Pharmaceutical compositions comprising (s)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1h-pyrrolo[2,3-b]pyridin-3-YL)pyridin-2(1H)-one hydrochloride and at least one carboxylic acid

Abstract

The present invention concerns pharmaceutical compositions and dosage forms comprising the hydrochloride salt 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 formula (I) below: Formula (I), (I) or a solvate thereof, and at least one carboxylic acid.

Description

[0001] PHARMACEUTICAL COMPOSITIONS COMPRISING (S)-1-(1-(3-CHLOROPHENYL)-2-(DIMETHYLAMINO)ETHYL)-4-(5-MORPHOLINO-1H-PYRROLO[2,3-B]PYRIDIN-3-YL)PYRIDIN-2(1H)-ONE HYDROCHLORIDE AND AT LEAST ONE CARBOXYLIC ACID

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to novel pharmaceutical compositions and dosage forms comprising (5)- 1 -( 1 -(3 -chlorophenyl)-2-(dimethylamino)ethyl)-4-(5 -morpholino- 1H-pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(U7)-one hydrochloride salt or a solvate thereof and at least one carboxylic acid, which are inhibitors of ERK kinases (ERK1 and ERK2), and to the therapeutic uses thereof.

[0004] BACKGROUND OF THE INVENTION 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.

[0005] 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).

[0006] 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).

[0007] 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).

[0008] However, resistances ultimately appear after current treatment with RAF and MEK inhibitors (Lito etal., 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 etal., Oncogene. 2013).

[0009] Furthermore, RAF or MEK inhibition suppresses ERK negative feedback that restores upward signaling and finally ERK activity (Lito etal., Nat. Med., 2013).

[0010] Considering the resistance phenomena that emerged after current treatment with RAF and MEK inhibitors, it is essential to develop new therapeutic options.

[0011] 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).

[0012] Azaindole derivative (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino- l / / -pyrrolo[2,3 -Z>]pyri din-3 -yl)pyridin-2(l / 7)-one of formula (I), depicted below, is an inhibitor of ERK kinases (ERK1 and ERK2) reported in international patent application WO 2023 / 135233 Al. It may be used in particular as an anticancer agent.

[0013]

[0014] (I)

[0015] (5)- 1 -( 1 -(3 -chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino- 1 / / -pyrrol o[2, 3 - Z>]pyridin-3-yl)pyridin-2(l / 7)-one is a dibasic compound with pKa values of approximately 2.9 and 6.8 and has been developed in a free base form which solubility could be improved. Indeed, it is desired that such ERK inhibitor shows high solubility when it is used for a pharmaceutical formulation, in particular a pharmaceutical formulation for oral administration.

[0016] In addition, it is desired that the solubility profile of such ERK inhibitor does not depend on the pH conditions. Indeed, it has been discovered that the free base of such ERK inhibitor has a solubility profile that is strongly dependent on pH. Thus, at acidic pH the free base isslightly soluble, but its solubility decreases strongly when the pH is higher than 3, which is not favorable to an oral administration.

[0017] The oral absorption and bioavailability of a therapeutic agent can furthermore be influenced by various factors, including the subject's fed or fasted state, the use of medications like proton pump inhibitors (PPIs) or histamine H2 receptor antagonists (H2RAs), and certain medical conditions. Compounds with pH-dependent solubility, especially basic ones, may show undesirable pharmacokinetic properties, such as poor absorption and reduced bioavailability, leading to significant dosage variability between and within patients.

[0018] There is therefore a need to provide new means for improving the solubility profile versus pH of (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-Uf-pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(U7)-one.

[0019] SUMMARY OF THE INVENTION

[0020] A first aspect of the invention concerns a pharmaceutical composition comprising the hydrochloride salt of (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-lJH-pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(U7)-one of formula (I) below:

[0021]

[0022] (I)

[0023] or a solvate thereof, and at least one carboxylic acid.

[0024] While it has been discovered that the dissolution of (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-l / / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(U7)-one hydrochloride is influenced by the pH of the dissolution medium, the addition of carboxylic acid(s) in the pharmaceutical compositions of this invention surprisingly ensures consistent dissolution extent and kinetics, thereby enhancing the bioavailability of (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-lJH-pyrrolo[2,3-Z>]pyri din-3-yl)pyridin-2(U7)-one regardless of stomachal pH variations.These pharmaceutical compositions therefore have particular 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.

[0025] Another aspect concerns dosage forms containing the pharmaceutical compositions according to the invention, in particular for oral administration.

[0026] A further aspect concerns the pharmaceutical compositions of the compound of formula (I) and the dosage forms containing the pharmaceutical compositions for their use especially in medicaments for preventing and / or inhibiting and / or treating a disease or a condition mediated by ERK kinases activity, in particular by ERK2 kinase activity.

[0027] ABBREVIATIONS AND DEFINITIONS

[0028] In the context of the present invention, the following abbreviations and empirical formulae are used:

[0029] ACN Acetonitrile

[0030] Cl 8 column Reversed-phase C18 column

[0031] DCM Dichloromethane

[0032] DMF Dimethylformamide

[0033] DMSO Dimethylsulfoxide

[0034] DSC Differential Scanning Calorimetry

[0035] DVS Dynamic Vapor Sorption

[0036] °C Degree(s) Celsius

[0037] ee Enantiomeric Excess

[0038] Eq. Equivalent(s)

[0039] Et2O Diethyl ether

[0040] EtOAc Ethyl acetate

[0041] EtOH Ethanol

[0042] FaSSGF Fasted State Simulated Gastric Fluid

[0043] FaSSIF Fasted State Simulated Intestinal Fluid

[0044] FT-IR Fourier Transform Infrared Spectroscopy

[0045] g gram(s)

[0046] h hour(s)

[0047] HPLC High Performance Liquid ChromatographyHPLC-CAD High Performance Liquid Chromatography with Charged Aerosol Detection

[0048] IR Infrared Spectroscopy

[0049] LC / MS Liquid Chromatography / Mass Spectrometry

[0050] LiHMDS Lithium bis(trimethylsilyl)amide

[0051] M Mole(s) per liter

[0052] MeOH Methanol

[0053] Me-THF 2-Methyltetrahydrofuran

[0054] mg Milligram(s)

[0055] MH+ Pseudo-molecular ion (positive ion mode in mass spectrometry) MHz Megahertz

[0056] µL Microliter(s)

[0057] min minute(s)

[0058] mL Milliliter(s)

[0059] mmol Millimole(s)

[0060] mol Mole(s)

[0061] MPA Mobile Phase A

[0062] MPB Mobile Phase B

[0063] MS Mass Spectrometry

[0064] NaCl Sodium chloride

[0065] Na2CO3Sodium carbonate

[0066] NaHCO3 Sodium hydrogen carbonate

[0067] NaOH Sodium hydroxide

[0068] Na2SO4Sodium sulfate

[0069] NH4Cl Ammonium chloride

[0070] NMR Nuclear Magnetic Resonance

[0071] PLM Polarised Light Microscopy

[0072] PSD Particle Size Distribution

[0073] RH Relative Humidity

[0074] RuPhos 2-Di cyclohexylphosphino-2’, 6 ’ -dii sopropoxybiphenyl RuPhos Pd G2 Chloro(2-dicyclohexylphosphino-2’,6’ -diisopropoxy- 1, 1’ -bi- phenyl)[2-(2’ -amino- 1,1’ -biphenyl)]palladium(II)TBAF Tetrabutylammonium Fluoride

[0075] TEA Triethylamine

[0076] TGA Thermogravimetric Analysis

[0077] THF Tetrahydrofuran

[0078] UV Ultraviolet

[0079] XRPD X-Ray Powder Diffraction

[0080] 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.

