427 (3.93), 3.432 (2.41), 3.444 (1.16), 3.451 (2.30), 3.502 (0.46), 3.508 (0.60), 3.530 (1.13), 3.537 (1.16), 3.558 (0.85), 3.566 (0.78), 3.711 (1.87), 3.718 (1.04), 3.740 (2.36), 3.768 (0.89), 3.775 (0.60), 3.796 (1.27), 3.802 (1.36), 3.825 (1.15), 3.831 (1.16), 3.883 (1.23), 3.909 (0.88), 3.994 (0.48), 4.001 (0.77), 4.009 (0.80), 4.018 (0.79), 4.025 (0.69), 4.033 (0.55), 4.104 (1.32), 4.120 (0.96), 4.130 (1.76), 4.146 (1.34), 4.223 (1.59), 4.232 (1.56), 4.249 (1.15), 4.258 (1.00), 6.190 (1.73), 6.194 (1.69), 6.210 (2.01), 6.213 (1.79), 6.718 (0.97), 6.722 (1.27), 6.738 (3.59), 6.742 (2.81), 6.751 (2.54), 6.771 (2.47), 6.790 (0.80), 7.184 (2.17), 7.234 (3.49), 7.247 (3.51), 7.364 (4.36), 7.999 (3.35), 8.012 (3.08), 8.365 (4.78), 11.044 (2.32). LC-MS (method 6): Rt = 0.70 min; MS (ESlpos): m / z = 469 [M+H] +<

[0606] Enantioselective synthesis starting from 1-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)methanamine (intermediate 2-8) confirmed the title compound as 3-(3-chloro-2-methylanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one.Example 51 3-(3-chloro-2-methylanilino)-2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0607]

[0608] For the preparation of the racemic title compound see example 50. Separation of enantiomers by preparative chiral HPLC (method see example 50) gave 13.4 mg of the title compound (Rt = 21.1 - 25.3 min).

[0609] Analytical chiral HPLC (method see example 50): R t = 5.22 min.

[0610] Optical rotation: α D = 20.4 ° + / − 1.23 ° c = 2 , 69 mg / ml in chloroform

[0611] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.173 (0.44), 1.234 (0.51), 2.355 (16.00), 2.521 (2.29), 2.525 (1.50), 2.848 (1.58), 2.865 (3.44), 2.882 (1.83), 3.346 (0.44), 3.399 (1.49), 3.410 (1.19), 3.416 (1.34), 3.428 (3.98), 3.432 (2.45), 3.444 (1.19), 3.452 (2.35), 3.503 (0.46), 3.508 (0.62), 3.531 (1.13), 3.538 (1.20), 3.558 (0.84), 3.567 (0.81), 3.711 (1.90), 3.718 (1.09), 3.740 (2.39), 3.768 (0.88), 3.775 (0.62), 3.797 (1.26), 3.803 (1.39), 3.825 (1.14), 3.832 (1.17), 3.883 (1.25), 3.910 (0.90), 3.995 (0.49), 4.001 (0.76), 4.010 (0.82), 4.018 (0.79), 4.026 (0.71), 4.035 (0.56), 4.042 (0.40), 4.104 (1.30), 4.121 (0.95), 4.130 (1.77), 4.147 (1.36), 4.224 (1.60), 4.233 (1.58), 4.250 (1.15), 4.259 (0.99), 6.191 (1.74), 6.195 (1.73), 6.210 (1.96), 6.214 (1.81), 6.719 (0.94), 6.723 (1.27), 6.738 (3.57), 6.743 (2.82), 6.752 (2.56), 6.771 (2.49), 6.791 (0.81), 7.185 (2.19), 7.235 (3.09), 7.248 (3.12), 7.365 (4.33), 8.000 (2.48), 8.013 (2.34), 8.366 (3.75), 11.045 (2.33). LC-MS (method 6): Rt = 0.70 min; MS (ESlpos): m / z = 469 [M+H] +< Example 52 3-(3-chloro-2-ethyl-anilino)-2-[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one

[0612]

