Azaindole derivatives and their use as ERK kinase inhibitors - Patents.com

Abstract

The present invention relates to a compound of formula (I) below or one of its pharma- ceutically acceptable salts, in particular to a compound of formula (I) above or one of its pharma-ceutically acceptable salts, for use as an inhibitor of ERK kinase activity, in particular ERK2 activity. JPEG2025502377000274.jpg59170

Description

[Technical field]

[0001] The present invention relates to azaindole derivatives that are inhibitors of ERK kinases (ERK1 and ERK2), to processes for their preparation, and to their therapeutic use. [Background technology]

[0002] The ERK protein belongs to the RAS / RAF / MEK / ERK pathway, which plays a key role in cell cycle, proliferation, growth and survival. The RAS / RAF / MEK / ERK pathway is activated by growth factors through receptor tyrosine kinases that enable the activation of the GTPase RAS. In turn, RAS activates the RAF protein. RAF then activates MEK, which activates ERK.

[0003] Finally, it allows the phosphorylation of many substrates that have important roles in metabolism, protein synthesis, cell growth and survival.

[0004] RAF gene mutations, in particular those that lead to overactivation of the RAS / RAF / MEK / ERK pathway, account for 7% of all human cancers (Davies et al., Nature. 2002; Garnett et al., Cancer Cell. 2004).

[0005] In fact, RAF mutations are frequently observed in melanoma (27-70%), thyroid cancer (36-53%), colorectal cancer (5-22%), and ovarian cancer (30%). Similarly, RAS mutations occur in approximately 30% of cancers and are present in pancreatic (90%), lung (35%), colon (45%), and liver (30%) cancers (Downward, Nat. Rev. Cancer. 2003).

[0006] Thus, proteins in the RAS / RAF / MEK / ERK pathway represent interesting targets for cancer treatment, and in fact pharmaceutical companies are focusing on the upstream kinases (RAF, MEK).

[0007] However, resistance eventually emerges following current treatment with RAF and MEK inhibitors (Lito et al., Nat. Med. 2013; Caunt et al., Nat. Rev. Cancer, 2015).

[0008] Moreover, most resistance to MEK or RAF inhibitors induces ERK reactivation through various mechanisms, e.g., MEK mutation, B-RAF amplification, and C-RAF mutation (Little et al., Oncogene. 2013).

[0009] Moreover, inhibition of RAF or MEK suppresses ERK negative feedback, restoring up-signaling and ultimately ERK activity (Lito et al., Nat. Med., 2013).

[0010] Given the phenomenon of resistance that has emerged after current treatment with RAF and MEK inhibitors, it is essential to develop new therapeutic approaches.

[0011] Apart from its important role in hyperproliferative diseases, ERK signaling has been implicated in neurodegenerative disorders, e.g., Parkinson's, Alzheimer's and Huntington's diseases (Cheung et al., Sci. STKE. 2004; Bodai et al., Bioessays., 2012), and inflammation, e.g., in the pathogenesis of rheumatoid arthritis (Thalhamer et al., Rheumatology. 2008).

[0012] Thus, the present invention relates to the development of ERK inhibitors for the treatment of a wide range of diseases.

[0013] Several ERK inhibitors have already been described in the prior art. Thus, US Pat. No. US8,697,697 B2 describes substituted pyrazole derivatives as inhibitors of ERK2 kinase activity.

[0014] Pyrrolo[2,3-b]pyrazine derivatives have also been reported as ERK inhibitors in International Publication No. WO2014 / 060395A1, and azaindole derivatives have been reported as ERK inhibitors in International Publication No. WO2017 / 085230A1.

[0015] However, there is a need for efficient compounds that can selectively inhibit ERK1 and / or ERK2 kinases.

[0016] The present invention is specifically directed to novel compounds and their use as inhibitors of ERK kinase activity.

[0017] The compounds of the present invention are novel azaindole derivatives that have at least enhanced antiproliferative activity.

[0018] The compounds according to the invention are also characterized by their low toxicity, high penetrance and kinase inhibition selectivity.

[0019] Overall, the compounds according to the invention are notable for their drug-like properties.

[0020] A first subject of the invention relates to compounds corresponding to the following general formula (I) or one of its pharma- ceutically acceptable salts: [ka] Where: R1 represents a (C1-C6) alkyl group; R2 represents a (C1-C6) alkyl group, a (C3-C6) cycloalkyl group, or a (C1-C6) alkyl group substituted by one or more groups selected from a halogen atom, a cyano group, a (C1-C6) alkoxy group, and a (C3-C6) cycloalkyl group; or R1 and R2 together with the nitrogen atom form a 3- to 6-membered heterocyclic group; R3, R4, R5, R6, R7, R8 and R9 each independently represent a hydrogen atom, a halogen atom, a (C1-C6) alkyl group, a trifluoromethyl group or a cyano group, wherein the (C1-C6) alkyl group may itself be substituted with a (C1-C6) alkoxy group.

[0021] After extensive searching of ERK crystal structures and structural screening studies, the present inventors have determined that the novel azaindole derivatives of formula (I) selectively target the active site of ERK kinase and act as effective inhibitors of ERK kinase activity, as demonstrated in the Examples below.

[0022] In the sense of the present invention, a "kinase inhibitor" is intended to mean a compound which reduces or inhibits the activity of a targeted kinase compared to the kinase activity determined in the absence of said inhibitor.

[0023] In the sense of the present invention, the terms "prevent" or "prevention" in relation to an event are intended to mean the reduction of the risk of occurrence of said event.

[0024] As described below, these compounds are useful in the treatment of conditions or diseases, particularly cancer, where modulating the activity of ERK has a positive therapeutic effect.

[0025] Another subject matter relates to a process for preparing the compounds of general formula (I).

[0026] Another subject matter relates to compounds of general formula (I) especially for use in medicines or in pharmaceutical compositions.

[0027] A further subject matter relates to the compounds according to the invention for use as inhibitors of ERK kinase activity, in particular for use as inhibitors of ERK1 and / or ERK2 kinase activity.

[0028] Abbreviations and Definitions In the context of the present invention, the following abbreviations and empirical formulas are used: ATP Adenosine 5'-triphosphate Brij-35 Polyoxyethylene glycol dodecyl ether Boc tert-Butyloxycarbonyl Bs Brosyl C18 column Reversed phase C18 column CMC Carboxymethylcellulose Cs2CO3 Cesium carbonate DABCO 1,4-diazabicyclo[2.2.2]octane DIEA N,N-Diisopropylethylamine DMF Dimethylformamide DMEM Dulbecco's Modified Eagle's Medium DMSO Dimethyl sulfoxide ℃ Celsius DCM Dichloromethane ee Enantiomeric excess EGTA Egtadic Acid Eq Equivalent Et3N Triethylamine Et2O Diethyl ether EtOAc Ethyl acetate EtOH Ethanol FBS Fetal Bovine Serum g grams h time HBSS Hanks Balanced Salt Solution HCl Hydrochloric acid H2CO2Formic Acid HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid hERG human ether-a-go-go-related gene HPLC High Performance Liquid Chromatography IPA Isopropanol K2CO3 Potassium Carbonate LC / MS Liquid Chromatography / Mass Spectrometer LiAlH4 Lithium Aluminum Hydride LiHMDS Lithium bis(trimethylsilyl)amide M moles per liter MeCN Acetonitrile MeOH Methanol MeTHF 2-Methyltetrahydrofuran mg milligram MH+ pseudo-molecular ion (positive ion mode in mass spectrometry) MHz Megahertz Ms. Meshir μl microliter ml milliliter mmol mol Na2CO3 Sodium Carbonate NaHCO3 Sodium bicarbonate NaH2PO2 Sodium hypophosphite NaOH Sodium hydroxide Na2SO4 Sodium Sulfate NH4Cl Ammonium chloride Raney Nickel NMR nuclear magnetic resonance Ns Nosil PdCl2(PPh3)2 Bis(triphenylphosphine)palladium(II) dichloride PG protecting group RuPhos 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl RuPhos Pd G2 Chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) SDS Sodium dodecyl sulfate TBAF Tetrabutylammonium fluoride tBuONa Sodium tert-butoxide TEA Triethylamine Tf Trifle THF Tetrahydrofuran TIPS Triisopropylsilyl TMS Trimethylsilyl Ts Tosil

[0029] In the context of the present invention, the following definitions apply: Halogen atom: a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The halogen atom may in particular be chosen from among chlorine and fluorine atoms. C t ~C z : a carbon-based chain that may contain t to z carbon atoms, where t and z may take values ​​from 1 to 10. For example, C1-C3 is a carbon-based chain that contains 1 to 3 carbon atoms. Alkyl: a linear or branched saturated aliphatic group, especially containing 1 to 6 carbon atoms. Examples which may be mentioned include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, etc. Alkoxy: an -O-alkyl moiety, the alkyl group being as defined above. Cyano group: the -C≡N moiety. Trifluoromethyl group: -CF3 moiety. Cycloalkyl group: a non-aromatic mono- or bicyclic saturated or partially saturated or unsaturated ring containing from 3 to 8 carbon atoms. Examples of cycloalkyl groups which may be mentioned include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane or cyclohexene. 3- to 6-membered heterocyclic group: a monocyclic saturated ring containing at least one heteroatom. Examples of 3- to 6-membered heterocyclic groups that may be mentioned include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 2-oxa-6-azaspiro[3.3]heptanyl, etc.

[0030] Other features, characteristics and advantages of the present invention will become more apparent from the ensuing description and examples.

[0031] Compounds of the Invention As mentioned above, one of the compounds according to the invention, or a pharma- ceutically acceptable salt thereof, corresponds to the following general formula (I): [ka] Where: R1 represents a (C1-C6) alkyl group; R2 represents a (C1-C6) alkyl group, a (C3-C6) cycloalkyl group, or a (C1-C6) alkyl group substituted by one or more groups selected from a halogen atom, a cyano group, a (C1-C6) alkoxy group, and a (C3-C6) cycloalkyl group; or R1 and R2 together with the nitrogen atom form a 3- to 6-membered heterocyclic group; R3, R4, R5, R6, R7, R8 and R9 each independently represent a hydrogen atom, a halogen atom, a (C1-C6) alkyl group, a trifluoromethyl group or a cyano group, wherein the (C1-C6) alkyl group may itself be substituted with a (C1-C6) alkoxy group.

[0032] The compounds of formula (I) may contain one or more asymmetric carbon atoms. Thus, the compounds of formula (I) may exist in the form of enantiomers or diastereomers. These enantiomers and diastereomers and their mixtures, such as the above mixtures, including racemic mixtures, form part of the present invention.

[0033] According to a preferred embodiment, the asymmetric carbon bearing the -CH2NR1R2 group in the compound of formula (I) is in the S configuration.

[0034] The compounds of formula (I) may also exist in the form of free bases or of acid addition salts. These salts may be prepared with pharma- ceutically acceptable acids, but also salts of other acids, useful, for example, for purifying or isolating the compounds of formula (I), form part of the invention.

[0035] The compounds of formula (I) may also exist in the form of hydrates or solvates, i.e. in the form of associations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates also form part of the invention.

[0036] According to one embodiment, R1 represents a methyl, ethyl, propyl, butyl, pentyl or hexyl group, in particular R1 represents a methyl, ethyl or propyl group, preferably R1 represents a methyl or ethyl group.

[0037] According to a preferred embodiment, R1 represents a methyl group.

[0038] According to a preferred embodiment, R2 represents a (C1-C6) alkyl group.

[0039] According to one embodiment, R2 represents a methyl, ethyl, propyl, butyl, pentyl or hexyl group, in particular R2 represents a methyl, ethyl or propyl group, preferably R2 represents a methyl or ethyl group.

[0040] Preferably, R2 represents a methyl group.

[0041] According to another embodiment, R2 represents a (C3-C6)cycloalkyl group, preferably a cyclopropyl group.

[0042] According to another embodiment, R2 represents a (C1-C6) alkyl group substituted by one or more groups selected from a halogen atom, a cyano group, a (C1-C6) alkoxy group and a (C3-C6) cycloalkyl group.

[0043] Preferably, R2 represents a (C1-C6) alkyl group, in particular a methyl or ethyl group, a cyclopropyl group, -CH2-CF2, -CH2-CN, -CH2-CH2-O-CH3, or -CH2-cyclopropyl.

[0044] According to another embodiment, R1 and R2 together with the nitrogen atom form an aziridinyl group.

[0045] According to a preferred embodiment, both R1 and R2 represent a methyl group.

[0046] According to a preferred embodiment, R3 represents a halogen atom, a (C1-C6) alkyl group, a trifluoromethyl group or a cyano group, wherein the (C1-C6) alkyl group may itself be substituted with a (C1-C6) alkoxy group.

[0047] According to a preferred embodiment, R3 represents a halogen atom, a (C1-C6) alkyl group, in particular a methyl or ethyl group, a -CH2-O-CH3 group, a trifluoromethyl group or a cyano group.

[0048] In particular, R3 represents a halogen atom, in particular a chlorine, fluorine, bromine or iodine atom.

[0049] Preferably, R3 represents a chlorine or fluorine atom.

[0050] According to a preferred embodiment, R3 represents a chlorine atom.

[0051] According to another preferred embodiment, R3 represents a fluorine atom.

[0052] According to a preferred embodiment, R4 represents a hydrogen atom or a halogen atom, in particular a chlorine, fluorine, bromine or iodine atom.

[0053] More particularly, R4 represents a hydrogen atom, a chlorine atom or a fluorine atom.

[0054] Preferably, R4 represents a hydrogen atom or a chlorine atom.

[0055] According to a preferred embodiment, R4 represents a chlorine atom.

[0056] According to another preferred embodiment, R4 represents a fluorine atom.

[0057] According to another preferred embodiment, R4 represents a hydrogen atom.

[0058] According to another preferred embodiment, R5 represents a hydrogen atom or a halogen atom, in particular a chlorine, fluorine, bromine or iodine atom.

[0059] More particularly, R5 represents a hydrogen atom, a chlorine atom or a fluorine atom.

[0060] According to a preferred embodiment, R5 represents a chlorine atom.

[0061] According to another preferred embodiment, R5 represents a fluorine atom.

[0062] According to another preferred embodiment, R5 represents an iodine atom.

[0063] According to another preferred embodiment, R5 represents a hydrogen atom.

[0064] According to a preferred embodiment, at least one of R3, R4 and R5 does not represent a hydrogen atom.

[0065] According to a preferred embodiment, at least one of R3, R4 and R5 represents a halogen atom, and the other two independently represent a hydrogen atom or a halogen atom.

[0066] According to a preferred embodiment, one of R3, R4 and R5 represents a chlorine atom and the other two independently represent a hydrogen atom or a halogen atom.

[0067] According to a preferred embodiment, at least one of R3, R4 and R5 is a fluorine atom, and the other two independently represent a hydrogen atom or a halogen atom.

[0068] According to a preferred embodiment, two of R3, R4 and R5 represent a chlorine atom and the other one represents a hydrogen atom.

[0069] According to a preferred embodiment, R6 represents a hydrogen atom or a (C1-C6) alkyl group.

[0070] More particularly, R6 represents a hydrogen atom or a methyl group.

[0071] According to a preferred embodiment, R6 represents a hydrogen atom.

[0072] According to another preferred embodiment, R6 represents a (C1-C6) alkyl group, in particular a methyl or ethyl group, preferably a methyl group.

[0073] According to a preferred embodiment, R7 represents a hydrogen atom or a halogen atom, in particular a chlorine, fluorine, bromine or iodine atom.

[0074] More particularly, R7 represents a hydrogen atom, a chlorine atom or a fluorine atom.

[0075] According to a preferred embodiment, R7 represents a hydrogen atom.

[0076] According to another preferred embodiment, R7 represents a halogen atom, in particular a chlorine, fluorine, bromine or iodine atom, preferably a fluorine atom.

[0077] According to a preferred embodiment, both R6 and R7 represent a hydrogen atom.

[0078] According to a preferred embodiment, R8 represents a hydrogen atom or a halogen atom, in particular a chlorine, fluorine, bromine or iodine atom.

[0079] More particularly, R8 represents a hydrogen atom, a chlorine atom or a fluorine atom.

[0080] According to a preferred embodiment, R8 represents a hydrogen atom.

[0081] According to another preferred embodiment, R8 represents a halogen atom, in particular a chlorine, fluorine, bromine or iodine atom, preferably a fluorine atom.

[0082] According to a preferred embodiment, R9 represents a hydrogen atom, a halogen atom or a trifluoromethyl group.

[0083] More particularly, R9 represents a hydrogen atom or a trifluoromethyl group.

[0084] According to a preferred embodiment, R9 represents a hydrogen atom.

[0085] According to another preferred embodiment, R9 represents a trifluoromethyl group.

[0086] According to a preferred embodiment, R6, R7, R8 and R9 all represent a hydrogen atom.

[0087] According to a preferred embodiment, R1 and R2 both represent a methyl group and R6, R7, R8 and R9 all represent a hydrogen atom.

[0088] According to a preferred embodiment, R1 and R2 both represent a methyl group, R6, R7, R8 and R9 all represent a hydrogen atom, and R3 represents a halogen atom, preferably a chlorine atom.

[0089] According to another preferred embodiment, R1 and R2 both represent a methyl group, R6, R7, R8 and R9 all represent a hydrogen atom, and R3 represents a halogen atom, preferably a chlorine atom, and R4 and R5 independently represent a hydrogen atom or a halogen atom.

[0090] According to another preferred embodiment, R1 and R2 both represent a methyl group, R6, R7, R8 and R9 all represent a hydrogen atom, R3 represents a halogen atom, preferably a chlorine atom, R4 and R5 independently represent a hydrogen atom or a halogen atom, and the asymmetric carbon bearing the -CH2NR1R2 group is in the S configuration.

[0091] It will be apparent that, unless otherwise stated, features of the above-described embodiments may be combined with each other.

[0092] Among the compounds of formula (I), particular mention may be made of the following compounds, or one of their pharma- ceutically acceptable salts: [ka] JPEG2025502377000005.jpg226170JPEG2025502377000006.jpg196170

[0093] Of the compounds of formula (I), particular mention may be made of the following compounds, or one of their pharma- ceutically acceptable salts: [ka] JPEG2025502377000008.jpg53170

[0094] Preparation of the Compounds of the Invention The compounds of the present invention may be prepared according to well-known methods by those skilled in the art, as illustrated in the examples below.

[0095] According to a first embodiment, the synthesis of synthetic intermediates for compounds of the invention may be carried out according to Schemes 1 and 2 below.

[0096] More precisely, the synthetic intermediate of formula (V) can be prepared according to Scheme 1 below, in which R8 and R9 are as defined in formula (I) above and PG is a protecting group as defined below. [ka]

[0097] The 5-morpholino-7-azaindole derivative of formula (III) shown in Scheme 1 above can be obtained from the commercially available compound of formula (II) above by carrying out a Buchwald-Hartwig coupling reaction using a base such as LiHMDS, a catalyst such as RuPhos, and a RuPhos ligand such as RuPhos Pd G2 (step a). Other RuPhos ligands such as RuPhos Pd G3 or RuPhos Pd G4 can also be used to obtain the compound of formula (III). This reaction is generally carried out in an anhydrous solvent such as THF at a temperature of 60-70°C.

[0098] The pyrrolyl moiety of the 7-azaindole core is then protected with a protecting group, such as Ts or another sulfonyl group, and the compound of formula (IV) above is obtained by using a base, such as NaH or K2CO3, in an anhydrous solvent, such as DMF, DCM or THF (step b). This reaction can also be carried out using other protecting groups, such as Boc, trimethylsilylethoxymethyl, TMS or TIPS.

[0099] Finally, compounds of formula (V) can be obtained by selective boronation of the azaindole core at the 3-position using (1,5-cyclooctadiene)(methoxy)iridium(I) in the presence of a ligand such as 4,4'-di-tert-butylbiphenyl and a boron source such as bis(pinacolato)diboron (step c). This reaction is typically carried out in methyl THF under argon at reflux for 30 minutes to several hours.

[0100] The present invention therefore also relates to a process for preparing a compound of general formula (V), in which R8 and R9 are as defined in formula (I) above and PG is a protecting group as defined below, in which the following steps are carried out in this order starting from a compound of formula (II) above: a) Buchwald-Hartwig coupling reaction to obtain 5-morpholino-7-azaindole of formula (III), b) protecting the pyrrolyl moiety of the 7-azindole core to obtain a compound of formula (IV); c) Selective boronation of the azaindole core at the 3-position finally gives compounds of formula (V).

[0101] The synthetic intermediate of formula (XI) may be prepared according to Scheme 2, where R1, R2, R3, R4, R5, R6 and R7 are as defined above, X is Cl, Br or OM, and Y is a halogen atom as defined below. [ka]

[0102] Compounds of formula (VII) can be obtained by direct olefination of commercially available aldehydes of formula (VI). The reaction is typically carried out with methyltriphenylphosphonium bromide in the presence of a base, such as NaH, in an anhydrous solvent, such as EtO, DCM or THF (Step 1).

[0103] The alkene of formula (VII) is then converted to the corresponding epoxide of formula (VIII) (step 2), typically using NBS / AcOH couple at 0° C. followed by NaOH solution. The epoxide formation can also be carried out using other reducing agents, such as peroxides or NaOCl.

[0104] Selective epoxide ring opening of compounds of formula (VIII) is then carried out using commercially available disubstituted amines HNR1R2 (Step 3). The reaction is preferably carried out in 96% EtOH at room temperature for 24 hours to obtain the best regioselectivity, but can also be carried out in EtOH / water mixtures and / or heated for several hours.

[0105] The benzyl alcohol derivative of formula (IX) is then converted to the corresponding benzyl chloride or mesylate derivative of formula (X) (step 4) using MsCl in an anhydrous solvent such as DCM at 0° C. Benzyl bromides of formula (X) can also be prepared using thionyl bromide instead of MsCl in DCM at 0° C.

[0106] Compounds of formula (XI) are finally obtained by displacement of halogen or OMs moiety using commercially available 4-halogenopyridin-2-ones in the presence of base such as K2CO3 or Na2CO3 in DMF or DMA. The reaction can also be carried out in other solvents such as THF, Et2O, DCM or acetone using other bases such as NaOH or tBuOK, but more formation of O-alkylated by-products may be observed (step 5).