[0081] 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.

[0082] 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.

[0083] A hydrochloride salt is a salt of hydrochloric acid.

[0084] A carboxylic acid is an organic acid that contains at least one carboxyl group (-C(=O)-OH). The terms “aliphatic carboxylic acid", as used in the present invention, refer to a linear or branched hydrocarbon chain bearing at least one carboxyl group. The hydrocarbon chain is completely saturated or contains one or more unsaturations, but is not aromatic. Preferably, the hydrocarbon chain is completely saturated or contains one or more double bonds. The hydrocarbon chain can further comprise other substituents, such as at least one hydroxyl group (-OH).

[0085] The term "about" means having a value falling within an accepted standard of error of the mean when considered by one of ordinary skill in the art. Frequently, the term "about" refers to ±15%, preferably ±10%, and more preferably ±5% of the value or range to which it refers. For example, "about 10 wt%" means 10 wt% ±1.5 wt%, preferably 10 wt% ±1 wt%, and more preferably 10 wt% ±0.5 wt%.

[0086] 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.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.

[0087] 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.

[0088] Other features, properties and advantages of the invention will emerge more clearly from the description and examples that follow.

[0089] DESCRIPTION OF THE FIGURES

[0090] Figure 1 illustrates an X-ray powder diffractogram of mono-hydrochloride anhydrate salt of (5)- 1 -( 1 -(3 -chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino- l / Z-pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(U7)-one (see Example 3).

[0091] Figure 2 illustrates the pH 1.2 buffer dissolution profiles of (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-U / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(U7)-one hydrochloride alone or with tartaric acid (2.1 molar equivalent), in gelatin capsules (see Example 5).

[0092] Figure3 illustrates the dissolution profiles of (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-lZZ-pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(U7)-one hydrochloride in gelatin capsules, tested in pH 1.2 and pH 5.1 buffers (see Example 5). Figure 4 illustrates the pH 5.1 buffer dissolution profiles of (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-lZZ-pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(U7)-one hydrochloride alone or with 1.0, 2.1, or 4.5 molar equivalent of tartaric acid, in gelatin capsules (see Example 5).Figure 5 illustrates the pH 5.1 buffer dissolution profiles of (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-U / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(U7)-one hydrochloride alone or with 2.1 or 4.5 molar equivalent of succinic acid, in gelatin capsules (see Example 5).

[0093] Figure 6 illustrates the pH 5.1 buffer dissolution profiles of (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-lZZ-pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(U7)-one hydrochloride alone or with 0.92 or 4.1 molar equivalent of citric acid, in gelatin capsules (see Example 5).

[0094] Figure 7 illustrates the pH 5.1 buffer dissolution profiles of (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-U / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(U7)-one hydrochloride alone or with tartaric acid (4.5 molar equivalent), citric acid (4.1 molar equivalent), or succinic acid (4.5 molar equivalent), in gelatin capsules (see Example 5).

[0095] DETAILED DESCRIPTION

[0096] Pharmaceutical Compositions

[0097] As mentioned above, an object of the present invention is a pharmaceutical composition comprising the hydrochloride salt of (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-lZZ-pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(lJ7)-one (Compound 1) of the formula (I) below:

[0098]

[0099] or a solvate thereof, and

[0100] at least one carboxylic acid.

[0101] According to a preferred embodiment, Compound 1 hydrochloride is a solid.

[0102] According to a preferred embodiment, Compound 1 hydrochloride is anhydrous.

[0103] According to a preferred embodiment, Compound 1 hydrochloride is a solvate.

[0104] More particularly, Compound 1 hydrochloride is a hydrate.According to a preferred embodiment, Compound 1 hydrochloride is amorphous.

[0105] According to a preferred embodiment, Compound 1 hydrochloride is crystalline.

[0106] According to a preferred embodiment, Compound 1 hydrochloride is anhydrous crystalline hydrochloride salt, preferably anhydrous crystalline mono-hydrochloride salt.

[0107] More particularly, anhydrous crystalline hydrochloride salt of (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-l / Z-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 11.50; 13.00; 15.23; 15.72; 16.10; 16.55; 17.46; 17.86; 18.29; 19.99; 22.23; 22.99; 23.15; 25.18 and 30.76 (each time ±0.2), as illustrated in Figure 1 and / or has a single endotherm with an onset temperature of 258.0 °C (±2 °C).

[0108] According to a preferred embodiment, the anhydrous crystalline Compound 1 hydrochloride 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 11.50; 13.00; 15.23; 15.72; 16.10; 16.55; 17.46; 17.86; 18.29; 19.99; 22.23; 22.99; 23.15; 25.18 and 30.76 (each time ±0.2).

[0109] According to a preferred embodiment, the anhydrous crystalline Compound 1 hydrochloride has an XRPD substantially similar to that depicted in Figure 1.

[0110] According to a preferred embodiment, the at least one carboxylic acid contains one, two or three carboxyl groups.

[0111] More particularly, the at least one carboxylic acid contains two or three carboxyl groups. Advantageously, the at least one carboxylic acid contains two carboxyl groups.

[0112] According to a preferred embodiment, the at least one carboxylic acid is anhydrous.

[0113] According to a preferred embodiment, the at least one carboxylic acid is a solvate.

[0114] More particularly, the at least one carboxylic acid is a hydrate.

[0115] According to a preferred embodiment, the at least one carboxylic acid is a pharmaceutically acceptable carboxylic acid.

[0116] According to a preferred embodiment, the at least one carboxylic acid is an aliphatic carboxylic acid.

[0117] According to a preferred embodiment, the at least one carboxylic acid, in particular the at least one aliphatic carboxylic acid, contains from 2 to 12 carbon atoms, preferably from 2 to10 carbon atoms, more preferably from 2 to 8 carbon atoms, even more preferably from 2 to 6 carbon atoms.

[0118] According to a preferred embodiment, the at least one carboxylic acid is selected from adipic acid, citric acid, fumaric acid, maleic acid, malonic acid, oxalic acid, glutaric acid, oxoglutaric acid, lactic acid, sorbic acid, succinic acid, tartaric acid, and mixtures thereof. More particularly, the at least one carboxylic acid is selected from citric acid, succinic acid, tartaric acid, and mixtures thereof.

[0119] Advantageously, the at least one carboxylic acid is tartaric acid.

[0120] According to a preferred embodiment, the molar ratio between the amount of Compound 1 hydrochloride and the amount of carboxylic acid(s) ranges from 0.5 to 5, preferably from 1 to 4.5, more preferably from 1.5 to 3, even more preferably from 2.0 to 2.5.

