Salts of ((2,3-dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-1-YL)-1h-benzo[d]imidazol-1-YL)pyrido[3,2-d]pyrimidin-4-YL)amino)phenyl)amide, their preparation and their use as RAF kinase inhibitors

Abstract

The present invention concerns pharmaceutically acceptable salts of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)- 1H-benzo[d]imidazol-1-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide of the formula (I) below: (I) wherein said salt is selected from a sodium salt, a choline salt, a potassium salt, and a calcium salt.

Description

[0001] SALTS OF ((2,3-DICHLOROPHENYL)SULFONYL)(2,4-DIFLUORO-3-((6-(4-(4- HYDROXY-4-(TRIFLUOROMETHYL)PIPERIDIN-l-YL)-lH-

[0002] BENZO [D] IMIDAZOL-1-YL)PYRIDO [3,2-D] PYRIMIDIN-4-

[0003] YL)AMINO)PHENYL)AMIDE, THEIR PREPARATION AND THEIR USE AS RAF KINASE INHIBITORS

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to novel salts of ((2,3-dichlorophenyl)sulfonyl)(2,4-difluoro-3- ((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin- 1 -yl)- 1 H-benzo [d] imidazol- 1 -yl)pyrido[3 ,2- d]pyrimidin-4-yl)amino)phenyl)amide which are inhibitors of the RAS-ERK signaling pathway without substantial paradoxical induction, their preparation and to the therapeutic use thereof.

[0006] BACKGROUND OF THE INVENTION

[0007] The RAS-RAF-MEK-ERK (RAS: rat sarcoma; RAF: rapidly accelerated fibrosarcoma; MEK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinase) signaling pathway (hereafter referred to as the RAS-ERK pathway) plays a critical role in transmitting proliferation signals generated by growth factor receptors from the plasma membrane to the nucleus. The pathway is dysregulated in a large proportion of cancers by activation of receptor tyrosine kinases (RTKs) (e.g. ERBB1, ERBB2, FLT3, RET, KIT), activation or inactivation of RAS regulators (SOS1 and NF1) as well as constitutively activating mutations in RAS genes (H-, K- and NRAS,' overall 30% of cancers) and in the BRAF gene (8% of cancers). The prevalence of KRAS mutations is especially high in pancreatic (>90%), colorectal (50%), and lung (30%) cancers. For their part, BRAF mutations are found with notably high frequencies in malignant melanoma (70%), thyroid cancer (40%) and colorectal cancer (10%) (mutation frequencies based on COSMIC (Catalogue Of Somatic Mutations In Cancer; Wellcome Trust Sanger Institute) release v95, November 24th2021).

[0008] RAS proteins are small GTPases that convey extracellular growth signals to intracellular effectors to control vital processes like cell differentiation, proliferation, and survival (Nat. Rev. Cancer 2003, 3, 459). Physiological activation of RAS occurs at the plasma membrane after stimulation of RTKs, which leads to GTP loading of the GTPase and thus its activation. Activated RAS interacts and activates a battery of effector molecules, with the RAF kinases being the most critical RAS interactors in the context of cancer development (Nature Rev. Drug Discov. 2014, 13, 828). Oncogenic mutations at Glycine 12, Glycine 13 or Glutamine 61 in RAS isoforms lead to aberrant and constitutive signaling in human cancer (Nat. Rev. Cancer 2003, 3, 459) (COSMIC release v95, November 24th2021).

[0009] Downstream of RAS, mammalian cells express three RAF paralogs (ARAF, BRAF and CRAF) that share a conserved C-terminal kinase domain (KD) (Nat. Rev. Mol. Cell Biol. 2015, 16, 281) and an N-terminal regulatory region (NTR) comprising a RAS-binding domain (RBD). In unstimulated cells, RAF proteins are sequestered in the cytoplasm as monomers. Binding of GTP-bound activated RAS to the RBD induces membrane anchoring of RAF kinases (Nat. Rev. Mol. Cell Biol. 2015, 16, 281). Concomitantly, RAF proteins undergo kinase domain side-to- side dimerization and catalytic activation (Nature 2009, 461, 542). Activated RAF proteins convey signals through a phosphorylation cascade from RAF to MEK and then MEK to ERK, leading to phosphorylation by ERK of an array of substrates eliciting cell-specific responses (Nat. Rev. Mol. Cell Biol. 2020, Oct;21(10), 607).

[0010] Activating mutations in RAF isoforms have so far been mostly restricted to the BRAF gene, although rare variants were observed in ARAF and CRAF, underlining the functional importance of this isoform (COSMIC release v95, November 24th2021). The most common cancer mutation in BRAF, a valine to glutamic acid substitution at position 600 (referred to as BRAFV600E), enhances BRAF activity by stabilizing its active form (Cell 2004, 116, 855). Apart from the V600E allele, a diverse set of mutations occur at other residues (e.g. G466V, D594G, etc.) that lead to increased RAF signaling through a variety of mechanisms (Nat. Rev. Mol. Cell Biol. 2015, 16, 281). These have been grouped in three main classes (1 to 3) depending on their level of dependence to RAS activity and to RAF dimerization (Nature 2017 Aug 10;548(7666):234-238). The key role of wild-type BRAF and CRAF in mediating RAS-driven oncogenesis by stimulating ERK signaling is extensively validated (Cancer Cell 2011, 79, 652; Cancer Discov. 2012, 2, 685; Nat. Commun. 2017, 8, 15262). Tumor cells thus rely on elevated and continued signaling of the RAS-ERK pathway through RAS and RAF activation, providing strong support for the concept of targeting RAF family kinases in cancers.

[0011] To address existing medical needs, the past decade has seen the development of a broad set of ATP-competitive RAF inhibitors (Nat. Rev. Cancer 2017 , 17, 676).

[0012] In particular, pyrido[3,2-d]pyrimidine derivatives are reported as RAF inhibitors in the international patent application WO 2022 / 221939 Al.

[0013] More particularly, ((2,3-dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4- (trifluoromethyl)piperidin- 1 -yl)- 1 H-benzo[d] imidazol- 1 -yl)pyrido [3 ,2-d]pyrimidin-4- yl)amino)phenyl)amide of formula (I), depicted below, is an inhibitor of RAF kinases (ARAF, BRAF, and CRAF). It may be used in particular as anticancer agent.

[0014] Such a compound has been developed in a free form which solubility could be improved. Indeed, it is desired that such RAF inhibitor shows high solubility when it is used for a pharmaceutical formulation, in particular a pharmaceutical formulation for oral administration. To improve the developability properties of a drug, a salt is preferable to the free compound as the salt usually has improved solubility and bioavailability when compared to the free compound.