[0613] In analogy to example 1 N-(3-chloro-2-ethyl-phenyl)-4-[[3-(1,4-dioxan-2-ylmethoxy)-4-pyridyl]methylamino]-6-oxo-2,3-dihydro-1H-pyridine-5-carbothioamide (intermediate 6-52, 150 mg, 290 µmol) was used to prepare 23.2 mg of the title compound (95% purity, 16% yield) after stirring for 4 h at 60 °C and purification by preparative HPLC (method 10, gradient: 0.00-0.50 min 10% B, 0.50-8.06 min 10-20% B, 8.06-9.02 min 20% B, 9.02-24.12 min 20-50% B, 24.12-27.44 min 50% B). 1< H-NMR (400 MHz, DMSO-d 6 ): δ ppm= 1.23 (t, 3 H), 2.86 (s, 4 H), 3.38 - 3.46 (m, 4 H), 3.49 - 3.58 (m, 1 H), 3.68 - 3.78 (m, 2 H), 3.78 - 3.85 (m, 1 H), 3.86 - 3.92 (m, 1 H), 3.98 - 4.06 (m, 1 H), 4.09 - 4.17 (m, 1 H), 4.21 - 4.28 (m, 1 H), 6.22 (dd, 1 H), 6.67 - 6.78 (m, 2 H), 7.20 (d, 2 H), 7.45 (s, 1 H), 7.98 (d, 1 H), 8.32 - 8.39 (m, 1 H). LC-MS (method 2): Rt = 1.08 min; MS (ESlpos): m / z = 483 [M+H] +< Example 53 3-(3-chloro-2-ethylanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0614]

[0615] The title compound from example 52 (23.2 mg) was separated into enantiomers by preparative chiral HPLC to give title compound (enantiomer 1, 6.0 mg, R t = 6.6 - 7.-3 min) and enantiomer 2 (5.0 mg, R t = 10.7 - 11.6 min, see example 54).Preparative chiral HPLC method: MTBE

[0616] Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5µ, 250x30; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50%A+50%B; flow: 60 ml / min; temperature: 25°C; UV: 254 nmAnalytical chiral HPLC method: MTBE

[0617] Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3µ, 100x4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50%A+50%B; flow: 1.4 ml / min; temperature: 25°C; UV: 254 nm

[0618] Analytical chiral HPLC: Rt = 2.40 min.

[0619] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.23 (t, 3H), 2.81 - 2.91 (m, 4H), 3.40 -3.45 (m, 3H), 3.53 (dt, 1H), 3.69 - 3.79 (m, 2H), 3.79 - 3.85 (m, 1H), 3.86 - 3.93 (m, 1H), 3.99 - 4.06 (m, 1H), 4.12 (dd, 1H), 4.24 (dd, 1H), 6.23 (dd, 1H), 6.69 - 6.78 (m, 2H), 7.15 - 7.23 (m, 2H), 7.43 - 7.47 (m, 1H), 7.98 (d, 1H) 8.36 (s, 1 H), 11.03 (br s, 1H).

[0620] Enantioselective synthesis confirmed the title compound as 3-(3-chloro-2-ethylanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. In analogy to example 1 the title compound (25 mg, 7.6% yield) was prepared by using N-(3-chloro-2-ethylphenyl)-4-{[(3-{[(2S)-1,4-dioxan-2-yl]methoxy} pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-53, 320 mg, 0.62 mmol) as starting material, followed by purification with preparative HPLC (method 10, gradient: 0.00-0.50 min 5% B, 0.50-7.99 min 5-60% B, 7.99-11.20 min 60% B).

[0621] 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 11.03 (s, 1H), 8.36 (s, 1H), 7.98 (d, 1H), 7.43 - 7.49 (m, 1H), 7.15 - 7.24 (m, 2H), 6.68 - 6.80 (m, 2H), 6.14 - 6.28 (m, 1H), 4.21 - 4.33 (m, 1H), 4.10 - 4.17 (m, 1H), 4.00 - 4.05 (m, 1H), 3.70 - 3.92 (m, 4H), 3.51 - 3.59 (m, 1H), 3.39 - 3.47 (m, 3H), 2.81 - 2.90 (m, 4H), 1.23 (t, 3H).Example 54 3-(3-chloro-2-ethylanilino)-2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0622]

[0623] For the preparation of the racemic title compound see example 52. Separation of enantiomers by preparative chiral HPLC (method see example 53) gave 5.0 mg of the title compound (Rt = 10.7 - 11.6 min).