[0121] According to a preferred embodiment, the molar ratio between the amount of Compound 1 hydrochloride and the amount of carboxyl groups in the carboxylic acid(s) ranges from 0.25 to 2.5, preferably from 0.5 to 2, more preferably from 0.75 to 1.5, even more preferably from 1.0 to 1.25.

[0122] According to a preferred embodiment, the pharmaceutical composition comprises from 25% to 40% by weight of Compound 1 free base equivalent, preferably from 25% to 35%, more preferably from 30% to 35%, even more preferably about 30% or 35%, most preferably about 30%.

[0123] According to a preferred embodiment, the pharmaceutical composition comprises from 10% to 50% by weight of carboxylic acid, preferably from 10% to 40%, more preferably from 15% to 40%, even more preferably from 15% to 35%, most preferably from 20% to 35%. According to a preferred embodiment, the pharmaceutical composition comprises from 25% to 40% by weight of Compound 1 free base equivalent and from 10% to 35% by weight of succinic acid.

[0124] According to a preferred embodiment, the pharmaceutical composition comprises from 25% to 40% by weight of Compound 1 free base equivalent and from 20% to 50% by weight of citric acid.

[0125] According to a preferred embodiment, the pharmaceutical composition comprises from 25% to 40% by weight of Compound 1 free base equivalent and from 15% to 40% by weight of tartaric acid.More particularly, the pharmaceutical composition comprises from 25% to 35% by weight of Compound 1 base equivalent and from 15% to 25% by weight of tartaric acid, preferably from 30% to 35% by weight of Compound 1 free base equivalent and from 20% to 25% by weight of tartaric acid.

[0126] Advantageously, the pharmaceutical composition comprises about 30% or 35% by weight of Compound 1 free base equivalent and about 20% or 35% by weight of tartaric acid, preferably about 30% by weight of Compound 1 free base and about 35% by weight of tartaric acid, about 30% by weight of Compound 1 free base and about 20% by weight of tartaric acid, or about 35% by weight of Compound 1 base and about 20% by weight of tartaric acid.

[0127] Most particularly, the pharmaceutical composition comprises about 30% by weight of Compound 1 free base equivalent and about 20% by weight of tartaric acid.

[0128] Dosage Forms

[0129] As mentioned above, an object of the present invention is a dosage form containing a pharmaceutical composition according to the present invention.

[0130] According to a preferred embodiment, the dosage form contains an effective dose of Compound 1 hydrochloride salt.

[0131] According to a preferred embodiment, the dosage form is suitable for oral, nasal, sublingual, aural, ophthalmic, topical, rectal, vaginal, urethral, or parenteral injection route.

[0132] More particularly, the dosage form is suitable for oral administration.

[0133] According to a preferred embodiment, the dosage form is provided as a tablet, capsule, powder, granule, lozenge, thin film, or pastille.

[0134] According to a preferred embodiment, the dosage form contains any known suitable pharmaceutically acceptable excipients according to the dose, the galenic form, the route of administration and the likes, including, for example, diluents, disintegrants, binders, lubricants, glidants, and surface-active agents. Dosage forms of the invention may also contain excipients like preservatives, antioxidants, flavors, and colorants, along with other excipients known in the art.

[0135]

[0136] As specified previously and clearly illustrated by the following examples, the compositions according to the present invention are useful as inhibitors of the ERK kinases activity. According to a first aspect, the compositions of the invention are used as inhibitors of the ERK2 kinase activity, preferably as selective inhibitors of the ERK2 kinase activity.

[0137] More specifically, the compositions of the invention are 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.

[0138] 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 composition in accordance with the invention.

[0139] The present invention also provides the compositions of the invention for their 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.

[0140] The present invention also provides the use of compositions 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.

[0141] 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.

[0142] 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 tumors, 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 particularserous ovarian cancers, seminoma cancers, cancers of the respiratory tract and chest, thyroid cancers, in particular papillary or follicular thyroid cancers, or other tumors expressing ERK. 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).

[0143] According to yet another embodiment, the compositions of the invention may be used for preventing and / or inhibiting and / or treating the Human Immunodeficiency Virus (HIV).

[0144] The compositions of the present invention may be used alone or combined with chemotherapeutic agents or radiotherapeutic regimen.

[0145] Thus, according to one embodiment, a method of the invention may comprise the step of administering a composition in accordance with the invention, separately, sequentially, or simultaneously with a chemotherapeutic agent.

[0146] 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.

[0147] 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.

[0148] The compositions 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.

[0149] Thus, according to yet another of its aspects, the present invention relates to a medicament comprising at least one composition according to the invention.

[0150] A composition according to the invention may be administered in an effective dose by any of the accepted modes of administration in the art.In one embodiment, a composition of the invention is intended to be administrated by oral, nasal, sublingual, aural, ophthalmic, topical, rectal, vaginal, urethral, or parenteral injection route.

[0151] The route of administration and the galenic formulation will be adapted by one skilled in the art pursuant to the desired pharmaceutical effect.

[0152] In a preferred embodiment, a composition of the invention is intended to be administrated by oral route.

[0153] 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 a composition of the invention for a given indication.

[0154] 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.

[0155] A pharmaceutical composition or dosage form 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).

[0156] The applications also include a novel kit-of-parts that is suitable for use in the treatment of cancers.

[0157] A kit-of-part according to the invention may comprise (i) a composition 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 the compound of formula (I). An agent useful for the prevention and / or treatment of a cancer condition may be a chemotherapeutic agent or a radiotherapeutic agent.

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

[0159]

[0160] and methods used for the

[0161] Unless otherwise stated, the following equipments and analytical methods are used in the examples.

[0162] 1. X-ray Powder Diffraction (XRPD)

[0163] XRPD analysis was carried out on a PANalytical Xpert pro with PIXcel detector (128 channels), scanning the samples between 3 and 35° 29. The material was gently ground with mortar and pestle to release any agglomerates and loaded onto a multi-well plate with Mylar polymer film to support the sample. The multi-well plate was then placed into the diffractometer and analyzed using Cu K radiation (al X = 1.54060 A; a2 = 1.54443 A; P = 1.39225 A; al: a2 ratio = 0.5) running in transmission mode (step size 0.0130° 29, step time 18.87s) using 40 kV / 40 mA generator settings. Data were visualized and images generated using the HighScore Plus 4.9 desktop application (PANalytical, 2020).

[0164]

[0165] 2.

[0166] The presence of crystallinity (birefringence) was determined using an Olympus BX53 microscope, equipped with cross-polarising lenses and a Motic camera. Images were captured using Motic Images Plus 3.0. All images were recorded using the 20 x objective, unless otherwise stated.

[0167] 3. Thermogravimetric Analysis / Differential Scanning Calorimetry (TGA / DSC) Approximately 5-10 mg of material was added into a pre-tared open aluminium pan and loaded into a TA Instruments Discovery SDT 650 Auto - Simultaneous DSC and held at room temperature. The sample was then heated at a rate of 10 °C / min from 30 °C to 400 °C during which time the change in sample weight was recorded along with the heat flow response (DSC). Nitrogen was used as the sample purge gas, at a flow rate of 200 cm3 / min.

[0168] 4. Differential Scanning Calorimetry (DSC)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 an 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.

