Crystalline form of (s)-1-(1- (3-chlorophenyl)-2-(dimethylamino) ethyl)-4- (5 -morpholino -1h-pyrrolo[2,3-b]pyridin -3-yl)pyridin-2 (1H)-one, its preparation and its use as erk kinase inhibitor

Abstract

The present invention concerns a crystalline form of (S)-1-(1-(3-chlorophenyl)-2- (dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one of the formula (I).

Description

[0001] CRYSTALLINE FORM OF (5)-l-(l-(3-CHLOROPHENYL)-2- (DIMETHYLAMINO)ETHYL)-4-(5-MORPHOLINO-lH-PYRROLO[2,3- B]PYRIDIN-3-YL)PYRIDIN-2(lH)-ONE, ITS PREPARATION AND ITS USE AS ERK KINASE INHIBITOR

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a novel crystalline form of (5)-l-(l-(3-chlorophenyl)-2- (dimethylamino)ethyl)-4-(5-morpholino-U / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(lJ7)-one which is an inhibitor of ERK kinases (ERK1 and ERK2), its preparation and to the therapeutic use thereof.

[0004] BACKGROUND OF THE INVENTION

[0005] ERK protein belongs to the RAS / RAF / MEK / ERK pathway which plays a major role in cell cycle, proliferation, growth, and survival. RAS / RAF / MEK / ERK pathway is activated by growth factors through their receptor tyrosine kinase that allows activation of GTPases RAS. In its turn, RAS activates RAF proteins. Then, RAF activates MEK, which activates ERK. Finally, this enables phosphorylation of many substrates that have key roles in metabolism, protein synthesis, cell proliferation and survival.

[0006] RAF mutations lead specifically to an over-activation of this RAS / RAF / MEK / ERK pathway and are responsible for 7% of all human cancers (Davies et al., Nature. 2002; Garnett et al., Cancer Cell. 2004).

[0007] Indeed, RAF mutations are frequently observed in melanomas (27-70%), thyroid cancers (36-53%), colorectal cancers (5-22%) and ovarian cancers (30%). Likewise, RAS mutations occur in almost 30% of cancers and are present in pancreatic (90%), lung (35%), colorectal (45%) and liver (30%) cancers (Downward, Nat. Rev. Cancer. 2003).

[0008] Thus, proteins of RAS / RAF / MEK / ERK pathway represent targets of interest for cancers treatment. Indeed, pharmaceutical companies are focusing on upstream kinases (RAF, MEK).

[0009] However, resistances ultimately appear after current treatment with RAF and MEK inhibitors (Lito et al., Nat. Med. 2013; Caunt et al, Nat. Rev. Cancer, 2015). Moreover, most resistances to MEK or RAF inhibitors induce ERK reactivation, through different mechanisms such as MEK mutation, B-RAF amplification, C-RAF mutation... (Little et al. , Oncogene. 2013).

[0010] Furthermore, RAF or MEK inhibition suppresses ERK negative feedback that restores upward signaling and finally ERK activity (Lito et al., Nat. Med., 2013).

[0011] Considering the resistance phenomena that emerged after current treatment with RAF and MEK inhibitors, it is essential to develop new therapeutic options.

[0012] Except for its key role in hyperproliferative diseases, ERK signaling has also been described as implied in neurodegenerative disorders such as in Parkinson’s, Alzheimer’s and Huntington’s diseases (Cheung et al. , Sci. STKE. 2004; Bodai et al., Bioessays., 2012) and in inflammation such as in the pathogenesis of Rheumatoid Arthritis (Thalhamer et al., Rheumatology. 2008).

[0013] Thus, the present invention relates to ERK inhibitors development to treat a broad spectrum of diseases.

[0014] Some ERK inhibitors are already described in the prior art. Thus, US 8,697,697 B2 describes substituted pyrazole derivatives as inhibitors of ERK2 kinase activity.

[0015] Pyrrolo[2,3-b]pyrazine derivatives are also reported as ERK inhibitors in the international patent application WO 2014 / 060395 Al, and azaindole derivatives are reported as ERK inhibitors in the international patent application WO 2017 / 085230 Al.

[0016] (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-lZ / -pyrrolo[2,3- Z>]pyridin-3-yl)pyridin-2(U7)-one of formula (I), depicted below, is an inhibitor of ERK kinases (ERK1 and ERK2). It may be used in particular as anticancer agent.

[0017] The present invention concerns a new crystalline form of such a compound.

[0018] Indeed, it is known that the identification of new crystalline forms of active principle may be particularly interesting for pharmaceutical development. Polymorphism occurs where the same chemical entity crystallizes in a different lattice arrangement, resulting in different thermodynamic properties and stabilities specific to the particular polymorphic form. When the chemical entity is a drug, the ability of the chemical entity to exist in more than one crystal can have a profound effect on the shelflife (stability), solubility, formulation properties, and / or processing properties of the drug. It is thus very important to be able to ensure, from a quality standpoint, that the manufacturing process leads to the specific polymorphic form whose marketing is allowed by regulatory agencies and that formation of other polymorphic forms, with different thermodynamic properties and stabilities, are controlled.

[0019] There is therefore a need to provide new crystalline form, or polymorph, of (S)-l-(l-(3- chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-l / Z-pyrrolo[2,3-Z>]pyridin-3- yl)pyridin-2(U7)-one, notably having good stability properties.

[0020] The present invention is precisely directed to a novel crystalline form of (S)-l-(l-(3- chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-l / Z-pyrrolo[2,3-Z>]pyridin-3- yl)pyridin-2(U7)-one, its preparation and its use as inhibitor of the ERK kinases activity. The compound of the present invention is a novel crystalline form with at least an enhanced anti-proliferative activity, and good stability.

[0021] The crystalline form according to the invention is also characterized by its low toxicity, high permeability, and kinase inhibition selectivity.

[0022] Overall, the crystalline form according to the invention is remarkable for its drug-like properties.

[0023] A first subject of the invention concerns a crystalline form of (S)-l-(l-(3-chlorophenyl)-2- (dimethylamino)ethyl)-4-(5-morpholino-lJ / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(lJ7)-one of the formula (I) below: Unexpectedly, the inventors have discovered that the free base of (5)-l-(l-(3-chlorophenyl)- 2-(dimethylamino)ethyl)-4-(5-morpholino-lZ / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(lJ7)- one can exist in a specific crystalline form.

[0024] After extensive searching and screening tests, the inventors have identified that the crystalline form of the compound of formula (I) selectively target the active sites of the ERK kinases, act as effective inhibitors of ERK kinases activity.

[0025] Advantageously, this novel crystalline form of the (S)-l-(l-(3-chlorophenyl)-2- (dimethylamino)ethyl)-4-(5-morpholino-U / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(U7)-one has very good stability, as illustrated in the examples.

[0026] Thus, this new crystalline form may be stored for a long time without the need for specific conditions.

[0027] This very good stability is also an advantage for the handling.

[0028] Furthermore, the obtention of the crystalline form according to the invention advantageously ensure the reproducibility of the compound, by defining a specific crystal form, and thus controlling its synthesis.

[0029] As will be seen below, this compound has utility in the treatment of conditions or diseases in which modification of the activity of ERK would have a positive therapeutic outcome, in particular cancers.

[0030] Another subject concerns processes for preparing the crystalline form of the compound of formula (I).

[0031] Another subject concerns the crystalline form of the compound of formula (I) for its use especially in medicaments or in pharmaceutical compositions.

[0032] A further subject concerns the crystalline form according to the invention for use as inhibitor of the ERK kinases activity, particularly for use as inhibitor of the ERK1 and / or ERK2 kinases activity.

[0033] ABBREVIATIONS AND DEFINITIONS

[0034] In the context of the present invention, the following abbreviations and empirical formulae are used:

[0035] ACN Acetonitrile

[0036] ATP adenosine 5 ’-triphosphate

[0037] Brij-35 Polyoxyethyleneglycol dodecyl ether Cl 8 column Reversed-phase C 18 column

[0038] CaCh Calcium Chloride

[0039] CMC Carboxymethylcellulose DABCO 1,4-Diazabicyclo[2.2.2]octane

[0040] DCM Dichloromethane

[0041] DMF Dimethylformamide DMEM Dulbecco’s Modified Eagle Medium

[0042] DMSO Dimethylsulfoxide

[0043] DSC Differential Scanning Calorimetry

[0044] °C Degree Celsius ee Enantiomeric excess

[0045] EGTA Egtazic acid

[0046] Eq Equivalent

[0047] EfzO Diethyl ether

[0048] EtOAc Ethyl acetate

[0049] EtOH Ethanol

[0050] FBS Fetal bovine serum

[0051] FT-IR Fourier Transform Infrared Spectroscopy g gram(s) h hour(s)

[0052] HBSS Hanks’ Balanced Salt Solution

[0053] HC1 Hydrochloric acid

[0054] HEPES (4-(2 -hydroxy ethyl)- 1 -piperazineethanesulfonic acid hERG Human Ether-a-go-go-Related gene

[0055] HPLC High performance liquid chromatography

[0056] IR Infrared Spectroscopy

[0057] K2CO3 Potassium carbonate

[0058] KC1 Potassium Chloride

[0059] KF Potassium Fluoride

[0060] KOH Potassium Hydroxide

[0061] LC Liquid chromathography

[0062] LC-MS Liquid chromatography / mass spectrometry LiAlH4Lithium aluminium hydride LiHMDS Lithium bis(trimethylsilyl)amide M Mole(s) per liter MeCN Acetonitrile MeOH Methanol mg Milligram(s) MH+ Pseudo-molecular ion (positive ion mode in mass spectrometry) MHz Megahertz MS Mass Spectrometry pl Microliter(s) MgCh Magnesium Chloride ml Milliliter(s) mmol Millimole(s) mol Mole(s) MPA Mobile Phase A MPB Mobile Phase B NaCl Sodium chloride Na2CO3Sodium carbonate NaHCCh Sodium hydrogen carbonate NaOH Sodium hydroxide Na2SO4Sodium sulfate NH4C1 Ammonium chloride NMR Nuclear Magnetic Resonance RH Relative Humidity RuPhos 2-Dicy clohexylphosphino-2 ’ , 6 ’ -dii sopropoxybiphenyl

[0063] RuPhos Pd G2 Chloro(2-dicyclohexylphosphino-2’,6’-diisopropoxy-l,r-bi- phenyl)[2-(2’ -amino- 1,1’ -biphenyl)]palladium(II)

[0064] SDS Sodium dodecyl sulfate TBAF Tetrabutylammonium fluoride TEA Triethylamine TG Thermal Gravimetric THF Tetrahydrofuran U(H)PLC Ultra (High) Performance Liquid Chromatography

[0065] UV Ultraviolet

[0066] XRPD X-ray powder Diffraction

[0067] In the meaning of the present invention, a “ kinase inhibitor” is intended to mean a compound that reduces or suppresses the activity of the targeted kinase, as compared with said activity determined without said inhibitor.