[0624] Analytical chiral HPLC (method see example 53): R t = 3.22 min.

[0625] 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 1.14 - 1.34 (m, 6H), 2.81 - 2.91 (m, 4H), 3.38 - 3.48 (m, 3H), 3.55 (dd, 1H), 3.69 - 3.85 (m, 3H), 3.85 - 3.93 (m, 1H), 3.99 - 4.06 (m, 1H), 4.09 - 4.17 (m, 1H), 4.25 (dd, 1H), 6.23 (dd, 1H), 6.69 - 6.79 (m, 2H), 7.14 - 7.23 (m, 2H), 7.39 - 7.49 (m, 1H), 7.91 - 8.04 (m, 1H), 8.31 - 8.40 (m, 1H), 10.97 - 11.12 (m, 1H).Example 55 3-(3-chloro-2-ethylanilino)-2-(3-{[(2R)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0626]

[0627] Using an analogous method as described for example 41 with 3-(3-chloro-2-ethylanilino)-2-(3-{[(2R)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (intermediate 55, 58.0 mg, 120 µmol) as the starting material; 27.5 mg (95% purity, 44% yield) of the title compound were prepared after purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 30% B, 0.50 - 7.00 min 30 - 70% B).

[0628] 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 1.23 (t, 3H), 1.90 (t, 1H), 1.99 - 2.09 (td, 1H), 2.21 (s, 3H), 2.63 - 2.71 (d, 1H), 2.73 - 2.78 (d, 1H), 2.78 - 2.89 (m, 4H), 3.40 - 3.47 (td, 2H), 3.67 (td, 1H), 3.92 - 3.98 (m, 2H), 4.14 (dd, 1H), 4.27 (dd, 1H), 6.23 (dd, 1H), 6.71 - 6.78 (m, 2H), 7.16 - 7.21 (m, 2H), 7.46 (s, 1H), 7.97 (d, 1H), 8.36 (s, 1H), 11.04 (s, 1H). LC-MS (method 2): Rt = 1.10 min; MS (ESlpos): m / z = 496 [M+H] +< Example 56 3-(3-chloro-2-ethylanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0629]

[0630] Using an analogous method as described for example 41 with 3-(3-chloro-2-ethylanilino)-2-(3-{[(2S)-morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (intermediate 56, 68.0 mg, 141 µmol) as the starting material; 37.8 mg (95% purity, 51% yield) of the title compound were prepared after purification by preparative HPLC (method 10, gradient: 0.00 - 0.50 min 30% B, 0.50 - 7.00 min 30 - 70% B).

[0631] 1< H-NMR (400MHz, DMSO-d 6 ): δ [ppm]= 1.23 (t, 3H), 1.90 (t, 1H), 2.00 - 2.08 (td, 1H), 2.21 (s, 3H), 2.63 - 2.72 (d, 1H), 2.72 - 2.81 (d, 1H), 2.81 - 2.90 (m, 4H), 3.44 (td, 2H), 3.67 (td, 1H), 3.91 - 3.99 (m, 2H), 4.13 (dd, 1H), 4.29 (dd, 1H), 6.23 (dd, 1H), 6.71 - 6.78 (m, 2H), 7.16 - 7.21 (m, 2H), 7.46 (s, 1H), 7.97 (d, 1H), 8.36 (s, 1H), 11.04 (s, 1H). LC-MS (method 2): Rt = 1.10 min; MS (ESlpos): m / z = 496 [M+H] +< Example 57 3-(3-chloro-2-methoxyanilino)-2-{3-[(1S)-1-(1 ,4-dioxan-2-yl)ethoxy]pyridin-4-yl}-1 ,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0632]

[0633] In a microwave tube, a solution of N-(3-chloro-2-methoxyphenyl)-4-([{3-[(1S)-1-(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-57, 380 mg, 713 µmol) in methanol (1.5 ml) was treated with TFA (55µl, 710µmol) followed by hydrogen peroxide (9.2µl, 0.106mmol), heated to 60°C and stirred for 16h. The reaction mixture was concentrated to dryness under reduced pressure, dissolved in DMSO and purified by preparative HPLC (method 10, gradient: 0.00-0.50 min 15% B, 0.50-5.00 min 15-50% B, 5.00-8.00 min 50% B) to give after freeze drying the desired product (174mg, 44% yield) as mixture of two stereoisomers.