[0107] The present invention also relates to a process for preparing a compound of general formula (XI), wherein R1, R2, R3, R4, R5, R6 and R7 are as defined in formula (I) and Y is a halogen atom as defined below, in which the following steps are carried out in the given order starting from a commercially available compound of formula (VI): 1) Olefination of an aldehyde to give the corresponding alkene of formula (VII); 2) epoxidizing an olefin to obtain a compound of formula (VIII); 3) Regioselective ring opening leading to the benzyl alcohol of formula (IX), 4) The alcohols are converted into their corresponding halogeno or mesylate derivatives to directly obtain the compounds of formula (X) according to 5) below. 5) N-alkylation of commercially available 4-halogenopyridin-2-ones finally gives compounds of formula (XI).

[0108] Finally, compounds of formula (I) may be prepared according to Scheme 3, where R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined above in formula (I), Y is a halogen atom as defined below, and PG is a protecting group as defined below. [ka]

[0109] Compounds of formula (XII) are prepared by coupling synthetic intermediates of formula (V) and formula (XI) as described above in schemes 1 and 2 (step i). The Suzuki coupling reaction is typically carried out in the presence of a base (powder or aqueous solution), such as K2CO3 or Na2CO3, a palladium II catalyst, such as bis(triphenylphosphine)palladium dichloride in MeCN, at a temperature between 60°C and 110°C. In this step, other conditions can be used, such as other solvents, such as 1,4-dioxane, DMSO, 1,2-dimethoxyethane, EtOH or DMF, other catalysts, such as palladium chloride or tris(dibenzylideneacetone)dipalladium, other bases, such as NaOH or Cs2CO3.

[0110] Compounds of formula (XII) are then deprotected by using NaOH in DMSO at room temperature or Na2CO3 solution at 110° C. to give azaindole derivatives of formula (XIII) (step ii). This step can also be carried out under other conditions, for example, TBAF in THF at 66° C. or MeONa in MeOH at room temperature.

[0111] The compound of formula (I) is finally obtained by chiral separation (step iii) of the racemate of formula (XIII), typically using a Daicel chiralflash IG. The (-,R)-enantiomer elutes first, followed by the (+,S)-enantiomer.

[0112] The present invention also relates to a method for preparing a compound of general formula (I), in which, starting from synthetic intermediates of formula (V) and formula (XI) below, the following steps are carried out in this order: i) Suzuki coupling reaction carried out at a temperature comprised between 60° C. and 110° C. to give a compound of formula (XII), ii) deprotecting the protecting group to give an azaindole of formula (XIII); iii) Separating the racemate by chiral chromatography.

[0113] Synthetic Intermediates The present invention also relates to a synthetic intermediate of formula (V): [ka] wherein R8 and R9 are as defined in formula (I) and PG is a protecting group selected from -tosyl, -mesyl, -brosyl, -nosyl, -triflyl, -tert-butyloxycarbonyl, -trimethylsilylethoxymethyl, -trimethylsilyl, -triisopropylsilyl.

[0114] Among the compounds of formula (V), particular mention may be made of compound (Va): [ka]

[0115] The present invention also relates to intermediates of formula (XI): [ka] wherein R1, R2, R3, R4, R5, R6 and R7 are as defined in formula (I), and Y is a halogen atom.

[0116] According to a preferred embodiment, at least one of R3, R4 and R5 is a halogen atom, and the other two independently represent a hydrogen atom or a halogen atom.

[0117] According to a preferred embodiment, at least one of R3, R4 and R5 represents a chlorine atom and the other two independently represent a hydrogen atom or a halogen atom.

[0118] According to a preferred embodiment, at least one of R3, R4 and R5 is a fluorine atom and the other two independently represent a hydrogen atom or a halogen atom.

[0119] According to a preferred embodiment, two of R3, R4 and R5 represent a chlorine atom and the others represent a hydrogen atom.

[0120] According to a preferred embodiment, Y is a bromine or iodine atom.

[0121] According to a preferred embodiment, when any of R3, R4 and R5 is an iodine atom, Y is an iodine atom.

[0122] According to a preferred embodiment, when none of R3, R4 and R5 is an iodine atom, Y is a bromine atom.

[0123] Among the compounds of formula (XI), particular mention may be made of the following compounds: [ka]

[0124] The present invention also relates to a synthetic intermediate of formula (XII): [ka] wherein R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined in formula (I), and PG is as defined in formula (V).

[0125] Among the compounds of formula (XII), particular mention may be made of the following compounds: [ka]

[0126] Another subject of the invention therefore relates to compounds of formula (V), formula (XI) and formula (XII), in which R1 represents a (C1-C6) alkyl group; R2 represents a (C1-C6) alkyl group, a (C3-C6) cycloalkyl group, or a (C1-C6) alkyl group substituted by one or more groups selected from a halogen atom, a cyano group, a (C1-C6) alkoxy group, and a (C3-C6) cycloalkyl group; or R1 and R2 together with the nitrogen atom form a 3- to 6-membered heterocyclic group; R3, R4, R5, R6, R7, R8 and R9 each independently represent a hydrogen atom, a halogen atom, a (C1-C6) alkyl group, a trifluoromethyl group or a cyano group, wherein the (C1-C6) alkyl group may itself be substituted with a (C1-C6) alkoxy group; Y is a halogen atom; and PG is a protecting group selected from -tosyl, -mesyl, -brosyl, -nosyl, -triflyl, -tert-butyloxycarbonyl, -trimethylsilylethoxymethyl, -trimethylsilyl, -triisopropylsilyl, preferably -tosyl.

[0127] Another subject of the present invention relates to compounds (Va), (XIa), (XIb), (XIc), (XId), (XIe), (XIf), (XIg), (XIh), (XIi), (XIj), (XIk), (XIl), (XIIa), (XIIb), (XIIc), (XIId), (XIIe), (XIIf), (XIIg), (XIIh), (XIIi), (XIIj), (XIIk) and (XIIl).

[0128] Purpose As defined above and as clearly demonstrated by the examples below, the compounds according to the present invention are useful as inhibitors of ERK kinase activity.

[0129] According to a first aspect, the compounds of the invention are for use as inhibitors of ERK2 kinase activity, preferably as selective inhibitors of ERK2 kinase activity.

[0130] More particularly, the compounds of the present invention are used to prevent and / or inhibit and / or treat diseases or conditions mediated by ERK kinase activity, in particular ERK2 kinase activity.

[0131] Therefore, the present invention provides a method for preventing and / or treating a disease or condition mediated by ERK kinase activity, said method comprising at least the step of administering to an individual in need thereof at least an effective amount of at least one compound according to the present invention.

[0132] The present invention also provides compounds of the present invention for preventing and / or inhibiting and / or treating, preferably for preventing and / or treating, more preferably for treating, a disease or condition mediated by ERK kinase activity, preferably ERK2 kinase activity.

[0133] The present invention also provides methods of using the compounds of the present invention for preventing and / or inhibiting and / or treating, preferably for preventing and / or treating, more preferably for treating, a disease or condition mediated by ERK kinase activity, preferably ERK2 kinase activity.

[0134] According to one embodiment, the disease or condition may be selected from cancer, metastasis and human immunodeficiency virus (HIV), preferably from cancer and metastasis.

[0135] More particularly, the disease or condition may be selected from glioblastomas, multiple myeloma, carcinoma, leukemia, in particular myeloid (AML), lymphocytic, myelocytic, myelogenous (CML) or lymphoblastic leukemia, myelodysplastic syndrome, Kaposi's sarcoma, cutaneous angiosarcoma, solid tumors, lymphoma, in particular non-Hodgkin's lymphoma, melanoma, in particular malignant melanoma, bladder cancer, breast cancer, gastric cancer, colon cancer, colorectal cancer, endometrial cancer, lung cancer including non-small cell carcinoma, pancreatic cancer, prostate cancer, rectal cancer, kidney cancer, head and neck cancer, liver cancer, ovarian cancer, in particular serous ovarian cancer, seminoma cancer, respiratory and thoracic cancer, thyroid cancer, in particular papillary or follicular thyroid cancer, or other tumors expressing ERK.

[0136] According to other embodiments, the disease or condition may be selected from a neoplastic disorder, an allergic disorder, an inflammatory disorder, an autoimmune disorder, a protozoan-associated disease, a mast cell-associated disease, a graft versus host disease, a metabolic syndrome, a CNS-associated disorder, a neurodegenerative disorder, a pain condition, a substance abuse disorder, a prion disease, a cardiac disease, a fibrotic disease, idiopathic arterial hypertension (IPAH), or primary pulmonary hypertension (PPH).

[0137] According to yet another embodiment, the compounds of the invention may be used for the prevention and / or inhibition and / or treatment of the Human Immunodeficiency Virus (HIV).

[0138] The compounds of the invention may be used alone or in combination with chemotherapeutic agents or radiotherapy regimens.

[0139] Thus, according to one embodiment, the method of the invention may comprise the step of administering a compound of formula (I) according to the invention separately, sequentially or simultaneously with a chemotherapeutic agent.

[0140] As examples of chemotherapeutic agents that may be suitable for the present invention, mention may be made of chemotherapeutic agents selected from alkylating agents, intercalating agents, antimicrotubule agents, antimitotics, antimetabolites, antiproliferative agents, antibiotics, immunomodulators, anti-inflammatory agents, kinase inhibitors, antiangiogenic agents, antivascular agents, estrogen and androgenic hormones.

[0141] A radiotherapy regimen can be administered by exposing an individual in need of the radiotherapy regimen to a source of ionizing radiation, such as X-rays, gamma rays, or beta rays.

[0142] According to another aspect, the present invention relates to a pharmaceutical composition comprising at least one compound according to the invention or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient.

[0143] The compounds according to the invention can be used for preparing a medicament, in particular a medicament for inhibiting the activity of ERK kinase, preferably ERK2 kinase activity.

[0144] Therefore, according to yet another aspect, the present invention relates to a medicament comprising at least one compound according to the invention or a pharma- ceutically acceptable salt thereof.

[0145] The term "pharmaceutical acceptable" means something that is generally safe, non-toxic, and useful for preparing pharmaceutical compositions that are biologically or otherwise undesirable, and includes veterinary acceptable as well as human pharmaceutical use.

[0146] Said pharmaceutical composition may more particularly comprise an effective dose of at least one compound according to the invention.

[0147] By "effective dosage" is meant an amount sufficient to induce a positive change in the condition to be modulated or treated, but low enough to avoid serious side effects. The effective amount may vary depending on the pharmaceutical effect to be obtained or the particular condition to be treated, the age and physical condition of the end user, the severity of the condition to be treated / prevented, the duration of the treatment, the nature of other treatments, the particular compound or composition used, the route of administration, and similar factors.

[0148] The compounds of formula (I) according to the present invention may be administered in an effective amount by any of the art-accepted modes of administration.

[0149] In one embodiment, the compounds of the invention may be used in compositions intended to be administered by oral, nasal, sublingual, auricular, ophthalmic, topical, rectal, vaginal, urethral, ​​or parenteral injection routes.

[0150] The route of administration and the galenic formulation will be adapted by the person skilled in the art depending on the desired pharmacological effect.

[0151] Those skilled in the art of therapeutic formulation will be able to ascertain therapeutically effective dosages of the compounds of the invention for a given indication without undue experimentation and relying on their personal knowledge.

[0152] The pharmaceutical composition of the present invention can be formulated with known suitable pharma- ceutical acceptable additives according to the dosage, galenic dosage form, administration route, etc.

[0153] As used herein, "pharmaceutical acceptable excipients" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. Except insofar as any conventional excipient is incompatible with the active compound, its use in the medicaments or pharmaceutical compositions of the invention is contemplated.

[0154] The medicaments or pharmaceutical compositions of the present invention may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, sprays, ointments, gels, creams, sticks, lotions, pastes, soft and hard gelatin capsules, suppositories, sterile injectable solutions, sterile packaged powders, and the like.

[0155] According to one embodiment, the pharmaceutical composition of the invention may be intended to be administered separately, sequentially or simultaneously with a drug useful for the prevention and / or treatment of a disease state, in particular a cancer state, wherein said drug is different from the compound of formula (I) of the invention.

[0156] The present application also encompasses novel kit-of-parts suitable for use in the treatment of cancer.

[0157] A kit-of-parts according to the invention may comprise (i) a compound of formula (I) according to the invention, and (ii) at least one agent useful for the prevention and / or treatment of a cancerous condition, wherein said agent is different from said compound of formula (I). The agent useful for the prevention and / or treatment of a cancerous condition may be a chemotherapeutic agent or a radiotherapeutic agent.

[0158] The present invention will be better understood by reference to the following examples, which are provided for illustrative purposes only and should not be construed as limiting the invention in any manner.

[0159] Working Example

[0160] Apparatus and analytical methods used for the synthesis of the examples

[0161] Microwave irradiation: Equipment: CEM Discover with Synergy Software. Method: 10mL or 30mL sealed tubes, power up to 50W, high stirring.

[0162] Flash Chromatography: Equipment: Biotage SP equipped with an autocollector and UV detector (dual wavelengths). Normal phase columns: Sigma-Aldrich 40-63 μm silica gel packed with Biotage external dry load cartridge kits of 10, 25 or 120 g Reverse phase column: 30g Biotage SNAP Cartridges, KP-C18-HS. Chiral column: Daicel ChiralFlash IG 100×30mm 20μM.

[0163] Liquid chromatography: Equipment: Waters alliance 2695 HPLC system equipped with an autosampler and a Waters 2996 diode array detector.

[0164] Out-of-phase condition: Column: Macherey-Nagel Nucleoshell RP18 plus (5 μm, 4 mm × 100 mm). Column temperature: 40°C. Solvents: Solvent A (99.9% H2O, 0.1% H2CO2); Solvent B (99.9% MeCN, 0.1% H2CO2). Flow rate: 1mL / min. Gradient (A / B v / v): 95 / 5 (t=0 min), 95 / 5 (t=1 min), 0 / 100 (t=7 min), 0 / 100 (t=10 min).

[0165] Chiral state: Column: Daicel ChiralPak IG (Amylose-based) 20μm, 4.6mm x 100mm. Column temperature: 25℃. Solvent: Heptane 50% / EtOH 40% containing 0.1% TEA / DCM 10%. Flow rate: 1mL / min.

[0166] Mass spectrometer: Instrument: Waters Micromass ZQ (simple quad). Mass detection method: electrospray positive mode (ESI+), mass range: 50-800 uma. Detection: 210-400nm range.

[0167] NMR spectrometer: Equipment: Bruker 400MHz. Methods: Performed in DMSO-d6 with DMSO-d5 as internal reference 1 H NMR spectrum, chemical shifts (expressed in parts per million (ppm)), signals designated as follows: s = singlet, d = doublet, t = triplet, q = quadruplet, sept = septuplet, dd = double doublet, dt = double triplet, m = multiplet or large singlet, br = broad, H = proton

[0168] Example 1: Synthesis of (S)-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0169] Step 1: 4-(1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine [ka]

[0170] In 487 ml of LiHMDS (1M in THF, 487 mmol, 2.4 eq), 947 mg (2.03 mmol, 0.01 eq) of RuPhos and 1.58 g (2.03 mmol, 0.01 eq) of RuPhos Pd G2 are dissolved. Then, under an argon atmosphere, 40 g (203 mmol, 1 eq) of 5-bromo-1H-pyrrolo[2,3-b]pyridine and 21.1 ml (244 mmol, 1.2 eq) of morpholine are added and the solution is heated at 66° C. for 1 h 30 min. The reaction mixture is then cooled to room temperature and dripped into 1.2 L of saturated NH4Cl solution, keeping the temperature below 10° C. with an ice-water bath. The mixture is stirred at this temperature for 10 min and then decanted. The aqueous layer is extracted three times with DCM. The combined organic layers are dried over Na2SO4, filtered, and evaporated under reduced pressure to give 44.4 g of a brown solid. The crude compound is triturated in 200 ml of a mixture of EtOAc and hexane (3 / 7) for 1 h. The solid is filtered, washed with 200 ml of a mixture of EtOAc and hexane (1 / 9), and dried under vacuum to give 38.98 g of a slightly brown powder. Yield: 94%. MH+:204.3(M+1).

[0171] Step 2: 4-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine [ka]

[0172] 38.98 g (192 mmol, 1 eq) of 4-(1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine (described in the previous step) is dissolved in 390 ml of dry DMF under argon atmosphere. The solution is cooled to 0° C. and 11.5 g (288 mmol, 1.5 eq) of sodium hydride (60% in paraffin oil) is slowly added. The mixture is stirred at this temperature for 10 minutes and then at room temperature for 40 minutes. The mixture is cooled again to 0° C., 47.5 g (249 mmol, 1.3 eq) of tosyl chloride is slowly added under argon atmosphere and the reaction mixture is stirred at 0° C. for 1 hour and then at room temperature for 1 hour. The mixture is added dropwise to 800 g of ice / water and stirred for 1 hour. A precipitate is obtained, which is filtered and washed several times with cold water. The precipitate is then dissolved in 1.2 L of DCM and the solution is washed twice with saturated NaHCO3 solution, twice with water and once with brine. The organic layer is dried over Na2SO4, filtered and evaporated under reduced pressure. The crude compound is triturated in 500 ml of a mixture of EtOAc and hexane (5 / 95) for 3 hours. The solid is filtered, washed with hexane and dried under vacuum to give 62.56 g of an off-white solid. Yield: 91%. MH+:358.6(M+1). 1 H NMR(DMSO-d6,400MHz):δ 8.18(d,J=2.7Hz,1H);7.92(d,J=8.3Hz,2H);7.78(d,J=4.0Hz,1H);7.52(d,J=2.7Hz,1H);7. 39(d,J=8.3Hz,2H);6.68(d,J=4.0Hz,1H);3.76-3.71(m,4H);3.12-3.07(m,4H);2.33(s,3H).

[0173] Step 3: 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine [ka]

[0174] 62.56 g (175 mmol, 1 eq) of 4-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine (described in the previous step) is suspended in 512 ml of Me-THF under an argon atmosphere. Then, 48.9 g of bis(pinacolato)diboron (193 mmol, 1.1 eq), 1.88 g of 4,4'-di-tert-butylbiphenyl (7 mmol, 0.036 eq) and 2.32 g of (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (3.5 mmol, 0.018 eq) are added. The reaction is heated to reflux for 45 minutes under an argon atmosphere. The reaction mixture is then cooled to -10°C in an ice / acetone bath and carefully quenched with MeOH (350 ml). The solution is stirred at room temperature for 15 min and evaporated under vacuum to give a brown oil. The dark oil is then dissolved in 1 L of DCM and washed three times with water and once with brine. The organic layer is evaporated under reduced pressure to give a black paste. 2 L of Et2O is added and the mixture is stirred at room temperature for 15 min, filtered over Celite and evaporated under reduced pressure to give 95 g of a brown solid foam. The crude mixture is finally purified by flash chromatography using a silica gel column and EtOAc / Hexane mixture as the eluting solvent. 75.5 g of the title compound is obtained. Yield: 89%. MH+:484.6(M+1). 1 H NMR(DMSO-d6,400MHz):δ 8.21(d,J=2.5Hz,1H);8.01(d,J=8.3Hz,2H);7.94(s,1H);7.50(d,J=2.4Hz,1H);7.4 1(d,J=8.0Hz,2H);3.78-3.72(m,4H);3.12-3.07(m,4H);2.33(s,3H);1.30(s,12H).

[0175] Step 4: 1-Fluoro-3-vinylbenzene [ka]

[0176] 5 g (40.3 mmol, 1 eq) of 3-fluorobenzaldehyde are dissolved in 50 ml of dry THF and the solution is cooled to -10°C using an ice / acetone bath. 17.3 g (48.4 mmol, 1.2 eq) of methyltriphenylphosphonium bromide are added, followed by 2.1 g (52.4 mmol, 1.3 eq) of sodium hydride (60% in paraffin oil). The suspension is then stirred overnight at room temperature under argon atmosphere. The mixture is diluted with 100 ml of Et2O and the precipitate is filtered on Celite. The filtrate is evaporated under reduced pressure to give an orange residue. The crude mixture is purified by flash chromatography using a silica gel column and an Et2O / pentane mixture (3 / 97) as the eluting solvent. 1.25 g of the title compound are obtained. Yield: 25%. MH+: Non-ionizable.

[0177] Step 5: 2-(3-fluorophenyl)oxirane [ka]

[0178] 1.25 g (10.2 mmol, 1 eq) of 1-fluoro-3-vinylbenzene (described in the previous step) is dissolved in 6 ml of 1,4-dioxane and 18 ml of water. The solution is cooled to 0° C. and 584 μL (10.2 mmol, 1 eq) of acetic acid is added, followed by 1.99 g (11.2 mmol, 1.1 eq) of N-bromosuccinimide. The reaction mixture is stirred at 0° C. for 5 min and then at room temperature for 2 h. The mixture is then cooled again to 0° C. and a 2N NaOH solution in water is slowly added. The solution is stirred at room temperature for 1 h. The reaction mixture is concentrated under reduced pressure and the resulting aqueous phase is extracted three times with DCM. The combined organic layers are dried over Na2SO4, filtered and evaporated under reduced pressure. The crude mixture is purified by flash chromatography using a silica gel column and a DCM / hexane mixture (2 / 98) as eluent to obtain 1.02 g of the title compound. Yield: 72%. MH+: Non-ionizable.

[0179] Step 6: 2-(Dimethylamino)-1-(3-fluorophenyl)ethan-1-ol [ka]

[0180] To a solution of 1.02 g (7.38 mmol, 1 eq) of 2-(3-fluorophenyl)oxirane (described in the previous step) in 14 ml of 96% EtOH is added 7.38 ml (14.76 mmol, 2 eq) of dimethylamine (2M in THF). The resulting clear solution is heated at 80° C. for 30 h under microwave irradiation. The reaction mixture is then concentrated under vacuum and diluted with water. The solution is extracted three times with DCM. The combined organic layers are dried over Na2SO4, filtered and evaporated under reduced pressure. The crude mixture is purified by flash chromatography using a silica gel column and a DCM / MeOH mixture as eluent. 0.927 g of the title compound is obtained. Yield: 69%. MH+:322.6(M+1).