[0068] Within the meaning of the invention, the term “prevent” or “prevention” with respect to an event is intended to mean the decrease of a risk of occurrence of said event.

[0069] As used herein, the term “ambient temperature” or “room temperature” refers to a temperature ranging from 15°C to 30°C, more particularly from 18°C to 25°C.

[0070] Other features, properties and advantages of the invention will emerge more clearly from the description and examples that follow.

[0071] BRIEF DESCRIPTION OF THE FIGURES

[0072] Figure 1 is a X-ray powder diagram of the crystalline form of (S)-l-(l-(3-chlorophenyl)-2- (dimethylamino)ethyl)-4-(5-morpholino-U / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(U7)-one (see example 11).

[0073] Figure 2 is aXH NMR spectrum of the crystalline form of (S)-l-(l-(3-chlorophenyl)-2- (dimethylamino)ethyl)-4-(5-morpholino-U / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(U7)-one (see example 11).

[0074] DETAILED DESCRIPTION

[0075] As explained above, the crystalline form in accordance with the present disclosure demonstrates very good stability.

[0076] Crystalline form of the invention

[0077] As mentioned above, an object of the present invention is a crystalline form of (S)-l-(l-(3- chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-U / -pyrrolo[2,3-Z>]pyridin-3- yl)pyridin-2(U7)-one of the formula (I) below:

[0078] The crystalline form of (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5- morpholino-lJ / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(lJ7)-one may be for example characterized by X-Ray Powder Diffraction (XRPD) and by Differential Scanning Calorimetry (DSC).

[0079] According to a preferred embodiment, the crystalline form of (S)-l-(l-(3-chlorophenyl)-2- (dimethylamino)ethyl)-4-(5-morpholino-lJ / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(lJ7)-one has a powder X-ray diffractogram displaying peaks expressed as degree 2-Theta angle at 14.72; 15.28; 17.18; 22.88; 23.08 and 24.00 (each time ±0.2), and optionally further shows the following additional peaks expressed as degree 2-Theta angle: 12.03; 17.42; 22.10; 22.47; 25.07 and 25.90 (each time ±0.2); and even optionally further the following additional peaks expressed as degree 2-Theta angle: 3.36; 12.49; 12.91; 13.42; 13.93 and 19.64 (each time ±0.2), as illustrated in figure 1 (powder X-ray diffractogram) and / or has a single endotherm with an onset temperature of 281 °C (±2°C).

[0080] A characteristic X-ray powder diffractogram of the crystalline form of (5)-l-(l-(3- chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-U / -pyrrolo[2,3-Z>]pyridin-3- yl)pyridin-2(U7)-one can be given in figure 1 and its characteristic signals are summarized in the following table:

[0081] According to a preferred embodiment, the crystalline form of (S)-l-(l-(3-chlorophenyl)-2- (dimethylamino)ethyl)-4-(5-morpholino-U / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(177)-one presents a powder X-ray diffractogram displaying at least one peak, in particular at least two peaks, preferably at least five peaks, and more preferably at least ten peaks, expressed as degree 2-Theta angle selected from 3.36; 12.03; 12.49; 12.91; 13.42; 13.93; 14.72; 15.28; 17.18; 17.42; 19.64; 22.10; 22.47; 22.88; 23.08; 24.00; 25.07 and 25.90 (each time ±0.2).

[0082] According to a preferred embodiment, the crystalline form of (S)-l-(l-(3-chlorophenyl)-2- (dimethylamino)ethyl)-4-(5-morpholino-17 / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(177)-one of the present invention has an XRPD substantially similar to that depicted in figure 1.

[0083] PREPARATION OF THE CRYSTALLINE FORM

[0084] The compound of formula (I) may be prepared according to the process illustrated in example 1.

[0085] Herein is further provided a method for preparing the crystalline form of (5)-l-(l-(3- chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-U / -pyrrolo[2,3-Z>]pyridin-3- yl)pyridin-2(U7)-one according to the present invention which comprises the following steps: a) suspending (5 -l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-UT- pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(U7)-one in a solvent or in a mixture of solvents, preferably in MeCN / H2O (70 / 30); b) optionally evaporating the solvent(s) at a temperature comprised between 0°C and the boiling point of the selected solvent(s) or mixture of solvent(s) of step a); c) optionally adding a solvent or a mixture of solvents, d) applying a temperature program; e) optionally filtrating; and f) optionally washing the obtained crystals with a solvent or a mixture of solvents, g) then optionally drying in order to obtain the desired crystalline form of (S)-l-(l-(3- chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino- IT / -pyrrolo[2,3- / i]pyri din-3- yl)pyridin-2(lJ7)-one.

[0086] According to a preferred embodiment, the solvent(s) used in step a) and step c) and step f) is(are) any solvent conventionally used in crystallization step, particularly is(are) organic solvents, more particularly may be selected from water, alcohol solvents such as 1 -propanol, 2 -propanol, ethanol, methanol, 1 -butanol and 2-butanol, glycol solvents such as propylene glycol, ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone, ether solvents such as 1,4-di oxane, tetrahydrofuran, 2-m ethyltetrahydrofuran, cyclopentyl methyl ether and methyl tert-butyl ether, acetate solvents such as ethyl acetate and isopropyl acetate, aromatic solvents such as toluene, hydrocarbons solvents such as N-heptane, chlorinated solvents such as di chloromethane and chloroform, organosulfur solvents such as dimethyl sulfoxide (DMSO), amine and amide solvents such as N-methyl-2-pyrrolidone (NMP), dimethylacetamide and acetonitrile, and mixtures thereof.

[0087] According to a preferred embodiment, the solvent used in step a) is MeCN / thO (70 / 30).

[0088] According to a preferred embodiment, the solvent used in step c) is MeCN / EEO (70 / 30).

[0089] According to a preferred embodiment, the solvent used in step f) is Et2O.

[0090] According to one embodiment, the solvent(s) used in step a) and step c) is(are) the same.

[0091] According to another embodiment, the solvent(s) used in step a) and step c) is(are) different. According to one embodiment, the solvent(s) used in step a) and step f) is(are) the same. According to another embodiment, the solvent(s) used in step a) and step f) is(are) different.

[0092] APPLICATIONS

[0093] As specified previously and clearly illustrated by the following examples, the crystalline form according to the present invention is useful as inhibitor of the ERK kinases activity. According to a first aspect, the crystalline form of the invention is used as inhibitor of the ERK2 kinase activity, preferably as selective inhibitor of the ERK2 kinase activity.

[0094] More specifically, the crystalline form of the invention is used for preventing and / or inhibiting and / or treating a disease or a condition mediated by ERK kinases activity, in particular by ERK2 kinase activity. The present invention therefore provides a method for preventing and / or treating a disease or a condition mediated by ERK kinases activity, comprising at least a step of administering to an individual in need thereof at least an effective amount of at least one crystalline form in accordance with the invention.

[0095] The present invention also provides the crystalline form of the invention for its use for preventing and / or inhibiting and / or treating, preferably for preventing and / or treating, more preferably for treating, a disease or a condition mediated by ERK kinases activity, preferably ERK2 kinases activity.

[0096] The present invention also provides the use of the crystalline form of the invention for preventing and / or inhibiting and / or treating, preferably for preventing and / or treating, more preferably for treating, a disease or a condition mediated by ERK kinases activity, preferably ERK2 kinases activity.

[0097] According to one embodiment, the disease or the condition may be chosen among cancers, metastases and the Human Immunodeficiency Virus (HIV), and preferably chosen among cancers and metastases.

[0098] More specifically, the disease or the condition may be chosen among glioblastomas, multiple myelomas, carcinomas, leukemia, in particular myeloid (AML), lymphocytic, myelocytic, myelogenous (CML) or lymphoblastic leukemias, myelodysplastic syndromes, Kaposi’s sarcomas, cutaneous angiosarcomas, solid tumours, lymphomas, in particular non-hodgkin’s lymphomas, melanomas, in particular malignant melanomas, bladder cancers, breast cancers, gastric cancers, colon cancers, colorectal cancers, endometrial cancers, lung cancers, including non-small-cell cancers, pancreatic cancers, prostate cancers, rectal cancers, kidney cancers, head and neck cancers, liver cancers, ovarian cancers, in particular serous ovarian cancers, seminoma cancers, cancers of the respiratory tract and chest, thyroid cancers, in particular papillary or follicular thyroid cancers, or other tumours expressing ERK.

[0099] According to another embodiment, the disease or condition may be chosen among a neoplastic disorder, an allergy disorder, an inflammatory disorder, an autoimmune disorder, a Plasmodium related disease, a mast cell associated disease, a graft- versus -host disease, a metabolic syndrome, a CNS related disorder, a neurodegenerative disorder, a pain condition, a substance abuse disorder, a prion disease, a heart disease, a fibrotic disease, idiopathic arterial hypertension (IP AH), or primary pulmonary hypertension (PPH). According to yet another embodiment, the crystalline form of the invention may be used for preventing and / or inhibiting and / or treating the Human Immunodeficiency Virus (HIV).