[0634] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.176 (0.47), 1.192 (0.46), 1.245 (3.61), 1.261 (3.63), 1.326 (5.41), 1.342 (5.34), 2.074 (0.90), 2.518 (2.00), 2.523 (1.30), 2.832 (0.58), 2.853 (1.78), 2.871 (2.29), 2.889 (1.20), 3.374 (0.58), 3.402 (1.93), 3.412 (1.77), 3.419 (2.47), 3.427 (2.74), 3.435 (1.67), 3.442 (1.31), 3.455 (1.30), 3.464 (0.88), 3.485 (1.04), 3.493 (0.81), 3.500 (0.81), 3.522 (0.58), 3.614 (0.42), 3.643 (1.28), 3.650 (1.69), 3.669 (0.97), 3.699 (1.00), 3.725 (1.81), 3.734 (0.89), 3.748 (1.07), 3.754 (0.91), 3.768 (0.44), 3.777 (0.54), 3.783 (0.42), 3.806 (1.65), 3.813 (2.16), 3.823 (1.17), 3.836 (1.62), 3.843 (1.75), 3.850 (1.00), 3.863 (9.50), 3.890 (16.00), 3.919 (0.92), 3.948 (0.61), 4.068 (2.33), 4.626 (0.70), 4.630 (0.86), 4.643 (1.15), 4.653 (0.66), 4.658 (0.86), 6.133 (0.95), 6.143 (2.18), 6.148 (0.96), 6.151 (1.32), 6.158 (1.98), 6.167 (1.48), 6.638 (1.70), 6.643 (2.02), 6.653 (3.46), 6.678 (0.58), 6.690 (6.05), 6.699 (2.71), 6.706 (2.31), 7.122 (0.98), 7.161 (1.50), 7.264 (0.72), 7.285 (0.52), 7.294 (1.80), 7.299 (2.64), 7.307 (1.85), 7.312 (2.64), 7.440 (2.17), 7.519 (3.36), 7.631 (0.44), 7.998 (3.33), 8.011 (3.08), 8.031 (2.20), 8.044 (1.98), 8.396 (4.10), 8.411 (2.66), 11.072 (1.20), 11.085 (1.69). LC-MS (method 6): Rt = 0.72 min; MS (ESlpos): m / z = 499 [M+H] +< Example 58 3-(3-chloro-2-methoxyanilino)-2-{3-[(1S)-1-(1 ,4-dioxan-2-yl)ethoxy]pyridin-4-yl}-1 ,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (Stereoisomer 1)

[0635]

[0636] The title compound from example 57 (170 mg) was separated into stereoisomers by preparative chiral HPLC to give title compound (stereoisomer 1, 58 mg, R t = 16.2-18.8 min) and stereoisomer 2 (35 mg, R t = 19.3-21.6 min, see example 60).Preparative chiral HPLC method:

[0637] Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SC 5µ, 250x30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; gradient: 0-15 min 20-30% B; flow: 40 ml / min; temperature: 25°C; UV: 254 nmAnalytical chiral analytical HPLC method:

[0638] Instrument: Waters Alliance 2695; Column: YMC Cellulose SC 3µ, 100x4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 70%A+30%B; flow: 1.4 ml / min; temperature: 25°C; UV: 254 nm

[0639] Analytical chiral HPLC: Rt = 5.19 min.