[0015] Therefore, salt screening is one approach to identify salt forms with improved solubility. However, the development of salts for compounds such as ((2,3-dichlorophenyl)sulfonyl)(2,4- difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-I-yl)-IH-benzo[d]imidazol-l- yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide is very difficult.

[0016] Indeed, such a compound is amphoteric. This means that it contains a hydrogen atom that can be released as a proton and it is also capable of accepting protons from other compounds.

[0017] This compound has at least one site that is a weak acid (sulfonamide predicted pKa 6.7), but it also has multiple weak basic sites, e.g. piperidine nitrogen (predicted pKa 5) and pyrimidine nitrogen (predicted pKa 2.7), as illustrated in Figure 20.

[0018] Therefore, salt development on amphoteric compounds is complex and time-consuming and is generally considered impractical.

[0019] In addition, during the production of solid dosage forms, an Active Pharmaceutical Ingredient (API) undergoes various rigorous processing steps, including wet granulation, drying, roller compaction, and compression. These conditions, combined with interactions with other formulation components, can cause an API salt to undergo disproportionation. In this process, the salt dissociates and reverts back to its less soluble, nonionic form. This proton exchange reaction alters the chemical composition of the API, potentially leading to negative effects on product stability and performance. These effects may include reduced potency, slow dissolution, and decreased bioavailability. Therefore, such phenomenon also makes the development of suitable salts difficult.

[0020] There is therefore a need to provide new means for improving the solubility of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- 1 H-benzo [d] imidazol- 1 -yl)pyrido[3 ,2-d]pyrimidin-4-yl)amino)phenyl)amide.

[0021] The present invention is precisely directed to novel salts of ((2,3-dichlorophenyl)sulfonyl)(2,4- difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)-lH-benzo[d]imidazol-l- yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide, their preparation and their use as inhibitors of RAF kinases activity.

[0022] The compounds of the present invention are novel salts with at least a good solubility in aqueous solutions, with an improved solubility in FaSSIF, and not subject to disproportionation. Overall, the salts according to the invention are remarkable for their drug-like properties.

[0023] A first subject of the invention concerns a pharmaceutically acceptable salt, and solvate thereof, of ((2,3-dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-

[0024] (trifluoromethyl)piperidin- 1 -yl) - 1 H-benzo[d] imidazol- 1 -yljpyrido [3 ,2-d]pyrimidin-4- yl)amino)phenyl)amide of the formula (I) below: wherein said salt is selected from a sodium salt, a choline salt, a potassium salt, and a calcium salt.

[0025] Advantageously, the solubility of the salts according to the invention is increased in water and / or simulated human gut fluids, compared to the free form. Advantageously, the solubility of the salts according to the invention is increased in FaSSIF.

[0026] Furthermore, the obtention of salts according to the invention advantageously ensure the reproducibility of the compound, by defining specific crystal forms, and thus controlling its synthesis. As will be seen below, these salts have utility in the treatment of conditions or diseases in which modification of the activity of RAF kinases would have a positive therapeutic outcome, in particular cancers.

[0027] Another subject concerns processes for preparing the salts of the compound of formula (I).

[0028] Another subject concerns the salts of the compound of formula (I) for their use especially in medicaments or in pharmaceutical compositions.

[0029] ABBREVIATIONS AND DEFINITIONS

[0030] In the context of the present invention, the following abbreviations and empirical formulae are used:

[0031] 2-MeTHF 2-Methyltetrahydrofuran

[0032] ACN Acetonitrile

[0033] ATP Adenosine 5 ’-triphosphate

[0034] Ca(OH)2 Calcium hydroxide

[0035] DMSO Dimethylsulfoxide

[0036] DSC Differential Scanning Calorimetry

[0037] °C Degree Celsius

[0038] Eq. Equivalent

[0039] EtOH Ethanol

[0040] FaSSIF Fasted State Simulated Intestinal Fluid

[0041] FaSSGF Fasted State Simulated Gastric Fluid g gram(s) h hour(s)

[0042] HC1 Hydrochloric acid

[0043] HPLC High performance liquid chromatography

[0044] KOH Potassium Hydroxide

[0045] M Mole(s) per liter

[0046] MeOH Methanol mg Milligram(s)

[0047] MHz Megahertz min Minutes pL Microliter(s) mL Milliliter(s) mmol Millimole(s) mol Mole(s)

[0048] MPA Mobile Phase A

[0049] MPB Mobile Phase B

[0050] NDSA 1,5-Naphthalenedisulfonic acid

[0051] NMR Nuclear Magnetic Resonance

[0052] PLM Polarized Light Microscopy

[0053] RH Relative Humidity rpm Revolutions per minute

[0054] TG / DTA Thermogravimetry Differential Thermal Analysis

[0055] TGA Thermogravimetric Analysis

[0056] THF Tetrahydrofuran

[0057] UPLC Ultra performance liquid chromatography

[0058] UV Ultraviolet

[0059] XRPD X-ray powder diffraction

[0060] 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.

[0061] 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.

[0062] 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.

[0063] A hydrochloride salt is a salt of hydrochloric acid.

[0064] A napadisylate salt is a salt of naphthalene- 1,5-disulfonic acid, also known as napadisylic acid. Within the meaning of the invention, a sodium salt is a salt containing at least one sodium cation.

[0065] Within the meaning of the invention, a potassium salt is a salt containing at least one potassium cation.

[0066] Within the meaning of the invention, a calcium salt is a salt containing at least one calcium cation.

[0067] Within the meaning of the invention, a choline salt is a salt containing at least one choline cation, also known as 2-hydroxy-AW,X-trimethylethanaminium. Other features, properties and advantages of the invention will emerge more clearly from the description and examples that follow.

[0068] BRIEF DESCRIPTION OF THE FIGURES

[0069] Figure 1 is an X-ray powder diffiractogram of ((2,3-dichlorophenyl)sulfonyl)(2,4-difluoro-3- ((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin- 1 -yl)- 1 H-benzo [d] imidazol- 1 -yl)pyrido[3 ,2- d]pyrimidin-4-yl)amino)phenyl)amide (Compound N°l) free form (see Example 1).

[0070] Figure 2 is an X-ray powder diffractogram of a sodium salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide (see Example 2). Figure 3 is an X-ray powder diffractogram of a choline salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide (see Example 3). Figure 4 is an X-ray powder diffractogram of a potassium salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide (see Example 4). Figure 5 is an X-ray powder diffractogram of a calcium salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide (see Example 5). Figure 6 is an X-ray powder diffractogram of a hydrochloride salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide (see Example 6). Figure 7 is an X-ray powder diffractogram of a napadisylate salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide (see Example 7). Figure 8 is a TG / DTA thermogram of ((2,3-dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4- hydroxy-4-(trifluoromethyl)piperidin-l-yl)-lH-benzo[d]imidazol-l-yl)pyrido[3,2- d]pyrimidin-4-yl)amino)phenyl)amide (Compound N°l) free form (see Example 1).