[0169] 5. Infrared Spectroscopy (IR)

[0170] Infrared spectroscopy was carried out on a Bruker ALPHA P spectrometer. Sufficient material was placed onto the centre of the plate of the spectrometer and the spectra were obtained using the following parameters:

[0171] - Resolution: 4 cm'1;

[0172] - Background Scan Time: 16 scans;

[0173] - Sample Scan Time: 16 scans;

[0174] - Data Collection: 4000 to 400 cm'1;

[0175] - Result Spectrum: Transmittance;

[0176] - Software: OPUS version 6.

[0177] 6. Nuclear Magnetic Resonance (NMR)

[0178] NMR experiments were performed on a Bruker AVIIIHD spectrometer equipped with a DCH cryoprobe operating at 500.12 MHz for protons. Experiments were performed in deuterated DMSO and each sample was prepared to ca. 10 mM concentration.

[0179] 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.

[0180] 7. Dynamic Vapour Sorption (DVS)

[0181] Approximately 10-20 mg of sample was placed into a mesh vapour sorption balance pan and loaded into a DVS Intrinsic or Advantage dynamic vapour sorption balance by Surface Measurement Systems. The sample was subjected to a ramping profile from 40 - 90% relative humidity (RH) at 10% increments, maintaining the sample at each step until a stableweight had been achieved (dm / dt 0.004%, minimum step length 30 minutes, maximum step length 500 minutes) at 25 °C. After completion of the sorption cycle, the sample was dried using the same procedure to 0 %RH and then a second sorption cycle back to 40 %RH. Two cycles were performed. The weight change during the sorption / desorption cycles were plotted, allowing for the hygroscopic nature of the sample to be determined. XRPD analysis was then carried out on any solid retained.

[0182] 8. High Performance Liquid Chromatography-Ultraviolet Detection (HPLC-UV) Column: Halo Cl 8 100 x 3.0 mm, 2.7 pm

[0183] Column Temperature: 40 °C

[0184] Flow Rate: l. O mL / min

[0185] Column Pressure at start of Run: 400 Bar

[0186] Injection Volume: 2 pL

[0187] Autosampler Temperature: Ambient (°C)

[0188] Detection parameters: UV at 219 nm

[0189] Sampling Rate: 10 Hz

[0190] Mobile Phase A: 0.1% formic acid in H2O

[0191] Mobile Phase B: 0.1% formic acid in ACN

[0192] Diluent: 50:50 MPA: MPB

[0193] Needle Wash: MPB

[0194] Gradient:

[0195] Time (minutes) MP A % MP B %

[0196] 0.0 90 10

[0197] 1.0 90 10

[0198] 7.0 0 100

[0199] 10.0 0 100

[0200] 10.1 90 10

[0201]

[0202] 15.0 90 10

[0203] 9. Mass Spectrometry

[0204] Column: X-Bridge C18, 50 mm x 3 mm, 3.5 pm

[0205] Column Temperature: 40 °C

[0206] Flow Rate: l. O mL / min

[0207] Injection Volume: 1 pLAutosampler Temperature: Ambient (°C)

[0208] Detection parameters: UV 210 nm Monitor only UV Scan 190 to 900 nm; MS + / - ESI Fragmentor 135 V

[0209] Mobile Phase A: 0.1% formic acid in water v / v

[0210] Mobile Phase B: 0.1% formic acid in ACN v / v

[0211] Diluent: 50:50 %v / v ACN: Water

[0212] Gradient:

[0213] Time (minutes) MP A % MP B %

[0214] Time (minutes) MP A % MP B %

[0215] 0 95 5

[0216] 8 5 95

[0217] 10 5 95

[0218] 10.1 95 5

[0219]

[0220] 14 95 5

[0221] Sample Preparation: Working Concentration: 0.1 mg / mL

[0222] 10. Particle Size Distribution (PSD)

[0223] Particle size distribution analysis was conducted using a Malvern Mastersizer 2000, stirring unit rinsed with 2-propanol before use. The following parameters were used:

[0224] PSD Parameters:

[0225] - Dispersant: 0.05 % w / v Span-85 in Heptane

[0226] - Dispersant Volume: 10 mL

[0227] - Sample Weight: 150 ± 3 mg

[0228] - Analysis Model: General Purpose

[0229] - Particle Shape: Irregular

[0230] - Sensitivity: Normal

[0231] - Particle RI: Fraunhofer

[0232] - Particle Absorption: Fraunhofer

[0233] - Dispersant RI: 1.39

[0234] - Measurements: 3

[0235] - Background / Measurement Time: 10 seconds

[0236] - Circulation Time Pre-Measurement: 3 minutes

[0237] - Circulation Rate: 2800 rpm- Sonication Time: N / A

[0238] - Obscuration Limits: 9-15 %

[0239] Sample Preparation: The bulk sample was gently inverted and rotated to achieve homogeneity. Ca. 150 mg of sample was weighed into a 20 mL scintillation vial and 10 mL of dispersant was added.

[0240] 11. Flash chromatography

[0241] Apparatus: Biotage SP with auto-collector and UV detection (2 wavelengths).

[0242] Normal phase columns: 10, 25 or 120 g Biotage external dry load cartridge kit, packed with Sigma- Aldrich 40-63 pm silica gel.

[0243] Reverse phase column: 30 g Biotage SNAP Cartridges, KP-C18-HS.

[0244] Chiral column: Daicel ChiralFlash IG 100 x 30 mm 20 pM.

[0245] 12. Thermodynamic Solubility Study

[0246] Prior to starting the solubility test, the purity of the salts was analyzed by HPLC.

[0247] A thermodynamic solubility study was carried out on the salts as follows:

[0248] Approximatively 25-30 mg of each sample, one sample per buffer, was weighed in 2 mL vials. A stirrer bar was added, and the samples were placed at ca. 37 °C. While stirring the sample, 75 pL of water / buffer was added until dissolution of the salt or until a total of 1.5 mL was added. If full dissolution was observed, more solid material was added until a slurry was obtained. Media used: Unbuffered water, FaSSIF (pH 6.5), FaSSGF (pH 1.6). At T = 0, T = 4 h and T = 24 h, aliquots of the slurries were filtered. The filtrate was analyzed by HPLC for concentration determination. pH measurements were taken at each timepoint when sufficient volume permitted it. The solids were analyzed by XRPD.

[0249] Example 1: Synthesis of (5l)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-

[0250]

[0251] iiiorpholino- 1 / / -pyrrolo|2.3- / i|pyridin-3-yl)pyridin-2( 1 / / )-one (Compound 1)

[0252]

[0253]

[0254] Step 1-1: l-Chloro-3-vinylbenzene

[0255] ci

[0256] ' y

[0257] 10 g (71.1 mmol) of 3 -chlorobenzaldehyde were dissolved in 50 mL of dry THF and the solution was cooled to -10 °C with an ice / acetone bath. 17.3 g (48.4 mmol, 1.2 eq.) of methyltriphenylphosphonium bromide were added followed by 2.1 g (52.4 mmol, 1.3 eq.) of sodium hydride (60% in paraffin oil). The suspension was then stirred at room temperature overnight under argon. The mixture was diluted with 100 mL of Et20 and the precipitate was filtered on Celite. The filtrate was evaporated under reduced pressure to give an orange residue. The crude mixture was 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 was obtained.