[0181] Step 7: 2-Chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine [ka]

[0182] 0.927 g (5.03 mmol, 1 eq) of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol (described in the previous step) is dissolved in 15 ml of DCM and placed at 0° C. 2.1 ml (15.1 mmol, 3 eq) of triethylamine is added followed by 0.781 ml (10.1 mmol, 2 eq) of mesyl chloride. The reaction is stirred at 0° C. for 2 hours under argon atmosphere. Water is added and the mixture is decanted. The aqueous layer is extracted twice with DCM. The combined organic layers are dried over Na2SO4, filtered and evaporated under reduced pressure. The crude compound is used directly in the next step without further purification. Yield: quantitative. MH+:202.3;204.3(M;M+2).

[0183] Step 8: 4-Bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one [ka]

[0184] To a mixture of 0.744 g (4.28 mmol, 1 eq) of 4-bromopyridin-2-(1H)-one and 1.39 g (4.28 mmol, 1 eq) of cesium carbonate in 10 ml of dry DMF, a solution of 1.02 g (5.08 mmol, 1.18 eq) of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine (described in the previous step) in 5 ml of dry DMF was added at 0° C. The solution was then stirred at room temperature for 2 hours. EtOAc was added and the mixture was washed 4 times with water and once with brine. The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude mixture was purified by flash chromatography using a deactivated silica gel column and a hexane / EtOAc mixture as eluent. 1.31 g of the title compound was obtained. Yield: 76%. MH+:339.4;341.5(M;M+2).

[0185] Step 9: 1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0186] 1.31 g (3.86 mmol, 1 eq) of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one (described in the previous step) and 2.45 g (5.01 mmol, 1.3 eq) of 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine (described in step 3) are dissolved in 13 ml of MeCN under argon atmosphere. Then, 13 ml of 2M Na2CO3 solution is bubbled with argon for 15 minutes to give a two-phase mixture. 135 mg (0.19 mmol, 0.05 eq) of bis(triphenylphosphine)palladium dichloride are added and the solution is bubbled with argon for another 15 min. The reaction is stirred at 70° C. for 2 h under argon atmosphere. The reaction mixture is then diluted with water and EtOAc and then decanted. The aqueous layer is extracted twice with EtOAc. The combined organic layers are dried over Na2SO4, filtered and evaporated under reduced pressure. The crude mixture is purified by flash chromatography using a silica gel column and DCM / MeOH mixtures as eluents. 2.05 g of the title compound are obtained. Yield: 86%. MH+:616.6(M+1).

[0187] Step 10: 1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0188] 2.05 g (3.33 mmol, 1 eq) of 1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) is dissolved in 15 ml of dry THF under argon atmosphere. Then, 10 ml (10 mmol, 3 eq) of TBAF (1M in THF) solution is added and the reaction is stirred at 66° C. for 1 h under argon atmosphere. The solvent is removed under reduced pressure and 100 ml of saturated NaHCO3 solution is added. The mixture is extracted three times with EtOAc. The combined organic layers are dried over Na2SO4, filtered and evaporated under reduced pressure. The crude mixture is purified by flash chromatography using a silica gel column and a DCM / MeOH mixture as eluent. 1.49 g of a yellow solid are obtained. Yield: 96%. MH+:462.7(M+1). 1 H NMR(DMSO-d6,400MHz):δ 12.04(br s,1H);8.16(d,J=2.4Hz,1H);8.09(d,J=1.8Hz,1H);7.74(d,J=8.0Hz,1H);7.70(d,J=2.5Hz,1H);7.45-7.36(m,1H);7.30-7.18(m,2H);7.18 -7.10(m,1H);6.72-6.64(m,2H);6.27-6.16(m,1H);3.84-3.73(m,4H) ;3.32-3.22(m,1H);3.20-3.08(m,4H);2.80-2.69(m,1H);2.21(s,6H).

[0189] Step 11: (S)-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0190] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a hexane / EtOH / DCM / 0.1% TEA mixture as mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 1.49 g of the racemate, 275 mg of the title compound are obtained. MH+:462.7(M+1). 1 H NMR(DMSO-d6,400MHz):δ 12.04(br s,1H);8.16(d,J=2.4Hz,1H);8.09(d,J=1.8Hz,1H);7.74(d,J=8.0Hz,1H);7.70(d,J=2.5Hz,1H);7.45-7.36(m,1H);7.30-7.18(m,2H);7.18 -7.10(m,1H);6.72-6.64(m,2H);6.27-6.16(m,1H);3.84-3.73(m,4H) ;3.32-3.22(m,1H);3.20-3.08(m,4H);2.80-2.69(m,1H);2.21(s,6H).

[0191] Example 2: Synthesis of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0192] Step 1: 1-Chloro-3-vinylbenzene [ka]

[0193] The compound is obtained by the procedure described in step 4 of example 1, starting from 10 g (71.1 mmol) of 3-chlorobenzaldehyde instead of 3-fluorobenzaldehyde. 4.05 g of the title compound are obtained. Yield: 41%. MH+: Non-ionizable.

[0194] Step 2: 2-(3-chlorophenyl)oxirane [ka]

[0195] This compound is obtained by the procedure described in step 5 of Example 1, starting from 4.05 g (29.2 mmol) of 1-chloro-3-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 3.85 g of the title compound are obtained. Yield: 85%. MH+: Non-ionizable.

[0196] Step 3: 1-(3-chlorophenyl)-2-(dimethylamino)ethan-1-ol [ka]

[0197] This compound is obtained by the procedure described in step 6 of Example 1, starting from 4.15 g (26.9 mmol) of 2-(3-chlorophenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 4.06 g of the title compound are obtained. Yield: 76%. MH+:200.2;202.3(M;M+2).

[0198] Step 4: 2-Chloro-2-(3-chlorophenyl)-N,N-dimethylethan-1-amine [ka]

[0199] This compound is obtained by the procedure described in step 7 of Example 1, starting from 4.06 g (20.3 mmol) of 1-(3-chlorophenyl)-2-(dimethylamino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 4.41 g of the title compound are obtained. Yield: 99%. MH+:218.4;220.4(M;M+2).

[0200] Step 5: 4-Bromo-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one [ka]

[0201] This compound is obtained by the procedure described in step 8 of Example 1, starting from 4.41 g (20.3 mmol) of 2-chloro-2-(3-chlorophenyl)-N,N-dimethylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 5.02 g of the title compound are obtained. Yield: 70%. MH+:355.2;357.2(M;M+2).

[0202] Step 6: 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0203] This compound is obtained by the procedure described in step 9 of Example 1, starting from 2 g (5.6 mmol) of 4-bromo-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 2.68 g of the title compound are obtained. Yield: 75%. MH+:632.8;634.8(M;M+2).

[0204] Step 7: 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0205] This compound is obtained by the procedure described in step 10 of Example 1, starting from 2.68 g (4.2 mmol) of 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 617 mg of racemate is obtained. Yield: 30%. MH+:478.5;480.6(M;M+2). 1H NMR(DMSO-d6,400MHz):δ 12.06(br s,1H);8.17(d,J=2.4Hz,1H);8.10(d,J=2.3Hz,1H);7.76(d,J=8.0Hz,1H);7.70(d,J=2.4Hz,1H);7.47(s,1H);7.44-7.32(m,3H) ;6.72-6.65(m,2H);6.23-6.13(m,1H);3.84-3.73(m,4H);3.34-3.23(m,1H);3.20-3.08(m,4H);2.78-2.67(m,1H);2.21(s,6H).

[0206] Step 8: (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0207] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a hexane / EtOH / DCM / 0.1% TEA mixture as mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 617 mg of the racemate, 227 mg of the title compound are obtained. MH+:478.5;480.6(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.06(br s,1H);8.17(d,J=2.4Hz,1H);8.10(d,J=2.3Hz,1H);7.76(d,J=8.0Hz,1H);7.70(d,J=2.4Hz,1H);7.47(s,1H);7.44-7.32(m,3H) ;6.72-6.65(m,2H);6.23-6.13(m,1H);3.84-3.73(m,4H);3.34-3.23(m,1H);3.20-3.08(m,4H);2.78-2.67(m,1H);2.21(s,6H).

[0208] Example 3: Synthesis of (S)-1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0209] Step 1: 1,3-Dichloro-5-vinylbenzene [ka]

[0210] The compound is obtained by the procedure described in step 4 of example 1, starting from 2.00 g (11.4 mmol) of 3,5-dichlorobenzaldehyde instead of 3-fluorobenzaldehyde. 495 mg of the title compound are obtained. Yield: 25%. MH+: Non-ionizable.

[0211] Step 2: 2-(3,5-dichlorophenyl)oxirane [ka]

[0212] This compound is obtained by the procedure described in step 5 of Example 1, starting from 495 mg (2.86 mmol) of 1,3-dichloro-5-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 433 mg of the title compound are obtained. Yield: 80%. MH+: Non-ionizable.

[0213] Step 3: 1-(3,5-dichlorophenyl)-2-(dimethylamino)ethan-1-ol [ka]

[0214] This compound is obtained by the procedure described in step 6 of Example 1, starting from 433 mg (2.29 mmol) of 2-(3,5-dichlorophenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 455 mg of the title compound are obtained. Yield: 85%. MH+:234.3;236.3(M;M+2).

[0215] Step 4: 2-Chloro-2-(3,5-dichlorophenyl)-N,N-dimethylethan-1-amine [ka]

[0216] This compound is obtained by the procedure described in step 7 of Example 1, starting from 455 mg (1.94 mmol) of 1-(3,5-dichlorophenyl)-2-(dimethylamino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 521 mg of the title compound is obtained. Yield: quantitative. MH+:252.3;254.4(M;M+2).

[0217] Step 5: 4-Bromo-1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one [ka]

[0218] This compound is obtained by the procedure described in step 8 of Example 1, starting from 521 mg (2.06 mmol) of 2-chloro-2-(3,5-dichlorophenyl)-N,N-dimethylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 276 mg of the title compound are obtained. Yield: 36%. MH+:389.5;391.5;393.5(M;M+2;M+4).

[0219] Step 6: 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0220] This compound is obtained by the procedure described in step 9 of Example 1, starting from 276 mg (0.71 mmol) of 4-bromo-1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 365 mg of the title compound is obtained. Yield: 77%. MH+:666.9;668.8(M;M+2).

[0221] Step 7: 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0222] 365 mg (0.55 mmol) of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) is suspended in 10 ml of DMSO and 1.37 ml (2.74 mmol, 5 eq) of 2N NaOH solution is added slowly. The mixture is stirred at room temperature for 2 hours, then cooled to 0° C. in an ice / water bath and carefully quenched with saturated NH4Cl solution. Cold water is added and a white precipitate breaks up, which is filtered, washed several times with water and dried under vacuum. The crude mixture is finally purified by flash chromatography using a silica gel column and a DCM / MeOH mixture as eluent. 226 mg of a slightly yellow solid is obtained. Yield: 80%. MH+:512.7;514.6(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.06(br s,1H);8.17(d,J=2.5Hz,1H);8.11(d,J=2.8Hz,1H);7.79(d,J=7.3Hz,1H);7.71(d,J=2.5Hz,1H);7.59-7.55(m,1H);7.46(d,J=1.8Hz ,2H);6.74-6.66(m,2H);6.17-6.08(m,1H);3.83-3.73(m,4H);3.34-3.23(m,1H);3.20-3.09(m,4H);2.80-2.70(m,1H);2.21(s,6H).

[0223] Step 8: (S)-1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0224] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a Hexane / EtOH / DCM / 0.1% TEA mixture as the mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. 25 mg of the title compound are obtained. MH+:512.7;514.6(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.06(br s,1H);8.17(d,J=2.5Hz,1H);8.11(d,J=2.8Hz,1H);7.79(d,J=7.3Hz,1H);7.71(d,J=2.5Hz,1H);7.59-7.55(m,1H);7.46(d,J=1.8Hz ,2H);6.74-6.66(m,2H);6.17-6.08(m,1H);3.83-3.73(m,4H);3.34-3.23(m,1H);3.20-3.09(m,4H);2.80-2.70(m,1H);2.21(s,6H).

[0225] Example 4: Synthesis of (S)-1-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0226] Step 1: 1,2-Dichloro-4-vinylbenzene [ka]

[0227] The compound is obtained by the procedure described in step 4 of example 1, starting from 2.00 g (11.4 mmol) of 3,4-dichlorobenzaldehyde instead of 3-fluorobenzaldehyde. 850 mg of the title compound are obtained. Yield: 43%. MH+: Non-ionizable.

[0228] Step 2: 2-(3,4-dichlorophenyl)oxirane [ka]

[0229] This compound is obtained by the procedure described in step 5 of Example 1, starting from 850 mg (4.91 mmol) of 1,2-dichloro-4-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 630 mg of the title compound are obtained. Yield: 68%. MH+: Non-ionizable.

[0230] Step 3: 1-(3,4-dichlorophenyl)-2-(dimethylamino)ethan-1-ol [ka]

[0231] This compound is obtained by the procedure described in step 6 of Example 1, starting from 630 mg (3.33 mmol) of 2-(3,4-dichlorophenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 692 mg of the title compound is obtained. Yield: 89%. MH+:234.3;236.2(M;M+2).

[0232] Step 4: 2-Chloro-2-(3,4-dichlorophenyl)-N,N-dimethylethan-1-amine [ka]

[0233] This compound is obtained by the procedure described in step 7 of Example 1, starting from 692 mg (2.96 mmol) of 1-(3,4-dichlorophenyl)-2-(dimethylamino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 760 mg of the title compound is obtained. Yield: quantitative. MH+:252.2;254.2(M;M+2).

[0234] Step 5: 4-Bromo-1-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one [ka]

[0235] This compound is obtained by the procedure described in step 8 of Example 1, starting from 760 mg (3.01 mmol) of 2-chloro-2-(3,4-dichlorophenyl)-N,N-dimethylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 553 mg of the title compound is obtained. Yield: 47%. MH+:389.4;391.3(M;M+2).

[0236] Step 6: 1-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0237] This compound is obtained by the procedure described in step 9 of Example 1, starting from 276 mg (0.71 mmol) of 4-bromo-1-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 334 mg of the title compound is obtained. Yield: 71%. MH+:666.6;668.4(M;M+2).

[0238] Step 7: 1-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0239] This compound is obtained by the procedure described in step 7 of Example 3, starting from 334 mg (0.50 mmol) of 1-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 199 mg of racemate is obtained. Yield: 77%. MH+:512.5;514.5(M;M+2). 1H NMR(DMSO-d6,400MHz):δ 12.08(br s,1H);8.17(d,J=2.5Hz,1H);8.11(d,J=2.9Hz,1H);7.76(d,J=7.2Hz,1H);7.69(d,J=2.1Hz,2H);7.64(d,J=8.4Hz,1H);7.39-7.33(m ,1H);6.73-6.66(m,2H);6.20-6.10(m,1H);3.82-3.73(m,4H);3.33-3.23(m,1H);3.18-3.09(m,4H);2.79-2.69(m,1H);2.20(s,6H).

[0240] Step 8: (S)-1-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0241] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a hexane / EtOH / DCM / 0.1% TEA mixture as mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 199 mg of the racemate, 39 mg of the title compound are obtained. MH+:512.5;514.5(M;M+2). 1H NMR(DMSO-d6,400MHz):δ 12.08(br s,1H);8.17(d,J=2.5Hz,1H);8.11(d,J=2.9Hz,1H);7.76(d,J=7.2Hz,1H);7.69(d,J=2.1Hz,2H);7.64(d,J=8.4Hz,1H);7.39-7.33(m ,1H);6.73-6.66(m,2H);6.20-6.10(m,1H);3.82-3.73(m,4H);3.33-3.23(m,1H);3.18-3.09(m,4H);2.79-2.69(m,1H);2.20(s,6H).

[0242] Example 5: Synthesis of (S)-1-(1-(3-bromophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0243] Step 1: 2-(3-bromophenyl)oxirane [ka]

[0244] The compound is obtained by the procedure described in step 5 of example 1, starting from 2 g (11 mmol) of 1-bromo-3-vinylbenzene instead of 1-fluoro-3-vinylbenzene. 2.12 g of the title compound are obtained. Yield: 98%. MH+: Non-ionizable.

[0245] Step 2: 1-(3-bromophenyl)-2-(dimethylamino)ethan-1-ol [ka]

[0246] This compound is obtained by the procedure described in step 6 of Example 1, starting from 2.12 g (10.7 mmol) of 2-(3-bromophenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 2.11 g of the title compound are obtained. Yield: 97%. MH+:244.3;246.4(M;M+2).

[0247] Step 3: 2-(3-bromophenyl)-2-chloro-N,N-dimethylethan-1-amine [ka]

[0248] This compound is obtained by the procedure described in step 7 of Example 1, starting from 2.11 g (8.6 mmol) of 1-(3-bromophenyl)-2-(dimethylamino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 2.30 g of the title compound are obtained. Yield: quantitative. MH+:262.4;264.3(M;M+2).

[0249] Step 4: 4-Bromo-1-(1-(3-bromophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one [ka]

[0250] This compound is obtained by the procedure described in step 8 of Example 1, starting from 2.30 g (20.3 mmol) of 2-(3-bromophenyl)-2-chloro-N,N-dimethylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 1.85 g of the title compound are obtained. Yield: 52%. MH+:399.3;401.4(M;M+2).

[0251] Step 5: 1-(1-(3-bromophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0252] This compound is obtained by the procedure described in step 9 of Example 1, starting from 1.85 g (4.6 mmol) of 4-bromo-1-(1-(3-bromophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 2.72 g of the title compound are obtained. Yield: 88%. MH+:676.8;678.8(M;M+2).

[0253] Step 6: 1-(1-(3-bromophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0254] This compound is obtained by the procedure described in step 7 of Example 3, starting from 1.04 g (1.54 mmol) of 1-(1-(3-bromophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 681 mg of racemate is obtained. Yield: 85%. MH+:522.6;524.5(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.04(br s,1H);8.17(d,J=2.5Hz,1H);8.09(s,1H);7.75(d,J=8.0Hz,1H);7.70(d, J=2.5Hz,1H);7.62-7.57(m,1H);7.53-7.47(m,1H);7.42-7.37(m,1H);7. 33(t,J=7.8Hz,1H);6.72-6.65(m,2H);6.20-6.12(m,1H);3.83-3.73(m,4 H);3.34-3.24(m,1H);3.20-3.08(m,4H);2.78-2.68(m,1H);2.21(s,6H).

[0255] Step 7: (S)-1-(1-(3-bromophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0256] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a hexane / EtOH / DCM / 0.1% TEA mixture as mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 681 mg of the racemate, 292 mg of the title compound are obtained. MH+:522.6;524.5(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.04(br s,1H);8.17(d,J=2.5Hz,1H);8.09(s,1H);7.75(d,J=8.0Hz,1H);7.70(d, J=2.5Hz,1H);7.62-7.57(m,1H);7.53-7.47(m,1H);7.42-7.37(m,1H);7. 33(t,J=7.8Hz,1H);6.72-6.65(m,2H);6.20-6.12(m,1H);3.83-3.73(m,4 H);3.34-3.24(m,1H);3.20-3.08(m,4H);2.78-2.68(m,1H);2.21(s,6H).

[0257] Example 6: Synthesis of (S)-1-(2-(dimethylamino)-1-(3-iodophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0258] Step 1: 1-Iodo-3-vinylbenzene [ka]

[0259] The compound is obtained by the procedure described in step 4 of example 1, starting from 5 g (21.5 mmol) of 3-iodobenzaldehyde instead of 3-fluorobenzaldehyde. 3.20 g of the title compound are obtained. Yield: 65%. MH+: Non-ionizable.

[0260] Step 2: 2-(3-iodophenyl)oxirane [ka]

[0261] This compound is obtained by the procedure described in step 5 of Example 1, starting from 3.20 g (13.91 mmol) of 1-iodo-3-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 2.78 g of the title compound are obtained. Yield: 81%. MH+: Non-ionizable.

[0262] Step 3: 2-(Dimethylamino)-1-(3-iodophenyl)ethan-1-ol [ka]

[0263] This compound is obtained by the procedure described in step 6 of Example 1, starting from 2.78 g (26.9 mmol) of 2-(3-iodophenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 2.54 g of the title compound are obtained. Yield: 77%. MH+:292.2(M+1).

[0264] Step 4: 2-Chloro-2-(3-iodophenyl)-N,N-dimethylethan-1-amine [ka]

[0265] This compound is obtained by the procedure described in step 7 of Example 1, starting from 1.25 g (4.3 mmol) of 2-(dimethylamino)-1-(3-iodophenyl)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 1.59 g of the title compound are obtained. Yield: quantitative. MH+:310.3;312.3(M;M+2).

[0266] Step 5: 1-(2-(dimethylamino)-1-(3-iodophenyl)ethyl)-4-iodopyridin-2(1H)-one [ka]

[0267] To a mixture of 1.04 g (4.70 mmol, 1 eq) of 4-iodopyridin-2-(1H)-one and 1.68 g (5.20 mmol, 1.1 eq) of cesium carbonate in 10 ml of dry DMF was added a solution of 1.59 g (5.14 mmol, 1 eq) of 2-chloro-2-(3-iodophenyl)-N,N-dimethylethan-1-amine (described in the previous step) in 5 ml of dry DMF at 0° C. The solution was then stirred at room temperature for 1 h 30 min. EtOAc was added and the mixture was washed 4 times with water and once with brine. The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude mixture was purified by flash chromatography using a deactivated silica gel column and a hexane / EtOAc mixture as eluent. 1.11 g of the title compound was obtained. Yield: 52%. MH+:495.6(M+1).

[0268] Step 6: 1-(2-(dimethylamino)-1-(3-iodophenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0269] This compound is obtained by the procedure described in step 9 of Example 1, starting from 1.11 g (22.5 mmol) of 1-(2-(dimethylamino)-1-(3-iodophenyl)ethyl)-4-iodopyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 589 mg of the title compound is obtained. Yield: 80%. MH+:724.5(M+1).

[0270] Step 7: 1-(2-(dimethylamino)-1-(3-iodophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0271] This compound is obtained by the procedure described in step 7 of Example 3, starting from 875 mg (1.21 mmol) of 1-(2-(dimethylamino)-1-(3-iodophenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 674 mg of racemate is obtained. Yield: 97%. MH+:570.5(M+1). 1H NMR(DMSO-d6,400MHz):δ 12.06(br s,1H);8.17(d,J=2.5Hz,1H);8.10(d,J=2.9Hz,1H);7.79-7.73(m,2H);7.72-7.64(m,2H);7.44-7.38(m,1H);7.17(t,J=7.8Hz,1H );6.72-6.65(m,2H);6.18-6.09(m,1H);3.85-3.73(m,4H);3.34-3.24(m,1H);3.20-3.08(m,4H);2.73-2.64(m,1H);2.20(s,6H).