[0071] Figure 9 is a TG / DTA thermogram of a sodium salt of ((2,3-dichlorophenyl)sulfonyl)(2,4- difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)-lH-benzo[d]imidazol-l- yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide (see Example 2).

[0072] Figure 10 is a TG / DTA thermogram of a choline salt of ((2,3-dichlorophenyl)sulfonyl)(2,4- difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)-lH-benzo[d]imidazol-l- yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide (see Example 3). Figure 11 is a TG / DTA thermogram of a potassium salt of ((2,3-dichlorophenyl)sulfonyl)(2,4- difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)-lH-benzo[d]imidazol-l- yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide (see Example 4).

[0073] Figure 12 is a TG / DTA thermogram of a calcium salt of ((2,3-dichlorophenyl)sulfonyl)(2,4- difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)-lH-benzo[d]imidazol-l- yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide (see Example 5).

[0074] Figure 13 is a TG / DTA thermogram of a hydrochloride salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide (see Example 6). Figure 14 is a TG / DTA thermogram of a napadisylate salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide (see Example 7). Figure 15 is a DSC thermogram of ((2,3-dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4- hydroxy-4-(trifluoromethyl)piperidin-l-yl)-lH-benzo[d]imidazol-l-yl)pyrido[3,2- d]pyrimidin-4-yl)amino)phenyl)amide (Compound N°l) free form (see Example 1).

[0075] Figure 16 is a DSC thermogram of a sodium salt of ((2,3-dichlorophenyl)sulfonyl)(2,4- difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)-lH-benzo[d]imidazol-l- yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide (see Example 2).

[0076] Figure 17 is a DSC thermogram of a choline salt of ((2,3-dichlorophenyl)sulfonyl)(2,4- difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)-lH-benzo[d]imidazol-l- yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide (see Example 3).

[0077] Figure 18 is a DSC thermogram of a potassium salt of ((2,3-dichlorophenyl)sulfonyl)(2,4- difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)-lH-benzo[d]imidazol-l- yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide (see Example 4).

[0078] Figure 19 is a DSC thermogram of a calcium salt of ((2,3-dichlorophenyl)sulfonyl)(2,4- difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)-lH-benzo[d]imidazol-l- yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide (see Example 5).

[0079] Figure 20 shows the locations and predicted pKa values of acidic and basic groups of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- 1 H-benzo [d] imidazol- 1 -yl)pyrido[3 ,2-d]pyrimidin-4-yl)amino)phenyl)amide. The pKa constants were calculated using the Classic model of ACD / pKasoftware (Advanced Chemistry Development, Inc.; Release 2023.2.3).

[0080] DETAILED DESCRIPTION As explained above, the salts in accordance with the present disclosure demonstrate improved solubility, in particular in FaSSIF, in comparison to the solubility of the free form of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- 1 H-benzo [d] imidazol- 1 -yl)pyrido[3 ,2-d]pyrimidin-4-yl)amino)phenyl)amide.

[0081] Salts of the invention

[0082] As mentioned above, an object of the present invention is a pharmaceutically acceptable salt, and solvate thereof, of ((2,3-dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4- (trifluoromethyl)piperidin- 1 -yl) - 1 H-benzo[d] imidazol- 1 -yljpyrido [3 ,2-d]pyrimidin-4- yl)amino)phenyl)amide of the formula (I) below: wherein said salt is selected from a sodium salt, a choline salt, a potassium salt, and a calcium salt.

[0083] According to a preferred embodiment, the salt is a sodium salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- 1 H-benzo [d] imidazol- 1 -yl)pyrido[3 ,2-d]pyrimidin-4-yl)amino)phenyl)amide.

[0084] According to a preferred embodiment, the salt is a choline salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- 1 H-benzo [d] imidazol- 1 -yl)pyrido[3 ,2-d]pyrimidin-4-yl)amino)phenyl)amide.

[0085] According to a preferred embodiment, the salt is a potassium salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- 1 H-benzo [d] imidazol- 1 -yl)pyrido[3 ,2-d]pyrimidin-4-yl)amino)phenyl)amide.

[0086] According to a preferred embodiment, the salt is a calcium salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- 1 H-benzo [d] imidazol- 1 -yl)pyrido[3 ,2-d]pyrimidin-4-yl)amino)phenyl)amide.

[0087] According to a preferred embodiment, said pharmaceutically acceptable salt is anhydrous and is selected from anhydrous crystalline ((2,3-dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4- hydroxy-4-(trifluoromethyl)piperidin-l-yl)-lH-benzo[d]imidazol-l-yl)pyrido[3,2- d]pyrimidin-4-yl)amino)phenyl)amide sodium salt, choline salt, potassium salt, and calcium salt.

[0088] According to a preferred embodiment, said pharmaceutically acceptable salt is a hydrate and is selected from crystalline ((2,3-dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4- (trifluoromethyl)piperidin- 1 -yl)- 1 H-benzo[d] imidazol- 1 -yl)pyrido [3 ,2-d]pyrimidin-4- yl)amino)phenyl)amide sodium hydrate salt, choline hydrate salt, potassium hydrate salt, and calcium hydrate salt.

[0089] According to a preferred embodiment, a pharmaceutically acceptable salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide as defined in the present invention is crystalline sodium hydrate salt.

[0090] According to a preferred embodiment, a pharmaceutically acceptable salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide as defined in the present invention is crystalline sodium hemihydrate, monohydrate, sesquihydrate, dihydrate, hemipentahydrate, trihydrate, hemiheptahydrate, or tetrahydrate salt. In a more preferred embodiment, the pharmaceutically acceptable salt is crystalline sodium dihydrate salt. In another more preferred embodiment, the pharmaceutically acceptable salt is crystalline sodium hemipentahydrate salt. In yet another more preferred embodiment, the pharmaceutically acceptable salt is crystalline sodium trihydrate salt.

[0091] According to a preferred embodiment, a pharmaceutically acceptable salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-I-yl)- IH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide as defined in the present invention is crystalline choline hydrate salt.

[0092] According to a preferred embodiment, a pharmaceutically acceptable salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-I-yl)- IH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide as defined in the present invention is crystalline choline hemihydrate, monohydrate, sesquihydrate, dihydrate, hemipentahydrate, trihydrate, hemiheptahydrate, or tetrahydrate salt. In a more preferred embodiment, the pharmaceutically acceptable salt is crystalline choline dihydrate salt. In another more preferred embodiment, the pharmaceutically acceptable salt is crystalline choline hemipentahydrate salt. In yet another more preferred embodiment, the pharmaceutically acceptable salt is crystalline choline trihydrate salt. According to a preferred embodiment, a pharmaceutically acceptable salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide as defined in the present invention is crystalline potassium hydrate salt.