[0258] Step 1-2: 2-(3-Chlorophenyl)oxirane

[0259] ^0

[0260]

[0261] 4.05 g (29.2 mmol) of 1 -chi oro-3 -vinylbenzene (described in the previous step) were dissolved in 6 mL of 1,4-di oxane and 18 mL of water. The solution was cooled to 0 °C and 584 pL (10.2 mmol, 1 eq.) of acetic acid were added, followed by 1.99 g (11.2 mmol, 1.1 eq.) of / ' / -bromosuccinimide. Reaction mixture was stirred at 0 °C for 5 min then at room temperature for 2 h. The mixture was then cooled again to 0 °C and a solution of NaOH 2N in water (35.7 mmol, 3.5 eq.) was slowly added. The solution was allowed to stir at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the resulting aqueous phase was extracted 3 times with DCM. The combined organic layers weredried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude mixture was 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 was obtained.

[0262] Step 1-3: 1-(3-Chlorophenyl)-2-(dimethylamino)ethan-1-ol

[0263]

[0264] 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% was added 7.38 mL (14.76 mmol, 2 eq.) of a solution of dimethylamine (2M in THF). The clear resulting solution was heated under microwave irradiation at 80 °C for 30 min. The reaction mixture was then concentrated under vacuum and diluted with water. The solution was extracted 3 times with DCM. The combined organic layers were dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude mixture was purified by flash chromatography using a silica gel column and a DCM / MeOH mixture as eluent. 4.06 g of the title compound was obtained.

[0265] Step 1-4: 2-Chloro-2-(3-chlorophenyl)-7V,7V-dimethylethan-l-amine

[0266]

[0267] 4.06 g (20.3 mmol) of l-(3-chlorophenyl)-2-(dimethylamino)ethan-l-ol (described in the previous step) was dissolved in 15 mL of DCM and placed at 0 °C. 2.1 mL (15.1 mmol, 3 eq.) of TEA was added, followed by 0.781 mL (10.1 mmol, 2 eq.) of mesyl chloride. The reaction was stirred at 0 °C under argon for 2 h. Water was then added, and the mixture was decanted. The aqueous layer was extracted 2 times with DCM. The combined organic layers were dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude compound was directly used in the next step without further purification. 4.41 g of the title compound was obtained.Step 1-5: 4-Bromo-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)pyridin-2(lH)-one

[0268] Br

[0269]

[0270] 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, was added at 0 °C a solution of 4.41 g (20.3 mmol) of 2-chloro-2-(3-chlorophenyl)-7V,7V-dimethylethan-l -amine (described in the previous step) in 5 mL of dry DMF. The solution was then stirred at room temperature for 2 h. 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. 5.02 g of the title compound was obtained.

[0271] Step 2-1: 4-( 1 / / -I’y rrolo|2.3- / > | pyridin-5-yl (morpholine

[0272]

[0273] In 487 mL of LiHMDS (IM in THF, 487 mmol, 2.4 eq.) were 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 were added under argon 40 g (203 mmol, 1 eq.) of 5-bromo-lJ / -pyrrolo[2,3-Z>]pyridine and 21.1 mL (244 mmol, 1.2 eq.) of morpholine and the solution was heated at 66 °C for 1.5 h. The reaction mixture was then cooled to room temperature and dropped into 1.2 L of a saturated NH4CI solution maintaining the temperature under 10 °C with an ice water bath. The mixture was stirred for 10 min at this temperature and decanted. The aqueous layer was extracted 3 times with DCM. The combined organic layers were dried over Na₂SO₄, filtered, and evaporated under reduced pressure to give 44.4 g of a brown solid. The crude was triturated in 200 mL of a mixture of EtOAc and hexane (3 / 7) for 1 h. The solid was filtered, rinsedwith 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.

[0274] Step 2-2: 4-(l-Tosyl-l / / -pyrrolo|2.3- / >|pyridin-5-yl)morpholine

[0275]

[0276] 38.98 g (192 mmol, 1 eq.) of 4-(17 / -pyrrolo[2,3-Z>]pyridin-5-yl)morpholine (described in the previous step) was dissolved in 390 mL of dry DMF, under argon. The solution was cooled to 0 °C, and 11.5 g (288 mmol, 1.5 eq.) of sodium hydride (60% in paraffin oil) was slowly added. The mixture was stirred for 10 min at this temperature and then 40 min at room temperature. The mixture was cooled again to 0 °C, 47.5 g (249 mmol, 1.3 eq.) of tosyl chloride were slowly added under argon and the reaction mixture was stirred at 0 °C for 1 h followed by 1 h at room temperature. The mixture was dropped into 800 g of ice / water and stirred for 1 h. A precipitate is obtained, which was filtered and rinsed several times with cold water. The precipitate was then dissolved with 1.2 L of DCM, and the solution was washed 2 times with a saturated NaHCO₃ solution, 2 times with water and once with brine. The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude compound was triturated in 500 mL of a mixture of EtOAc and hexane (5 / 95) for 3 h. The solid was filtered, rinsed with hexane and dried under vacuum to give 62.56 g of an off-white solid.

[0277] Step 2-3: 4-(3-(4.4.5.5-tetramethyl-1.3.2-dioxaborol:in-2-yl)-l-tosyl-l / / -pyrrolo|2.3- / >]pyridin-5-yl)morpholine

[0278]

[0279] 62.56 g (175 mmol, 1 eq.) of 4-(l-tosyl-17 / -pyrrolo[2,3-Z>]pyridin-5-yl)morpholine (described in the previous step) was 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.) were added. The reaction was heated to reflux for 45 min under argon. The reaction mixture was then cooled to -10 °C with an ice / acetone bath and quenched carefully with MeOH (350 mL). The solution was stirred at room temperature for 15 min and evaporated under vacuum to give a brown oil. This dark oil was then dissolved in 1 L of DCM, washed 3 times with water and once with brine. Organic layer was evaporated under reduced pressure to give a black paste. 2 L of Et2O were added and the mixture was stirred for 15 min at room temperature, filtered on Celite and evaporated under reduced pressure to give 95 g of a brown solid foam. The crude mixture was finally purified by flash chromatography using a silica gel column and an EtOAc / hexane mixture as eluent. 75.5 g of the title compound was obtained.

[0280] Step 3-1: 1 -( 1 -(3-Chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino- 1 -tosyl- 1 H-pyrrolo [2,3-6] pyridin-3-yl)pyridin-2(lH)-one

[0281]

[0282] 2 g (5.6 mmol) of 4-bromo-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)pyridin-2(177)-one (described in Step 1-5) 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- 1 J / -pyrrolo[2,3 -Z>]pyridin-5-yl)morpholine (described in Step 2-3) were dissolved in 13 mL of ACN under argon. Then 13 mL of a solution of Na₂CO₃ 2M were added to give a biphasic mixture which was bubbled with argon for 15 min. 135 mg (0.19 mmol, 0.05 eq.) of bis(triphenylphosphine)palladium dichloride was added and the solution was bubbled with argon for another 15 min. The reaction was stirred at 70 °C for 2 h under argon. The reaction mixture was then diluted with water and EtOAc, and then decanted. The aqueous layer was extracted 2 times with EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude mixture was purified by flash chromatography using a silica gel column and a DCM / MeOH mixture as eluent. 2.68 g of the title compound was obtained.