[0640] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 1.157 (0.42), 1.326 (5.83), 1.342 (5.94), 2.518 (2.45), 2.523 (1.64), 2.854 (1.00), 2.872 (2.23), 2.889 (1.30), 3.159 (0.76), 3.172 (0.81), 3.403 (0.88), 3.409 (0.98), 3.420 (1.66), 3.427 (1.98), 3.435 (0.89), 3.456 (1.40), 3.469 (0.49), 3.485 (1.09), 3.493 (0.89), 3.500 (0.89), 3.522 (0.63), 3.530 (0.42), 3.699 (1.04), 3.725 (1.77), 3.748 (1.00), 3.755 (0.79), 3.777 (0.55), 3.783 (0.42), 3.806 (1.16), 3.812 (1.76), 3.824 (0.88), 3.836 (1.39), 3.843 (1.20), 3.850 (0.51), 3.890 (16.00), 3.919 (1.02), 3.948 (0.70), 4.631 (0.81), 4.646 (0.95), 4.659 (0.80), 6.143 (1.46), 6.151 (1.29), 6.159 (1.42), 6.167 (1.47), 6.679 (0.61), 6.691 (6.25), 6.699 (2.81), 6.706 (2.43), 6.727 (0.42), 7.159 (1.65), 7.298 (2.69), 7.311 (2.69), 7.518 (3.71), 7.998 (3.52), 8.010 (3.22), 8.395 (4.49), 11.084 (1.82).

[0641] Optical rotation: α D = 30.21 ° + / − 0.60 ° c = 1.0 g / 100 ml in chloroform

[0642] LC-MS (method 6): Rt = 0.72 min; MS (ESlpos): m / z = 499 [M+H] +< Example 59 3-(3-chloro-2-methoxyanilino)-2-{3-[(1S)-1-(1 ,4-dioxan-2-yl)ethoxy]pyridin-4-yl}-1 ,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (Stereoisomer 2)

[0643]

[0644] The title compound from example 57 (170 mg) was separated into stereoisomers by preparative chiral HPLC to give title compound stereoisomer 2 (35 mg, Rt = 19.3-21.6 min, see example 58 for method of separation).

[0645] Analytical chiral HPLC: Rt = 5.91 min.

[0646] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm]= 0.798 (0.48), 0.815 (0.56), 0.822 (0.55), 0.905 (0.48), 1.084 (0.46), 1.137 (0.84), 1.156 (0.69), 1.233 (1.00), 1.246 (6.21), 1.261 (6.32), 2.084 (0.60), 2.332 (0.57), 2.518 (3.49), 2.522 (2.23), 2.673 (0.60), 2.833 (1.01), 2.850 (2.05), 2.867 (1.22), 3.308 (0.48), 3.373 (0.98), 3.402 (2.29), 3.412 (2.05), 3.418 (2.16), 3.427 (2.02), 3.435 (1.84), 3.442 (1.19), 3.465 (0.79), 3.607 (0.46), 3.614 (0.62), 3.643 (2.17), 3.670 (1.14), 3.726 (0.62), 3.732 (0.73), 3.738 (0.65), 3.744 (0.72), 3.751 (0.57), 3.757 (0.63), 3.762 (0.57), 3.768 (0.57), 3.805 (1.25), 3.815 (1.51), 3.821 (1.12), 3.834 (1.01), 3.844 (1.36), 3.850 (1.08), 3.863 (16.00), 3.889 (0.74), 4.625 (0.83), 4.637 (0.87), 4.641 (0.90), 4.653 (0.81), 6.133 (1.40), 6.143 (1.44), 6.147 (1.32), 6.157 (1.50), 6.639 (2.71), 6.643 (3.20), 6.653 (5.57), 6.663 (0.45), 7.120 (1.71), 7.294 (2.55), 7.307 (2.61), 7.438 (3.73), 8.031 (2.89), 8.043 (2.69), 8.411 (4.05), 11.071 (1.88).

[0647] Optical rotation: α D = 19.87 ° + / − 0.91 ° c = 1.0 g / 100 ml in chloroform

[0648] LC-MS (method 6): Rt = 0.72 min; MS (ESlpos): m / z = 499 [M+H] +< Example 60 3-(3-chloro-2-methoxyanilino)-2-{3-[(1R)-1-(1,4-dioxan-2-yl)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (Stereoisomer 1)

[0649]

[0650] Using an analogous method as described for example 57 with N-(3-chloro-2-methoxyphenyl)-4-{[(3-{(1R)-1-[1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-60, 340 mg, 638 µmol) as the starting material; 76.0 mg (99% purity, 24% yield) of the title compound (stereoisomer 1, Rt = 18.7-22.0 min) were prepared after purification by preparative H...