[0100] The crystalline form of the present invention may be used alone or combined with chemotherapeutic agents or radiotherapeutic regimen.

[0101] Thus, according to one embodiment, a method of the invention may comprise the step of administering the crystalline form in accordance with the invention, separately, sequentially, or simultaneously with a chemotherapeutic agent.

[0102] As examples of chemotherapeutic agents that may be suitable for the invention, one may mention chemotherapeutic agents chosen from alkylating agents, intercalating agents, antimicrotubule agents, antimitotics, antimetabolites, antiproliferative agents, antibiotics, immunomodulatory agents, anti-inflammatories, kinases inhibitors, anti -angiogenic agents, antivascular agents, oestrogenic and androgenic hormones.

[0103] A radiotherapeutic regimen may be administrated by exposing an individual in need thereof to a source of ionizing radiation such as X-ray, gamma-ray or beta-ray.

[0104] According to another of its aspects, the present invention relates to a pharmaceutical composition comprising at least one crystalline form according to the invention and at least one pharmaceutically acceptable excipient.

[0105] The crystalline form according to the invention may be used for the preparation of medicaments, in particular of medicaments for inhibiting the activity of ERK kinases preferably ERK2 kinases activity.

[0106] Thus, according to yet another of its aspects, the present invention relates to a medicament comprising at least one crystalline form according to the invention.

[0107] The term “pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes what is acceptable for veterinary as well as human pharmaceutical use.

[0108] The pharmaceutical compositions may contain more particularly an effective dose of at least one crystalline form according to the invention.

[0109] An “effective dose" means an amount sufficient to induce a positive modification in the condition to be regulated or treated, but low enough to avoid serious side effects. An effective amount may vary with the pharmaceutical effect to obtain or with the particular condition being treated, the age and physical condition of the end user, the severity of the condition being treated / prevented, the duration of the treatment, the nature of other treatments, the specific compound or composition employed, the route of administration, and like factors.

[0110] The crystalline form according to the invention may be administered in an effective dose by any of the accepted modes of administration in the art.

[0111] In one embodiment, the crystalline form of the invention may be used in a composition intended to be administrated by oral, nasal, sublingual, aural, ophthalmic, topical, rectal, vaginal, urethral, or parenteral injection route.

[0112] The route of administration and the galenic formulation will be adapted by one skilled in the art pursuant to the desired pharmaceutical effect.

[0113] In a preferred embodiment, the crystalline form of the invention may be used in a composition intended to be administrated by oral.

[0114] One of ordinary skill in the art of therapeutic formulations will be able, without undue experimentation and in reliance upon personal knowledge, to ascertain a therapeutically effective dose of the crystalline form of the invention for a given indication.

[0115] A pharmaceutical composition of the invention may be formulated with any known suitable pharmaceutically acceptable excipients according to the dose, the galenic form, the route of administration and the likes.

[0116] As used herein, “pharmaceutically acceptable excipients’" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. Except insofar as any conventional excipient is incompatible with the active compounds, its use in a medicament or pharmaceutical composition of the invention is contemplated.

[0117] A medicament or pharmaceutical composition of the 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 gelatine capsules, suppositories, sterile injectable solutions, sterile packages powders and the like. According to one embodiment, a pharmaceutical composition of the invention may be intended to be administered separately, sequentially, or simultaneously with an agent useful for the prevention and / or the treatment of a disease condition, in particular a cancer condition, said agent being different from the compound of formula (I) of the invention. The applications also include a novel kit-of-parts that is suitable for use in the treatment of cancers.

[0118] A kit-of-part according to the invention may comprise (i) the crystalline form according to the invention, and (ii) at least one agent useful for the prevention and / or the treatment of a cancer condition, said agent being different from said crystalline form. An agent useful for the prevention and / or treatment of a cancer condition may be a chemotherapeutic agent or a radiotherapeutic agent.

[0119] The present invention will be better understood by referring to the following examples which are provided for illustrative purpose only and should not be interpreted as limiting in any manner the instant invention.

[0120] EXAMPLES

[0121] Equipment and analytical methods used for the syntheses of examples

[0122] Unless otherwise stated, the following equipments and analytical methods are used in the examples.

[0123] 1. X-ray Powder Diffraction (XRPD)

[0124] XRPD analysis was carried out on a PANalytical X’ pert pro with PIXcel detector (128 channels), scanning the samples between 3 and 35° 2 6 . The material was gently ground to release any agglomerates and loaded onto a multi-well plate with Kapton or Mylar polymer film to support the sample. The multi-well plate was then placed into the diffractometer and analysed using Cu K radiation ( a 1 1 = 1.54060 A; a 2 = 1.54443 A; = 1.39225 A; a l : a 2 ratio = 0.5) running in transmission mode (step size 0.0130° 2 d , step time 18.87s) using 40 kV / 40 mA generator settings. Data were visualised and images generated using the HighScore Plus 4.7 desktop application (PANalytical, 2017).

[0125] 2. Differential Scanning Calorimetry (DSC)

[0126] Approximately 1-5 mg of material was weighed into an aluminium DSC pan and sealed nonhermetically with an aluminium lid. The sample pan was then loaded into a TA Instruments Discovery DSC 2500 differential scanning calorimeter equipped with a RC90 cooler. The sample and reference were heated to a maximum of 300°C at a scan rate of 10°C / min and the resulting heat flow response monitored. The sample was re-cooled to 20°C and then reheated again to a maximum of 300°C all at 10°C / min. Nitrogen was used as the purge gas, at a flow rate of 50 cm3 / min.

[0127] 3. Nuclear Magnetic Resonance (NMR)

[0128] Apparatus: Bruker 400 MHz.

[0129] Methods:1H NMR spectra performed in DMSO-d6 using DMSO-d5 as internal reference, chemical shifts expressed in parts per million (ppm), signals expressed 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.

[0130] 4. Mass Spectrometry

[0131] Apparatus: Waters Micromass ZQ (simple quad).

[0132] Mass detection method: Electrospray positive mode (ESI+), mass range: 50-800 uma.

[0133] 5. Flash chromatography

[0134] Apparatus: Biotage SP with auto-collector and UV detection (2 wavelengths).

[0135] Normal phase columns: 120 g or 300 g Biotage external dry load cartridge kit, packed with Sigma-Aldrich 40-63 pm silica gel.

[0136] 6. Liquid Chromatography

[0137] Apparatus: Waters alliance 2695 HPLC system with autosampler and Waters 2996 diode array detector.

[0138] Column: Macherey -Nagel Nucleoshell RP18 plus (5 pm, 4 mm x 100 mm).

[0139] Column temperature: 40°C.

[0140] Solvents: A (H2O 99.9%, H2CO2 0.1%); B (CH3CN 99.9%, H2CO2 0.1%).

[0141] Flow rate: ImL / min.

[0142] Gradient (A / B v / v): 90 / 10 (t = Omin), 90 / 10 (t = Imin), 0 / 100 (t = 7min), 0 / 100 (t =10min). Detection: 210-400 nm range.

[0143] Chiral column: Daicel ChiralPak IG (Amylose-based) 20 pm, 4.6 mm x 100 mm.

[0144] Chiral column: Daicel ChiralPak IG (Amylose-based) 5 pm, 4.6 mm x 250 mm.

[0145] Column temperature: 25°C.

[0146] Analysis of final compound (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5- morpholino-U / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(lJ7)-one (Isocratic conditions): Solvents Heptane 50% / EtOH containing 0.1% EtsN 40% and DCM 10%, flow rate: ImL / min.

[0147] 8. Three Month Stability Study

[0148] The compound was set down for a stability study to investigate the chemical and physical stability over a total of three months. The conditions assessed were:

[0149] - Ambient light and temperature (closed vial) at 2 weeks, 1 month and 3 months

[0150] - 80°C (closed vial) at 2 weeks, 1 month and 3 months

[0151] - 25°C / 60 %RH (open vial) at 2 weeks, 1 month and 3 months

[0152] - 40°C / 75 %RH (open vial) at 2 weeks, 1 month and 3 months

[0153] The samples were analyzed by XRPD and HPLC at each timepoint.

[0154] Example 1: Synthesis of (.S)-l-(l-(3-cliloroplieiiyl)-2-(diiiietliyl:iinino)ethyl)-4-(5- i-lZ7-pyrrolo[2,3-61pyridin-3-yl)pyridin-2(lEZ)-one (Compound N°l) 10 g (71.1 mmol) of 3 -chlorobenzaldehyde are dissolved in 50 ml of dry THF and the solution is cooled to -10°C with an ice / acetone bath. 17.3 g (48.4 mmol,

[0155] 1.2 eq) of methyltriphenylphosphonium bromide are added followed by 2.1 g (52.4 mmol,

[0156] 1.3 eq) of sodium hydride (60% in paraffin oil). The suspension is then stirred at room temperature overnight under argon. The mixture is diluted with 100 ml of Et2O and the precipitate is filtrated on Celite. The filtrate is evaporated under reduced pressure to give an orange residue. Crude mixture is finally purified by flash chromatography using a silica gel column and an Et2O / pentane mixture as eluent (3 / 97). 4.05 g of the title compound are obtained.

[0157] Yield: 41%.

[0158] MH+: Non ionizable.

[0159] Step 2: 2-(3-Chlorophenyl)oxirane

[0160] 4.05 g (29.2 mmol) of 1 -chi oro-3 -vinylbenzene (described in the previous step) are dissolved in 6 ml of 1,4-dioxane and 18 ml of water. The solution is cooled to 0°C and 584 pl (10.2 mmol, 1 eq) of acetic acid are added, followed by 1.99 g (11.2 mmol, 1.1 eq) of N- bromosuccinimide. Reaction mixture is stirred at 0°C for 5 min then at room temperature for 2h. Mixture is then cooled again to 0°C and a solution of NaOH 2N in water (35.7 mmol, 3.5 eq) is slowly added. The solution is allowed to stir at room temperature for Ih. Reaction mixture is concentrated under reduced pressure and aqueous resulting phase is extracted 3 times with DCM. Combined organic layers are dried over Na2SO4, filtrated and evaporated under reduced pressure. Crude mixture is purified by flash chromatography using a silica gel column and a DCM / hexane mixture as eluent (2 / 98). 3.85 g of the title compound are obtained.