[0272] Step 8: (S)-1-(2-(dimethylamino)-1-(3-iodophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0273] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a hexane / EtOH / DCM / 0.1% TEA mixture as mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 674 mg of the racemate, 262 mg of the title compound are obtained. MH+:570.5(M+1). 1 H NMR(DMSO-d6,400MHz):δ 12.06(br s,1H);8.17(d,J=2.5Hz,1H);8.10(d,J=2.9Hz,1H);7.79-7.73(m,2H);7.72-7.64(m,2H);7.44-7.38(m,1H);7.17(t,J=7.8Hz,1H );6.72-6.65(m,2H);6.18-6.09(m,1H);3.85-3.73(m,4H);3.34-3.24(m,1H);3.20-3.08(m,4H);2.73-2.64(m,1H);2.20(s,6H).

[0274] Example 7: Synthesis of (S)-1-(1-(3-bromo-4-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0275] Step 1: 2-Bromo-1-fluoro-4-vinylbenzene [ka]

[0276] The compound is obtained by the procedure described in step 4 of example 1, starting from 2.61 g (12.9 mmol) of 3-bromo-4-fluorobenzaldehyde instead of 3-fluorobenzaldehyde. 1.37 g of the title compound are obtained. Yield: 53%. MH+: Non-ionizable.

[0277] Step 2: 2-(3-bromo-4-fluorophenyl)oxirane [ka]

[0278] This compound is obtained by the procedure described in step 5 of Example 1, starting from 1.37 g (6.81 mmol) of 2-bromo-1-fluoro-4-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 1.13 g of the title compound are obtained. Yield: 76%. MH+: Non-ionizable.

[0279] Step 3: 1-(3-bromo-4-fluorophenyl)-2-(dimethylamino)ethan-1-ol [ka]

[0280] This compound is obtained by the procedure described in step 6 of Example 1, starting from 1.13 g (5.21 mmol) of 2-(3-bromo-4-fluorophenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 1.05 g of the title compound are obtained. Yield: 77%. MH+:262.2;264.3(M;M+2).

[0281] Step 4: 2-(3-bromo-4-fluorophenyl)-2-chloro-N,N-dimethylethan-1-amine [ka]

[0282] This compound is obtained by the procedure described in step 7 of Example 1, starting from 1.05 g (4.00 mmol) of 1-(3-bromo-4-fluorophenyl)-2-(dimethylamino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 1.30 g of the title compound are obtained. Yield: quantitative. MH+:280.3;282.3(M;M+2).

[0283] Step 5: 4-Bromo-1-(1-(3-bromo-4-fluorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one [ka]

[0284] This compound is obtained by the procedure described in step 8 of Example 1, starting from 1.30 g (4.64 mmol) of 2-(3-bromo-4-fluorophenyl)-2-chloro-N,N-dimethylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 733 mg of the title compound are obtained. Yield: 38%. MH+:417.3;419.3;421.2(M;M+2;M+4).

[0285] Step 6: 1-(1-(3-bromo-4-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0286] This compound is obtained by the procedure described in step 9 of Example 1, starting from 733 mg (1.74 mmol) of 4-bromo-1-(1-(3-bromo-4-fluorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 1.00 g of the title compound is obtained. Yield: 82%. MH+:694.6;696.5(M;M+2).

[0287] Step 7: 1-(1-(3-bromo-4-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0288] This compound is obtained by the procedure described in step 7 of Example 3, starting from 640 mg (0.92 mmol) of 1-(1-(3-bromo-4-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 464 mg of racemate is obtained. Yield: 93%. MH+:540.5;542.4(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.06(br s,1H);8.17(d,J=2.5Hz,1H);8.10(s,1H);7.80-7.73(m,2H);7.69(d,J=2.5Hz,1H);7.48-7.41(m,1H);7.38(t,J=8.7Hz,1H); 6.72-6.66(m,2H);6.21-6.12(m,1H);3.83-3.74(m,4H);3.34-3.24(m,1H);3.18-3.08(m,4H);2.77-2.67(m,1H);2.20(s,6H).

[0289] Step 8: (S)-1-(1-(3-bromo-4-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0290] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a hexane / EtOH / DCM / 0.1% TEA mixture as mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 464 mg of the racemate, 206 mg of the title compound are obtained. MH+:540.5;542.4(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.06(br s,1H);8.17(d,J=2.5Hz,1H);8.10(s,1H);7.80-7.73(m,2H);7.69(d,J=2.5Hz,1H);7.48-7.41(m,1H);7.38(t,J=8.7Hz,1H); 6.72-6.66(m,2H);6.21-6.12(m,1H);3.83-3.74(m,4H);3.34-3.24(m,1H);3.18-3.08(m,4H);2.77-2.67(m,1H);2.20(s,6H).

[0291] Example 8: Synthesis of (S)-1-(2-(dimethylamino)-1-(4-fluoro-3-iodophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0292] Step 1: 1-Fluoro-2-iodo-4-vinylbenzene [ka]

[0293] The compound is obtained by the procedure described in step 4 of example 1, starting from 3.5 g (14.0 mmol) of 4-fluoro-3-iodobenzaldehyde instead of 3-fluorobenzaldehyde. 2.13 g of the title compound are obtained. Yield: 61%. MH+: Non-ionizable.

[0294] Step 2: 2-(4-fluoro-3-iodophenyl)oxirane [ka]

[0295] The compound is obtained by the procedure described in step 5 of Example 1, starting from 2.13 g (8.58 mmol) of 1-fluoro-2-iodo-4-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 1.99 g of the title compound are obtained. Yield: 88%. MH+: Non-ionizable.

[0296] Step 3: 2-(Dimethylamino)-1-(4-fluoro-3-iodophenyl)ethan-1-ol [ka]

[0297] This compound is obtained by the procedure described in step 6 of Example 1, starting from 1.99 g (7.54 mmol) of 2-(4-fluoro-3-iodophenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 1.57 g of the title compound are obtained. Yield: 67%. MH+:310.5(M+1).

[0298] Step 4: 2-Chloro-2-(4-fluoro-3-iodophenyl)-N,N-dimethylethan-1-amine [ka]

[0299] This compound is obtained by the procedure described in step 7 of Example 1, starting from 1.57 g (5.08 mmol) of 2-(dimethylamino)-1-(4-fluoro-3-iodophenyl)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 1.64 g of the title compound is obtained. Yield: 98%. MH+:328.4(M+1).

[0300] Step 5: 1-(2-(dimethylamino)-1-(4-fluoro-3-iodophenyl)ethyl)-4-iodopyridin-2(1H)-one [ka]

[0301] This compound is obtained by the procedure described in step 5 of Example 6, starting from 1.57 g (5.08 mmol) of 2-chloro-2-(4-fluoro-3-iodophenyl)-N,N-dimethylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-iodophenyl)-N,N-dimethylethan-1-amine. 555 mg of the title compound is obtained. Yield: 22%. MH+:513.5(M+1).

[0302] Step 6: 1-(2-(dimethylamino)-1-(4-fluoro-3-iodophenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0303] This compound is obtained by the procedure described in step 9 of Example 1, starting from 555 mg (1.08 mmol) of 1-(2-(dimethylamino)-1-(4-fluoro-3-iodophenyl)ethyl)-4-iodopyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 780 mg of the title compound is obtained. Yield: 97%. MH+:742.8(M+1).

[0304] Step 7: 1-(2-(dimethylamino)-1-(4-fluoro-3-iodophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0305] This compound is obtained by the procedure described in step 7 of Example 3, starting from 760 mg (1.02 mmol) of 1-(2-(dimethylamino)-1-(4-fluoro-3-iodophenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 240 mg of racemate is obtained, followed by 87 mg of the title compound after chiral separation ((+)(S)-enantiomer). Yield: 40%. MH+:588.4(M+1). 1H NMR(DMSO-d6,400MHz):δ 12.06(br s,1H);8.16(d,J=2.5Hz,1H);8.10(s,1H);7.91-7.85(m,1H);7.75(d,J=8.0Hz,1H);7.69(d,J=2.6Hz,1H);7.49-7.41(m,1H);7.26(t,J=8 .3Hz,1H);6.72-6.64(m,2H);6.19-6.08(m,1H);3.84-3.72(m,4H);3.34-3.24(m,1H);3.18-3.08(m,4H);2.73-2.65(m,1H);2.20(s,6H).

[0306] Step 8: (S)-1-(2-(dimethylamino)-1-(4-fluoro-3-iodophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0307] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a hexane / EtOH / DCM / 0.1% TEA mixture as mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 240 mg of the racemate, 87 mg of the title compound are obtained. MH+:588.4(M+1). 1H NMR(DMSO-d6,400MHz):δ 12.06(br s,1H);8.16(d,J=2.5Hz,1H);8.10(s,1H);7.91-7.85(m,1H);7.75(d,J=8.0Hz,1H);7.69(d,J=2.6Hz,1H);7.49-7.41(m,1H);7.26(t,J=8 .3Hz,1H);6.72-6.64(m,2H);6.19-6.08(m,1H);3.84-3.72(m,4H);3.34-3.24(m,1H);3.18-3.08(m,4H);2.73-2.65(m,1H);2.20(s,6H).

[0308] Example 9: Synthesis of (S)-1-(1-(3-chloro-5-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0309] Step 1: 1-Chloro-3-fluoro-5-vinylbenzene [ka]

[0310] The compound is obtained by the procedure described in step 4 of example 1, starting from 5 g (31.5 mmol) of 3-chloro-5-fluorobenzaldehyde instead of 3-fluorobenzaldehyde. 3.07 g of the title compound are obtained. Yield: 62%. MH+: Non-ionizable.

[0311] Step 2: 2-(3-chloro-5-fluorophenyl)oxirane [ka]

[0312] This compound is obtained by the procedure described in step 5 of Example 1, starting from 3.07 g (20 mmol) of 1-chloro-3-fluoro-5-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 1.55 g of the title compound are obtained. Yield: 46%. MH+: Non-ionizable.

[0313] Step 3: 1-(3-chloro-5-fluorophenyl)-2-(dimethylamino)ethan-1-ol [ka]

[0314] This compound is obtained by the procedure described in step 6 of Example 1, starting from 300 mg (1.74 mmol) of 2-(3-chloro-5-fluorophenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 136 mg of the title compound is obtained. Yield: 36%. MH+:218.4;220.4(M;M+2).

[0315] Step 4: 2-Chloro-2-(3-chloro-5-fluorophenyl)-N,N-dimethylethan-1-amine [ka]

[0316] This compound is obtained by the procedure described in step 7 of Example 1, starting from 136 mg (0.62 mmol) of 1-(3-chloro-5-fluorophenyl)-2-(dimethylamino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 145 mg of the title compound is obtained. Yield: 98%. MH+:236.2;238.2(M;M+2).

[0317] Step 5: 4-Bromo-1-(1-(3-chloro-5-fluorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one [ka]

[0318] This compound is obtained by the procedure described in step 8 of Example 1, starting from 145 mg (0.61 mmol) of 2-chloro-2-(3-chloro-5-fluorophenyl)-N,N-dimethylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 90 mg of the title compound is obtained. Yield: 39%. MH+:373.3;375.5(M;M+2).

[0319] Step 6: 1-(1-(3-chloro-5-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0320] This compound is obtained by the procedure described in step 9 of Example 1, starting from 90 mg (0.24 mmol) of 4-bromo-1-(1-(3-chloro-5-fluorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 94 mg of the title compound is obtained. Yield: 60%. MH+:650.5;652.6(M;M+2).

[0321] Step 7: 1-(1-(3-chloro-5-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0322] 94 mg (0.14 mmol) of 1-(1-(3-chloro-5-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) is suspended in 5 ml of MeCN and 2.5 ml of 2M Na2CO3 solution. The mixture is stirred at 120° C. for 1 h under microwave irradiation in a sealed tube (150 W). The mixture is cooled to room temperature, diluted with EtOAc and washed three times with water. The organic layer is dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product is finally purified by flash chromatography using a silica gel column and a DCM / MeOH mixture as eluent. 16 mg of a white solid is obtained. Yield: 23%. MH+:588.7(M+1). 1 H NMR(DMSO-d6,400MHz):δ 12.06(br s,1H);8.17(d,J=2.5Hz,1H);8.11(s,1H);7.77(d,J=7.6Hz,1H);7.70(d,J=2.6Hz,1H);7.43-7.36(m,1H);7.34-7.24(m,2H); 6.74-6.67(m,2H);6.20-6.11(m,1H);3.83-3.73(m,4H);3.34-3.23(m,1H);3.19-3.09(m,4H);2.81-2.71(m,1H);2.21(s,6H).

[0323] Step 8: (S)-1-(1-(3-chloro-5-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0324] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a Hexane / EtOH / DCM / 0.1% TEA mixture as mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 16 mg of the racemate, 5 mg of the title compound are obtained. MH+:588.7(M+1). 1 H NMR(DMSO-d6,400MHz):δ 12.06(br s,1H);8.17(d,J=2.5Hz,1H);8.11(s,1H);7.77(d,J=7.6Hz,1H);7.70(d,J=2.6Hz,1H);7.43-7.36(m,1H);7.34-7.24(m,2H); 6.74-6.67(m,2H);6.20-6.11(m,1H);3.83-3.73(m,4H);3.34-3.23(m,1H);3.19-3.09(m,4H);2.81-2.71(m,1H);2.21(s,6H).

[0325] Example 10: Synthesis of (S)-1-(2-(dimethylamino)-1-(3-fluoro-5-iodophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0326] Step 1: 1-Fluoro-3-iodo-4-vinylbenzene [ka]

[0327] The compound is obtained by the procedure described in step 4 of example 1, starting from 2 g (7.96 mmol) of 3-fluoro-5-iodobenzaldehyde instead of 3-fluorobenzaldehyde. 873 mg of the title compound are obtained. Yield: 44%. MH+: Non-ionizable.

[0328] Step 2: 2-(3-fluoro-5-iodophenyl)oxirane [ka]

[0329] This compound is obtained by the procedure described in step 5 of Example 1, starting from 873 mg (3.5 mmol) of 1-fluoro-3-iodo-4-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 432 mg of the title compound are obtained. Yield: 47%. MH+: Non-ionizable.

[0330] Step 3: 2-(Dimethylamino)-1-(3-fluoro-5-iodophenyl)ethan-1-ol [ka]

[0331] This compound is obtained by the procedure described in step 6 of Example 1, starting from 376 mg (1.40 mmol) of 2-(3-fluoro-5-iodophenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 295 mg of the title compound are obtained. Yield: 67%. MH+:310.3(M+1).

[0332] Step 4: 2-Chloro-2-(3-fluoro-5-iodophenyl)-N,N-dimethylethan-1-amine [ka]

[0333] This compound is obtained by the procedure described in step 7 of Example 1, starting from 351 mg (1.14 mmol) of 2-(dimethylamino)-1-(3-fluoro-5-iodophenyl)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 328 mg of the title compound is obtained. Yield: 88%. MH+:388.3(M+1).

[0334] Step 5: 1-(2-(dimethylamino)-1-(3-fluoro-5-iodophenyl)ethyl)-4-iodopyridin-2(1H)-one [ka]

[0335] This compound is obtained by the procedure described in step 5 of Example 6, starting from 328 mg (0.85 mmol) of 2-chloro-2-(3-fluoro-5-iodophenyl)-N,N-dimethylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-iodophenyl)-N,N-dimethylethan-1-amine. 236 mg of the title compound are obtained. Yield: 54%. MH+:513.2(M+1).

[0336] Step 6: 1-(2-(dimethylamino)-1-(3-fluoro-5-iodophenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0337] This compound is obtained by the procedure described in step 9 of Example 1, starting from 236 mg (0.46 mmol) of 1-(2-(dimethylamino)-1-(3-fluoro-5-iodophenyl)ethyl)-4-iodopyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 340 mg of the title compound is obtained. Yield: 99%. MH+:742.5(M+1).

[0338] Step 7: 1-(2-(dimethylamino)-1-(3-fluoro-5-iodophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0339] This compound is obtained by the procedure described in step 7 of Example 3, starting from 207 mg (0.28 mmol) of 1-(2-(dimethylamino)-1-(3-fluoro-5-iodophenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 97 mg of racemate is obtained. Yield: 59%. MH+:588.6(M+1). 1H NMR(DMSO-d6,400MHz):δ 12.06(br s,1H);8.17(d,J=2.5Hz,1H);8.10(s,1H);7.77(d,J=7.8Hz,1H);7.71(d,J=2.6Hz,1H);7.64-7.57(m,2H);7.35-7.28(m,1H); 6.74-6.67(m,2H);6.17-6.08(m,1H);3.83-3.74(m,4H);3.34-3.22(m,1H);3.19-3.08(m,4H);2.78-2.68(m,1H);2.20(s,6H).

[0340] Step 8: (S)-1-(2-(dimethylamino)-1-(3-fluoro-5-iodophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0341] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a Hexane / EtOH / DCM / 0.1% TEA mixture as the mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. 2.9 mg of the title compound are obtained. MH+:588.6(M+1). 1 H NMR(DMSO-d6,400MHz):δ 12.06(br s,1H);8.17(d,J=2.5Hz,1H);8.10(s,1H);7.77(d,J=7.8Hz,1H);7.71(d,J=2.6Hz,1H);7.64-7.57(m,2H);7.35-7.28(m,1H); 6.74-6.67(m,2H);6.17-6.08(m,1H);3.83-3.74(m,4H);3.34-3.22(m,1H);3.19-3.08(m,4H);2.78-2.68(m,1H);2.20(s,6H).

[0342] Example 11: Synthesis of (S)-1-(1-(3-chlorophenyl)-2-((2,2-difluoroethyl)(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0343] Step 1: 1-(3-chlorophenyl)-2-((2,2-difluoroethyl)(methyl)amino)ethan-1-ol [ka]

[0344] This compound is obtained by the procedure described in step 6 of example 1, starting with 500 mg (3.23 mmol) of 2-(3-chlorophenyl)oxirane (described in step 2 of example 2) instead of 2-(3-fluorophenyl)oxirane and 843 mg (6.46 mmol) of (2,2-difluoroethyl)(methyl)amine hydrochloride instead of dimethylamine. 277 mg of the title compound are obtained. Yield: 34%. MH+:250.4;252.3(M;M+2).

[0345] Step 2: 2-Chloro-2-(3-chlorophenyl)-N-(2,2-difluoroethyl)-N-methylethan-1-amine [ka]

[0346] This compound is obtained by the procedure described in step 7 of Example 1, starting from 277 mg (1.10 mmol) of 1-(3-chlorophenyl)-2-((2,2-difluoroethyl)(methyl)amino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 302 mg of the title compound is obtained. Yield: quantitative. MH+:268.4;270.3(M;M+2).

[0347] Step 3: 4-Bromo-1-(1-(3-chlorophenyl)-2-((2,2-difluoroethyl)(methyl)amino)ethyl)pyridin-2(1H)-one [ka]

[0348] This compound is obtained by the procedure described in step 8 of Example 1, starting from 302 mg (1.10 mmol) of 2-chloro-2-(3-chlorophenyl)-N-(2,2-difluoroethyl)-N-methylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 197 mg of the title compound is obtained. Yield: 44%. MH+:405.4;407.4;409.3(M;M+2;M+4).

[0349] Step 4: 1-(1-(3-chlorophenyl)-2-((2,2-difluoroethyl)(methyl)amino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0350] This compound is obtained by the procedure described in step 9 of Example 1, starting from 197 mg (0.49 mmol) of 4-bromo-1-(1-(3-chlorophenyl)-2-((2,2-difluoroethyl)(methyl)amino)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 341 mg of the title compound is obtained. Yield: quantitative. MH+:682.6;684.0(M;M+2).

[0351] Step 5: 1-(1-(3-chlorophenyl)-2-((2,2-difluoroethyl)(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0352] This compound is obtained by the procedure described in step 7 of Example 3, starting from 341 mg (0.49 mmol) of 1-(1-(3,4-difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 137 mg of racemate is obtained. Yield: 51%. MH+:528.5;530.5(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.04(br s,1H);8.17(d,J=2.6Hz,1H);8.11(d,J=2.9Hz,1H);7.73(d,J=8.1Hz,1H );7.70(d,J=2.6Hz,1H);7.50-7.46(m,1H);7.43-7.33(m,3H);6.73-6.67 (m,2H);6.24-6.17(m,1H);6.06(dt,J=55.8 and 4.3Hz,1H);3.83-3.74(m,4 H);3.50-3.41(m,1H);3.18-3.08(m,5H);2.99-2.79(m,2H);2.37(s,3H).

[0353] Step 6: (S)-1-(1-(3-chlorophenyl)-2-((2,2-difluoroethyl)(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0354] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a hexane / EtOH / DCM / 0.1% TEA mixture as mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 137 mg of the racemate, 19 mg of the title compound are obtained. MH+:528.5;530.5(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.04(br s,1H);8.17(d,J=2.6Hz,1H);8.11(d,J=2.9Hz,1H);7.73(d,J=8.1Hz,1H );7.70(d,J=2.6Hz,1H);7.50-7.46(m,1H);7.43-7.33(m,3H);6.73-6.67 (m,2H);6.24-6.17(m,1H);6.06(dt,J=55.8 and 4.3Hz,1H);3.83-3.74(m,4 H);3.50-3.41(m,1H);3.18-3.08(m,5H);2.99-2.79(m,2H);2.37(s,3H).

[0355] Example 12: Synthesis of (S)-2-((2-(3-chlorophenyl)-2-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)(methyl)amino)acetonitrile [ka]

[0356] Step 1: 2-((2-(3-chlorophenyl)-2-hydroxyethyl)(methyl)amino)acetonitrile [ka]

[0357] This compound is obtained by the procedure described in step 6 of example 1, starting with 500 mg (3.23 mmol) of 2-(3-chlorophenyl)oxirane (described in step 2 of example 2) instead of 2-(3-fluorophenyl)oxirane and 688 mg (6.46 mmol) of 2-(methylamino)acetonitrile hydrochloride instead of dimethylamine. 398 mg of the title compound are obtained. Yield: 55%. MH+:225.4;227.1(M;M+2).