Claims

1. A compound of formula (I) in which: R1 represents methyl, ethyl, trifluoromethyl, 2,2-difluoroethyl, cyano, chloro, bromo, methoxy or difluoromethoxy; R2 represents hydrogen, methyl, ethyl, fluoro, chloro or bromo; R3 represents hydrogen or fluoro; R4 represents hydrogen or methyl; R5 independently at each occurrence represents hydrogen, trifluoromethyl or C1-C3 alkyl, R5 being bound to any carbon atom of the ring; R6 independently at each occurrence represents hydrogen, C1-C3-alkyl or C1-C3-haloalkyl; R7 represents C1-C3-alkyl or C2-C3-haloalkyl; R8 represents C1-C3-alkyl or C2-C3-haloalkyl; X represents NR7 or O; Y represents NR8 or O; m represents 0, 1, 2 or 3; n represents 0 or 1; or an N-oxide, a salt or a tautomer of said compound, or a salt of said N-oxide or tautomer.

2. The compound of formula (I) according to claim 1, wherein: R1 represents methyl, ethyl, chloro, methoxy or difluoromethoxy; R2 represents methyl, ethyl, fluoro or chloro; R3 represents hydrogen or fluoro; R4 represents hydrogen or methyl; R5 represents hydrogen, methyl or trifluoromethyl, R5 being bound to any carbon atom of the ring; R6 represents hydrogen, methyl or trifluoromethyl; R7 represents C1-C2-alkyl or C2-C3-fluoroalkyl; R8 represents C1-C2-alkyl or C2-C3-fluoroalkyl; X represents NR7 or O; Y represents NR8 or O; m represents 0, 1 or 2; n represents 0 or 1; or an N-oxide, a salt or a tautomer of said compound, or a salt of said N-oxide or tautomer.

3. The compound of formula (I) according to claim 1 or 2, wherein: R1 represents methyl, ethyl, chloro or methoxy; R2 represents, fluoro or chloro; R3 represents hydrogen or fluoro; R4 represents hydrogen; R5 represents hydrogen or methyl, R5 being bound to any carbon atom of the ring; R8 represents hydrogen; R7 represents methyl; R8 represents methyl, 2,2,2-trifluoroethyl or 2,2-difluoroethyl; X represents NR7 or O; Y represents NR8 or O; m represents 0, 1, or 2; n represents 0 or 1; or an N-oxide, a salt or a tautomer of said compound, or a salt of said N-oxide or tautomer.

4. The compound of formula (I) according to any of claims 1 to 3, which is selected from the group consisting of: 3-(3-chloro-2-methoxyanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(2,3-dichloroanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(2,3-dichloroanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(2,3-dichloroanilino)-2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methoxyanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(2R)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2R)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(3S)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-4-(2,2-difluoroethyl)morpholin-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(2S)-4-(2,2,2-trifluoroethyl)morpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-{3-[2-(4-dioxan-2-yl)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{2-[(2R)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{2-[(2S)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-5-fluoro-2-methoxyanilino)-2-(3-{[(2S)-4-(2,2,2-trifluoroethyl)ymorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-ethylanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2R)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2R)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{2-[(2R)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{2-[(2S)-1,4-dioxan-2-yl]lethoxy}pyridin-4-yl)-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. 3-(3-fluoro-2-methoxyanilino)-2-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methylanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methylanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-(3-{[(3R)-4-methylmorpholin-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-{3-[(5,5-dimethyl-1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-(3-{[(2S)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-(3-{[(2R)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-3-(3-fluoro-2-methylanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methylanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(3-fluoro-2-methylanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methylanilino)-2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-ethylanilino)-2-{3-[(1,4-dioxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-ethylanilino)-2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-ethylanilino)-2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-ethylanilino)-2-(3-{[(2R)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-ethylanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{1-[1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{(1S)-1-[(2S)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{(1S)-1-[(2R)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{(1R)-1-[(2S)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-(3-{(1R)-1-[(2R)-1,4-dioxan-2-yl]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methylanilino)-2-{3-[(4-methylmorpholin-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methylanilino)-2-(3-{[(2R)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-fluoro-2-methylanilino)-2-(3-{[(2S)-4-methylmorpholin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2R)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 2-(3-{[(2S)-5,5-dimethyl-1,4-dioxan-2-yl]methoxy}pyridin-4-yl)-3-(2-ethyl-3-fluoroanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-[3-({1-[4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-[3-({(1R)-1-[(2R)-4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-[3-({(1S)-1-[(2S)-4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-[3-({(1R)-1-[(2S)-4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 3-(3-chloro-2-methoxyanilino)-2-[3-({(1S)-1-[(2R)-4-methylmorpholin-2-yl]ethyl}oxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one5. A compound of general formula (I) according to any of claims 1 to 4 for use in the treatment or prophylaxis of diseases.