[0161] Yield: 85%.

[0162] MH+: Non ionizable.

[0163] Step 3: l-(3-Chlorophenyl)-2-(dimethylamino)ethan-l-ol

[0164] To a solution of 4.15 g (26.9 mmol) of 2-(3-chlorophenyl)oxirane (described in the previous step) in 14 ml of EtOH 96%, are added 7.38 ml (14.76 mmol, 2 eq) of a solution of dimethylamine (2M in THF). The clear resulting solution is heated under microwave irradiation at 80°C for 30 min. Reaction mixture is then concentrated under vacuum and diluted with water. The solution is extracted 3 times with DCM. Combined organic layers are dried over Na2SO4, filtrated and evaporated under reduced pressure. Crude mixture is purified by flash chromatography using a silica gel column and a DCM / MeOH mixture as eluent. 4.06 g of the title compound are obtained.

[0165] Yield: 76%.

[0166] MH+: 200.2; 202.3 (M; M+2).

[0167] Step 4: 2-Chloro-2-(3-chlorophenyl)- V, V-dimethylethan-l-amine

[0168] 4.06 g (20.3 mmol) of l-(3-chlorophenyl)-2-(dimethylamino)ethan-l-ol (described in the previous step) are dissolved in 15 ml of DCM and placed at 0°C. 2.1 ml (15.1 mmol, 3 eq) of triethylamine are added, followed by 0.781 ml (10.1 mmol, 2 eq) of mesyl chloride. The reaction is stirred at 0°C under argon for 2h. Water is then added and the mixture is decanted. Aqueous layer is extracted 2 times with DCM. Combined organic layers are dried over Na2SO4, filtrated and evaporated under reduced pressure. Crude compound is directly used in the next step without further purification. 4.41 g of the title compound are obtained. Yield: 99%.

[0169] MH+: 218.4; 220.4 (M; M+2).

[0170] Step 5: 4-Bromo-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)pyridin-2(LH)-one

[0171] To a mixture of 0.744 g (4.28 mmol, 1 eq) of 4-bromopyridin-2-(177)-one and 1.39 g (4.28 mmol, 1 eq) of cesium carbonate in 10 ml of dry DMF, is added at 0°C a solution of 4.41 g (20.3 mmol) of 2-chloro-2-(3-chlorophenyl)-A,A-dimethylethan-l -amine (described in the previous step) in 5 ml of dry DMF. The solution is then stirred at room temperature for 2h. EtOAc is added, and the mixture is washed 4 times with water and once with brine. Organic layer is dried over Na2SO3, filtrated and evaporated under reduced pressure. Crude mixture is purified by flash chromatography using a deactivated silica gel column and an HexaneZEtOAcmixture as eluent. 5.02 g of the title compound are obtained.

[0172] Yield: 70%.

[0173] MH+: 355.2; 357.2 (M; M+2).

[0174] Step 6: 1 -( 1 -(3-Chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino- 1 -tosyl- 1 / / - pyrrolo [2.3- / ? | pyridin-3-yl)pyridin-2(LH)-one

[0175] 2 g (5.6 mmol) of 4-bromo-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)pyridin-2(177)- one (described in the previous step) and 2.45 g (5.01 mmol, 1.3 eq) of 4-(3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-lJ / -pyrrolo[2,3-Z>]pyridin-5-yl)morpholine (described in Step 3) are dissolved in 13 ml of MeCN under argon. Then 13 ml of a solution of Na2CO32M are added to give a biphasic mixture which is bubbled with argon for 15 min. 135 mg (0.19 mmol, 0.05 eq) of bis(triphenylphosphine)palladium dichloride are added and the solution was bubbled with argon for another 15 min. The reaction is stirred at 70°C for 2h under argon. Reaction mixture is then diluted with water and EtOAc and then decanted. Aqueous layer is extracted 2 times with EtOAc. Combined organic layer are dried over Na2SO4, filtrated and evaporated under reduced pressure. Crude mixture is purified by flash chromatography using a silica gel column and a DCM / MeOH mixture as eluent. 2.68 g of the title compound are obtained.

[0176] Yield: 75%.

[0177] MH+: 632.8; 634.8 (M; M+2).

[0178] Step 7: 1 -( 1 -(3-<CIi I o roplieny I )-2-( d i ni el Iiy I a ni in o )et hy 1 )-4-( 5- ni or pliol in o- 1 / / - pyrrolo [2.3- / ? | pyridin-3-yl)pyridin-2(LH)-one

[0179] 2.68 g (4.2 mmol) of l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-l- tosyl-17 / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(177)-one (described in the previous step) are dissolved in 15 ml of dry THF under argon. Then 10 ml (10 mmol, 3 eq) of a solution of TBAF (IM in THF) are added and the reaction is stirred at 66°C for Ih under argon. Solvent is removed under reduced pressure and 100 ml of a saturated NaHCCh solution are added. Mixture is extracted 3 times with EtOAc. Combined organic layer are dried over ISfeSCU, filtrated and evaporated under reduced pressure. Crude mixture is purified by flash chromatography using a silica gel column and a DCM / MeOH mixture as eluent. 617 mg of racemate are obtained.

[0180] Yield: 30%.

[0181] MH+: 478.5; 480.6 (M; M+2).

[0182] 'H NMR (DMSO-d6, 400 MHz): 5 12.06 (br s, IH); 8.17 (d, J=2.4Hz, IH); 8.10 (d, J=2.3Hz, IH); 7.76 (d, J=8.0Hz, IH); 7.70 (d, J=2.4Hz, IH); 7.47 (s, IH); 7.44-7.32 (m, 3H); 6.72-6.65 (m, 2H); 6.23-6.13 (m, IH); 3.84-3.73 (m, 4H); 3.34-3.23 (m, IH); 3.20-3.08 (m, 4H); 2.78-2.67 (m, IH); 2.21 (s, 6H). Step 8: (S)-l-( l-(3-Chloroplieiiyl)-2-(diinetliyl:iiniiio)etliyl)-4-(5-inorpholino-l / / - pyrrolo [2.3- / ? | pyridin-3-yl)pyridin-2(LH)-one

[0183] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane / EtOH / DCM / 0.1%TEA mixture as the mobile phase. First fraction to be eluted is the (-) (A’)-enantiomer, followed by the (+) fS')-enantiomer with ee > 98%. 227 mg of the title compound are obtained starting from 617 mg of racemate. MH+: 478.5; 480.6 (M; M+2).

[0184] 'H NMR (DMSO-d6, 400 MHz): 5 12.06 (br s, 1H); 8.17 (d, .7=2, 4 Hz, 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).

[0185] Example 2: Synthesis of comparative compound CS)-l-(2-amino-l-(3- cliloroplienyl)ethyl)-4-(5-iiiorpholino- l / / -pyrrolo|2.3- / ?|pyridin-3-yl)pyridin-2( 1 / / )-

[0186] To a solution of 5 g (36 mmol, 1 eq) of 3 -chlorobenzaldehyde in 50 ml of dry DCM under argon, are added 399 mg (36 mmol, 1 eq) of DABCO, followed by 4.45 ml (36 mmol, 1 eq) of trimethyl silyl cyanide and the resulting mixture is stirred at 40°C for 2h. Reaction mixture is then diluted with DCM and washed 2 times with water and once with brine. Organic layer is dried over Na2SO4, filtered, and evaporated under reduced pressure. Crude compound is used in the next step without further purification. 7.80 g of the title compound are obtained. Yield: 91%.

[0187] MH+: Non ionizable.

[0188] Step 2: 2-Amino-l-(3-chlorophenyl)ethan-l-ol

[0189] 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 with an ice / water bath, are added in portions 1.85 g (49 mmol, 1.5 eq) of LiAlEU. The resulting mixture is stirred at 0°C for Ih. Then ice is slowly added into the reaction at 0°C until no more gas is formed and finally 100 ml of water are added. The mixture is stirred at room temperature for 30 min, the precipitate is filtrated on Celite and washed 2 times with Et2O. Filtrate is decanted and aqueous layer is extracted 2 times with Et2O. Combined organic layers are dried over Na2SO4, filtered, and evaporated under reduced pressure. Crude compound is used in the next step without further purification. 5.95 g of the title compound are obtained.

[0190] Yield: Quantitative.

[0191] MH+: 172.3; 174.3 (M; M+2).

[0192] Step 3: Tert-butyl (2-(3-chlorophenyl)-2-hydroxyethyl)carbamate

[0193] To a solution of 5.95 g (35 mmol, 1 eq) of 2-amino-l-(3-chlorophenyl)ethan-l-ol (described in the previous step) in 60 ml of THF, are added 8.32 g (38 mmol, 1.1 eq) of di-tert-butyl dicarbonate and the resulting mixture is stirred at room temperature for Ih. Solvent is then removed under reduced pressure and the mixture is diluted with 100 ml of EtOAc. Organic layer is washed 2 times with water and once with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. 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 are obtained.

[0194] Yield: 72%.

[0195] MH+: 272.6; 274.7 (M; M+2).

[0196] Step 4: 2-((Tert-butoxycarbonyl)amino)-l-(3-chlorophenyl)ethyl methanesulfonate

[0197] 6.78 g (25 mmol) of tert-butyl (2-(3-chlorophenyl)-2-hydroxyethyl)carbamate (described in the previous step) are dissolved in 15 ml of DCM and placed at 0°C. 2.1 ml (15.1 mmol, 3 eq) of triethylamine are added, followed by 0.781 ml (10.1 mmol, 2 eq) of mesyl chloride. The reaction is stirred at 0°C under argon for 2h. Water is then added and the mixture is decanted. Aqueous layer is extracted 2 times with DCM. Combined organic layers are dried over Na2SO4, filtrated and evaporated under reduced pressure. Crude compound is directly used in the next step without further purification. 9.28 g of the title compound are obtained. Yield: Quantitative.