[0358] Step 2: 2-((2-chloro-2-(3-chlorophenyl)ethyl)(methyl)amino)acetonitrile [ka]

[0359] This compound is obtained by the procedure described in step 7 of Example 1, starting from 398 mg (1.77 mmol) of 2-((2-(3-chlorophenyl)-2-hydroxyethyl)(methyl)amino)acetonitrile (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 430 mg of the title compound is obtained. Yield: quantitative. MH+:243.3;245.2(M;M+2).

[0360] Step 3: 2-((2-(4-bromo-2-oxopyridin-1(2H)-yl)-2-(3-chlorophenyl)ethyl)(methyl)amino)acetonitrile [ka]

[0361] This compound is obtained by the procedure described in step 8 of Example 1, starting from 430 mg (1.77 mmol) of 2-((2-chloro-2-(3-chlorophenyl)ethyl)(methyl)amino)acetonitrile (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 205 mg of the title compound are obtained. Yield: 30%. MH+:380.4;382.3;384.3(M;M+2;M+4).

[0362] Step 4: 2-((2-(3-chlorophenyl)-2-(4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)(methyl)amino)acetonitrile [ka]

[0363] This compound is obtained by the procedure described in step 9 of Example 1, starting from 205 mg (0.54 mmol) of 2-((2-(4-bromo-2-oxopyridin-1(2H)-yl)-2-(3-chlorophenyl)ethyl)(methyl)amino)acetonitrile (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 346 mg of the title compound is obtained. Yield: 98%. MH+:657.6;659.6(M;M+2).

[0364] Step 5: 2-((2-(3-chlorophenyl)-2-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)(methyl)amino)acetonitrile [ka]

[0365] This compound is obtained by the procedure described in step 7 of Example 3, starting from 346 mg (0.52 mmol) of 2-((2-(3-chlorophenyl)-2-(4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)(methyl)amino)acetonitrile (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 150 mg of racemate is obtained. Yield: 56%. MH+:503.5;505.5(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.07(br s,1H);8.17(d,J=2.5Hz,1H);8.11(s,1H);7.73(d,J=8.1Hz,1H);7.70(d,J=2.6Hz,1H);7.51-7.47(m,1H);7.46-7.34(m,3H); 6.74-6.68(m,2H);6.26-6.17(m,1H);3.84-3.73(m,6H);3.52-3.41(m,1H);3.18-3.09(m,4H);3.00-2.90(m,1H);2.33(s,3H).

[0366] Step 6: (S)-2-((2-(3-chlorophenyl)-2-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)(methyl)amino)acetonitrile [ka]

[0367] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a Hexane / EtOH / DCM / 0.1% TEA mixture as mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 150 mg of the racemate, 58 mg of the title compound are obtained. MH+:503.5;505.5(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.07(br s,1H);8.17(d,J=2.5Hz,1H);8.11(s,1H);7.73(d,J=8.1Hz,1H);7.70(d,J=2.6Hz,1H);7.51-7.47(m,1H);7.46-7.34(m,3H); 6.74-6.68(m,2H);6.26-6.17(m,1H);3.84-3.73(m,6H);3.52-3.41(m,1H);3.18-3.09(m,4H);3.00-2.90(m,1H);2.33(s,3H).

[0368] Example 13: Synthesis of (S)-1-(1-(3-chlorophenyl)-2-((2-methoxyethyl)(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0369] Step 1: 1-(3-chlorophenyl)-2-((2-methoxyethyl)(methyl)amino)ethan-1-ol [ka]

[0370] This compound is obtained by the procedure described in step 6 of example 1, starting with 400 mg (2.59 mmol) of 2-(3-chlorophenyl)oxirane (described in step 2 of example 2) instead of 2-(3-fluorophenyl)oxirane and 462 mg (5.18 mmol) of N-(2-methoxyethyl)methylamine instead of dimethylamine. 470 mg of the title compound are obtained. Yield: 74%. MH+:244.4;246.2(M;M+2).

[0371] Step 2: 2-Chloro-2-(3-chlorophenyl)-N-(2-methoxyethyl)-N-methylethan-1-amine [ka]

[0372] This compound is obtained by the procedure described in step 7 of Example 1, starting from 470 mg (1.93 mmol) of 1-(3-chlorophenyl)-2-((2-methoxyethyl)(methyl)amino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 552 mg of the title compound is obtained. Yield: quantitative. MH+:262.4;264.3(M;M+2).

[0373] Step 3: 4-Bromo-1-(1-(3-chlorophenyl)-2-((2-methoxyethyl)(methyl)amino)ethyl)pyridin-2(1H)-one [ka]

[0374] This compound is obtained by the procedure described in step 8 of Example 1, starting from 506 mg (1.92 mmol) of 2-chloro-2-(3-chlorophenyl)-N-(2-methoxyethyl)-N-methylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 525 mg of the title compound are obtained. Yield: 68%. MH+:399.3;401.4;403.2(M;M+2;M+4).

[0375] Step 4: 1-(1-(3-chlorophenyl)-2-((2-methoxyethyl)(methyl)amino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0376] This compound is obtained by the procedure described in step 9 of Example 1, starting from 262 mg (0.66 mmol) of 4-bromo-1-(1-(3-chlorophenyl)-2-((2-methoxyethyl)(methyl)amino)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 421 mg of the title compound is obtained. Yield: 95%. MH+:676.7;678.0(M;M+2).

[0377] Step 5: 1-(1-(3-chlorophenyl)-2-((2-methoxyethyl)(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0378] This compound is obtained by the procedure described in step 7 of Example 3, starting from 421 mg (0.62 mmol) of 1-(1-(3-chlorophenyl)-2-((2-methoxyethyl)(methyl)amino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 240 mg of racemate is obtained. Yield: 74%. MH+:522.6;524.6(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.08(br s,1H);8.17(d,J=2.5Hz,1H);8.12(s,1H);7.75(d,J=7.8Hz,1H);7.70( d,J=2.5Hz,1H);7.49-7.45(m,1H);7.43-7.30(m,3H);6.73-6.67(m,2H );6.23-6.14(m,1H);3.83-3.73(m,4H);3.45-3.31(m,3H);3.20(s,3H) ;3.18-3.09(m,4H);3.00-2.91(m,1H);2.65-2.57(m,2H);2.26(s,3H).

[0379] Step 6: (S)-1-(1-(3-chlorophenyl)-2-((2-methoxyethyl)(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0380] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a Hexane / EtOH / DCM / 0.1% TEA mixture as mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 240 mg of the racemate, 56 mg of the title compound are obtained. MH+:522.6;524.6(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.08(br s,1H);8.17(d,J=2.5Hz,1H);8.12(s,1H);7.75(d,J=7.8Hz,1H);7.70( d,J=2.5Hz,1H);7.49-7.45(m,1H);7.43-7.30(m,3H);6.73-6.67(m,2H );6.23-6.14(m,1H);3.83-3.73(m,4H);3.45-3.31(m,3H);3.20(s,3H) ;3.18-3.09(m,4H);3.00-2.91(m,1H);2.65-2.57(m,2H);2.26(s,3H).

[0381] Example 14: Synthesis of (S)-1-(1-(3-chlorophenyl)-2-(cyclopropyl(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0382] Step 1: 1-(3-chlorophenyl)-2-(cyclopropyl(methyl)amino)ethan-1-ol [ka]

[0383] This compound is obtained by the procedure described in step 6 of example 1, starting with 400 mg (2.59 mmol) of 2-(3-chlorophenyl)oxirane (described in step 2 of example 2) instead of 2-(3-fluorophenyl)oxirane and 557 mg (5.18 mmol) of N-cyclopropylmethylamine hydrochloride instead of dimethylamine. 412 mg of the title compound are obtained. Yield: 70%. MH+:226.4;228.3(M;M+2).

[0384] Step 2: N-(2-chloro-2-(3-chlorophenyl)ethyl)-N-methylcyclopropanamine [ka]

[0385] This compound is obtained by the procedure described in step 7 of Example 1, starting from 402 mg (1.78 mmol) of 1-(3-chlorophenyl)-2-(cyclopropyl(methyl)amino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 505 mg of the title compound is obtained. Yield: 58%. MH+:244.3;246.3(M;M+2).

[0386] Step 3: 4-Bromo-1-(1-(3-chlorophenyl)-2-(cyclopropyl(methyl)amino)ethyl)pyridin-2(1H)-one [ka]

[0387] This compound is obtained by the procedure described in step 8 of Example 1, starting from 505 mg (2.07 mmol) of N-(2-chloro-2-(3-chlorophenyl)ethyl)-N-methylcyclopropanamine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 253 mg of the title compound are obtained. Yield: 32%. MH+:381.3;383.3;385.3(M;M+2;M+4).

[0388] Step 4: 1-(1-(3-chlorophenyl)-2-(cyclopropyl(methyl)amino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0389] This compound is obtained by the procedure described in step 9 of Example 1, starting from 253 mg (0.66 mmol) of 4-bromo-1-(1-(3-chlorophenyl)-2-(cyclopropyl(methyl)amino)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 210 mg of the title compound is obtained. Yield: 48%. MH+:658.4;659.7;660.6(M;M+1;M+2).

[0390] Step 5: 1-(1-(3-chlorophenyl)-2-(cyclopropyl(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0391] This compound is obtained by the procedure described in step 7 of Example 3, starting from 210 mg (0.32 mmol) of 1-(1-(3-chlorophenyl)-2-(cyclopropyl(methyl)amino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 146 mg of racemate is obtained. Yield: 91%. MH+:504.6;506.5(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.08(br s,1H);8.17(d,J=2.5Hz,1H);8.12(s,1H);7.77(d,J=8.1Hz,1H);7.69(d,J=2 .5Hz,1H);7.50-7.46(m,1H);7.43-7.33(m,3H);6.72-6.65(m,2H);6.30-6.2 0(m,1H);3.83-3.74(m,4H);3.53-3.41(m,1H);3.18-3.10(m,4H);3.08-2.99 (m,1H);2.32(s,3H);1.78-1.69(m,1H);0.45-0.36(m,2H);0.25-0.14(m,2H).

[0392] Step 6: (S)-1-(1-(3-chlorophenyl)-2-(cyclopropyl(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0393] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a Hexane / EtOH / DCM / 0.1% TEA mixture as mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 146 mg of the racemate, 38 mg of the title compound are obtained. MH+:504.6;506.5(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.08(br s,1H);8.17(d,J=2.5Hz,1H);8.12(s,1H);7.77(d,J=8.1Hz,1H);7.69(d,J=2 .5Hz,1H);7.50-7.46(m,1H);7.43-7.33(m,3H);6.72-6.65(m,2H);6.30-6.2 0(m,1H);3.83-3.74(m,4H);3.53-3.41(m,1H);3.18-3.10(m,4H);3.08-2.99 (m,1H);2.32(s,3H);1.78-1.69(m,1H);0.45-0.36(m,2H);0.25-0.14(m,2H).

[0394] Example 15: Synthesis of (S)-1-(1-(3-chlorophenyl)-2-(ethyl(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0395] Step 1: 1-(3-chlorophenyl)-2-(ethyl(methyl)amino)ethan-1-ol [ka]

[0396] This compound is obtained by the procedure described in step 6 of example 1, starting with 400 mg (2.59 mmol) of 2-(3-chlorophenyl)oxirane (described in step 2 of example 2) instead of 2-(3-fluorophenyl)oxirane and 495 mg (5.18 mmol) of N-methylethanamine hydrochloride instead of dimethylamine. 103 mg of the title compound are obtained. Yield: 19%. MH+:214.3;216.2(M;M+2).

[0397] Step 2: 2-Chloro-2-(3-chlorophenyl)-N-ethyl-N-methylethan-1-amine [ka]

[0398] This compound is obtained by the procedure described in step 7 of Example 1, starting from 103 mg (0.48 mmol) of 1-(3-chlorophenyl)-2-(ethyl(methyl)amino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 125 mg of the title compound is obtained. Yield: quantitative. MH+:232.3;234.2(M;M+2).

[0399] Step 3: 4-Bromo-1-(1-(3-chlorophenyl)-2-(ethyl(methyl)amino)ethyl)pyridin-2(1H)-one [ka]

[0400] This compound is obtained by the procedure described in step 8 of Example 1, starting from 125 mg (0.54 mmol) of 2-chloro-2-(3-chlorophenyl)-N-ethyl-N-methylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 78 mg of the title compound are obtained. Yield: 39%. MH+:369.4;371.3;373.3(M;M+2;M+4).

[0401] Step 4: 1-(1-(3-chlorophenyl)-2-(ethyl(methyl)amino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0402] This compound is obtained by the procedure described in step 9 of Example 1, starting from 78 mg (0.21 mmol) of 4-bromo-1-(1-(3-chlorophenyl)-2-(ethyl(methyl)amino)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 128 mg of the title compound is obtained. Yield: 94%. MH+:646.7;648.6(M;M+2).

[0403] Step 5: 1-(1-(3-chlorophenyl)-2-(ethyl(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0404] This compound is obtained by the procedure described in step 7 of Example 3, starting from 128 mg (0.20 mmol) of 1-(1-(3-chlorophenyl)-2-(ethyl(methyl)amino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 45 mg of racemate is obtained. Yield: 46%. MH+:492.6;494.6(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.03(br s,1H);8.16(d,J=2.6Hz,1H);8.09(s,1H);7.74(d,J=8.0Hz,1H);7.70(d, J=2.6Hz,1H);7.49-7.45(m,1H);7.43-7.34(m,3H);6.71-6.66(m,2H);6. 22-6.15(m,1H);3.82-3.74(m,4H);3.34-3.24(m,1H);3.17-3.10(m,4H); 2.91-2.83(m,1H);2.51-2.40(m,2H);2.21(s,3H);0.95(t,J=7.1Hz,3H).

[0405] Step 6: (S)-1-(1-(3-chlorophenyl)-2-(ethyl(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0406] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a Hexane / EtOH / DCM / 0.1% TEA mixture as mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 45 mg of the racemate, 16 mg of the title compound are obtained. MH+:492.6;494.6(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.03(br s,1H);8.16(d,J=2.6Hz,1H);8.09(s,1H);7.74(d,J=8.0Hz,1H);7.70(d, J=2.6Hz,1H);7.49-7.45(m,1H);7.43-7.34(m,3H);6.71-6.66(m,2H);6. 22-6.15(m,1H);3.82-3.74(m,4H);3.34-3.24(m,1H);3.17-3.10(m,4H); 2.91-2.83(m,1H);2.51-2.40(m,2H);2.21(s,3H);0.95(t,J=7.1Hz,3H).

[0407] Example 16: Synthesis of (S)-1-(1-(3-chlorophenyl)-2-((cyclopropylmethyl)(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0408] Step 1: 1-(3-chlorophenyl)-2-((cyclopropylmethyl)(methyl)amino)ethan-1-ol [ka]

[0409] This compound is obtained by the procedure described in step 6 of example 1, starting with 400 mg (2.59 mmol) of 2-(3-chlorophenyl)oxirane (described in step 2 of example 2) instead of 2-(3-fluorophenyl)oxirane and 630 mg (5.18 mmol) of 1-cyclopropyl-N-methylmethanamine hydrochloride instead of dimethylamine. 183 mg of the title compound are obtained. Yield: 29%. MH+:240.4;242.2(M;M+2).

[0410] Step 2: 2-Chloro-2-(3-chlorophenyl)-N-(cyclopropylmethyl)-N-methylethan-1-amine [ka]

[0411] This compound is obtained by the procedure described in step 7 of Example 1, starting from 183 mg (0.76 mmol) of 1-(3-chlorophenyl)-2-((cyclopropylmethyl)(methyl)amino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 220 mg of the title compound are obtained. Yield: quantitative. MH+:258.4;260.2(M;M+2).

[0412] Step 3: 4-Bromo-1-(1-(3-chlorophenyl)-2-((cyclopropylmethyl)(methyl)amino)ethyl)pyridin-2(1H)-one [ka]

[0413] This compound is obtained by the procedure described in step 8 of Example 1, starting from 220 mg (0.85 mmol) of 2-chloro-2-(3-chlorophenyl)-N-(cyclopropylmethyl)-N-methylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 115 mg of the title compound are obtained. Yield: 34%. MH+:395.4;397.4;399.3(M;M+2;M+4).

[0414] Step 4: 1-(1-(3-chlorophenyl)-2-((cyclopropylmethyl)(methyl)amino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0415] This compound is obtained by the procedure described in step 9 of Example 1, starting from 115 mg (0.29 mmol) of 4-bromo-1-(1-(3-chlorophenyl)-2-((cyclopropylmethyl)(methyl)amino)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 144 mg of the title compound is obtained. Yield: 73%. MH+:672.7;674.7(M;M+2).

[0416] Step 5: 1-(1-(3-chlorophenyl)-2-((cyclopropylmethyl)(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0417] This compound is obtained by the procedure described in step 7 of Example 3, starting from 144 mg (0.21 mmol) of 1-(1-(3-chlorophenyl)-2-((cyclopropylmethyl)(methyl)amino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 68 mg of racemate is obtained. Yield: 61%. MH+:518.7;520.6(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.03(br s,1H);8.14(d,J=2.5Hz,1H);8.09(s,1H);7.71(d,J=7.3Hz,1H);7.69(d,J=2.6Hz, 1H);7.49-7.45(m,1H);7.42-7.32(m,3H);6.71-6.64(m,2H);6.24-6.16(m,1H);3. 83-3.74(m,4H);3.36-3.26(m,1H);3.17-3.09(m,4H);2.99-2.91(m,1H);2.31(d,J =6.6Hz,2H);2.29(s,3H);0.88-0.78(m,1H);0.48-0.38(m,2H);0.09-0.03(m,2H).

[0418] Step 6: (S)-1-(1-(3-chlorophenyl)-2-((cyclopropylmethyl)(methyl)amino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0419] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a hexane / EtOH / DCM / 0.1% TEA mixture as mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 68 mg of the racemate, 29 mg of the title compound are obtained. MH+:518.7;520.6(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.03(br s,1H);8.14(d,J=2.5Hz,1H);8.09(s,1H);7.71(d,J=7.3Hz,1H);7.69(d,J=2.6Hz, 1H);7.49-7.45(m,1H);7.42-7.32(m,3H);6.71-6.64(m,2H);6.24-6.16(m,1H);3. 83-3.74(m,4H);3.36-3.26(m,1H);3.17-3.09(m,4H);2.99-2.91(m,1H);2.31(d,J =6.6Hz,2H);2.29(s,3H);0.88-0.78(m,1H);0.48-0.38(m,2H);0.09-0.03(m,2H).

[0420] Example 17: Synthesis of (S)-1-(1-(3,4-difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0421] Step 1: 1,2-Difluoro-4-vinylbenzene [ka]

[0422] The compound is obtained by the procedure described in step 4 of example 1, starting from 2.5 g (17.6 mmol) of 3,4-difluorobenzaldehyde instead of 3-fluorobenzaldehyde. 1.38 g of the title compound are obtained. Yield: 56%. MH+: Non-ionizable.

[0423] Step 2: 2-(3,4-difluorophenyl)oxirane [ka]

[0424] The compound is obtained by the procedure described in step 5 of Example 1, starting from 1.38 g (9.85 mmol) of 1,2-difluoro-4-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 884 mg of the title compound are obtained. Yield: 57%. MH+: Non-ionizable.

[0425] Step 3: 1-(3,4-difluorophenyl)-2-(dimethylamino)ethan-1-ol [ka]

[0426] This compound is obtained by the procedure described in step 6 of Example 1, starting from 884 mg (5.66 mmol) of 2-(3,4-difluorophenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 784 mg of the title compound are obtained. Yield: 69%. MH+:202.2(M+1).

[0427] Step 4: 2-Chloro-2-(3,4-difluorophenyl)-N,N-dimethylethan-1-amine [ka]

[0428] This compound is obtained by the procedure described in step 7 of Example 1, starting from 784 mg (3.90 mmol) of 1-(3,4-difluorophenyl)-2-(dimethylamino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 770 mg of the title compound is obtained. Yield: 90%. MH+:220.3;222.1(M;M+2).

[0429] Step 5: 4-Bromo-1-(1-(3,4-difluorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one [ka]

[0430] This compound is obtained by the procedure described in step 8 of Example 1, starting from 770 mg (3.51 mmol) of 2-chloro-2-(3,4-difluorophenyl)-N,N-dimethylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 560 mg of the title compound is obtained. Yield: 45%. MH+:357.3;359.3(M;M+2).

[0431] Step 6: 1-(1-(3,4-difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0432] This compound is obtained by the procedure described in step 9 of Example 1, starting from 560 mg (1.57 mmol) of 4-bromo-1-(1-(3,4-difluorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 685 mg of the title compound is obtained. Yield: 69%. MH+:634.5(M+1).

[0433] Step 7: 1-(1-(3,4-difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0434] This compound is obtained by the procedure described in step 7 of Example 3, starting from 685 mg (1.08 mmol) of 1-(1-(3,4-difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 400 mg of racemate is obtained. Yield: 77%. MH+:480.6(M+1). 1H NMR(DMSO-d6,400MHz):δ 12.03(br 7.25 -7.20(m,1H);6.70-6.65(m,2H);6.20-6.14(m,1H);3.81-3.74(m,4H) ;3.28-3.21(m,1H);3.17-3.09(m,4H);2.79-2.70(m,1H);2.21(s,6H).

[0435] Step 8: (S)-1-(1-(3,4-difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0436] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a Hexane / EtOH / DCM / 0.1% TEA mixture as the mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. 16 mg of the title compound are obtained. MH+:480.6(M+1). 1 H NMR(DMSO-d6,400MHz):δ 12.03(br 7.25 -7.20(m,1H);6.70-6.65(m,2H);6.20-6.14(m,1H);3.81-3.74(m,4H) ;3.28-3.21(m,1H);3.17-3.09(m,4H);2.79-2.70(m,1H);2.21(s,6H).