6. The compound for use according to claim 5, wherein the diseases are hyperproliferative diseases and / or disorders responsive to induction of cell death.

7. The compound for use according to claim 6, wherein the hyperproliferative diseases and / or disorders responsive to induction of cell death are haematological tumours, solid tumours and / or metastases thereof.

8. The compound for use according to claim 7, wherein the tumour harbors a mutant EGFR and / or metastases thereof.

9. The compound for use according to claim 7, wherein the tumour is lung cancer, particularly lung cancer harboring a mutant EGFR with exon 20 insertion mutation, and / or metastases thereof.

10. The compound for use according to claim 7, wherein the tumour is lung cancer, particularly lung cancer harboring a mutant EGFR with in-frame deletions in exon 19 or point mutations in exon 21, and / or metastases thereof.

11. The compound for use according to claim 10, wherein the mutant EGFR with in-frame deletions in exon 19 is EGFR E746_A750del.

12. The compound for use according to claim 10, wherein the mutant EGFR with point mutations in exon 21 is L858R.

13. The compound for use according to claim 7, wherein the tumour is lung cancer, particularly lung cancer harboring a mutant EGFR with a D770_N771insSVD C797S, E746_A750del C797S, or L858R C797S acquired resistance mutation, and / or metastases thereof.

14. The compound for use according to claim 7, wherein the tumour is lung cancer, particularly lung cancer harboring a mutant ERBB2 with exon 20 insertion mutations, and / or metastases thereof.

15. The compound for use according to claim 14, wherein the mutant ERBB2 with exon 20 insertion mutations is ERBB2 A775_G776insYVMA.

16. A pharmaceutical composition comprising at least one compound of general formula (I) according to any of claims 1 to 4, together with at least one pharmaceutically acceptable auxiliary.

17. The composition according to claim 16 for use in the treatment of haematological tumours, solid tumours and / or metastases thereof.

18. A combination comprising one or more first active ingredients selected from a compound of general formula (I) according to any of claims 1 to 4, and one or more second active ingredients selected from chemotherapeutic anti-cancer agents and target-specific anti-cancer agents.

19. A compound of general formula (I) according to any of claims 1 to 4 for use in a method of inhibiting EGF-receptor kinase activity in a cancer cell, the method comprising contacting the cancer cell with a compound of general formula (I) according to any of claims 1 to 4, wherein the cancer cell is derived from a cancer selected from the group consisting of leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours, skin tumours, and sarcomas.

20. The compound for use of claim 19, wherein the cancer cell is in vitro or in vivo.

21. A compound of general formula (I) according to any of claims 1 to 4 for use in a method of reducing the survival of a cancer cell or inducing death in a cancer cell, the method comprising contacting a cancer cell comprising a mutation in an EGF-receptor with a compound of general formula (I) according to any of claims 1 to 4.

22. The compound for use of any one of claims 19 to 21, wherein the EGF-receptor comprises a mutation in exon 20.

23. The compound for use of claim 21 or 22, wherein the cancer cell is derived from a cancer selected from the group consisting of leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours, skin tumours, and sarcomas.

24. The compound for useof claim 23, wherein the cancer cell is derived from a cancer selected from the group consisting of inverted sinonasal papilloma or inverted sinonasal papilloma associated sinanonasal squamous cell carcinoma.

25. A compound of general formula (I) according to any of claims 1 to 4 for use in a method of treating cancer in a subject, the method comprising administering to the subject an effective amount of a compound of general formula (I) according to any of claims 1 to 4.