[0198] MH+ (dimer): 700.2; 702.2 (M; M+2).

[0199] Step 5: Tert-butyl (2-(4-bromo-2-oxopyridin-l(2Z7)-yl)-2-(3- chlorophenyl)ethyl)carbamate

[0200] To a mixture of 0.744 g (4.28 mmol, 1 eq) of 4-bromopyridin-2-(177)-one and 1.39 g (4.28 mmol, 1 eq) of cesium carbonate in 10 ml of dry DMF, is added at 0°C a solution of 8.73 g (25 mmol) of 2-((tert-butoxycarbonyl)amino)-l-(3-chlorophenyl)ethyl methanesulfonate (described in the previous step) in 5 ml of dry DMF. The solution is then stirred at room temperature for 2h. EtOAc is added, and the mixture is washed 4 times with water and once with brine. Organic layer is dried over Na2SO4, filtrated and evaporated under reduced pressure. Crude mixture is purified by flash chromatography using a deactivated silica gel column and an Hexane / EtOAcmixture as eluent. 5.56 g of the title compound are obtained. Yield: 52%.

[0201] MH+: 427.7; 429.7; 431.7 (M; M+2; M+4).

[0202] Step 6: 4-( 1 / / -I’yrrolo [2,3-6] pyridin-5-yl)morpholine

[0203] In 487 ml of LiHMDS (IM in THF, 487 mmol, 2.4 eq) are dissolved 947 mg (2.03 mmol, 0.01 eq) of RuPhos and 1.58 g (2.03 mmol, 0.01 eq) of RuPhos Pd G2. Then are added under argon 40 g (203 mmol, 1 eq) of 5-bromo-17 / -pyrrolo[2,3-6]pyridine and 21.1 ml (244 mmol, 1.2 eq) of morpholine and the solution is heated at 66°C for lh30. The reaction mixture is then cooled to room tempareature and dropped into 1.2 1 of a saturated NH4CI solution maintaining the temperature under 10°C with an ice water bath. The mixture is stirred for 10 min at this temperature and decanted. Aqueous layer is extracted 3 times with DCM. Combined organic layers are dried over Na2SO4, filtered, and evaporated under reduced pressure to give 44.4 g of a brown solid. Crude is triturated in 200 ml of a mixture of EtOAc and hexane (3 / 7) for Ih. The solid is filtrated, rinsed 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.

[0204] Yield: 94%.

[0205] MH+: 204.3 (M+l).

[0206] Step 7: 4-( 1 -Tosyl- l / / -pyrrolo|2.3- / i|pyridiii-5-yl)inorpholine 38.98 g (192 mmol, 1 eq) of 4-(U / -pyrrolo[2,3-Z>]pyridin-5-yl)morpholine (described in the previous step) are dissolved in 390 ml of dry DMF, under argon. The solution is cooled to 0°C, and 11.5 g (288 mmol, 1.5 eq) of sodium hydride (60% in paraffin oil) are slowly added. The mixture is stirred for 10 min at this temperature and then 40 min at room temperature. The mixture is cooled again to 0°C, 47.5 g (249 mmol, 1.3 eq) of tosyl chloride are slowly added under argon and the reaction mixture is stirred at 0°C for Ih followed by Ih at room temperature. The mixture is dropped into 800 g of ice / water and stirred for Ih. A precipitate is obtained, which is filtrated and rinsed several times with cold water. The precipitate is then dissolved with 1.2 1 of DCM, and the solution is washed 2 times with a saturated NaHCCh solution, 2 times with water and once with brine. The organic layer is dried over Na2SO4, filtered, and evaporated under reduced pressure. Crude compound is triturated in 500 ml of a mixture of EtOAc and hexane (5 / 95) for 3h. The solid is filtrated, rinsed with hexane and dried under vacuum to give 62.56 g of an off-white solid.

[0207] Yield: 91%.

[0208] MH+: 358.6 (M+l).

[0209] 'H NMR (DMSO-d6, 400 MHz): 5 8.18 (d, J=2.7Hz, IH); 7.92 (d, J=8.3Hz, 2H); 7.78 (d, J=4.0Hz, IH); 7.52 (d, J=2.7Hz, IH); 7.39 (d, J=8.3Hz, 2H); 6.68 (d, J=4.0Hz, IH); 3.76- 3.71 (m, 4H); 3.12-3.07 (m, 4H); 2.33 (s, 3H).

[0210] Step 8 : 4-(3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1-tosyl- 1 / / -py r rolo [2,3- 6] pyridin-5-yl)mor pholine

[0211] 62.56 g (175 mmol, 1 eq) of 4-(l-tosyl-U / -pyrrolo[2,3-Z>]pyridin-5-yl)morpholine (described in the previous step) are suspended in 512 ml of Me-THF under argon. Then 48.9 g of bis(pinacolato)diboron (193 mmol, 1.1 eq), 1.88 g of 4,4’-di- / c / 7-butylbiphenyl (7 mmol, 0.036 eq) and 2.32 g of (l,5-cyclooctadiene)(methoxy)iridium(I) dimer (3.5 mmol, 0.018 eq) are added. The reaction is heated to reflux for 45 min under argon. The reaction mixture is then cooled to -10°C with an ice / acetone bath and quenched carefully with MeOH (350 ml). The solution is stirred at room temperature for 15 min and evaporated under vacuum to give a brown oil. Dark oil is then dissolved in 1 1 of DCM, washed 3 times with water and once with brine. Organic layer is evaporated under reduced pressure to give a black paste. 2 1 of Et2O are added and the mixture is stirred for 15 min at room temperature, filtrated on Celite and evaporated under reduced pressure to give 95 g of a brown solid foam. Crude mixture is finally purified by flash chromatography using a silica gel column and an EtOAc / hexane mixture as eluent. 75.5 g of the title compound are obtained.

[0212] Yield: 89%.

[0213] MH+: 484.6 (M+l).

[0214] 'H NMR (DMSO-d6, 400 MHz): 5 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); 7.41 (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).

[0215] Step 9: Tert-butyl (2-(3-chlorophenyl)-2-(4-(5-morpholino-l-tosyl-l / / -pyrrolo|2.3- b] pyridin-3-yl)-2-oxopyridin- 1 (2Z7)-yl)ethyl)carbamate

[0216] 2.8 g (6.50 mmol, 1 eq) of tert-butyl (2-(4-bromo-2-oxopyridin-l(2J7)-yl)-2-(3- chlorophenyl)ethyl)carbamate (described in the step 5), 3.16 g (6.50 mmol, 1 eq) of 4-(3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridin-5- yl)morpholine (described in the previous step) and 905 mg (6.50 mmol, 1 eq) of K2CO3 are placed in 140 ml of MeCN under argon. The mixture is bubbled with argon for 15 min and 459 mg (0.65 mmol, 0.1 eq) of bis(triphenylphosphine)palladium dichloride are added. The mixture is bubbled for another 15 min and then the reaction is stirred at 80°C for Ih under argon. Reaction mixture is diluted with 140 ml of EtOAc and washed 3 times with water. Organic layer is dried over Na2SO4, filtrated and evaporated under reduced pressure. Crude mixture is purified by flash chromatography using a silica gel column and a DCM / MeOH mixture as eluent. 4.79 g of the title compound are obtained.

[0217] Yield: Quantitative.

[0218] Step 10: Tert-butyl (2-(3-chlorophenyl)-2-(4-(5-morpholino-l / / -pyrrolo|2.3- / >|pyridin-

[0219] 3-yl)-2-oxopyridin- 1 (2ZZ)-yl)ethyl)carbamate

[0220] 1.0 g (1.4 mmol) of tert-butyl (2-(3 -chi orophenyl)-2-(4-(5 -morpholino- 1 -tosyl- 1H- pyrrolo[2,3-Z>]pyridin-3-yl)-2-oxopyridin-l(2J7)-yl)ethyl)carbamate (described in the previous step) are suspended in 5 ml of MeCN and 2.5 ml of a Na2COs 2M solution. The mixture is stirred at 120°C under microwave irradiation in a sealed tube (150W) for Ih. The mixture is cooled to room temperature, diluted with EtOAc and washed 3 times with water. Organic layer is dried over Na2SO4, filtrated and evaporated under reduced pressure. Crude product is finally purified by flash chromatography using a silica gel column and a DCM / MeOH mixture as eluent. 644 mg of racemate are obtained.

[0221] Yield: 82%.

[0222] MH+: 550.6; 552.6 (M; M+2).

[0223] Step 11: 1 -(2- niino- 1 -(3-chlorophenyl)ethyl)-4-(5-niorpholino- 1 / / -pyrrolo|2.3-

[0224] 6] pyridin-3-yl)pyridin-2(LH)-one To a solution of 644 mg (1.17 mmol, 1 eq) of tert-butyl (2-(3-chlorophenyl)-2-(4-(5- morpholino-U / -pyrrolo[2,3-Z>]pyridin-3-yl)-2-oxopyridin-l(2J7)-yl)ethyl)carbamate (described in the previous step) in 6 ml of DCM, placed at 0°C with an ice / water bath, are added 3 ml of trifluoroacetic acid. The solution is stirred at 0°C for lh30, then solvent is removed under reduced pressure and the mixture is diluted with 100 ml of a saturated NaHCCh solution. The solution is extracted 3 times with DCM. Combined organic layers are dried over Na2SO4, filtered, and evaporated under reduced pressure. Crude mixture is purified by flash chromatography using a C18 column and a water / MeOH mixture as eluent. 340 mg of the title compound are obtained.

[0225] Yield: 64%.