[0093] According to a preferred embodiment, a pharmaceutically acceptable salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide as defined in the present invention is crystalline potassium hemihydrate, monohydrate, sesquihydrate, dihydrate, hemipentahydrate, trihydrate, hemiheptahydrate, or tetrahydrate salt. In a more preferred embodiment, the pharmaceutically acceptable salt is crystalline potassium dihydrate salt. In another more preferred embodiment, the pharmaceutically acceptable salt is crystalline potassium hemipentahydrate salt. In yet another more preferred embodiment, the pharmaceutically acceptable salt is crystalline potassium trihydrate salt. In yet another more preferred embodiment, the pharmaceutically acceptable salt is crystalline potassium hemiheptahydrate salt. In yet another more preferred embodiment, the pharmaceutically acceptable salt is crystalline potassium tetrahydrate salt.

[0094] According to a preferred embodiment, a pharmaceutically acceptable salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-I-yl)- IH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide as defined in the present invention is crystalline calcium hydrate salt.

[0095] According to a preferred embodiment, a pharmaceutically acceptable salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-I-yl)- IH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide as defined in the present invention is crystalline calcium hemihydrate, monohydrate, sesquihydrate, dihydrate, hemipentahydrate, trihydrate, hemiheptahydrate, or tetrahydrate salt. In a more preferred embodiment, the pharmaceutically acceptable salt is crystalline calcium monohydrate salt. In another more preferred embodiment, the pharmaceutically acceptable salt is crystalline calcium sesquihydrate salt.

[0096] The pharmaceutically acceptable salts of ((2,3-dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4- (4-hydroxy-4-(trifluoromethyl)piperidin- 1 -yl)- 1 H-benzo [d] imidazol- 1 -yl)pyrido [3 ,2- d]pyrimidin-4-yl)amino)phenyl)amide may be for example characterized by X-Ray Powder Diffraction (XRPD) and by Differential Scanning Calorimetry (DSC). According to a preferred embodiment, a pharmaceutically acceptable salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide as defined in the present invention is a crystalline sodium hydrate salt.

[0097] More particularly, crystalline sodium hydrate salt of ((2,3-dichlorophenyl)sulfonyl)(2,4- difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)-lH-benzo[d]imidazol-l- yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide has a powder X-ray diffiractogram displaying peaks expressed as degree 2-Theta angle at 8.5, 12.0, 12.5, and 21.7 (each time ±0.2), and optionally further shows the following additional peaks expressed as degree 2-Theta angle: 10.0, 10.5, 15.6, 16.9, 17.4, and 23.1 (each time ±0.2), and optionally even further the following additional peaks expressed as degree 2-Theta angle: 9.1, 14.6, 14.8, 15.5, 17.1, 18.3, 23.4, 24.2, 25.4, 26.4, 28.7, and 29.4 (each time ±0.2), as illustrated in Figure 2 (powder X-ray diffiractogram) and / or has an endotherm with onset temperatures at 209.4 °C (±2 °C).

[0098] A characteristic X-ray powder diffiractogram of a crystalline sodium hydrate salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide is given in Figure 2 and its characteristic signals are summarized in the following table:

[0099] According to a preferred embodiment, the crystalline sodium hydrate salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- 1 H-benzo [d] imidazol- 1 -yl)pyrido[3 ,2-d]pyrimidin-4-yl)amino)phenyl)amide 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 8.5, 9.1, 10.0, 10.5, 12.0, 12.5, 14.6, 14.8, 15.5, 15.6, 16.9, 17.1, 17.4, 18.3, 21.7, 23.1, 23.4, 24.2, 25.4, 26.4, 28.7, and 29.4 (each time ±0.2).

[0100] According to a preferred embodiment, the crystalline sodium hydrate salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide of the present invention has an X-ray powder diffractogram substantially similar to that depicted in Figure 2.

[0101] According to a preferred embodiment, a pharmaceutically acceptable salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide as defined in the present invention is a crystalline choline hydrate salt.

[0102] More particularly, crystalline choline hydrate salt of ((2,3-dichlorophenyl)sulfonyl)(2,4- difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)-lH-benzo[d]imidazol-l- yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide has a powder X-ray diffractogram displaying peaks expressed as degree 2-Theta angle at 10.9, 17.6, 18.8, and 21.9 (each time ±0.2), and optionally further shows the following additional peaks expressed as degree 2-Theta angle: 10.0, 13.4, 17.3, 17.8, 19.6, 22.6, 25.1, and 26.2 (each time ±0.2); and optionally even further the following additional peaks expressed as degree 2-Theta angle: 5.0, 6.3, 8.5, 11.5, 11.8, 13.8, 14.4, 14.8, 15.2, 15.6, 18.6, 19.1, 20.4, 21.0, 21.6, 23.1, 23.4, 23.9, 24.3, 27.6, and 31.8 (each time ±0.2), as illustrated in Figure 3 (powder X-ray diffractogram) and / or has an endotherm with onset temperatures at 97.4 °C and 207.3 °C (±2 °C).

[0103] A characteristic X-ray powder diffractogram of a crystalline choline hydrate salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide is given in Figure 3 and its characteristic signals are summarized in the following table:

[0104] According to a preferred embodiment, the crystalline choline hydrate salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- 1 H-benzo [d] imidazol- 1 -yl)pyrido[3 ,2-d]pyrimidin-4-yl)amino)phenyl)amide 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 5.0, 6.3, 8.5, 10.0, 10.9, 11.5, 11.8, 13.4, 13.8, 14.4, 14.8, 15.2, 15.6, 17.3, 17.6, 17.8, 18.6, 18.8, 19.1, 19.6, 20.4, 21.0, 21.6, 21.9, 22.6, 23.1, 23.4, 23.9, 24.3, 25.1, 26.2, 27.6, and 31.8 (each time ±0.2).

[0105] According to a preferred embodiment, the crystalline choline hydrate salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide of the present invention has an X-ray powder diffractogram substantially similar to that depicted in Figure 3.

[0106] According to a preferred embodiment, a pharmaceutically acceptable salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide as defined in the present invention is a crystalline potassium hydrate salt.