26. A compound of general formula (I) according to any of claims 1 to 4 for use in a method of treating cancer in a subject, wherein the cancer is or has acquired resistance to an anti-EGF receptor therapy, the method comprising administering to the subject an effective amount of a compound of general formula (I) according to any of claims 1 to 4.

27. A compound of general formula (I) according to any of claims 1 to 4 for use in a method of enhancing the efficacy of an anti-EGF-receptor therapy, the method comprising administering to the subject an anti-EGF receptor therapy in combination with a compound of general formula (I) according to any of claims 1 to 4, wherein the cancer is selected from the group consisting of leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumours, tumours of the thorax, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours, skin tumours, and sarcomas.

28. The compound for use of claim 25 or 26, wherein the cancer is selected from the group consisting of leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumours, tumours of the thorax, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours, skin tumours, and sarcomas.

29. The compound for use of claim 28, wherein the cancer is selected from the group consisting of inverted sinonasal papilloma or inverted sinonasal papilloma associated sinanonasal squamous cell carcinoma.

30. The compound for use of claim 28, wherein the tumour of the thorax is non-small cell lung cancer.

31. The compound for use of any one of claims 19 to 30, wherein the EGF-receptor comprises a mutation.

32. The compound for use of claim 31, wherein the EGF-receptor comprises a mutation in exon 20.

33. The compound for use of claim 32, wherein the EGF-receptor comprises an insertion in exon 20.

34. The compound for use of claim 33, wherein the EGF-receptor comprises an insertion between amino acids V769-D770 and / or between D770-N771.

35. The compound for use of claim 34, wherein the insertion is an ASV and / or SVD insertion.

36. The compound for use of claim 33, wherein the EGF-receptor comprising an ASV insertion between amino acids V769-D770 and / or a SVD insertion between amino acids D770-N771.

37. A method of selecting a patient for cancer treatment with a compound of general formula (I) according to any of claims 1 to 4, the method comprising detecting the presence of a mutation in exon 20 of the EGF-receptor in a biological sample of the subject, thereby determining that the patient should be treated with said compound.

38. A compound of general formula (I) according to any of claims 1 to 4 for use in a method for treating a patient with cancer, the method comprising administering to the subject an anti-EGF receptor therapy in combination with a compound of general formula (I) according to any of claims 1 to 4, wherein the subject is selected for therapy by detecting the presence of a mutation in exon 20 of the EGF-receptor in a biological sample of the subject.

39. The compound for use of claim 37 or 38, wherein the EGF-receptor comprises an insertion in exon 20.

40. The compound for use of claim 39, wherein the EGF-receptor comprises an insertion between amino acids V769-D770 and / or between amino acids D770-N771.

41. The compound for use of claim 40, wherein the insertion is an ASV and / or SVD insertion.

42. The compound for use of claim 39, wherein the EGF-receptor comprising an ASV insertion between amino acids V769-D770 and / or a SVD insertion between amino acids D770-N771.

43. The compound for use of any one of claims 19, 21, 27, 37 and 38, wherein the cancer is lung cancer, particularly lung cancer harboring a mutant EGFR with in-frame deletions in exon 19 or point mutations in exon 21, and / or metastases thereof.

44. The compound for use of claim 43, wherein the mutant EGFR with in-frame deletions in exon 19 is EGFR E746_A750del.

45. The compound for use of claim 43, wherein the mutant EGFR with point mutations in exon 21 is L858R.

46. The compound for use of any one of claims 19, 21, 27, 37 and 38, wherein the cancer is lung cancer, particularly lung cancer harboring a mutant EGFR with a D770_N771insSVD C797S, E746_A750del C797S, or L858R C797S acquired resistance mutation, and / or metastases thereof.

47. The compound for use of any one of claims 19, 21, 27, 37 and 38, wherein the cancer is lung cancer, particularly lung cancer harboring a mutant ERBB2 with exon 20 insertion mutations, and / or metastases thereof.

48. The compound for use of claim 47, wherein the mutant ERBB2 with exon 20 insertion mutations is ERBB2 A775_G776insYVMA.