[0226] MH+: 450.7; 452.7 (M; M+2).

[0227] 'H NMR (DMSO-d6, 400 MHz): 5 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, .7=2, 6 Hz, 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).

[0228] Step 12: (S)- 1 -(2- mino- 1 -(3-chlorophenyl)ethyl)-4-(5-morpholino- 1 / / -pyrrolo|2.3-

[0229] 6] pyridin-3-yl)pyridin-2(LH)-one

[0230] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane / EtOH / DCM / 0.1%TEA mixture as the mobile phase. First fraction to be eluted is the (-) (A)-enantiomer, followed by the (+) fS')-enantiomer with ee > 98%. 33 mg of the title compound are obtained starting from 120 mg of racemate. MH+: 450.7; 452.7 (M; M+2).

[0231] 'H NMR (DMSO-d6, 400 MHz): 5 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, .7=2, 6 Hz, 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);

[0232] 3.18-3.09 (m, 4H); 1.60 (br s, 2H).

[0233] Example 3: Synthesis of comparative compound (>y)-l-(l-(3.,4-dichlorophenyl)-2-

[0234] (iiietliylaiiiino)ethyl)-4-(5-iiiorpholino- 1 / / -pyrrolo|2.3- / ?|pyridin-3-yl)pyridin-2( 1 / / )-

[0235] To a solution of 2.5 g (14.3 mmol) of 3, 4-di chlorobenzaldehyde in 50 ml of dry DCM under argon, are added 399 mg (36 mmol, 1 eq) of DABCO, followed by 4.45 ml (36 mmol, 1 eq) of trimethyl silyl cyanide and the resulting mixture is stirred at 40°C for 2h. Reaction mixture is then diluted with DCM and washed 2 times with water and once with brine. Organic layer is dried over Na2SO4, filtered, and evaporated under reduced pressure. Crude compound is used in the next step without further purification. 3.70 g of the title compound are obtained. Yield: 94%.

[0236] MH+: Non ionizable.

[0237] Step 2: 2-Amino-l-(3,4-dichlorophenyl)ethan-l-ol

[0238] To a solution of 3.70 g (13.5 mmol) of 2-(3, 4-di chi orophenyl)-2- ((trimethylsilyl)oxy)acetonitrile (described in the previous step) in 80 ml of dry Et2O, placed at 0°C with an ice / water bath, are added in portions 1.85 g (49 mmol, 1.5 eq) of LiAlE . The resulting mixture is stirred at 0°C for Ih. Then ice is slowly added into the reaction at 0°C until no more gas is formed and finally 100 ml of water are added. The mixture is stirred at room temperature for 30 min, the precipitate is filtrated on Celite and washed 2 times with Et20. Filtrate is decanted and aqueous layer is extracted 2 times with Et2O. Combined organic layers are dried over ISfeSCU, filtered, and evaporated under reduced pressure. Crude compound is used in the next step without further purification. 1.66 g of the title compound are obtained.

[0239] Yield: 60%.

[0240] MH+: 206.1; 208.2; 210.1 (M; M+2; M+4).

[0241] Step 3: Tert-butyl (2-(3,4-dichlorophenyl)-2-hydroxyethyl)carbamate

[0242] To a solution of 1.66 g (8.03 mmol) of 2-amino-l-(3,4-dichlorophenyl)ethan-l-ol (described in the previous step) in 60 ml of THF, are added 8.32 g (38 mmol, 1.1 eq) of di-tert-butyl dicarbonate and the resulting mixture is stirred at room temperature for Ih. Solvent is then removed under reduced pressure and the mixture is diluted with 100 ml of EtOAc. Organic layer is washed 2 times with water and once with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. Crude mixture is purified by flash chromatography using a silica gel column and a DCM / MeOH mixture as eluent. 2.55 g of the title compound are obtained.

[0243] Yield: Quantitative.

[0244] MH+: 306.3; 308.3 (M; M+2).

[0245] Step 4: 2-((Tert-butoxycarbonyl)amino)-l-(3,4-dichlorophenyl)ethyl methanesulfonate

[0246] 2.46 g (8.03 mmol) of tert-butyl (2-(3,4-dichlorophenyl)-2-hydroxyethyl)carbamate (described in the previous step) are dissolved in 15 ml of DCM and placed at 0°C. 2.1 ml (15.1 mmol, 3 eq) of triethylamine are added, followed by 0.781 ml (10.1 mmol, 2 eq) of mesyl chloride. The reaction is stirred at 0°C under argon for 2h. Water is then added and the mixture is decanted. Aqueous layer is extracted 2 times with DCM. Combined organic layers are dried over Na2SO4, filtrated and evaporated under reduced pressure. Crude compound is directly used in the next step without further purification. 3.23 g of the title compound are obtained.

[0247] Yield: Quantitative.

[0248] MH+ (dimer): 767.5; 769.4; 771.6 (M; M+2; M+4).

[0249] Step 5: Tert-butyl (2-(4-bromo-2-oxopyridin-l(2ET)-yl)-2-(3,4- dichlorophenyl)ethyl)carbamate

[0250] To a mixture of 0.744 g (4.28 mmol, 1 eq) of 4-bromopyridin-2-(177)-one and 1.39 g (4.28 mmol, 1 eq) of cesium carbonate in 10 ml of dry DMF, is added at 0°C a solution 3.09 g (8.03 mmol) of 2-((tert-butoxycarbonyl)amino)-l-(3,4-dichlorophenyl)ethyl methanesulfonate (described in the previous step) in 5 ml of dry DMF. The solution is then stirred at room temperature for 2h. EtOAc is added, and the mixture is washed 4 times with water and once with brine. Organic layer is dried over Na2SO4, filtrated and evaporated under reduced pressure. Crude mixture is purified by flash chromatography using a deactivated silica gel column and an Hexane / EtOAcmixture as eluent. 1.74 g of the title compound are obtained.

[0251] Yield: 47%.

[0252] MH+: 461.3; 463.3; 465.2 (M; M+2; M+4).

[0253] Step 6: Tert-butyl (2-(4-bromo-2-oxopyridin-l(2ET)-yl)-2-(3,4- dichlorophenyl)ethyl)(methyl)carbamate To a solution of 840 mg (1.82 mmol, 1 eq) of tert-butyl (2-(4-bromo-2-oxopyridin- 1(277)- yl)-2-(3,4-dichlorophenyl)ethyl)carbamate (described in the previous step) in 9 ml of dry DMF, placed at 0°C with an ice / water bath, are added under argon 87 mg (2.18 mmol, 1.2 eq) of sodium hydride (60% in paraffin oil), followed by 170 pl (2.73 mmol, 1.5 eq) of methyl iodide. The solution is stirred at 0°C for lh30, then the mixture is diluted with 100 ml of EtOAc. The solution is washed 4 times with water and once with brine. Organic layer is dried over Na2SO4, filtered, and evaporated under reduced pressure. Crude mixture is purified by flash chromatography using a silica gel column and a EtOAc / Hexane mixture as eluent. 750 mg of the title compound are obtained.

[0254] Yield: 86%.

[0255] MH+: 475.4; 477.3; 479.3 (M; M+2; M+4).

[0256] Step 7: Tert-butyl (2-(3.4-dichlorophenyl)-2-(4-(5-morpholino-l-tosyl-l / / -pyrrolo|2.3-

[0257] / >]pyridin-3-yl)-2-oxopyridin-l(2Z / )-yl)ethyl)(methyl)carbamate

[0258] 750 mg (1.57 mmol) of tert-butyl (2-(4-bromo-2-oxopyridin-l(277)-yl)-2-(3,4- dichlorophenyl)ethyl)(methyl)carbamate (described in the previous step) and 2.45 g (5.01 mmol, 1.3 eq) of 4-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-177- pyrrolo[2,3-Z>]pyridin-5-yl)morpholine (described in Step 3) are dissolved in 13 ml of MeCN under argon. Then 13 ml of a solution of ISfeCOs 2M are added to give a biphasic mixture which is bubbled with argon for 15 min. 135 mg (0.19 mmol, 0.05 eq) of bis(triphenylphosphine)palladium dichloride are added and the solution was bubbled with argon for another 15 min. The reaction is stirred at 70°C for 2h under argon. Reaction mixture is then diluted with water and EtOAc and then decanted. Aqueous layer is extracted 2 times with EtOAc. Combined organic layer are dried over Na2SO4, filtrated and evaporated under reduced pressure. Crude mixture is purified by flash chromatography using a silica gel column and a DCM / MeOH mixture as eluent. 1.27 g of the title compound are obtained. Yield: Quantitative.

[0259] MH+: 753.4; 755.2 (M; M+2).

[0260] Step 8: Tert-butyl (2-(3.4-dichlorophenyl)-2-(4-(5-morpholino-l / / -pyrrolo|2.3-

[0261] / >]pyridin-3-yl)-2-oxopyridin-l(2Z / )-yl)ethyl)(methyl)carbamate

[0262] 1.27 g (1.69 mmol) of tert-butyl (2-(3, 4-di chi orophenyl)-2-(4-(5 -morpholino- 1 -tosyl- 1H- pyrrolo[2,3-Z>]pyridin-3-yl)-2-oxopyridin-l(2J7)-yl)ethyl)(methyl)carbamate (described in the previous step) are suspended in 5 ml of MeCN and 2.5 ml of a Na2COs 2M solution. The mixture is stirred at 120°C under microwave irradiation in a sealed tube (150W) for Ih. The mixture is cooled to room temperature, diluted with EtOAc and washed 3 times with water. Organic layer is dried over Na2SO4, filtrated and evaporated under reduced pressure. Crude product is finally purified by flash chromatography using a silica gel column and a DCM / MeOH mixture as eluent. 730 mg of racemate are obtained.

[0263] Yield: 72%.

[0264] MH+: 598.7; 600.5 (M; M+2).