[0283] Step 3-2: 1-(1-(3-Chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0284]

[0285] 2.68 g (4.2 mmol) of l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-l-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step) was dissolved in 15 mL of dry THF under argon. Then 10 mL (10 mmol, 3 eq.) of a solution of TBAF (IM in THF) were added and the reaction was stirred at 66 °C for 1 h under argon. Solvent was removed under reduced pressure and 100 mL of a saturated NaHCO₃ solution was added. The mixture was extracted 3 times with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude mixture was purified by flash chromatography using a silica gel column and a DCM / MeOH mixture as eluent. 617 mg of racemate are obtained.

[0286] Step 3-3: (S)-1-(1-(3-Chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one

[0287]

[0288] Enantiomers obtained in the previous step were 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 was the (-) ( / / (-enantiomer, followed by the (+) (A')-enantiomer with ee > 98%. 227 mg of the title compound was obtained starting from 617 mg of racemate. MH+: 478.5; 480.6 (M; M+2).

[0289] ¹H NMR (DMSO-d6, 400 MHz): 5 12.06 (br s, 1H); 8.17 (d,.7=2,4 Hz, 1H); 8.10 (d, J=2.3 Hz, 1H); 7.76 (d, J=8.0 Hz, 1H); 7.70 (d,.7=2,4 Hz, 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).

[0290] Example 2: Amorphization of Compound 1 according to Example 1

[0291] The compound was rendered amorphous in the following manner to provide a material free from the presence of crystalline seeds, prior to further experimentation:

[0292] The compound was weighed into a 20 mL vial and transferred into a 100 mL round bottom flask.

[0293] DCM: MeOH (1:2 v / v) (15 mL) was added and a slurry was observed after gentle heating. DCM (15 mL) was added resulting in a clear solution. The solvent was rapidly removed using a rotary evaporator resulting in the appearance of yellow solids.

[0294] The solids were analyzed by XRPD to confirm the form. The resulting solids from the fast evaporation of a DCM: MeOH mixture were predominantly amorphous.

[0295] XRPD analysis showed a crystalline material designated as Free base Pattern 1.

[0296] Example 3: Synthesis of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-

[0297]

[0298] morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (Compound 1) Mono-

[0299]

[0300] Hydrochloride anhydrate salt

[0301] The mono-hydrochloride salt of Compound 1 was prepared as follows:

[0302] Compound according to Example 2 (800 mg) was weighed into a 20 mL vial and suspended in 2-propanol (15 mL). 1.05 eq. of hydrochloric acid was added neat to the experiment. The experiment was then allowed to temperature cycle from 50 to 20 °C at 0.1 °C / min with an hour hold at each temperature with stirring for 48 hours.

[0303] After this time, a predominantly amorphous diffractogram was observed.

[0304] The solids were isolated by Buchner filtration under vacuum. 15 mL of acetone was added to the solids and the slurry was further cycled for 48 hours.

[0305] After this time, the diffractogram showed the hydrochloride salt had been formed.1

[0306] The solids were isolated and allowed to dry under vacuum at 40 °C for approximately 24 h. Upon drying, no changes to the diffractogram were observed.

[0307] This salt was fully characterized, the following observations and results were obtained:

[0308] - XRPD analysis indicated that the material was consistent with hydrochloride Pattern 1. A characteristic X-ray powder diffractogram can be given in Figure 1 and its characteristic signals are summarized in the following table:

[0309] Table 1

[0310] Angle (2-Theta) Relative intensity

[0311] (each time ±0.2) (%)

[0312] 11.50 28.33

[0313] 13.00 23.40

[0314] 15.23 78.30

[0315] 15.72 42.35

[0316] 16.10 24.91

[0317] 16.55 26.60

[0318] 17.46 20.07

[0319] 17.86 31.95

[0320] 18.29 21.53

[0321] 19.99 47.64

[0322] 22.23 86.86

[0323] 22.99 100.00

[0324] 23.15 76.38

[0325] 25.18 34.60

[0326]

[0327] 30.76 19.26

[0328] - PLM analysis showed very small birefringent needles shaped crystals.

[0329] - TGA / DSC analysis: TGA analysis indicated that there was a no loss of weight until the melting point, indicating an anhydrous salt. The melting point occurred with the beginning of molecular degradation / disproportionation. Simultaneous DSC analysis indicated that there was an endothermic event with an onset of 256 °C (peak at 267 °C).

[0330] - DSC analysis was carried out with the material sealed non-hermetically with a pierced lid. The first heating step of the DSC analysis revealed that there was an endothermic event observed with an onset of 273 °C with a peak at 275 °C. A vitrification event (anticipated after the initial melt) was not observed during the cool cycle. Similarly, on the second heating step no clear thermal events were observed.

[0331] - DVS analysis indicated that hydrochloride Pattern 1 was slightly hygroscopic, with a moisture uptake of 0.97 wt.% at 80 % RH (0.4 mol eq. water). There was no evidence of form change during the DVS experiment, and equilibration at each step was rapid. XRPDanalysis indicated that there was no change in form of hydrochloride Pattern 1 after the DVS experiment was completed.

[0332] - HPLC-UV analysis indicated that the hydrochloride salt had a purity of 98.39 %area. - HPLC-CAD analysis resulted in a chloride content of 7.0 %w / w (average of two replicates) which was consistent with a mono hydrochloride salt.

[0333] - FT-IR analysis showed no indication of hydration of the crystalline form.

[0334] - 'H NMR analysis of hydrochloride Pattern 1 indicated that there was 0.06 mol eq. of 2-propanol (a trace amount) and the chemical shifts were in line with salt formation.

[0335] - PSD analysis of hydrochloride salt Pattern 1 gave the following values:

[0336] • DIO - 0.824 pm

[0337] • D50 - 2.705 pm

[0338] • D90 - 11.635 pm

[0339] Thermodynamic solubility

[0340] The thermodynamic solubility carried out on Compound 1 hydrochloride salt Pattern 1 showed:

[0341] Table 2

[0342] Buffer Timepoint (h) Solubility (mg / mL)

[0343] Water 0 15.3

[0344] 4 14.5

[0345] FaSSIF 0 1.8

[0346] (pH = 6.5) 4 2.3

[0347] FaSSGF 0 17.9

[0348]

[0349] (pH = 1.6) 4 20.3

[0350] The thermodynamic solubility assessment of hydrochloride Pattern 1 showed a solubility of ca. 20 mg / mL across the study in water and in FaSSGF.

[0351] In FaSSIF the solubility was only around 3 mg / mL at each timepoint.

[0352] Furthermore, analysis of the XRPD diffractograms after 24 hours from water and FaSSGF showed that hydrochloride Pattern 1 was recovered unchanged, albeit a poorly crystalline Pattern 1 was observed after 24 hours in water.