[0107] More particularly, crystalline potassium hydrate salt of ((2,3-dichlorophenyl)sulfonyl)(2,4- difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)-lH-benzo[d]imidazol-l- yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide has a powder X-ray diffractogram displaying peaks expressed as degree 2-Theta angle at 7.7 and 8.6 (each time ±0.2), and optionally further shows the following additional peaks expressed as degree 2-Theta angle: 12.1, 15.8, 16.2, 18.2, 21.2, 23.0, and 23.6 (each time ±0.2); and optionally even further the following additional peaks expressed as degree 2-Theta angle: 5.8, 8.1, 9.2, 12.7, 15.6, 16.8, 17.8, 19.9, 20.5, 21.9, 22.4, 24.5, 29.6, 32.0, and 32.5 (each time ±0.2), as illustrated in Figure 4 (powder X-ray diffractogram) and / or has an endotherm with onset temperatures at 128.1 °C (±2 °C).

[0108] A characteristic X-ray powder diffractogram of a crystalline potassium hydrate salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide is given in Figure 4 and its characteristic signals are summarized in the following table:

[0109] According to a preferred embodiment, the crystalline potassium hydrate salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- 1 H-benzo [d] imidazol- 1 -yl)pyrido[3 ,2-d]pyrimidin-4-yl)amino)phenyl)amide 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 5.8, 7.7, 8.1, 8.6, 9.2, 12.1, 12.7, 15.6, 15.8, 16.2, 16.8, 17.8, 18.2, 19.9, 20.5, 21.2, 21.9, 22.4, 23.0, 23.6, 24.5, 29.6, 32.0, and 32.5 (each time ±0.2).

[0110] According to a preferred embodiment, the crystalline potassium hydrate salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide of the present invention has an X-ray powder diffractogram substantially similar to that depicted in Figure 4.

[0111] According to a preferred embodiment, a pharmaceutically acceptable salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide as defined in the present invention is a crystalline calcium hydrate salt.

[0112] More particularly, crystalline calcium hydrate salt of ((2,3-dichlorophenyl)sulfonyl)(2,4- difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)-lH-benzo[d]imidazol-l- yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide has a powder X-ray diffractogram displaying peaks expressed as degree 2-Theta angle at 8.1, 10.0, 11.4, 12.0, and 23.1 (each time ±0.2), and optionally further shows the following additional peaks expressed as degree 2-Theta angle: 14.3, 18.1, 19.3, and 22.1 (each time ±0.2); and optionally even further the following additional peaks expressed as degree 2-Theta angle: 4.8, 6.9, 12.9, 15.1, 16.1, 17.2, 17.6, 17.9, 18.6, 19.0, 19.7, 20.4, 20.6, 20.9, 21.4, 21.9, 22.5, 22.7, 24.0, 24.4, 25.2, 25.9, 26.1, 27.8, 28.0, 29.3, 29.6, 30.9, and 32.0 (each time ±0.2), as illustrated in Figure 5 (powder X-ray diffractogram) and / or has an endotherm with onset temperatures at 234.4 °C (±2 °C). A characteristic X-ray powder diffractogram of a crystalline calcium hydrate salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide is given in Figure 5 and its characteristic signals are summarized in the following table:

[0113] According to a preferred embodiment, the crystalline calcium hydrate salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- 1 H-benzo [d] imidazol- 1 -yl)pyrido[3 ,2-d]pyrimidin-4-yl)amino)phenyl)amide 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 4.8, 6.9, 8.1, 10.0, 11.4, 12.0, 12.9, 14.3, 15.1, 16.1, 17.2, 17.6, 17.9, 18.1, 18.6, 19.0, 19.3, 19.7, 20.4, 20.6, 20.9, 21.4, 21.9, 22.1, 22.5, 22.7, 23.1, 24.0, 24.4, 25.2, 25.9, 26.1, 27.8, 28.0, 29.3, 29.6, 30.9, and 32.0 (each time ±0.2).

[0114] According to a preferred embodiment, the crystalline calcium hydrate salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide of the present invention has an X-ray powder diffractogram substantially similar to that depicted in Figure 5. PREPARATION OF THE SALTS

[0115] Firstly, the compound of formula (I) may be prepared according to well-known methods by the skilled artisan, as illustrated in the examples that follow.

[0116] Preferably, the compound of formula (I) may be prepared according to the process illustrated in Example 1.

[0117] Herein is further provided a method for preparing a pharmaceutically acceptable salt of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- 1 H-benzo [d] imidazol- 1 -yl)pyrido[3 ,2-d]pyrimidin-4-yl)amino)phenyl)amide which comprises the following steps: a) mixing ((2,3-dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4- (trifluoromethyl)piperidin- 1 -yl)- 1 H-benzo[d] imidazol- 1 -yl)pyrido [3 ,2-d]pyrimidin-4- yl)amino)phenyl)amide in a solvent or in a mixture of solvents; b) adding to the thus obtained mixture of step a) a counter ion under the form of a base which may be itself already dissolved in a solvent or in a mixture of solvents so as to obtain a ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide:counter ion molar ratio comprised between 3:1 and 1:5, particularly between 5:2 and 1:4; more particularly between 2:1 and 1:4, and still more particularly of 2:1 or 1:1; c) 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) and step b), particularly between room temperature and 60 °C, more particularly between room temperature and 50 °C; d) optionally adding a solvent or a mixture of solvents, e) optionally applying a temperature program; f) optionally filtrating; and g) then optionally drying at a temperature comprised between room temperature and 60 °C in order to obtain the desired salt of ((2,3-dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4- hydroxy-4-(trifluoromethyl)piperidin-l-yl)-lH-benzo[d]imidazol-l-yl)pyrido[3,2- d]pyrimidin-4-yl)amino)phenyl)amide.

[0118] The solvent(s) used in step a), step b) and step d) is(are) any solvent conventionally used in crystallization step, particularly is(are) organic solvents, and 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-dioxane, tetrahydrofuran, 2- methyltetrahydrofuran, 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 / / -heptane, chlorinated solvents such as dichloromethane and chloroform, organosulfur solvents such as dimethyl sulfoxide (DMSO), amine and amide solvents such as ,V-mcthyl-2 -pyrrolidone (NMP) and dimethylacetamide, and acetonitrile, and mixtures thereof. Seed crystals may be added to any crystallization mixture to promote crystallization. Seeding may be employed to control growth of a particular polymorph or to control the particle size distribution of the crystalline product. Accordingly, calculation of the amount of seeds needed depends on the size of the seed available and the desired size of an average product particle. In general, seeds of small size are needed to control effectively the growth of crystals in the batch. Seeds of small size may be generated by sieving, milling, or micronizing of large crystals, or by micro-crystallization of solutions. Care should be taken that milling or micronizing of crystals does not result in any change in crystallinity form the desired crystal form (i.e., change to amorphous or to another polymorph).