[0265] Step 9: 1 -( l-(3.4-l)ichlorophenyl)-2-(inethylainino)ethyl)-4-(5-morpholino- 1 / / - pyrrolo [2 ,3-b] pyridin-3-yl)pyridin-2(lH)-one

[0266] To a solution of 730 mg (1.20 mmol) of tert-butyl (2-(3,4-dichlorophenyl)-2-(4-(5- morpholino-lJ / -pyrrolo[2,3-Z>]pyridin-3-yl)-2-oxopyridin-l(2J7)- yl)ethyl)(methyl)carbamate (described in the previous step) in 6 ml of DCM, placed at 0°C with an ice / water bath, are added 3 ml of trifluoroacetic acid. The solution is stirred at 0°C for lh30, then solvent is removed under reduced pressure and the mixture is diluted with 100 ml of a saturated NaHCCh solution. The solution is extracted 3 times with DCM. Combined organic layers are dried over Na2SO4, filtered, and evaporated under reduced pressure. Crude mixture is purified by flash chromatography using a C18 column and a water / MeOH mixture as eluent. 543 mg of racemate are obtained.

[0267] Yield: 89%.

[0268] MH+: 498.6; 500.5 (M; M+2).

[0269] 'H NMR (DMSO-d6, 400 MHz): 5 12.08 (br s, 1H); 8.17 (d, J=2.5Hz, 1H); 8.10 (d, .7=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).

[0270] Step 10: (S)- 1 -( l-(3.4-l)icliloroplieiiyl)-2-(nietliyl:iiniiio)etliyl)-4-(5-morpholino- 1 / / - pyrrolo [2.3- / ? | pyridin-3-yl)pyridin-2(LH)-one

[0271] Enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and an Hexane / EtOH / DCM / 0.1%TEA mixture as the mobile phase. First fraction to be eluted is the (-) (A’)-enantiomer, followed by the (+) fS')-enantiomer with ee > 98%. 54 mg of the title compound are obtained starting from 150 mg of racemate. MH+: 498.6; 500.5 (M; M+2).

[0272] 'H NMR (DMSO-d6, 400 MHz): 5 12.08 (br s, 1H); 8.17 (d, J=2.5Hz, 1H); 8.10 (d, .7=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).

[0273] Example 4: ERK2 (MAPK1) Enzymatic assay To assess the capacity of the compound N°1 according to example 1 to inhibit ERK2 enzymatic activity, Z’-Lyte biochemical assay from Life technologies was used according to manufacturer’s instructions. Briefly, black 384-well plates containing 100 nl of 100X compound solution in 100% DMSO, 2.4 pl kinase buffer, 5 pl 2X MAPK1 (ERK2) / Ser / Thr 03 mixture and 2.5 pl 4X ATP solution were used. Plates were shaken for 30 seconds and incubated for 60 minutes at room temperature. Then, 5 pl of a 1 : 1024 dilution of Development Reagent A was added. Plates were shaken for 30 seconds and incubated for 60 minutes at room temperature. A plate reader was used to read fluorescence. In this assay, ERK2 enzyme was used at a concentration of 0.4 pg / ml (5.74 nM) at ATP Km (100 pM). Kinase buffer consisted of 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCh, 1 mM EGTA. Compound IC50 were determined with a 3-fold serial dilution (10 point titrations in duplicate).

[0274] Compound N°1 of example 1 has an ERK2 inhibitory activity (IC50) of 2.1 nM. Therefore, it exhibits a capacity to inhibit ERK2 enzymatic activity.

[0275] Example 5: Cell line proliferation assay

[0276] A cell line assay was used to determine the capacity of the compound N°1 according to example 1 to inhibit cell proliferation. A375 cells (malignant melanoma) were grown to near 80% confluence and seeded at 3000 cells per 100 pl per well in DMEM with 10% FBS in 96-well flat bottom plates. Cells were incubated for 24 hours at 37°C under 5% CO2. 100 pl compound solutions were added to cells and incubated for 72 hours at 37°C. Total volume of media was 200 pl per well. The compound was screened in 0.15% DMSO (final) using 10 titration points in duplicate. Negative control wells consisted of vehicle only (0.15% DMSO in 10% FBS DMEM). After 72 hours of compound treatment, SDS 1% (final) was added to positive control wells for 15 minutes at 37°C. Then, medium was discarded and replaced by 100 pl per well of a 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 for 4 hours at 37°C. MTT reaction was stopped and homogenized by the addition of lOOpl per well of SDS 10% 0.01M HC1. After 16 hours at 37°C, absorbance was measured at 570 nm in a Bio-Tek plate reader (PowerWave HT). Percent of proliferation inhibition was calculated using negative controls (0.15% DMSO) as 0% growth inhibition and positive controls (1% SDS) as 100% growth inhibition. IC50 values (concentration inducing a half-maximal growth inhibition) were determined by non-linear regression analysis of the inhibition curve generated by mean replicate values (using a sigmoid doseresponse with variable Hill Slope and constraining the top to a constant value of 100 and the bottom to a value between 0 and 50). Analysis was performed using GraphPad Prism software.

[0277] Cell proliferation inhibitory activity of the compound N°1 according to example 1 (“MTT A375 IC50”) is 35 nM. Therefore, it exhibits a capacity to inhibit A375 cell proliferation.

[0278] Example 6: hERG channel inhibition assay

[0279] Evaluation of hERG channel inhibition of the compound N°1 according to example 1 has been performed. The compound was used as a lOmM stock in DMSO before dilution in HEPES-buffered saline to 30 pM. 6-point concentration-response curves were generated using 3.16-fold serial dilutions from the top test concentration. Electrophysiological recordings were made from a Chinese Hamster Ovary cell line stably expressing the full- length ion channel. Single cell ionic currents were measured in whole-cell configuration at room temperature (21-23°C) using a Patchliner (Nanion Technologies). The internal solution for hERG contained (mM): 120 KF, 20 KC1, 10 EGTA, 10 HEPES and was buffered to pH 7.3. The external solution (HEPES-buffered saline, HEPES-buffered saline) contained (mM): 138 NaCl, 4.5 KC1, 1.8 CaCh, 1.0 MgCh, 10 HEPES, 10 glucose, buffered to pH 7.4. Voltage protocol is given below. Currents were measured from the step and referenced to the holding current. The compound was then incubated for 2 minutes to achieve steady state prior to addition of the next concentration. hERG channel inhibition properties of the compound N° 1 according to example 1 (“hERG

[0280] IC50”) 10.9 p. Therefore, it exhibits a safe hERG profile with patch clamp assay. Example 7: CYP 3A4 inhibition assay

[0281] To assess the capacity of the compound N°1 according to example 1 to inhibit CYP 3A4 enzymatic activity, the test compounds (0.1 pM - 25 pM) were incubated with cryopreserved human hepatocytes for 10 min in the presence of the specific CYP3A4 probe substrate, midazolam.

[0282] 1 -Hydroxymidazolam was monitored by LC-MS / MS and a decrease in the formation of the metabolite compared to the vehicle control was used to calculate an IC50 value.

[0283] CYP 3A4 inhibitory activity of the compounds (“CYP 3A4 IC50”) is reported in the Table below:

[0284] Compound N°1 according to example 1 exhibits a low inhibition of CYP 3A4. Indeed, it has an IC50 value greater than 5 pM. By contrast, the comparative compound A has an IC50 value of 0.74 pM. Comparative compound A is therefore a highly potent inhibitor of CYP 3A4.

[0285] Example 8: Kinase panel

[0286] To assess the kinase selectivity of the compound n°l according to example 1 (S), Z’-Lyte biochemical assay, and Adapta / Lanthascreen binding assays from Life technologies were used according to manufacturer’s instructions. Pourcentages of inhibition at 500 nM of test compounds were performed towards 58 kinases: ABL1, ACVR1B (ALKA), 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 alpha 1), DAPK3 (ZIPK), DYRK1A, EGFR (ErbBl), 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), MAPK1 1 (p38 beta), MAPKAPK2, MARK2, MET (cMet), NEK2, NTRK1 (TRKA), PAK2 (PAK65), PDGFRB (PDGFR beta), PDK1 Direct, PHKG2, PIK3CA / PIK3R1 (pl 10 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). The concentration of ATP was used at apparent Km for all kinases except for MAPK10 (JNK3) which was at 100 mM and for BRAF and MAP2K1 (MEK1) which are binding assays.

[0287] The results are reported in the Table below:

[0288] Compound n°l according to example 1 exhibits a favorable kinase selectivity score in the representative kinase panel. Indeed, only 1 kinase over 58 was inhibited with a percentage of inhibition higher than 80%, and 10 kinases at most were inhibited with a percentage of inhibition higher than 50%.

[0289] By contrast, comparative compounds A and B exhibit a poor selectivity score. Indeed, comparative compounds A and B inhibited respectively 15 / 58 and 10 / 58 kinases with a percentage of inhibition higher than 80%, and 26 / 58 and 20 / 58 kinases with a percentage of inhibition higher than 50%.

[0290] Example 9: Permeability assay

[0291] Caco 2 cell lines were used for the in vitro transport studies and were obtained from ATCC. Cells were split every other day at a split ratio of 1:3~I:5 and grown 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 onto polycarbonate Transwell filter membranes (Millipore) at a density of 60,000 cells / well. After 24h post seeding, changed medium and cultured for another 21 days before transport experiments. For transport studies, donor solutions were prepared by diluting the stock solutions of test compounds in transport medium (HBSS buffer with 10 mM HEPES, pH 7.4). Receiver solutions were the same HBSS buffer with lOmM HEPES, pH 7.4. The transport of test compounds (5 pM) was measured in duplicate in two directions [apical to basolateral (A— B) and basolateral to apical (B— >A)].

[0292] The permeability coefficient for membrane transport of test compounds was determined using the following equation: Papp (cm / sec) = (Vr / CO) (1 / S) (dC / dt); Papp = apparent permeability, Vr = volume of medium in the receiver chamber, CO = PAR of the test drug in the receiver chamber, S = surface area of monolayer, dC / dt = drug PAR in the receiver chamber with time). Efflux Ratio was defined as: Efflux Ratio = Papp B-A / Papp A-B Bioanalysis was done on LC-MS / MS.