[0437] Example 18: Synthesis of (S)-1-(1-(3,5-difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0438] Step 1: 1,3-Difluoro-5-vinylbenzene [ka]

[0439] The compound is obtained by the procedure described in step 4 of example 1, starting from 2.5 g (17.6 mmol) of 3,5-difluorobenzaldehyde instead of 3-fluorobenzaldehyde. 0.52 g of the title compound is obtained. Yield: 21%. MH+: Non-ionizable.

[0440] Step 2: 2-(3,5-difluorophenyl)oxirane [ka]

[0441] This compound is obtained by the procedure described in step 5 of Example 1, starting from 0.52 g (3.71 mmol) of 1,3-difluoro-5-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 226 mg of the title compound are obtained. Yield: 39%. MH+: Non-ionizable.

[0442] Step 3: 1-(3,5-difluorophenyl)-2-(dimethylamino)ethan-1-ol [ka]

[0443] This compound is obtained by the procedure described in step 6 of Example 1, starting from 226 mg (1.45 mmol) of 2-(3,5-difluorophenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 120 mg of the title compound is obtained. Yield: 41%. MH+:202.2(M+1).

[0444] Step 4: 2-Chloro-2-(3,5-difluorophenyl)-N,N-dimethylethan-1-amine [ka]

[0445] This compound is obtained by the procedure described in step 7 of Example 1, starting from 120 mg (0.60 mmol) of 1-(3,5-difluorophenyl)-2-(dimethylamino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 105 mg of the title compound is obtained. Yield: 80%. MH+:220.3;221.1(M;M+2).

[0446] Step 5: 4-Bromo-1-(1-(3,5-difluorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one [ka]

[0447] This compound is obtained by the procedure described in step 8 of Example 1, starting from 105 mg (0.48 mmol) of 2-chloro-2-(3,5-difluorophenyl)-N,N-dimethylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 57 mg of the title compound are obtained. Yield: 33%. MH+:3573;359.3(M;M+2).

[0448] Step 6: 1-(1-(3,5-difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0449] This compound is obtained by the procedure described in step 9 of Example 1, starting from 57 mg (0.16 mmol) of 4-bromo-1-(1-(3,5-difluorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 65 mg of the title compound is obtained. Yield: 64%. MH+:634.5(M+1).

[0450] Step 7: 1-(1-(3,5-difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0451] This compound is obtained by the procedure described in step 7 of Example 3, starting from 65 mg (0.10 mmol) of 1-(1-(3,5-difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 12 mg of racemate is obtained. Yield: 25%. MH+:480.5(M+1). 1 H NMR(DMSO-d6,400MHz):δ 12.05(br s,1H);8.16(d,J=2.6Hz,1H);8.10(s,1H);7.75(d,J=8.0Hz,1H);7.70(d,J=2.6Hz,1H);7.22-7.16(m,1H);7.16-7.10(m,2H); 6.73-6.66(m,2H);6.21-6.14(m,1H);3.84-3.74(m,4H);3.31-3.22(m,1H);3.17-3.10(m,4H);2.81-2.72(m,1H);2.21(s,6H).

[0452] Step 8: (S)-1-(1-(3,5-difluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0453] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a Hexane / EtOH / DCM / 0.1% TEA mixture as mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 12 mg of the racemate, 3 mg of the title compound are obtained. MH+:480.5(M+1). 1 H NMR(DMSO-d6,400MHz):δ 12.05(br s,1H);8.16(d,J=2.6Hz,1H);8.10(s,1H);7.75(d,J=8.0Hz,1H);7.70(d,J=2.6Hz,1H);7.22-7.16(m,1H);7.16-7.10(m,2H); 6.73-6.66(m,2H);6.21-6.14(m,1H);3.84-3.74(m,4H);3.31-3.22(m,1H);3.17-3.10(m,4H);2.81-2.72(m,1H);2.21(s,6H).

[0454] Example 19: Synthesis of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-5-fluoro-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0455] Step 1: 4-Bromo-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-5-fluoropyridin-2(1H)-one [ka]

[0456] This compound is obtained by the procedure described in step 8 of example 1, starting from 220 mg (1.15 mmol) of 4-bromo-5-fluoro-1H-pyridin-2-one instead of 4-bromopyridin-2-(1H)-one and 250 mg (1.15 mmol) of 2-chloro-2-(3-chlorophenyl)-N,N-dimethylethan-1-amine (described in step 4 of example 2) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 145 mg of the title compound is obtained. Yield: 34%. MH+:373.3;375.3;377.2(M;M+2;M+4).

[0457] Step 2: 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-5-fluoro-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0458] This compound is obtained by the procedure described in step 9 of Example 1, starting from 145 mg (0.39 mmol) of 4-bromo-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-5-fluoropyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 211 mg of the title compound is obtained. Yield: 84%. MH+:650.5;651.9;652.7(M;M+1;M+2).

[0459] Step 3: 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-5-fluoro-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0460] This compound is obtained by the procedure described in step 7 of Example 3, starting from 211 mg (0.32 mmol) of 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-5-fluoro-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 95 mg of racemate is obtained. Yield: 59%. MH+:496.5;498.5(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.16(br s,1H);8.19(d,J=2.6Hz,1H);8.12(d,J=7.7Hz,1H);7.92(d,J=2.8Hz,1H);7.63-7.59(m,1H);7.54-7.51(m,1H);7.44-7.36(m,3H) ;6.67(d,J=7.7Hz,1H);6.18-6.10(m,1H);3.82-3.73(m,4H);3.43-3.35(m,1H);3.16-3.08(m,4H);2.72-2.63(m,1H);2.22(s,6H).

[0461] Step 4: (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-5-fluoro-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0462] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a hexane / EtOH / DCM / 0.1% TEA mixture as mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 95 mg of the racemate, 34 mg of the title compound are obtained. MH+:496.5;498.5(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.16(br s,1H);8.19(d,J=2.6Hz,1H);8.12(d,J=7.7Hz,1H);7.92(d,J=2.8Hz,1H);7.63-7.59(m,1H);7.54-7.51(m,1H);7.44-7.36(m,3H) ;6.67(d,J=7.7Hz,1H);6.18-6.10(m,1H);3.82-3.73(m,4H);3.43-3.35(m,1H);3.16-3.08(m,4H);2.72-2.63(m,1H);2.22(s,6H).

[0463] Example 20: Synthesis of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-6-methyl-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0464] Step 1: 4-Bromo-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-6-methylpyridin-2(1H)-one [ka]

[0465] The compound is obtained by the procedure described in step 8 of Example 1, starting from 216 mg (1.15 mmol) of 4-bromo-6-methylpyridin-2(1H)-one instead of 4-bromopyridin-2-(1H)-one and 250 mg (1.15 mmol) of 2-chloro-2-(3-chlorophenyl)-N,N-dimethylethan-1-amine (described in step 4 of Example 2) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 40 mg of the title compound is obtained. Yield: 9%. MH+:369.3;371.3;373.2(M;M+2;M+4).

[0466] Step 2: 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-6-methyl-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0467] This compound is obtained by the procedure described in step 9 of Example 1, starting from 40 mg (0.39 mmol) of 4-bromo-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-6-methylpyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 78 mg of the title compound is obtained. Yield: quantitative. MH+:646.6;648.4(M;M+2).

[0468] Step 3: 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-6-methyl-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0469] This compound is obtained by the procedure described in step 7 of Example 3, starting from 78 mg (0.12 mmol) of 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-6-methyl-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 12 mg of racemate is obtained. Yield: 20%. MH+:492.5;494.5(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.05(br s,1H);8.17(m,1H);8.06(m,1H);7.80-7.64(m,1H);7.47-7.18(m,4H);6.77-6.53(m,1H);6.50-6.40(m,1H);5.40- 5.30(m,1H);3.87-3.71(m,4H);3.33-3.21(m,1H);3.21-3.07(m,4H);2.90-2.78(m,1H);2.54(s,3H);2.26(s,6H).

[0470] Step 4: (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-6-methyl-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0471] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a heptane / EtOH / DCM / 0.1% TEA mixture as mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 12 mg of the racemate, 4 mg of the title compound are obtained. MH+:492.5;494.5(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.05(br s,1H);8.17(m,1H);8.06(m,1H);7.80-7.64(m,1H);7.47-7.18(m,4H);6.77-6.53(m,1H);6.50-6.40(m,1H);5.40- 5.30(m,1H);3.87-3.71(m,4H);3.33-3.21(m,1H);3.21-3.07(m,4H);2.90-2.78(m,1H);2.54(s,3H);2.26(s,6H).

[0472] Example 21: Synthesis of 1-((S)-1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-(2-(trifluoromethyl)morpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0473] Step 1: 4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(trifluoromethyl)morpholine [ka]

[0474] The compound is obtained by the procedure described in step 1 of example 1, starting from 119 mg (0.62 mmol) of 2-(trifluoromethyl)morpholine hydrochloride instead of morpholine. 161 mg of the title compound are obtained. Yield: quantitative. MH+:272.4(M+1).

[0475] Step 2: 4-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(trifluoromethyl)morpholine [ka]

[0476] This compound is obtained by the procedure described in step 2 of Example 1, starting from 161 mg (0.59 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(trifluoromethyl)morpholine (described in the previous step) instead of 4-(1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine. 305 mg of the title compound is obtained. Yield: quantitative. MH+:426.6(M+1).

[0477] Step 3: 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(trifluoromethyl)morpholine [ka]

[0478] This compound is obtained by the procedure described in step 3 of Example 1, starting from 305 mg (0.72 mmol) of 4-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(trifluoromethyl)morpholine (described in the previous step) instead of 4-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine. 330 mg of the title compound is obtained. Yield: 84%. MH+:552.5(M+1).

[0479] Step 4: 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(1-tosyl-5-(2-(trifluoromethyl)morpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0480] The compound was prepared by the procedure described in step 9 of Example 1, using 160 mg (0.29 mmol) of 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl) ... )-2-(trifluoromethyl)morpholine (described in the previous step) and 103 mg (0.29 mmol) of 4-bromo-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one (described in step 5 of Example 2) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 155 mg of the title compound are obtained. Yield: 76%. MH+:700.6;701.9;702.7(M;M+1;M+2).

[0481] Step 5: 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-(2-(trifluoromethyl)morpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0482] This compound is obtained by the procedure described in step 7 of Example 3, starting from 155 mg (0.22 mmol) of 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(1-tosyl-5-(2-(trifluoromethyl)morpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 73 mg of racemate is obtained. Yield: 60%. MH+:546.6;548.6(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.10(br s,1H);8.21(d,J=2.5Hz,1H);8.12(s,1H);7.83(d,J=2.5Hz,1H);7.76(d,J=7.4Hz ,1H);7.49-7.44(m,1H);7.44-7.33(m,3H);6.76-6.66(m,2H);6.23-6.13(m,1H); 4.46-4.33(m,1H);4.15-4.05(m,1H);3.91-3.78(m,1H);3.78-3.63(m,1H);3.54- 3.44(m,1H);3.32-3.23(m,1H);2.96-2.79(m,2H);2.79-2.69(m,1H);2.21(s,6H).

[0483] Step 6: 1-((S)-1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-(2-(trifluoromethyl)morpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0484] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a Hexane / EtOH / DCM / 0.1% TEA mixture as mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 73 mg of the racemate, 30 mg of the title compound are obtained. MH+:546.6;548.6(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.10(br s,1H);8.21(d,J=2.5Hz,1H);8.12(s,1H);7.83(d,J=2.5Hz,1H);7.76(d,J=7.4Hz ,1H);7.49-7.44(m,1H);7.44-7.33(m,3H);6.76-6.66(m,2H);6.23-6.13(m,1H); 4.46-4.33(m,1H);4.15-4.05(m,1H);3.91-3.78(m,1H);3.78-3.63(m,1H);3.54- 3.44(m,1H);3.32-3.23(m,1H);2.96-2.79(m,2H);2.79-2.69(m,1H);2.21(s,6H).

[0485] Example 22: Synthesis of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(4-fluoro-5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0486] Step 1: 4-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine [ka]

[0487] This compound is obtained by the procedure described in step 1 of Example 1, starting from 145 mg (0.67 mmol) of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine instead of 5-bromo-1H-pyrrolo[2,3-b]pyridine. 35 mg of the title compound are obtained. Yield: 23%. MH+:222.3(M+1).

[0488] Step 2: 4-(4-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine [ka]

[0489] This compound is obtained by the procedure described in step 2 of Example 1, starting from 35 mg (0.16 mmol) of 4-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine (described in the previous step) instead of 4-(1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine. 53 mg of the title compound is obtained. Yield: 53%. MH+:376.4(M+1).

[0490] Step 3: 4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine [ka]

[0491] This compound is obtained by the procedure described in step 3 of Example 1, starting from 53 mg (0.14 mmol) of 4-(4-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine (described in the previous step) instead of 4-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine. 22 mg of the title compound is obtained. Yield: 31%. MH+:502.5(M+1).

[0492] Step 4: 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(4-fluoro-5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0493] The compound was prepared by the procedure described in step 9 of Example 1, using 22 mg (0.044 mmol) of 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(4-fluoro-5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine instead of 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine. Starting from lysine-3-yl)pyridin-2(1H)-one (described in the previous step) and 16 mg (0.044 mmol) of 4-bromo-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)pyridin-2(1H)-one (described in step 5 of example 2) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one, 17 mg of the title compound is obtained. Yield: 61%. MH+:700.6;701.9;702.8(M;M+1;M+2).

[0494] Step 5: 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(4-fluoro-5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0495] This compound is obtained by the procedure described in step 7 of Example 3, starting from 17 mg (0.026 mmol) of 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(4-fluoro-5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 5 mg of racemate is obtained. Yield: 42%. MH+:496.6;498.5(M;M+2)

[0496] Step 6: (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(4-fluoro-5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0497] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a Hexane / EtOH / DCM / 0.1% TEA mixture as the mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 5 mg of the racemate, 2 mg of the title compound are obtained. MH+:496.6;498.5(M;M+2)

[0498] Example 23: Synthesis of (S)-1-(1-(3-chloro-5-(methoxymethyl)phenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0499] Step 1: 3-Chloro-5-(methoxymethyl)benzonitrile [ka]

[0500] 500 mg (2.98 mmol, 1 eq) of 3-chloro-5-cyanobenzyl alcohol is dissolved in 30 ml of dry DMF and the solution is cooled to 0° C. in an ice / water bath. 155 mg (3.88 mmol, 1.3 eq) of sodium hydride (60% in paraffin oil) is slowly added and the slurry is stirred for 15 min. Then, 441 μL (8.95 mmol) of methyl iodide is added at 0° C. and the mixture is stirred for another 30 min. The mixture is diluted with 100 ml of Et2O, washed three times with water and once with brine. The organic layer is dried over Na2SO4, filtered and evaporated under reduced pressure to give 664 mg of crude compound, which is purified by flash chromatography using a silica gel column and an Et2O / Hexane mixture as eluent. 497 mg of the title compound is obtained. Yield: 92%. MH+:182.2(M+1).

[0501] Step 2: 3-Chloro-5-(methoxymethyl)benzaldehyde [ka]

[0502] 437 mg (2.40 mmol, 1 eq) of 3-chloro-5-(methoxymethyl)benzonitrile (described in the previous step) are dissolved in a mixture of 1.25 ml of pyridine, 1.25 ml of acetic acid and 1.25 ml of water. The solution is cooled to 0° C. and 2.04 g (19.25 mmol, 8 eq) of NaH2PO2 monohydrate are added, followed by a small amount of Raney Ni (50% in water). The reaction is stirred at 0° C. for 1 h and at room temperature for another 3 h. The mixture is filtered over Celite and the precipitate is rinsed several times with EtOAc. The combined filtrates are washed with saturated NaHCO3 solution and the organic layer is dried over Na2SO4, filtered and evaporated under reduced pressure. The crude compound is finally purified by flash chromatography using a silica gel column and an EtOAc / Hexane mixture as eluent. 278 mg of the title compound are obtained. Yield: 59%. MH+:185.2;187.1(m+1;M+3).

[0503] Step 3: 1-Chloro-3-(methoxymethyl)-5-vinylbenzene [ka]

[0504] The compound is obtained by the procedure described in step 4 of Example 1, starting from 278 mg (1.50 mmol) of 3-chloro-5-(methoxymethyl)benzaldehyde (described in the previous step) instead of 3-fluorobenzaldehyde. 100 mg of the title compound are obtained. Yield: 36%. MH+: Non-ionizable.

[0505] Step 4: 2-(3-chloro-5-(methoxymethyl)phenyl)oxirane [ka]

[0506] This compound is obtained by the procedure described in step 5 of Example 1, starting from 100 mg (0.55 mmol) of 1-chloro-3-(methoxymethyl)-5-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 66 mg of the title compound are obtained. Yield: 60%. MH+: Non-ionizable.

[0507] Step 5: 1-(3-chloro-5-(methoxymethyl)phenyl)-2-(dimethylamino)ethan-1-ol [ka]

[0508] This compound is obtained by the procedure described in step 6 of Example 1, starting from 66 mg (0.33 mmol) of 2-(3-chloro-5-(methoxymethyl)phenyl)oxirane (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 58 mg of the title compound is obtained. Yield: 71%. MH+:244.3;246.2(M;M+2).

[0509] Step 6: 2-Chloro-2-(3-chloro-5-(methoxymethyl)phenyl)-N,N-dimethylethan-1-amine [ka]

[0510] This compound is obtained by the procedure described in step 7 of Example 1, starting from 58 mg (0.24 mmol) of 1-(3-chloro-5-(methoxymethyl)phenyl)-2-(dimethylamino)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 70 mg of the title compound is obtained. Yield: quantitative. MH+:262.3;264.3(M;M+2).

[0511] Step 7: 1-(1-(3-chloro-5-(methoxymethyl)phenyl)-2-(dimethylamino)ethyl)-4-iodopyridin-2(1H)-one [ka]

[0512] This compound is obtained by the procedure described in step 5 of Example 6, starting from 70 mg (0.27 mmol) of 2-chloro-2-(3-chloro-5-(methoxymethyl)phenyl)-N,N-dimethylethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-iodophenyl)-N,N-dimethylethan-1-amine. 35 mg of the title compound are obtained. Yield: 33%. MH+:448.2;450.3(M;M+2).

[0513] Step 8: 1-(1-(3-chloro-5-(methoxymethyl)phenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0514] This compound is obtained by the procedure described in step 9 of Example 1, starting from 136 mg (0.30 mmol) of 1-(1-(3-chloro-5-(methoxymethyl)phenyl)-2-(dimethylamino)ethyl)-4-iodopyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 168 mg of the title compound is obtained. Yield: 81%. MH+:676.5;678.5(M;M+2).

[0515] Step 9: 1-(1-(3-chloro-5-(methoxymethyl)phenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0516] This compound is obtained by the procedure described in step 7 of Example 3, starting from 150 mg (0.22 mmol) of 1-(1-(3-chloro-5-(methoxymethyl)phenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 57 mg of racemate is obtained. Yield: 49%. MH+:522.5;524.7(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.06(br s,1H);8.17(d,J=2.5Hz,1H);8.10(s,1H);7.76(d,J=8.1Hz,1H);7.70(d,J=2.6Hz,1H);7.42-7.37(m,1H);7.33-7.27(m,2H);6.73-6.65(m ,2H);6.22-6.12(m,1H);4.40(s,2H);3.83-3.73(m,4H);3.43-3.35(m ,1H);3.29(s,3H);3.18-3.08(m,4H);2.75-2.64(m,1H);2.20(s,6H).

[0517] Step 10: (S)-1-(1-(3-chloro-5-(methoxymethyl)phenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0518] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a Hexane / EtOH / DCM / 0.1% TEA mixture as mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 57 mg of the racemate, 24 mg of the title compound are obtained. MH+:522.5;524.7(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.06(br s,1H);8.17(d,J=2.5Hz,1H);8.10(s,1H);7.76(d,J=8.1Hz,1H);7.70(d,J=2.6Hz,1H);7.42-7.37(m,1H);7.33-7.27(m,2H);6.73-6.65(m ,2H);6.22-6.12(m,1H);4.40(s,2H);3.83-3.73(m,4H);3.43-3.35(m ,1H);3.29(s,3H);3.18-3.08(m,4H);2.75-2.64(m,1H);2.20(s,6H).

[0519] Example 24: Synthesis of (S)-1-(2-(aziridin-1-yl)-1-(3-chlorophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0520] Step 1: 2-(aziridin-1-yl)-1-(3-chlorophenyl)ethan-1-ol [ka]

[0521] To a solution of 450 mg (3.88 mmol, 2 eq) of 2-chloroethanamine hydrochloride in 1 ml of water is added a solution of 310 mg (7.76 mmol, 4 eq) of sodium hydroxide in 1 ml of water. The resulting mixture is stirred at 50° C. for 45 min. Then, a solution of 300 mg (1.94 mmol, 1 eq) of 2-(3-chlorophenyl)oxirane (described in step 2 of example 2) in 3 ml of 1,4-dioxane is added. The mixture is stirred at 50° C. for 4 h. Then, the reaction is diluted with water and extracted with DCM. The combined organic layers are washed three times with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude compound is used directly in the next step without further purification. 460 mg of the title compound is obtained. Yield: quantitative. MH+:198.1;200.1(M;M+2).

[0522] Step 2: 1-(2-bromo-2-(3-chlorophenyl)ethyl)aziridine [ka]

[0523] To a solution of 165 mg (0.83 mmol, 1 eq) of 2-(aziridin-1-yl)-1-(3-chlorophenyl)ethan-1-ol (described in the previous step) in 3 ml of dry DCM at 0° C. in an ice / water bath, 129 μL (1.67 mmol, 2 eq) of thionyl bromide is added dropwise. The resulting mixture is allowed to reach room temperature overnight. The reaction mixture is then directly purified by flash chromatography using a silica gel column and a DCM / MeOH mixture as eluent. 176 mg of the title compound is obtained. Yield: 76%. MH+:260.2;262.2;264.1(M;M+2;M+4).

[0524] Step 3: 1-(2-(aziridin-1-yl)-1-(3-chlorophenyl)ethyl)-4-bromopyridin-2(1H)-one [ka]

[0525] This compound is obtained by the procedure described in step 8 of Example 1, starting from 166 mg (0.64 mmol) of 1-(2-bromo-2-(3-chlorophenyl)ethyl)aziridine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 77 mg of the title compound are obtained. Yield: 34%. MH+:353.3;355.3;357.2(M;M+2;M+4).