[0119] According to a preferred embodiment, the solvent(s) used in step a), step b), and step d) is(are) selected from water, 2-propanol, acetone, acetonitrile, ethanol, ethyl acetate, tetrahydrofuran, 2-m ethyltetrahydro furan, dichloromethane, DMSO, / / -heptane, methanol, 1,4-dioxane, and mixtures thereof.

[0120] According to a preferred embodiment, the solvent(s) used in step a), step b), and step d) is(are) selected from water, acetone, acetonitrile, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, DMSO, / / -heptane, 1,4-dioxane, and mixtures thereof.

[0121] According to a preferred embodiment, the solvent used in step a), step b) and / or step d) is water. According to a preferred embodiment, the solvent used in step a), step b) and / or step d) is acetone.

[0122] According to a preferred embodiment, the solvent used in step a), step b) and / or step d) is an acetone / water mixture.

[0123] According to a preferred embodiment, the solvent used in step a), step b) and / or step d) is acetonitrile.

[0124] According to a preferred embodiment, the solvent used in step a), step b) and / or step d) is ethanol.

[0125] According to a preferred embodiment, the solvent used in step a), step b) and / or step d) is tetrahydrofuran.

[0126] According to a preferred embodiment, the solvent used in step a), step b) and / or step d) is a tetrahydrofuran / water mixture. According to a preferred embodiment, the solvent used in step a), step b) and / or step d) is 2- methyltetrahydrofuran.

[0127] According to a preferred embodiment, the solvent used in step a), step b) and / or step d) is DMSO.

[0128] According to a preferred embodiment, the solvent used in step a), step b) and / or step d) is a 2- methyltetrahydrofuran / DMSO mixture.

[0129] According to a preferred embodiment, the solvent used in step a), step b) and / or step d) is n- heptane.

[0130] According to a preferred embodiment, the solvent used in step a), step b) and / or step d) is 1,4- dioxane.

[0131] The skilled person would know how to determine the more appropriate solvent(s) in each step a), b) and d) so as to obtain the desired pharmaceutically acceptable salt.

[0132] According to one embodiment, the solvent(s) used in step a), step b) and / or step d) is(are) the same.

[0133] According to another embodiment, the solvent(s) used in step a), step b) and / or step d) is(are) different.

[0134] According to a preferred embodiment, the counter ion under the form of a base of step b) is selected from sodium hydroxide, choline hydroxide, potassium hydroxide, and calcium hydroxide.

[0135] According to a preferred embodiment, the counter ion under the form of a base of step b) is sodium.

[0136] According to a preferred embodiment, the counter ion under the form of a base of step b) is choline.

[0137] According to a preferred embodiment, the counter ion under the form of a base of step b) is potassium.

[0138] According to a preferred embodiment, the counter ion under the form of a base of step b) is calcium.

[0139] According to a preferred embodiment, a process for the preparation of a sodium salt according to the invention comprises the step of adding sodium hydroxide to a compound of formula (I) in a solvent chosen from water, 2-propanol, acetone, acetonitrile, ethanol, ethyl acetate, tetrahydro furan, 2-methyltetrahydrofuran, dichloromethane, DMSO, / / -heptane, methanol, 1,4- dioxane, and mixtures thereof, in particular chosen from water, acetone, acetonitrile, ethanol, tetrahydro furan, 2-methyltetrahydrofuran, DMSO, / / -heptane, 1,4-dioxane, and mixtures thereof, and preferably chosen from water, ethanol, and mixtures thereof. According to a preferred embodiment, a process for the preparation of a choline salt according to the invention comprises the step of adding choline hydroxide to a compound of formula (I) in a solvent chosen water, 2-propanol, acetone, acetonitrile, ethanol, ethyl acetate, tetrahydro furan, 2-methyltetrahydrofuran, dichloromethane, DMSO, / / -heptane, methanol, 1,4- dioxane, and mixtures thereof, in particular chosen from water, acetone, acetonitrile, ethanol, tetrahydro furan, 2-methyltetrahydrofuran, DMSO, / / -heptane, 1,4-dioxane, and mixtures thereof, and preferably chosen from tetrahydrofuran / / -heptane, and mixtures thereof.

[0140] According to a preferred embodiment, a process for the preparation of a potassium salt according to the invention comprises the step of adding potassium hydroxide to a compound of formula (I) in a solvent chosen from water, 2-propanol, acetone, acetonitrile, ethanol, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, DMSO, / / -heptane, methanol, 1,4-dioxane, and mixtures thereof, in particular chosen from water, acetone, acetonitrile, ethanol, tetrahydro furan, 2-methyltetrahydrofuran, DMSO, / / -heptane, 1,4- dioxane, and mixtures thereof, and preferably chosen from water, acetone, tetrahydrofuran, n- heptane, and mixtures thereof.

[0141] According to a preferred embodiment, a process for the preparation of a calcium salt according to the invention comprises the step of adding calcium hydroxide to a compound of formula (I) in a solvent chosen from water, 2-propanol, acetone, acetonitrile, ethanol, ethyl acetate, tetrahydro furan, 2-methyltetrahydrofuran, dichloromethane, DMSO, / / -heptane, methanol, 1,4- dioxane, and mixtures thereof, in particular chosen from water, acetone, acetonitrile, ethanol, tetrahydro furan, 2-methyltetrahydrofuran, DMSO, / / -heptane, 1,4-dioxane, and mixtures thereof, and preferably chosen from water, acetone, 2-methyltetrahydrofuran, DMSO, n- heptane, and mixtures thereof.

[0142] According to a preferred embodiment, the process for the preparation of the salts according to the invention is carried out at a temperature ranging from 40 °C to 80 °C and more particularly ranging from 45 °C to 60 °C.

[0143] According to a preferred embodiment, the process for the preparation of the salts according to the invention comprises a step of cooling at a temperature ranging from -5 °C to 30 °C and more particularly from 5 °C to room temperature.

[0144] APPLICATIONS

[0145] As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in treatment, healing, prevention, or amelioration of a disease, disorder, or symptom thereof, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

[0146] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0147] In one embodiment, the disease or condition to be treated is a proliferative disease or disorder or a kinase-mediated disease or disorder. More specifically, the disease or disorder to be treated include a proliferative disease or disorder, a developmental anomaly caused by dysregulation of the RAS-ERK signaling cascade (RASopathies), an inflammatory disease or an immune system disorder.