[0353] In FaSSIF some small peaks that could be assigned to the free base were observed across the duration of the study.For comparison, the thermodynamic solubility carried out on Compound 1 free base (compound 1 according to example 1) showed:

[0354] Table 3

[0355] Buffer Timepoint (h) Solubility (mg / mL)

[0356] FaSSIF 4 0.3

[0357] (pH = 5.0) 24 0.3

[0358] FaSSGF 4 6.9

[0359]

[0360] (pH = 1.6) 24 6.7

[0361] In the try to dissolve the compound according to example 1 in FaSSIF medium at pH 6.5 and at 37 °C, the quantity of compound according to example 1 introduced in the donor compartments at a mean concentration of 61 pg / mL was not completely dissolved. The mean solubility at equilibrium and at 37 °C was determined at 3.44 + / - 0.17 pg / mL at the plateau from Ih to 3.3h. pH was decreased to 5.0 for solubility data.

[0362] Example 4: Capsules manufacturing

[0363] Binary mixtures of carboxylic acid and Compound 1 hydrochloride using tartaric, succinic and citric acid at different molar ratios were prepared and distributed in capsules each containing 200 mg of Compound 1 (free base equivalent).

[0364] Materials:

[0365] - Crystalline tartaric acid, Ph. Eur. (Merck)

[0366] - Citric acid monohydrate, Ph. Eur. (Merck)

[0367] - Succinic acid, Ph. Eur. (Merck)

[0368] - Gelatine capsule size 00, Ph. Eur. (Lonza)

[0369] LotLO: Compound 1 hydrochloride alone

[0370] Approximately 5 g of Compound 1 hydrochloride was manually sieved using a 2 mm sieve. The sieved material was then filled into size 00 gelatin capsules, each weighing 216.2 mg ±5%. The net weight of each capsule was checked and adjusted as necessary using a laboratory scale. A total of 15 capsules were prepared for testing, and the required amount was sampled for dissolution testing.

[0371] Lots L1-L7: Compound 1 hydrochloride + carboxylic acidsCompound 1 hydrochloride was sieved manually and in excess on a 2 mm sieve to cover production of all batches. The selected carboxylic acid was weighed in excess to cover production of all batches. For each batch, the sieved Compound 1 hydrochloride and selected carboxylic acid were weighed and co-sieved on a 1 mm sieve. The resulting mixture was then loaded into a 100 mL glass vial fitted with a Teflon stopper and blended for 20 min with a WAB Turbula® mixer. The bulk drug product was then filled into size 00 capsules at the targeted weight (see Table 4). The net weight was checked on a laboratory scale and adjusted accordingly. A total of 20 capsules per lot were prepared for testing, and the required amount was sampled for dissolution testing.

[0372] Table 4. Composition of lots L0-L7 capsules (mg per capsule)

[0373] Lot L0 L1 L2 L3 L4 L5 L6 L7 Compound 1 HC1 216.2 216.2 216.2 216.2 216.2 216.2 216.2 216.2 (Equivalent free base) (200) (200) (200) (200) (200) (200) (200) (200) Tartaric Acid - 133.0 283.0 63.0 - - - - Succinic acid - - - - 104.0 222.0 - - Citric acid

[0374] - - - - - - 81.0 363.0 monohydrate

[0375] Total

[0376] 216.2 349.2 499.2 279.2 320.2 438.2 297.2 579.2 (Molar eq. carboxylic

[0377] (0) (2.7) (4.5) f7.0) (2.7) (4.5) (0.92) (4.7) acid)

[0378]

[0379] Example 5: Capsules dissolution testing

[0380] 4.1 Dissolution method

[0381] The dissolution tests were conducted using a Sotax AT70 smart apparatus equipped with USP Apparatus 2 paddles. The dissolution medium consisted of either 40 g NaCl and 140 mL concentrated HC1 in 860 mL ultrapure water (pH 1.2 medium), or USP acetate buffer at pH 5.1, prepared by a l / 10th dilution of concentrated acetate buffer (pH 5.1 medium). A total volume of 900 mL of dissolution medium was used in each vessel, with a circulation volume of 30 mL.

[0382] During the dissolution testing process, a water bath temperature of 37.2 ± 0.3 °C and a paddle rotation speed of 50 rpm were maintained. Sotax type 10049 sinkers were employed toensure proper capsule immersion. Samples were filtered using Pall Acrodisc Premium 25 mm syringe filters with 10.0 μm Versapor® membranes. The dissolution profile was monitored by collecting samples at 5, 10, 15, 30, 45, and 60 min. For each lot L0-L7, dissolution testing was performed on three vessels, with one capsule per vessel. Compound 1 hydrochloride dissolution was quantified using online UV spectrophotometry at a wavelength of 264 nm.

[0383] 4.2 Dissolution profiles

[0384] 4.2.1 pH 1.2 medium

[0385] At pH 1.2, Compound 1 hydrochloride dissolves rapidly on its own (>85% in 15 min). However, with the addition of 2.1 eq. of tartaric acid, it dissolves even faster in the initial time points (see Figure 2 and Table 5).

[0386] Table 5. Dissolution results (% dissolved) in pH 1.2 medium

[0387] % Dissolved

[0388] Time (min)

[0389] L0 L1

[0390] 0 0 0

[0391] 5 20 70

[0392] 10 71 80

[0393] 15 88 88

[0394] 20 95 93

[0395] 30 99 97

[0396] 45 100 98

[0397] 60 100 98

[0398] 75 100 99

[0399]

[0400] 4.2.2 pH 5.1 medium

[0401] At pH 5.1, Compound 1 hydrochloride alone shows minimal dissolution, plateauing at 10% (see Figure 3). However, the addition of carboxylic acid significantly improves the dissolution profile at this pH (see Figures 4-7 and Table 6).

[0402] Table 6. Dissolution results (% dissolved) in pH 5.1 medium% Dissolved

[0403] Time (min)

[0404] L0 L1 L2 L3 L4 L5 L6 L7 0 0 0 0 0 0 0 0 0 5 6 70 75 48 48 43 54 64 10 7 80 90 55 70 72 65 85 15 7 88 95 63 80 92 73 92 20 8 93 96 72 87 97 79 96 30 8 97 97 83 94 98 86 98 45 8 98 97 88 94 98 90 98 60 8 98 97 88 91 97 87 98 75 10 99 97 84 87 96 82 97

[0405]

[0406] Example 6: Besylate salt (Counter-Example)

[0407] Besylate salt of compound 1 was prepared as follows:

[0408] Compound according to example 2 (250 mg) of the was weighed into a 20 mL vial. 5 mL of 2-propanol was added followed by a magnetic stirrer bar. 88.8 mg (1.05 equiv.) of benzenesulfonic acid was added neat. The vial was washed with 3.5 mL of 2-propanol and the washes were added to the reaction mixture. The solution was stirred at 40°C for 5 minutes.

[0409] The experiments were thermally cycled between 20 and 50°C at a rate of 0.1°C / min with a 1 hour hold at 20 and 50°C.

[0410] An aliquot of the mixture was taken after 72 hours, was isolated by centrifugation, and analyzed by XRPD. The XRPD analysis showed that the Pattern 1 of the besylate salt was obtained.