[0526] Step 4: 1-(2-(aziridin-1-yl)-1-(3-chlorophenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0527] This compound is obtained by the procedure described in step 9 of Example 1, starting from 77 mg (0.23 mmol) of 1-(2-(aziridin-1-yl)-1-(3-chlorophenyl)ethyl)-4-bromopyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 69 mg of the title compound is obtained. Yield: 48%. MH+:630.6;631.9;632.7(M;M+1;M+2).

[0528] Step 5: 1-(2-(aziridin-1-yl)-1-(3-chlorophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0529] This compound is obtained by the procedure described in step 7 of Example 3, starting from 69 mg (0.11 mmol) of 1-(2-(aziridin-1-yl)-1-(3-chlorophenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 32 mg of racemate is obtained. Yield: 61%. MH+:476.5;478.5(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.03(br s,1H);8.17(d,J=2.5Hz,1H);8.03(s,1H);7.67(d,J=2.6Hz,1H);7.52(d,J=7.2Hz,1H);7.30-7.22(m,2H);7.21-7.12(m,2H);6.6 7-6.63(m,1H);6.55-6.50(m,1H);4.11-4.00(m,2H);3.84-3.74(m,4H);3.19-3.10(m,4H);2.77-2.58(m,3H);1.83-1.74(m,2H).

[0530] Step 6: (S)-1-(2-(aziridin-1-yl)-1-(3-chlorophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0531] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a hexane / IPA / 0.1% TEA mixture as the mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 32 mg of the racemate, 14 mg of the title compound are obtained. MH+:476.5;478.5(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.03(br s,1H);8.17(d,J=2.5Hz,1H);8.03(s,1H);7.67(d,J=2.6Hz,1H);7.52(d,J=7.2Hz,1H);7.30-7.22(m,2H);7.21-7.12(m,2H);6.6 7-6.63(m,1H);6.55-6.50(m,1H);4.11-4.00(m,2H);3.84-3.74(m,4H);3.19-3.10(m,4H);2.77-2.58(m,3H);1.83-1.74(m,2H).

[0532] Example 25: Synthesis of (S)-3-(2-(dimethylamino)-1-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)benzonitrile [ka]

[0533] Step 1: 3-Vinylbenzonitrile [ka]

[0534] The compound is obtained by the procedure described in step 4 of example 1, starting from 0.5 g (3.8 mmol) of 3-cyanobenzaldehyde instead of 3-fluorobenzaldehyde. 180 mg of the title compound are obtained. Yield: 37%. MH+: Non-ionizable.

[0535] Step 2: 3-(oxiran-2-yl)benzonitrile [ka]

[0536] This compound is obtained by the procedure described in step 5 of Example 1, starting from 180 mg (1.39 mmol) of 3-vinylbenzonitrile (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 136 mg of the title compound are obtained. Yield: 67%. MH+: Non-ionizable.

[0537] Step 3: 3-(2-(dimethylamino)-1-hydroxyethyl)benzonitrile [ka]

[0538] This compound is obtained by the procedure described in step 6 of Example 1, starting from 136 mg (0.94 mmol) of 3-(oxiran-2-yl)benzonitrile (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 156 mg of the title compound are obtained. Yield: 88%. MH+:191.2(M+1).

[0539] Step 4: 3-(1-chloro-2-(dimethylamino)ethyl)benzonitrile [ka]

[0540] This compound is obtained by the procedure described in step 7 of Example 1, starting from 156 mg (0.82 mmol) of 3-(2-(dimethylamino)-1-hydroxyethyl)benzonitrile (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 188 mg of the title compound are obtained. Yield: quantitative. MH+:209.2;211.1(M;M+2).

[0541] Step 5: 3-(1-(4-bromo-2-oxopyridin-1(2H)-yl)-2-(dimethylamino)ethyl)benzonitrile [ka]

[0542] This compound is obtained by the procedure described in step 8 of Example 1, starting from 171 mg (0.82 mmol) of 3-(1-chloro-2-(dimethylamino)ethyl)benzonitrile (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 109 mg of the title compound is obtained. Yield: 38%. MH+:346.4;348.4(M;M+2).

[0543] Step 6: 3-(2-(dimethylamino)-1-(4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)benzonitrile [ka]

[0544] This compound is obtained by the procedure described in step 9 of Example 1, starting from 109 mg (0.31 mmol) of 3-(1-(4-bromo-2-oxopyridin-1(2H)-yl)-2-(dimethylamino)ethyl)benzonitrile (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 138 mg of the title compound is obtained. Yield: 70%. MH+:623.7(M+1).

[0545] Step 7: 3-(2-(dimethylamino)-1-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)benzonitrile [ka]

[0546] This compound is obtained by the procedure described in step 7 of Example 3, starting from 138 mg (0.22 mmol) of 3-(2-(dimethylamino)-1-(4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)benzonitrile (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyridin-2(1H)-one. 32 mg of racemate is obtained. Yield: 30%. MH+:469.7(M+1). 1 H NMR(DMSO-d6,400MHz):δ 12.07(br s,1H);8.17(d,J=2.5Hz,1H);8.10(s,1H);7.93-7.88(m,1H);7.82-7.74(m,2H);7.73-7.67(m,2H);7.58(t,J=7.8Hz,1H);6. 74-6.66(m,2H);6.25-6.15(m,1H);3.84-3.73(m,4H);3.34-3.24(m,1H);3.18-3.08(m,4H);2.83-2.72(m,1H);2.21(s,6H).

[0547] Step 8: (S)-3-(2-(dimethylamino)-1-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)benzonitrile [ka]

[0548] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a Hexane / EtOH / DCM / 0.1% TEA mixture as mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 32 mg of the racemate, 8 mg of the title compound are obtained. MH+:469.7(M+1). 1 H NMR(DMSO-d6,400MHz):δ 12.07(br s,1H);8.17(d,J=2.5Hz,1H);8.10(s,1H);7.93-7.88(m,1H);7.82-7.74(m,2H);7.73-7.67(m,2H);7.58(t,J=7.8Hz,1H);6. 74-6.66(m,2H);6.25-6.15(m,1H);3.84-3.73(m,4H);3.34-3.24(m,1H);3.18-3.08(m,4H);2.83-2.72(m,1H);2.21(s,6H).

[0549] Example 26: Synthesis of (S)-1-(2-(dimethylamino)-1-(3-(trifluoromethyl)phenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0550] Step 1: 1-(trifluoromethyl)-3-vinylbenzene [ka]

[0551] The compound is obtained by the procedure described in step 4 of example 1, starting from 0.5 g (2.87 mmol) of 3-(trifluoromethyl)benzaldehyde instead of 3-fluorobenzaldehyde. 295 mg of the title compound are obtained. Yield: 60%. MH+: Non-ionizable.

[0552] Step 2: 2-(3-(trifluoromethyl)phenyl)oxirane [ka]

[0553] This compound is obtained by the procedure described in step 5 of Example 1, starting from 295 mg (1.71 mmol) of 1-(trifluoromethyl)-3-vinylbenzene (described in the previous step) instead of 1-fluoro-3-vinylbenzene. 176 mg of the title compound are obtained. Yield: 55%. MH+: Non-ionizable.

[0554] Step 3: 2-(Dimethylamino)-1-(3-(trifluoromethyl)phenyl)ethan-1-ol [ka]

[0555] This compound is obtained by the procedure described in step 6 of Example 1, starting from 176 mg (0.94 mmol) of 1-(trifluoromethyl)-3-vinylbenzene (described in the previous step) instead of 2-(3-fluorophenyl)oxirane. 183 mg of the title compound are obtained. Yield: 84%. MH+:234.4(M+1).

[0556] Step 4: 2-Chloro-N,N-dimethyl-2-(3-(trifluoromethyl)phenyl)ethan-1-amine [ka]

[0557] This compound is obtained by the procedure described in step 7 of Example 1, starting from 183 mg (0.78 mmol) of 2-(dimethylamino)-1-(3-(trifluoromethyl)phenyl)ethan-1-ol (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 203 mg of the title compound is obtained. Yield: quantitative. MH+:252.2;254.2(M;M+2).

[0558] Step 5: 4-Bromo-1-(2-(dimethylamino)-1-(3-(trifluoromethyl)phenyl)ethyl)pyridin-2(1H)-one [ka]

[0559] This compound is obtained by the procedure described in step 8 of Example 1, starting from 197 mg (0.78 mmol) of 2-chloro-N,N-dimethyl-2-(3-(trifluoromethyl)phenyl)ethan-1-amine (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 126 mg of the title compound is obtained. Yield: 41%. MH+:389.4;391.3(M;M+2).

[0560] Step 6: 1-(2-(dimethylamino)-1-(3-(trifluoromethyl)phenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0561] This compound is obtained by the procedure described in step 9 of Example 1, starting from 126 mg (0.32 mmol) of 4-bromo-1-(2-(dimethylamino)-1-(3-(trifluoromethyl)phenyl)ethyl)pyridin-2(1H)-one (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 178 mg of the title compound is obtained. Yield: 83%. MH+:666.7(M+1).

[0562] Step 7: 1-(2-(dimethylamino)-1-(3-(trifluoromethyl)phenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0563] This compound is obtained by the procedure described in step 7 of Example 3, starting from 178 mg (0.26 mmol) of 1-(2-(dimethylamino)-1-(3-(trifluoromethyl)phenyl)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) instead of 1-(1-(3,5-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one. 106 mg of racemate is obtained. Yield: 77%. MH+:512.6(M+1). 1H NMR(DMSO-d6,400MHz):δ 12.07(br s,1H);8.17(d,J=2.5Hz,1H);8.11(s,1H);7.83-7.78(m,1H);7.78-7.74(m,1H);7.73-7.65(m,3H);7.61(t,J=7.7Hz,1H);6. 74-6.66(m,2H);6.30-6.20(m,1H);3.83-3.73(m,4H);3.38-3.28(m,1H);3.18-3.09(m,4H);2.82-2.72(m,1H);2.22(s,6H).

[0564] Step 8: (S)-1-(2-(dimethylamino)-1-(3-(trifluoromethyl)phenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0565] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a Hexane / EtOH / DCM / 0.1% TEA mixture as mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 106 mg of the racemate, 41 mg of the title compound are obtained. MH+:512.6(M+1). 1 H NMR(DMSO-d6,400MHz):δ 12.07(br s,1H);8.17(d,J=2.5Hz,1H);8.11(s,1H);7.83-7.78(m,1H);7.78-7.74(m,1H);7.73-7.65(m,3H);7.61(t,J=7.7Hz,1H);6. 74-6.66(m,2H);6.30-6.20(m,1H);3.83-3.73(m,4H);3.38-3.28(m,1H);3.18-3.09(m,4H);2.82-2.72(m,1H);2.22(s,6H).

[0566] Example 27: Comparative Example Compound Synthesis of (S)-1-(2-amino-1-(3-chlorophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (Compound A) [ka]

[0567] Step 1: 2-(3-chlorophenyl)-2-((trimethylsilyl)oxy)acetonitrile [ka]

[0568] To a solution of 5 g (36 mmol, 1 eq) of 3-chlorobenzaldehyde in 50 ml of dry DCM, under argon atmosphere, 399 mg (36 mmol, 1 eq) of DABCO is added followed by 4.45 ml (36 mmol, 1 eq) of trimethylsilyl cyanide, and the resulting mixture is stirred at 40° C. for 2 h. The reaction mixture is then diluted with DCM and washed twice with water and once with brine. The organic layer is dried over Na2SO4, filtered and evaporated under reduced pressure. The crude compound is used in the next step without further purification. 7.80 g of the title compound are obtained. Yield: 91%. MH+: Non-ionizable.

[0569] Step 2: 2-Amino-1-(3-chlorophenyl)ethan-1-ol [ka]

[0570] To a solution of 7.80 g (33 mmol, 1 eq) of 2-(3-chlorophenyl)-2-((trimethylsilyl)oxy)acetonitrile (described in the previous step) in 80 ml of dry Et2O placed at 0° C. in an ice / water bath, 1.85 g (49 mmol, 1.5 eq) of LiAlH4 is added in portions. The resulting mixture is stirred at 0° C. for 1 h. Then, ice is slowly added at 0° C. until no gas is evolved in the reaction, and finally, 100 ml of water is added. The mixture is stirred at room temperature for 30 min, the precipitate is filtered on Celite and washed twice with Et2O. The filtrate is decanted and the aqueous layer is extracted twice with Et2O. The combined organic layers are dried over Na2SO4 and evaporated under reduced pressure. The crude compound is used in the next step without further purification. 5.95 g of the title compound are obtained. Yield: quantitative. MH+:172.3;174.3(M;M+2).

[0571] Step 3: Tert-butyl (2-(3-chlorophenyl)-2-hydroxyethyl)carbamate [ka]

[0572] To a solution of 5.95 g (35 mmol, 1 eq) of 2-amino-1-(3-chlorophenyl)ethan-1-ol (described in the previous step) in 60 ml of THF, 8.32 g (38 mmol, 1.1 eq) of di-tert-butyl dicarbonate is added and the resulting mixture is stirred at room temperature for 1 h. Then, the solvent is removed under reduced pressure and the mixture is diluted with 100 ml of EtOAc. The organic layer is washed twice with water and once with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude mixture is purified by flash chromatography using a silica gel column and a DCM / MeOH mixture as eluent. 6.78 g of the title compound is obtained. Yield: 72%. MH+:272.6;274.7(M;M+2).

[0573] Step 4: 2-((Tert-butoxycarbonyl)amino)-1-(3-chlorophenyl)ethyl methanesulfonate [ka]

[0574] This compound is obtained by the procedure described in step 7 of Example 1, starting from 6.78 g (25 mmol) of tert-butyl (2-(3-chlorophenyl)-2-hydroxyethyl)carbamate (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 9.28 g of the title compound are obtained. Yield: quantitative. MH+ (dimer):700.2;702.2(M;M+2).

[0575] Step 5: Tert-butyl (2-(4-bromo-2-oxopyridin-1(2H)-yl)-2-(3-chlorophenyl)ethyl)carbamate [ka]

[0576] This compound is obtained by the procedure described in step 8 of Example 1, starting from 8.73 g (25 mmol) of 2-((tert-butoxycarbonyl)amino)-1-(3-chlorophenyl)ethyl methanesulfonate (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 5.56 g of the title compound are obtained. Yield: 52%. MH+:427.7;429.7;431.7(M;M+2;M+4).

[0577] Step 6: Tert-butyl (2-(3-chlorophenyl)-2-(4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)carbamate [ka]

[0578] 2.8 g (6.50 mmol, 1 eq) of tert-butyl (2-(4-bromo-2-oxopyridin-1(2H)-yl)-2-(3-chlorophenyl)ethyl)carbamate (described in the previous step), 3.16 g (6.50 mmol, 1 eq) of 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine (described in step 3 of Example 1) and 905 mg (6.50 mmol, 1 eq) of K2CO3 are placed in 140 ml of MeCN under an argon atmosphere. The mixture is bubbled with argon for 15 min and 459 mg (0.65 mmol, 0.1 eq) of bis(triphenylphosphine)palladium dichloride is added. The mixture is bubbled for another 15 min and then the reaction is stirred at 80° C. for 1 h under argon atmosphere. The reaction mixture is diluted with 140 ml of EtOAc and washed three times with water. The organic layer is dried over Na2SO4, filtered and evaporated under reduced pressure. The crude mixture is purified by flash chromatography using a silica gel column and DCM / MeOH mixture as eluent. 4.79 g of the title compound is obtained. Yield: quantitative.

[0579] Step 7: Tert-butyl (2-(3-chlorophenyl)-2-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)carbamate [ka]

[0580] This compound is obtained by the procedure described in step 7 of Example 9, starting from 1.0 g (1.4 mmol) of tert-butyl (2-(3-chlorophenyl)-2-(4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)carbamate (described in the previous step) instead of 1-(1-(3-chloro-5-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyridin-2(1H)-one. 644 mg of racemate is obtained. Yield: 82%. MH+:550.6;552.6(M;M+2).

[0581] Step 8: 1-(2-amino-1-(3-chlorophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0582] To a solution of 644 mg (1.17 mmol, 1 eq) of tert-butyl (2-(3-chlorophenyl)-2-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)carbamate (described in the previous step) in 6 ml of DCM placed at 0° C. in an ice / water bath, 3 ml of trifluoroacetic acid is added. The solution is stirred at 0° C. for 1 h 30 min, then the solvent is removed under reduced pressure and the mixture is diluted with 100 ml of saturated NaHCO3 solution. The solution is extracted three times with DCM. The combined organic layers are dried over Na2SO4, filtered and evaporated under reduced pressure. The crude mixture is purified by flash chromatography using a C18 column and a water / MeOH mixture as eluent. 340 mg of the title compound is obtained. Yield: 64%. MH+:450.7;452.7(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.06(br s,1H);8.17(d,J=2.5Hz,1H);8.09(s,1H);7.75(d,J=8.1Hz,1H);7.70(d,J=2.6Hz,1H);7.44-7.29(m,4H); 6.74-6.67(m,2H);5.90(t,J=7.5Hz,1H);3.84-3.72(m,4H);3.34-3.25(m,2H);3.18-3.09(m,4H);1.60(br s,2H).

[0583] Step 9: (S)-1-(2-amino-1-(3-chlorophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0584] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a Hexane / EtOH / DCM / 0.1% TEA mixture as mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 120 mg of the racemate, 33 mg of the title compound are obtained. MH+:450.7;452.7(M;M+2). 1 H NMR(DMSO-d6,400MHz):δ 12.06(br s,1H);8.17(d,J=2.5Hz,1H);8.09(s,1H);7.75(d,J=8.1Hz,1H);7.70(d,J=2.6Hz,1H);7.44-7.29(m,4H); 6.74-6.67(m,2H);5.90(t,J=7.5Hz,1H);3.84-3.72(m,4H);3.34-3.25(m,2H);3.18-3.09(m,4H);1.60(br s,2H).

[0585] Example 28: Comparative Example Compound Synthesis of (S)-1-(1-(3,4-dichlorophenyl)-2-(methylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (Compound B) [ka]

[0586] Step 1: 2-(3,4-dichlorophenyl)-2-((trimethylsilyl)oxy)acetonitrile [ka]

[0587] The compound is obtained by the procedure described in step 1 of Example 27, starting from 2.5 g (14.3 mmol) of 3,4-dichlorobenzaldehyde instead of 3-chlorobenzaldehyde. 3.70 g of the title compound are obtained. Yield: 94%. MH+: Non-ionizable.

[0588] Step 2: 2-Amino-1-(3,4-dichlorophenyl)ethan-1-ol [ka]

[0589] This compound is obtained by the procedure described in step 2 of Example 27, starting from 3.70 g (13.5 mmol) of 2-(3,4-dichlorophenyl)-2-((trimethylsilyl)oxy)acetonitrile (described in the previous step) instead of 2-(3-chlorophenyl)-2-((trimethylsilyl)oxy)acetonitrile. 1.66 g of the title compound are obtained. Yield: 60%. MH+:206.1;208.2;210.1(M;M+2;M+4).

[0590] Step 3: Tert-butyl (2-(3,4-dichlorophenyl)-2-hydroxyethyl)carbamate [ka]

[0591] This compound is obtained by the procedure described in step 3 of Example 27, starting from 1.66 g (8.03 mmol) of 2-amino-1-(3,4-dichlorophenyl)ethan-1-ol (described in the previous step) instead of 2-amino-1-(3-chlorophenyl)ethan-1-ol. 2.55 g of the title compound are obtained. Yield: quantitative. MH+:306.3;308.3(M;M+2).

[0592] Step 4: 2-((Tert-butoxycarbonyl)amino)-1-(3,4-dichlorophenyl)ethyl methanesulfonate [ka]

[0593] This compound is obtained by the procedure described in step 7 of Example 1, starting from 2.46 g (8.03 mmol) of tert-butyl (2-(3,4-dichlorophenyl)-2-hydroxyethyl)carbamate (described in the previous step) instead of 2-(dimethylamino)-1-(3-fluorophenyl)ethan-1-ol. 3.23 g of the title compound are obtained. Yield: quantitative. MH+ (dimer):767.5;769.4;771.6(M;M+2;M+4).

[0594] Step 5: Tert-butyl (2-(4-bromo-2-oxopyridin-1(2H)-yl)-2-(3,4-dichlorophenyl)ethyl)carbamate [ka]

[0595] This compound is obtained by the procedure described in step 8 of Example 1, starting from 3.09 g (8.03 mmol) of 2-((tert-butoxycarbonyl)amino)-1-(3,4-dichlorophenyl)ethyl methanesulfonate (described in the previous step) instead of 2-chloro-2-(3-fluorophenyl)-N,N-dimethylethan-1-amine. 1.74 g of the title compound are obtained. Yield: 47%. MH+:461.3;463.3;465.2(M;M+2;M+4).

[0596] Step 6: Tert-butyl (2-(4-bromo-2-oxopyridin-1(2H)-yl)-2-(3,4-dichlorophenyl)ethyl)(methyl)carbamate [ka]

[0597] To a solution of 840 mg (1.82 mmol, 1 eq) of tert-butyl (2-(4-bromo-2-oxopyridin-1(2H)-yl)-2-(3,4-dichlorophenyl)ethyl)carbamate (described in the previous step) in 9 ml of dry DMF placed in an ice / water bath at 0° C., under an argon atmosphere, 87 mg (2.18 mmol, 1.2 eq) of sodium hydride (60% in paraffin oil) is added, followed by 170 μl (2.73 mmol, 1.5 eq) of methyl iodide. The solution is stirred at 0° C. for 1 h 30 min, then the mixture is diluted with 100 ml of EtOAc. The solution is washed 4 times with water and once with brine. The organic layer is dried over Na2SO4, filtered and evaporated under reduced pressure. The crude mixture is purified by flash chromatography using a silica gel column and EtOAc / hexane mixtures as eluent. 750 mg of the title compound are obtained. Yield: 86%. MH+:475.4;477.3;479.3(M;M+2;M+4).

[0598] Step 7: Tert-butyl (2-(3,4-dichlorophenyl)-2-(4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)(methyl)carbamate [ka]

[0599] This compound is obtained by the procedure described in step 9 of Example 1, starting from 750 mg (1.57 mmol) of tert-butyl (2-(4-bromo-2-oxopyridin-1(2H)-yl)-2-(3,4-dichlorophenyl)ethyl)(methyl)carbamate (described in the previous step) instead of 4-bromo-1-(2-(dimethylamino)-1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one. 1.27 g of the title compound is obtained. Yield: quantitative. MH+:753.4;755.2(M;M+2).