[0148] According to some examples, the proliferative disease or disorder to be treated is a neoplasm, an inflammatory disease or condition or a developmental anomaly, involving a constitutively activating mutation in RAS and / or RAF genes (e.g. KRAS and / or ARAF, BRAF, or CRAF mutations). The disease or disorder may also be further associated with a receptor tyrosine kinase mutation or amplification (e.g. EGFR, HER2) or a mutation in a regulator of RAS downstream of the receptor (e.g. SOS1 gain of function, NF1 loss of function). For instance, the salts of the invention are inhibitors of signal enzymes (ex. B- and CRAF) which are involved in controlling cell proliferation not only in tumors harboring RAF mutations (e.g. BRAFV600E) but importantly also in the context of mutated RAS-driven cancers. Thus, the present salts may be used for example for the treatment of diseases connected with the activity of these signal enzymes and characterized by excessive or abnormal cell proliferation.

[0149] According to one embodiment, the disease or disorder is characterized by uncontrolled cell proliferation, i.e. a “proliferative disorder” or “proliferative disease”. More specifically, these diseases and disorders relate to cells having the capacity for autonomous growth, i.e. an abnormal state of condition characterized by rapidly proliferating cell growth which generally forms a distinct mass that show partial or total lack of structural organization and functional coordination with normal tissue.

[0150] In one embodiment, the salts of the invention are inhibitors of RAS-ERK signaling and cellular proliferation in tumor cells bearing at least one mutated RAS or RAF genotype, without or substantially without inducing the paradoxical pathway.

[0151] The term "patient or subject" as used herein refers to an animal such as a mammal. A subject may therefore refer to, for example, mice, rats, dogs, cats, horses, cows, pigs, guinea pigs, primates including humans and the like. Preferably the subject is a human.

[0152] The present description therefore further relates to a method of treating a subject, such as a human subject, suffering from a proliferative disease or disorder, e.g. a RAF-mutated and / or mutated RAS-driven cancer. The method comprises administering a therapeutically effective amount of a salt of the invention, to a subject in need of such treatment.

[0153] In certain embodiments, the present description provides a method of treating a disorder (as described herein) in a subject, comprising administering to the subject identified as in need thereof, a salt of the present description. The identification of those patients who are in need of treatment for the disorders described above is well within the ability and knowledge of one skilled in the art. A clinician skilled in the art can readily identify such candidate patients.

[0154] In some embodiments, the therapeutically effective amount of a salt of the invention can be administered to a patient alone or in a composition, admixed with a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0155] The expression "pharmaceutically acceptable carrier, adjuvant, or vehicle" and equivalent expressions, refer to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the salt with which it is formulated.

[0156] Compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Other modes of administration also include intradermal or transdermal administration.

[0157] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active salt is mixed with at least one inert, pharmaceutically acceptable excipient or carrier and / or a) fillers or extenders, b) binders, c) humectants, d) disintegrating agents, e) solution retarding agents, I) absorption accelerators, g) wetting agents, h) absorbents, and i) lubricants, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0158] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0159] The amount of salt that may be combined with carrier materials to produce a composition in a single dosage form will vary depending upon the patient to be treated and the particular mode of administration.

[0160] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the symptoms associated with the proliferative disease or disorder. The amount of salt of the invention in the composition will also depend upon the particular salt in the composition.

[0161] Salts or compositions described herein may be administered using any amount and any route of administration effective for treating or lessening the severity of the symptoms as contemplated herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The salts of the invention are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the salts and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment.

[0162] Pharmaceutically acceptable compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. It will be understood, that the total daily usage of the salts and compositions of the present description will be decided by the attending physician within the scope of sound medical judgment.

[0163] Depending upon the disease or disorder to be treated, additional therapeutic agents may also be present in the compositions of this disclosure or administered separately as part of a dosage regimen, e.g. an additional chemotherapeutic agent.

[0164] The treatment may also be complemented with other treatments or interventions such as surgery, radiotherapy, a biologic response modifier, and agents used to attenuate an adverse effect.

[0165] The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0166] 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.

[0167] EXAMPLES

[0168] Equipment and analytical methods used for the syntheses of examples

[0169] Unless otherwise stated, the following equipment and analytical methods are used in the examples.

[0170] 1. X-rav Powder Diffraction (XRPD)

[0171] XRPD analysis was carried out on a Panalytical Empyrean diffractometer equipped with a Cu X-ray tube and a PIXcel1DMedipix3 detector system, scanning the samples between 3 and 40° 20. The samples were analyzed at ambient temperature and held between low density PVC / polyethylene films. Samples were analyzed using Cu Ka radiation running in transmission mode (range 3-40° 20, step size 0.01313°, counting time 92 s or range 3-40° 20, step size 0.01313°, counting time 23 s). Samples were spun at 60 rpm during data collection. Data were visualized and images generated using the HighScore Plus v4.9 software (Malvern Panalytical Inc.).

[0172] 2. Polarized Light Microscopy (PLM) The presence of crystallinity (birefringence) was determined using an Olympus BX51 stereomicroscope with cross-polarized light and a first order red compensator plate. Photomicrographic images were captured using a ColorView IIIu digital camera and SynchronizIR basic V5.0 imaging software with objective lens magnification of x 10.

[0173] 3. Thermogravimetrv Differential Thermal Analysis (TG / DTA)

[0174] Thermogravimetric analyses were carried out on a Mettler Toledo TGA / DSC1 STARe thermal analysis system. The calibration standards were indium and tin. Samples were placed in an aluminum pinhole sample pan, accurately weighed, and inserted into the TGA furnace. Under a stream of nitrogen at a rate of 10 °C / min, the heat flow signal was stabilized for one minute at 30 °C, prior to heating to 300 °C.

[0175] 4. Differential Scanning Calorimetry (DSC)

[0176] DSC analyses were carried out on a Perkin Elmer DSC8500 Differential Scanning Calorimeter. Indium metal was used as the calibration standard. Nitrogen was used as the protective gas (20 mL / min). Accurately weighed samples were placed in crimped aluminum pans (i.e. closed but not gas tight). Each sample was heated under nitrogen at a rate of 10 °C / min to a maximum of 300 °C.

[0177] 5. Nuclear Magnetic Resonance (NMR)

[0178] NMR analysis was carried out on a Bruker 500 MHz instrument in deuterated methanol or deuterated DMSO. Chemical shifts are expressed in parts per million (ppm), signals are expressed as follows: s = singlet, d = doublet, t = triplet, q = quadruplet, sept = septuple!, dd = double doublet, dt = double triplet, m = multiplet or large singlet, br = broad, H = proton.

[0179] 6. High Performance Liquid Chromatography-Ultraviolet Detection (HPLC-UV) Apparatus: Waters H-Class UPLC.

[0180] Column: AcquityUPLC HSS T3, 100A, 1.8 pm, 3 x 100 mm.

[0181] Column Temperature: 45 °C.

[0182] Sample Temperature: 5 °C.

[0183] Flow Rate: 0.5 mL / min.

[0184] Injection Volume: 2 pL.