[0411] The solids were isolated by Buchner filtration (42.5 mm 0 Grade 1 Whatman), washed with cold 2-propanol and dried under vacuum at 40°C for 16 h.

[0412] XRPD analysis was carried out on the dried solids.

[0413] The besylate salt was characterized by PLM, TG / DSC, DSC, 1H NMR and HPLC for purity. - XRPD analysis of the material isolated from 2-propanol showed a crystalline material consistent with Besylate Pattern 1.- PLM showed birefringence under crossed polarised light. However, the crystals were small with an irregular-shaped.

[0414] - The TGA trace showed a 1.2 wt.% loss (equivalent to 0.43 eq. of surface moisture) in agreement with an anhydrous besylate salt.

[0415] - The DSC trace showed an endothermic melting event at onset: 221 °C; peak: 224°C prior to decomposition onset. DSC analysis showed the melting event at onset: 221 °C; peak: 224°C during the first heating step. A vitrification event was observed at ca. 54°C during the first cooling step detailing an amorphous material. The second heating step showed a glass transition with a midpoint of ca. 62°C indicating no further recrystallisation from the amorphous material.

[0416] -1H NMR analysis was consistent with Besylate Pattern 1 with only trace solvent present. The spectrum indicated ca. 1 equivalent of benzenesulfonic acid indicating a mono-salt. - HPLC analysis indicated that the Besylate salt Pattern 1 had a purity of 98.95 %area.

[0417] Thermodynamic solubility

[0418] The thermodynamic solubility carried out on the salt showed:

[0419] Table 7

[0420] Buffer Timepoint (h) Solubility (mg / mL)

[0421] Water 0 2.1

[0422] 4 2.2

[0423] FaSSIF 0 < 0.1

[0424] (pH = 6.5) 4 1

[0425] FaSSGF 0 7.4

[0426]

[0427] (pH = 1.6) 4 8.2

[0428] A low solubility was observed for the besylate salt in all media, where solubilities below 10 mg / mL were obtained.

[0429] Example 7: Napsylate salt (Counter-example)

[0430] Napsylate salt of compound N°1 was prepared as follows:

[0431] Compound according to example 2 (250 mg) was weighed into a 20 mL vial. 5 mL of ethyl acetate was added followed by a magnetic stirrer bar. 117 mg (1.05 equiv.) of naphthalene-2-sulfonic acid was added neat. The vial was washed with 3.5 mL of ethyl acetate and the washes were added to the reaction mixture. The solution was stirred at 40°C for 5 minutes.The experiments were thermally cycled between 20 and 50°C at a rate of 0.1°C / min with a 1 hour hold at 20 and 50°C.

[0432] An aliquot of the mixture was taken after 72 hours, was isolated by centrifugation and analyzed by XRPD. The XRPD analysis showed that the Pattern 1 of the Napsylate salt was obtained.

[0433] The solids were isolated by Buchner filtration (42.5 mm 0 Grade 1 Whatman), washed with cold ethyl acetate and dried under vacuum at 40°C for 16 h.

[0434] XRPD analysis was carried out on the dried solids.

[0435] The napsylate salt was characterized by PLM, TG / DSC, DSC, 1H NMR and HPLC for purity.

[0436] The following results were obtained for the Napsylate Pattern 1:

[0437] - XRPD analysis of the material isolated from ethyl acetate showed a crystalline material consistent with pattern 1.

[0438] - PLM showed birefringence under crossed polarised light. The morphology was of smallfragmented plate like particles.

[0439] - The TGA trace showed a 1.4 wt.% loss (equivalent to 0.54 eq. of surface water) in agreement with an anhydrous mono-napsylate salt.

[0440] - The DSC trace showed an endothermic melting event at onset: 201 °C; peak: 207°C. DSC analysis showed the melting event at onset: 199°C; peak: 206°C during the first heating step. A vitrification event was observed at ca. 78°C during the first cooling step. The second heating step showed a glass transition with a midpoint of ca. 94°C.

[0441] -1H NMR analysis was consistent with Napsylate Pattern 1 with only trace solvent present.

[0442] The spectrum indicated ca. 0.8 equivalents of Naphthalensulfonic acid. Together with the TGA data napsylate pattern 1 could be considered as a likely mono-salt.

[0443] - HPLC analysis indicated that Napsylate salt Pattern 1 had a purity of 98.44 %area.

[0444] Thermodynamic solubility

[0445] The thermodynamic solubility carried out on the salt showed:

[0446] Table 8Buffer Timepoint (h) Solubility (mg / mL)

[0447] Water 0 0.1

[0448] 4 < 0.1

[0449] FaSSIF 0 < 0.1

[0450] (pH = 6.5) 4 < 0.1

[0451] FaSSGF 0 2.9

[0452]

[0453] (pH = 1.6) 4 2.8

[0454] A very low solubility was observed for the napsylate salt in all media, where a solubility below 3 mg / mL was obtained.

Claims

CLAIMS1. A pharmaceutical composition comprising the hydrochloride salt of (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-17 / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(U7)-one of formula (I) below:or a solvate thereof, and at least one carboxylic acid.

2. The pharmaceutical composition according to claim 1, wherein the at least one carboxylic acid contains two or three carboxyl groups.

3. The pharmaceutical composition according to claim 1, wherein the at least one carboxylic acid is selected from adipic acid, citric acid, fumaric acid, maleic acid, malonic acid, oxalic acid, glutaric acid, oxoglutaric acid, lactic acid, sorbic acid, succinic acid, tartaric acid, and mixtures thereof.

4. The pharmaceutical composition according to any one of the preceding claims, wherein the at least one carboxylic acid is selected from citric acid, succinic acid, tartaric acid, and mixtures thereof.

5. The pharmaceutical composition according to any one of the preceding claims, wherein the carboxylic acid is tartaric acid.

6. The pharmaceutical composition according to any one of the preceding claims wherein the molar ratio between the amount of (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-l / Z-pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(lJ7)-one hydrochloride and the amount of carboxylic acid(s) ranges from 0.5 to 5, preferably from 1 to 4.5, more preferably from 1.5 to 3, even more preferably from 2.0 to 2.5.

7. The pharmaceutical composition according to any one of the preceding claims wherein the molar ratio between the amount of (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-17 / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(lJ7)-one hydrochloride and the amount of carboxyl groups in the carboxylic acid(s) ranges from 0.25to 2.5, preferably from 0.5 to 2, more preferably from 0.75 to 1.5, even more preferably from 1.0 to 1.25.

8. The pharmaceutical composition according to any one of the preceding claims comprising from 25% to 35% by weight of (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-17 / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(lJ7)-one free base equivalent and from 15% to 25% by weight of tartaric acid.

9. The pharmaceutical composition according to any one of the preceding claims comprising about 30% by weight of (5)-l-(l-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-17 / -pyrrolo[2,3-Z>]pyridin-3-yl)pyridin-2(lJ7)-one free base equivalent and about 20% by weight of tartaric acid.

10. A dosage form containing the pharmaceutical composition according to any one of claims 1-9.

11. The dosage form according to claim 10, provided as a capsule.

12. The dosage form according to claim 10, provided as a tablet.

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