[0600] Step 8: Tert-butyl (2-(3,4-dichlorophenyl)-2-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)(methyl)carbamate [ka]

[0601] This compound is obtained by the procedure described in step 7 of Example 9, starting from 1.27 g (1.69 mmol) of tert-butyl (2-(3,4-dichlorophenyl)-2-(4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)(methyl)carbamate (described in the previous step) instead of 1-(1-(3-chloro-5-fluorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyridin-2(1H)-one. 730 mg of racemate is obtained. Yield: 72%. MH+:598.7;600.5(M;M+2).

[0602] Step 9: 1-(1-(3,4-dichlorophenyl)-2-(methylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0603] This compound is obtained by the procedure described in step 8 of Example 27, starting from 730 mg (1.20 mmol) of tert-butyl (2-(3,4-dichlorophenyl)-2-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)(methyl)carbamate (described in the previous step) instead of tert-butyl (2-(3-chlorophenyl)-2-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)carbamate. 543 mg of racemate is obtained. Yield: 89%. MH+:498.6;500.5(M;M+2). 1H NMR(DMSO-d6,400MHz):δ 12.08(br s,1H);8.17(d,J=2.5Hz,1H);8.10(d,J=2.6Hz,1H);7.76(d,J=7.3Hz,1H);7.69(d,J=2.5Hz,1H);7.66-7.61(m,2H);7.37-7.30(m,1H); 6.74-6.66(m,2H);6.08-5.98(m,1H);3.84-3.73(m,4H);3.34-3.24(m,1H);3.22-3.14(m,1H);3.14-3.09(m,4H);2.30(s,3H);1.94(br s,1H).

[0604] Step 10: (S)-1-(1-(3,4-dichlorophenyl)-2-(methylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one [ka]

[0605] The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a Hexane / EtOH / DCM / 0.1% TEA mixture as mobile phase. The (-)(R)-enantiomer elutes as the first fraction, followed by the (+)(S)-enantiomer with an ee>98%. Starting from 150 mg of the racemate, 54 mg of the title compound are obtained. MH+:498.6;500.5(M;M+2). 1H NMR(DMSO-d6,400MHz):δ 12.08(br s,1H);8.17(d,J=2.5Hz,1H);8.10(d,J=2.6Hz,1H);7.76(d,J=7.3Hz,1H);7.69(d,J=2.5Hz,1H);7.66-7.61(m,2H);7.37-7.30(m,1H); 6.74-6.66(m,2H);6.08-5.98(m,1H);3.84-3.73(m,4H);3.34-3.24(m,1H);3.22-3.14(m,1H);3.14-3.09(m,4H);2.30(s,3H);1.94(br s,1H).

[0606] The table below illustrates the chemical structures of compounds according to the invention.

[0607] [Table 1] JPEG2025502377000252.jpg233170JPEG2025502377000253.jpg217170JPEG2025502377000254.jpg209170JPEG2025502377000255.jpg174170

[0608] [Table 2]

[0609] Comparative Example Compounds A and B are disclosed in International Publication No. WO2017 / 085230, but their synthesis is not described.

[0610] Comparative Example Compounds A and B are not part of the present invention since neither R1 nor R2 in the general formula (I) of the present invention can represent a hydrogen atom.

[0611] Examples 33 and 34 below demonstrate that the compounds of the present invention are surprisingly superior to comparative compounds A and B from the prior art.

[0612] Example 29: ERK2 (MAPK1) Enzyme Assay

[0613] To evaluate the ability of compounds to inhibit ERK2 enzymatic activity, the Z'-Lyte biochemical assay from Life technologies was used according to the manufacturer's instructions. Briefly, 100 nl of 100X compound solution in 100% DMSO, 2.4 μl of kinase buffer, 5 μl of 2X MAPK1(ERK2) / Ser / Thr 03 mix, and 2.5 μl of 4X ATP solution were used. The plate was shaken for 30 seconds and incubated at room temperature for 60 minutes. Next, 5 μl of a 1:1024 dilution of Development Reagent A was added. The plate was shaken for 30 seconds and incubated at room temperature for 60 minutes. A plate reader was used to read the fluorescence. In this assay, ERK2 enzyme was used at a concentration of 0.4 μg / ml (5.74 nM) with an ATP Km (100 μM). The kinase buffer was 50 mM HEPES (pH 7.5), 0.01% BRIJ 登録商標 -35, 10 mM MgCl2, 1 mM EGTA. Compound IC 50 was determined by 3-fold serial dilutions (10-point titrations, determined in duplicate).

[0614] The ERK2 inhibitory activity of selected compounds (ERK2 IC 50 " ) are reported in Table 3 below.

[0615] [Table 3]

[0616] All of the compounds tested demonstrated the ability to inhibit the enzymatic activity of ERK2.

[0617] In fact, all compounds had IC<10 nM. 50 values, most of which are lower than 5 nM 50 It has a value.

[0618] Example 30: Cell line proliferation assay

[0619] A cell line assay was used to measure the ability of compounds to inhibit cell proliferation. A375 cells (malignant melanoma) were grown to near 80% confluence and seeded at 3000 cells per well in 100 μl in DMEM with 10% FBS in 96-well flat bottom plates. Cells were incubated at 37°C for 24 hours under 5% CO2. 100 μl of compound solution was added to the cells and incubated at 37°C for 72 hours. The total volume of medium was 200 μl per well. Compounds were screened using 10 titration points in duplicate in 0.15% DMSO (final concentration). Negative control wells consisted of vehicle only (0.15% DMSO in 10% FBS DMEM). After 72 hours of compound treatment, 1% SDS (final concentration) was added to the positive control wells for 15 minutes at 37°C. The medium was then discarded and replaced by 100 μl per well of MTT solution (3-[4.5-dimethylthiazol-2-yl]-2.5-diphenyltetrazolium bromide) (Sigma, Cat#M5655) at 0.5 mg / ml in 10% FBS DMEM. Cells were incubated at 37°C for 4 hours. The MTT reaction was stopped and homogenized by adding 100 μl per well of SDS 10% 0.01 M HCl. After 16 hours at 37°C, absorbance was measured at 570 nm on a Bio-Tek plate reader (PowerWave HT). The percentage of growth inhibition was calculated using the negative control (0.15% DMSO) as 0% growth inhibition and the positive control (1% SDS) as 100% growth inhibition. IC 50 The half-maximal inhibition value (the concentration inducing half-maximal growth inhibition) was determined by non-linear regression analysis (using a sigmoidal dose-response with a variable Hill Slope and constraining the top to a constant value of 100 and the bottom to values ​​between 0 and 50) of inhibition curves generated by the mean replicate values. Analysis was performed using GraphPad Prism software.

[0620] The cell proliferation inhibitory activity of selected compounds (A375 IC 50 " ) are reported in Table 4 below.

[0621] [Table 4]

[0622] All of the compounds tested demonstrated the ability to inhibit A375 cell proliferation.

[0623] In fact, all compounds had IC values ​​below 1 μM. 50 values, most of which are lower than 500 nM 50 It has a value.

[0624] Example 31: hERG Channel Inhibition Assay

[0625] Evaluation of hERG channel inhibition of selected compounds was performed. Compounds were used as 10 mM stocks in DMSO before dilution to 30 μM in HEPES-buffered saline. Six-point concentration-response curves were generated using 3.16-fold serial dilutions from the highest tested concentration. Electrophysiological recordings were performed from a Chinese Hamster Ovary cell line stably expressing the full-length ion channel. Single-cell ionic currents were measured in the whole-cell configuration at room temperature (21–23 °C) using a Patchliner (Nanion Technologies). The internal solution for hERG contained 120 mM KF, 20 mM KCl, 10 mM EGTA, 10 mM HEPES, and was buffered to pH 7.3. The external solution (HEPES-buffered saline, HEPES-buffered saline) contained 138 mM NaCl, 4.5 mM KCl, 1.8 mM CaCl2, 1.0 mM MgCl2, 10 mM HEPES, 10 mM glucose, and was buffered to pH 7.4. The voltage protocol is given below. Currents were measured from the step and holding currents were referenced. Compounds were incubated for 2 minutes to reach steady state before the next concentration was added.

[0626] [Table 4a]

[0627] The hERG channel inhibition properties of selected compounds ("hERG IC 50 " ) are reported in Table 5 below.

[0628] [Table 5]

[0629] All of the compounds tested demonstrate a safe hERG profile in the patch clamp assay.

[0630] In fact, all compounds had IC values ​​higher than 9.6 μM. 50 It has a value.

[0631] Example 32: CYP 3A4 Inhibition Assay

[0632] To evaluate the ability of compounds to inhibit CYP 3A4 enzyme activity, test compounds (0.1 μM to 25 μM) were incubated with cryopreserved human hepatocytes for 10 min in the presence of the specific CYP3A4 probe substrate midazolam. 1-Hydroxymidazolam was monitored by LC-MS / MS, and the reduction in metabolite formation compared to vehicle control was determined as IC 50 was used to calculate the value.

[0633] The CYP 3A4 inhibitory activity of selected compounds ("CYP 3A4 IC 50 " ) are reported in Table 6 below.

[0634] [Table 6]

[0635] All of the compounds tested according to the present invention exhibit low inhibition of CYP 3A4. In fact, all compounds have IC values ​​greater than 5 μM. 50 It has a value.

[0636] In contrast, comparative compound A had an IC of 0.74 μM. 50 Therefore, the comparative compound A is a very potent inhibitor of CYP 3A4.

[0637] Example 33: Kinase Panel

[0638] To evaluate the kinase selectivity of compounds, Z'-Lyte biochemical assays and Adapta / Lanthascreen binding assays from Life technologies were used according to the manufacturer's instructions. The inhibition rate of test compounds at 500 nM was determined against 58 kinases: ABL1, ACVR1B (ALK4), AKT2 (PKB beta), AMPK (A1 / B2 / G3), AURKA (Aurora A), AXL, BRAF, BTK, CAMK2B (CaMKII beta), CDK2 / cyclin A, CHEK1 (CHK1), CLK1, CSNK1A1 (CK1 alpha 1), CSNK2A1 (CK2 alpha1), DAPK3 (ZIPK), DYRK1A, EGFR (ErbB1), EPHB3, ERBB2 (HER2), FGFR2, FLT3, FRAP1 (mTOR), GSK3B (GSK3 beta), IGF1R, IKBKB (IKK beta), INSR, IRAK4, JAK2, KDR (VEGFR2), KIT, LCK, MAP2K1 (MEK1), MAPK10 (JNK3), MAPK11 (p38 beta), MAPKAPK2, MARK2, MET (cMet), NEK2, N TRK1 (TRKA), PAK2 (PAK65), PDGFRB (PDGFR beta), PDK1 Direct, PHKG2, PIK3CA / PIK3R1 (p110 alpha / p85 alpha), PIM1, PLK1, PRKACA (PKA), PRKCA (PKC alpha), PTK2 (FAK), RET, ROCK1, RPS6KA1 (RSK1), RPS6KB1 (p70S6K), SRC, STK3 (MST2), SYK, TEK (Tie2), TYRO3 (RSE). ATP concentrations were used at apparent Km for all kinases except MAPK10 (JNK3), which was 100 mM, and BRAF and MAP2K1 (mEK1) in binding assays.

[0639] The results are reported in Table 7 below.

[0640] [Table 7]

[0641] All of the compounds tested according to the invention show good kinase selectivity scores in a representative panel of kinases: in fact, for each compound, only one kinase out of 58 was inhibited by more than 80%, and at most 10 kinases were inhibited by more than 50%.

[0642] In contrast, comparative compounds A and B show poor selectivity scores: in fact, comparative compounds A and B inhibit 15 / 58 and 10 / 58 kinases with inhibition rates greater than 80%, and 26 / 58 and 20 / 58 kinases with inhibition rates greater than 50%, respectively.

[0643] Example 34: Permeability assay

[0644] The Caco 2 cell line was used for in vitro transport studies and was obtained from ATCC. Cells were split at a ratio of 1:3 to 1:5 every other day and cultured in Dulbecco's Modified Eagle Medium (GlutaMAX I, 4,500 mg / L D-glucose, sodium pyruvate) supplemented with 10% FBS in the presence of antibiotics. For transport studies, cells were seeded at a density of 60,000 cells / well onto polycarbonate Transwell filter membranes (millipore). The medium was changed 24 h after seeding and the cells were cultured for an additional 21 days before transport experiments. For transport studies, donor solutions were prepared by diluting stock solutions of test compounds in transport medium (HBSS buffer containing 10 mM HEPES, pH 7.4). Receiver solutions were the same HBSS buffer pH 7.4 containing 10 mM HEPES. Transport of test compounds (5 μM) was measured twice in two directions (apical → basolateral (A → B), basolateral → apical (B → A)).

[0645] The permeability coefficient for membrane transport of test compounds was determined using the following formula: Papp (cm / sec) = (Vr / C0) (1 / S) (dC / dt); Papp = apparent permeability, Vr = medium volume in the receiver chamber, C0 = PAR of test drug in the receiver chamber, S = surface area of ​​monolayer, dC / dt = time change of drug PAR in the receiver chamber. Efflux ratio was defined as follows: Efflux ratio = Papp BA / Papp AB Bioanalysis was performed by LC-MS / MS.

[0646] The results are reported in Table 8 below.

[0647] [Table 8]

[0648] All the tested compounds according to the invention show excellent Caco-2 permeability parameters.

[0649] In fact, all compounds are 10.10 -6 The Papp AB values ​​were higher than 20.10 cm / sec. -6 Moreover, all the compounds have an efflux ratio of less than 3.2, and most of them have a value of less than 2.

[0650] In contrast, comparative compounds A and B exhibited poor Caco-2 permeability parameters and low Papp AB values ​​(10.10 -6 cm / s), and high Efflux Ratios (higher than 3).

[0651] Example 35: PK experiments

[0652] To measure the absolute oral bioavailability of the compounds, the compounds were suspended in 0.5% CMC vehicle and administered to groups of male BalbC mice aged 5-6 weeks. For intravenous injection, a single dose of 1 mg / kg was injected into the tail vein and blood was collected at 0.12, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after injection. For oral administration, a single dose of 20 mg / kg was administered and blood was collected at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours after oral administration. Plasma separated from the blood samples was stored at -20°C until analysis. Vials containing test samples were removed and allowed to thaw to room temperature. A volume of 50 μl of sample was added to 200 μl of acetonitrile containing an internal standard (tolbutamide: 25 ng / mL), vortexed for 5 min, and centrifuged at 14000 rpm for 5 min at 4° C. 200 μl of the supernatant was separated and transferred to an HPLC vial for analysis. The pharmacokinetics of the prodrug was given by HPLC only for the parent drug.

[0653] The results are reported in Table 9 below.

[0654] [Table 9]

[0655] All of the tested compounds according to the invention show good PK parameters.

[0656] In fact, all compounds have a high oral bioavailability of 8.9 or higher, which will make it possible to reach the target concentration of the molecules in the plasma.

Claims

1. A compound of formula (I) below or one of its pharma- ceutically acceptable salts: 【Chemistry 1】 Where: R 1 is (C 1 ~C 6 ) an alkyl group; R 2 is (C 1 ~C 6 ) alkyl group, (C 3 ~C 6 ) a cycloalkyl group, a halogen atom, a cyano group, (C 1 ~C 6 ) alkoxy groups and (C 3 ~C 6 ) cycloalkyl groups substituted with one or more groups selected from 1 ~C 6 ) an alkyl group; or R 1 and R 2 forms, together with the nitrogen atom, a 3- to 6-membered heterocyclic group; R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently a hydrogen atom, a halogen atom, (C 1 ~C 6 ) an alkyl group, a trifluoromethyl group, or a cyano group, 1 ~C 6 ) alkyl is itself, (C 1 ~C 6 ) may be substituted with an alkoxy group.

2. R 1 2. The compound of claim 1, wherein represents a methyl group.

3. R 2 But (C 1 ~C 6 ) alkyl group, preferably R 2 3. The compound according to claim 1, wherein represents a methyl group.

4. R 1 and R 2 The compound according to any one of claims 1 to 3, wherein both represent a methyl group.

5. -CH 2 NR 1 R 2 The compound according to any one of claims 1 to 4, wherein the asymmetric carbon bearing a group is in an S configuration.

6. R 3 is a halogen atom, (C 1 ~C 6 ) an alkyl group, a trifluoromethyl group, or a cyano group, 1 ~C 6 ) alkyl is itself, (C 1 ~C 6 6. The compound according to claim 1, which may be substituted with an alkoxy group.

7. R 3 represents a halogen atom, in particular a chlorine atom, a fluorine atom, a bromine atom or an iodine atom, more particularly R 3 represents a chlorine atom or a fluorine atom, preferably R 3 A compound according to any one of claims 1 to 6, wherein represents a chlorine atom.

8. R 4 represents a hydrogen atom or a halogen atom, in particular a chlorine atom, a fluorine atom, a bromine atom or an iodine atom, more particularly R 4 represents a hydrogen atom, a chlorine atom or a fluorine atom, and preferably, R 4 The compound according to any one of claims 1 to 7, wherein represents a hydrogen atom or a chlorine atom.

9. R 5 represents a hydrogen atom or a halogen atom, in particular a chlorine atom, a fluorine atom, a bromine atom or an iodine atom, more particularly R 5 represents a hydrogen atom, a chlorine atom or a fluorine atom, and preferably, R 5 A compound according to any one of claims 1 to 8, wherein represents a hydrogen atom.

10. R 6 is a hydrogen atom or (C 1 ~C 6 ) alkyl group, more particularly R 6 represents a hydrogen atom or a methyl group, and preferably, R 6 A compound according to any one of claims 1 to 9, wherein represents a hydrogen atom.

11. R 7 represents a hydrogen atom or a halogen atom, in particular a chlorine atom, a fluorine atom, a bromine atom or an iodine atom, more particularly R 7 represents a hydrogen atom, a chlorine atom or a fluorine atom, and preferably, R 7 The compound according to any one of claims 1 to 10, wherein represents a hydrogen atom.

12. R 8 represents a hydrogen atom or a halogen atom, in particular a chlorine atom, a fluorine atom, a bromine atom or an iodine atom, more particularly R 8 represents a hydrogen atom, a chlorine atom or a fluorine atom, and preferably, R 8 A compound according to any one of claims 1 to 11, wherein represents a hydrogen atom.

13. R 9 represents a hydrogen atom, a halogen atom or a trifluoromethyl group, more particularly R 9 represents a hydrogen atom or a trifluoromethyl group, and preferably, R 9 A compound according to any one of claims 1 to 12, wherein represents a hydrogen atom.

14. 【Chemical 2】 【change】 【change】 2. The compound according to claim 1, selected from:

15. 【Chemical 3】 【change】 2. The compound according to claim 1, selected from:

16. A compound according to any one of claims 1 to 15 for use for preventing and / or inhibiting and / or treating a disease or condition mediated by ERK kinase activity, in particular ERK2 kinase activity.

17. 17. The compound of claim 16, wherein the disease or condition is selected from the group consisting of cancer and metastasis.

18. 18. The compound for use according to claim 16 or 17, wherein the disease or condition is selected from glioblastoma, multiple myeloma, carcinoma, leukemia, particularly myeloid (AML), lymphocytic, myelocytic, myelogenous (CML) or lymphoblastic leukemia, myelodysplastic syndrome, Kaposi's sarcoma, cutaneous angiosarcoma, solid tumors, lymphoma, particularly non-Hodgkin's lymphoma, melanoma, particularly malignant melanoma, bladder cancer, breast cancer, gastric cancer, colon cancer, colorectal cancer, endometrial cancer, lung cancer including non-small cell carcinoma, pancreatic cancer, prostate cancer, rectal cancer, kidney cancer, head and neck cancer, liver cancer, ovarian cancer, particularly serous ovarian cancer, seminoma cancer, respiratory and thoracic cancer, thyroid cancer, particularly papillary or follicular thyroid cancer, and other tumors expressing ERK.

19. 17. The compound for use according to claim 16, wherein the disease or condition is selected from the group consisting of neoplastic disorders, allergic disorders, inflammatory disorders, autoimmune disorders, protozoan-associated diseases, mast cell-associated diseases, graft versus host disease, metabolic syndrome, CNS-associated disorders, neurodegenerative disorders, pain conditions, substance abuse disorders, prion diseases, cardiac diseases, fibrotic diseases, idiopathic arterial hypertension (IPAH), and primary pulmonary hypertension (PPH).

20. 17. A compound for use according to claim 16 for use in preventing and / or inhibiting and / or treating human immunodeficiency virus (HIV).

21. Use of a compound according to any one of claims 1 to 15 for preventing and / or inhibiting and / or treating a disease or condition mediated by ERK kinase activity, preferably ERK2 kinase activity.

22. A medicament comprising at least one compound according to any one of claims 1 to 15 or a pharma- ceutically acceptable salt thereof.

23. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 15 or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient.

24. Compounds of formula (V), (XI) and (XII) below: 【Chemistry 4】 Where: R 1 is (C 1 ~C 6 ) an alkyl group; R 2 is (C 1 ~C 6 ) alkyl group, (C 3 ~C 6 ) a cycloalkyl group, a halogen atom, a cyano group, (C 1 ~C 6 ) alkoxy groups and (C 3 ~C 6 ) cycloalkyl groups substituted with one or more groups selected from 1 ~C 6 ) an alkyl group; or R 1 and R 2 forms, together with the nitrogen atom, a 3- to 6-membered heterocyclic group; R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently a hydrogen atom, a halogen atom, (C 1 ~C 6 ) an alkyl group, a trifluoromethyl group, or a cyano group, 1 ~C 6 ) alkyl is itself, (C 1 ~C 6 ) optionally substituted with an alkoxy group; Y is a halogen atom; and PG is a protecting group selected from -tosyl, -mesyl, -brosyl, -nosyl, -triflyl, -tert-butyloxycarbonyl, -trimethylsilylethoxymethyl, -trimethylsilyl, -triisopropylsilyl, preferably -tosyl.

25. 【Chemical 5】 【change】 25. The compound of claim 24, selected from the group consisting of:

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