[0293] The results are reported in the Table below:

[0294] Compound n°l according to example 1 exhibits excellent Caco-2 permeability parameters. Indeed, it has a Papp A-B value higher than 10.10'6cm / s. Moreover, it has an Efflux Ratio lower than 2.

[0295] By contrast, comparative compounds A and B exhibit poor Caco-2 permeability parameters, with low Papp A-B values (lower than 10.10'6cm / s) and high Efflux Ratios (higher than 3).

[0296] Example 10: PK experiments

[0297] To determine its absolute oral bioavailability, Compound n°l according to example 1 was suspended in a 0.5% CMC vehicle and administered to a group of 5-6 weeks old male BalbC mice. For intraveinous injection, a single 1 mg / kg dose was injected in tail vein and blood was collected at 0.12, 0.25, 0.5, 1, 2, 4, 8 and 24h after injection. For oral route, a single 20 mg / kg dose was administered, and blood was collected at 0.25, 0.5, 1, 2, 4, 8, 10 and 24h after gavage. Plasma separated from blood samples was stored at -20°C until analysis. Vials containing the study samples were retrieved and thawed to room temperature. A volume of 50 pl of sample was added to 200 pl of acetronitrile containing internal standard (tolbutamide; 25 ng / mL) and vortexed for 5 min and centrifuged at 14000 rpm for 5 min at 4°C. 200 pl of supernatant was separated and transferred to HPLC vial for analysis. For prodrug pharmacokinetics, only parent drug was dosed by HPLC.

[0298] The results are reported in the Table below:

[0299] Compound n°l according to example 1 exhibits good PK parameters. Indeed, it has an oral bioavailability upper than 8.9 which will permit to reach the target concentration of the molecule into the plasma.

[0300] Example 11: Preparation of the crystalline form of the compound N°1 according to example 1

[0301] 7 g of (5 -l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-UT- pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(U7)-one according to example 1 were suspended in 1.2 L of solvent MeCN / H20 (70 / 30).

[0302] The sample was filtrated after cooled down to room temperature and 4°C overnight yield crystals.

[0303] 4.1 g of pure (5 -l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-UT- pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(U7)-one is obtained.

[0304] The same procedure was repeated 6 times with 7 g to 9 g scale (volume total 1.3 L to 1.8 L of solvent).

[0305] After all recrystallizations, 33.4 g of product was obtained, and was triturated in Et2O (400 ml) to homogenize the final product to yield 33.4 g of (S)-l-(l-(3-chlorophenyl)-2- (dimethylamino)ethyl)-4-(5-morpholino-lJ / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(lJ7)-one, with a LC purity of 100% and LC chiral of 99.5%.

[0306] All filtrates of recrystallizations were gathered to obtain 26 g of product that was recrystallized in three batches to yield 16.8 g of product. The product was again triturated in 300 ml of Et2O to yield 16.5 g of (5)-l-(l-(3- chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino- l7 / -pyrrolo[2,3-A]pyri din-3- yl)pyridin-2(U7)-one, with a LC purity of 100% and LC chiral of 99.3%.

[0307] Characterization of the compound

[0308] The following results were obtained from the characterization of the compound:

[0309] - XRPD analysis showed a crystalline material designated as Pattern 1 (see Figure 1).

[0310] -JH NMR analysis also indicated that the material was consistent with the structure (see figure 2).

[0311] - Thin Layer Chromatography: Rf (retardation factor) = 0,25 (solvent 10% MeOH in DCM). - LC purity: 100%.

[0312] - LC chiral: 99.5%.

[0313] - MH+: 478.7; 480.7 (M; M+2).

[0314] Three Month Stability Study

[0315] The results of the three-month stability study are given in the following Table.

[0316] After storage for two weeks at each condition, the purity of the material was unchanged from the input purity (compound N°l : 98.56). The chemical stability was also unchanged.

[0317] The purity was slightly lower, albeit within 0.5 %area, potentially linked to analytical method and variation in sample preparation since the three-month stability is good compared with the T = 0. The diffractograms were unchanged, indicating that after one month the physical and chemical purity was stable.

[0318] At the three-month time point, the purity of the sample remained unchanged with respect to the input material. The diffractograms were unchanged, indicating that after three months the physical and chemical purity was stable under the conditions studied.

[0319] The stability study, over three months showed that the crystalline form is highly stable for three months under ambient and accelerated ageing conditions. The absence of a decrease in purity coupled with retention of the crystalline forms indicate that the crystalline form of (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-17 / -pyrrolo[2,3-

[0320] Z>]pyridin-3-yl)pyridin-2(U7)-one has superb stability.

[0321] Therefore, a three-month stability study of the crystalline form showed that the compound is of high purity and retained its crystalline form.

Claims

CLAIMS1. A crystalline form of (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4- (5-morpholino-lJ / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(lJ7)-one of the formula (I) below:wherein the crystalline form of (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5- morpholino-lJ / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(lJ7)-one presents a powder X-ray diffractogram displaying at least one peak, in particular at least two peaks, preferably at least five peaks, and more preferably at least ten peaks, expressed as degree 2-Theta angle selected from 3.36; 12.03; 12.49; 12.91; 13.42; 13.93; 14.72; 15.28; 17.18; 17.42; 19.64; 22.10; 22.47; 22.88; 23.08; 24.00; 25.07 and 25.90 (each time ±0.2).

2. A crystalline form according to anyone of the preceding claims, wherein the crystalline form of (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino- 17 / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(177)-one has a powder X-ray diffractogram displaying peaks expressed as degree 2-Theta angle at 14.72; 15.28; 17.18; 22.88; 23.08 and 24.00 (each time ± 0.2).

3. A crystalline form according to the preceding claim, wherein the crystalline form of (5)- 1 -( 1 -(3 -chi orophenyl)-2-(dimethylamino)ethyl)-4-(5 -morpholino- 1H- pyrrolo[2,3-A]pyridin-3-yl)pyridin-2( IT / )-one has a powder X-ray diffractogram further showing the following additional peaks expressed as degree 2-Theta angle: 12.03; 17.42; 22.10; 22.47; 25.07 and 25.90 (each time ± 0.2).

4. A crystalline form according to the preceding claim, wherein the crystalline form of (5)- 1 -( 1 -(3 -chi orophenyl)-2-(dimethylamino)ethyl)-4-(5 -morpholino- 1 H- pyrrolo[2,3-A]pyridin-3-yl)pyridin-2( IT / )-one has a powder X-ray diffractogram further showing the following additional peaks expressed as degree 2-Theta angle: 3.36; 12.49; 12.91; 13.42; 13.93 and 19.64 (each time ± 0.2).

5. A crystalline form according to anyone of the preceding claims, having single endotherm with an onset temperature of 281°C (±2°C).

6. A process for the preparation of a crystalline form according to anyone of the preceding claims, comprising the step of: a) suspending (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-lZ7- pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(U7)-one in a solvent or in a mixture of solvents, preferably in MeCN / EEO (70 / 30); b) optionally evaporating the solvent(s) at a temperature comprised between 0°C and the boiling point of the selected solvent(s) or mixture of solvent(s) of step a); c) optionally adding a solvent or a mixture of solvents, d) applying a temperature program; e) optionally filtrating; and f) optionally washing the obtained crystals with a solvent or a mixture of solvents, g) then optionally drying in order to obtain the desired crystalline form of (S)-l-(l-(3- chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-17 / -pyrrolo[2,3-Z>]pyridin-3- yl)pyridin-2(177)-one.

7. A crystalline form according to anyone of claims 1 to 5, for use for preventing and / or inhibiting and / or treating a disease or a condition mediated by ERK kinases activity, in particular by ERK2 kinase activity.

8. A crystalline form for use according to claim 7, wherein the disease or the condition is chosen among cancers and metastases.

9. A crystalline form for use according to claim 7 or 8, wherein the disease or the condition is chosen among glioblastomas, multiple myelomas, carcinomas, leukemia, in particular myeloid (AML), lymphocytic, myelocytic, myelogenous (CML) or lymphoblastic leukemias, myelodysplastic syndromes, Kaposi’s sarcomas, cutaneous angiosarcomas, solid tumours, lymphomas, in particular non-hodgkin’s lymphomas, melanomas, in particular malignant melanomas, bladder cancers, breast cancers, gastric cancers, colon cancers, colorectal cancers, endometrial cancers, lung cancers, including non-small-cell cancers, pancreatic cancers, prostate cancers, rectal cancers, kidney cancers, head and neck cancers, liver cancers, ovarian cancers, in particular serous ovarian cancers, seminoma cancers, cancers of the respiratory tract and chest, thyroid cancers, in particular papillary or follicular thyroid cancers, and other tumours expressing ERK.

10. A crystalline form for use according to claim 7, wherein the disease or the condition is chosen among a neoplastic disorder, an allergy disorder, an inflammatory disorder, an autoimmune disorder, a Plasmodium related disease, a mast cell associated disease, a graft- versus -host disease, a metabolic syndrome, a CNS related disorder, a neurodegenerative disorder, a pain condition, a substance abuse disorder, a prion disease, a heart disease, a fibrotic disease, idiopathic arterial hypertension (IP AH), and primary pulmonary hypertension (PPH).

11. A crystalline form for use according to claim 7, for use for preventing and / or inhibiting and / or treating the Human Immunodeficiency Virus (HIV).

12. Use of a crystalline form according to any one of claims 1 to 5, for preventing and / or inhibiting and / or treating a disease or a condition mediated by ERK kinases activity, preferably ERK2 kinases activity.

13. Medicament comprising at least one crystalline form according to anyone of claims 1 to 5.

14. A pharmaceutical composition comprising at least one crystalline form according to anyone of claims 1 to 5, and at least one pharmaceutically acceptable excipient.

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