[0185] Diluent: I00% MeOH.

[0186] Detector Wavelength: 220 nm. Mobile Phase A: 0.1% H3PO4 in H2O.

[0187] Mobile Phase B: 100% ACN.

[0188] Gradient:

[0189] 7. Thermodynamic Solubility

[0190] A thermodynamic solubility study was carried out on the salts as follows:

[0191] A suspension of the salt in water or simulated gastric or intestinal fluid was held at 37 °C for a period of 24 hours prior to solubility determination by UPLC. The solids were analyzed by XRPD.

[0192] The desired enhancement is an improvement in solubility in the intestinal fluid (FaSSIF), which is an absorption site. On the contrary, stomach is not an absorption site; in the gastrointestinal tract, substances can only cross the membrane from the intestine, there is no permeability in the stomach.

[0193] Example 1: Synthesis of ((2,3-dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy- 4-(trifluoromethyl)piperidm-l-yl)-lH-benzordlimidazol-l-yl)pyridof3,2-dlpyrimidm-4- yl)amino)phenyl)amide (Compound N°l)

[0194] Compound N°1 was prepared in free form as disclosed in international patent application WO 2022 / 221939 Al.

[0195] XRPD analysis was carried out on the dried solid. The solid was also characterized by PLM,

[0196] The following results were obtained:

[0197] - XRPD analysis (Figure 1) showed a disordered pattern suggesting an amorphous structure.

[0198] - PLM showed limited birefringence under crossed polarized light.

[0199] - The TGA trace of the TG / DTA (Figure 8) showed a 0.98 wt.% loss over the 42-136 °C temperature range (equivalent to 0.4 eq. water). - The DSC trace (Figure 15) showed an exothermic recrystallisation event at onset: 186 °C; peak: 199 °C, followed by a melting endotherm and decomposition at onset temperature 277 °C.

[0200] -!H NMR analysis was consistent with compound N°1 with negligible residual solvent detected.

[0201] Thermodynamic solubility

[0202] The thermodynamic solubility assessment carried out on compound N°1 free form showed:

[0203] A very slight solubility was observed for the free form of compound N° 1 in unbuffered water, where a solubility between 0.1 and 1 mg / mL was obtained. Compound N°1 free form was practically insoluble in FaSSIF where a solubility of only 0.001 mg / mL was obtained.

[0204] Example 2: Sodium salt

[0205] Sodium salt of compound N°1 was prepared as follows:

[0206] A solution of sodium hydroxide (14.8 g, 370 mmol) in EtOH (408 mL) was added to a suspension of compound N°1 (300 g, 392 mmol) in absolute EtOH (1.55 L), and the mixture was stirred at room temperature using a mechanical stirrer. The mixture was stirred at room temperature for 4 min and then sonicated for 3 min. The resulting suspension was stirred for 30 min at room temperature, then filtered. The solid was washed with a minimal amount of EtOH and dried under vacuum overnight. The solid was transferred to a crystallizing dish, placed in a vacuum oven at 50 °C for 6 days, and ground with a mortar and pestle after 3 days.

[0207] XRPD analysis was carried out on the dried solid. The solid was also characterized by PLM, TG / DTA, DSC, and1H NMR.

[0208] The following results were obtained:

[0209] - XRPD analysis (Figure 2) showed a crystalline material (Form 1).

[0210] - PLM showed birefringence under crossed polarized light. Crystals were uniform elongated particles under 40 pm in size. - The TGA trace of the TG / DTA (Figure 9) showed a 3.1 wt.% loss over the 42-155 °C temperature range (equivalent to 1.4 eq. water) and a 2.6 wt.% loss over the 156-244 °C temperature range (equivalent to 1.2 eq. water), suggesting a hydrate sodium salt.

[0211] - The DSC trace (Figure 16) showed no endothermic event.

[0212] -!H NMR analysis was consistent with compound N° 1 sodium salt with trace (ca. 0.185 eq.) ethanol present.

[0213] Thermodynamic solubility

[0214] The thermodynamic solubility assessment carried out on the salt showed:

[0215] A slight solubility was observed for the sodium salt in unbuffered water, where a solubility between 1 and 10 mg / mL was obtained. The solubility of the salt in FaSSIF is significantly improved (20 times).

[0216] Example 3: Choline salt

[0217] Choline salt of compound N°1 was prepared as follows:

[0218] Compound N°1 (1 g) was mixed with THF (8 mL), then heated to 50 °C under agitation (250 rpm). Choline hydroxide (46%w / w, 1 eq.) was added, and the mixture was held at 50 °C for 2 h. All materials dissolved. The mixture was cooled to room temperature, seeded with 1% w / w choline salt crystalline material obtained from 40 °C / 75% RH stressing of disordered material, and aged overnight. Significant crystallization occurred, and / / -heptane (5 mL) was added. This anti-solvent slurry was stirred for 1.5 h then filtered and air-dried prior to drying oven at 45 °C overnight.

[0219] XRPD analysis was carried out on the dried solid. The solid was also characterized by PLM,

[0220] The following results were obtained:

[0221] - XRPD analysis (Figure 3) showed a crystalline material (Form 2).

[0222] - PLM showed birefringence under crossed polarized light. Crystals were irregular particles under 40 pm in size. - The TGA trace of the TG / DTA (Figure 10) showed a 4.9 wt.% loss over the 42-166 °C temperature range (equivalent to 2.5 eq. water) and a 1.0 wt.% loss over the 170-228 °C temperature range (equivalent to 0.5 eq. water), suggesting a hydrate choline salt.

[0223] - The DSC trace (Figure 17) showed an endothermic event at onset: 37 °C; peak: 68 °C. A second endothermic event was observed at onset: 154 °C; peak: 170 °C.

[0224] -!H NMR analysis was consistent with compound N°1 monocholine salt (ca. 0.93 eq. choline) with trace THF (ca. 0.045 eq.) and / -heptane (ca. 0.033-0.043 eq.) present.

[0225] Thermodynamic solubility

[0226] The thermodynamic solubility assessment carried out on the salt showed:

[0227] A slight solubility was observed for the choline salt in unbuffered water, where a solubility between 1 and 10 mg / mL was obtained. The solubility of the salt in FaSSIF is significantly improved (about 50 times)

[0228] Example 4: Potassium salt

[0229] Potassium salt of compound N°1 was prepared as follows:

[0230] Compound N°1 (1 g) was mixed with THF / water (98:2 v / v, 5 mL), then heated to 50 °C under agitation (300 rpm) for ca. 10 min. KOH (~4 eq.) was charged, and the mixture was heated at 50 °C for ca. 30 min (precipitation observed), then cooled to room temperature, and stirred overnight. The resulting solids were worked up with / / -heptane (5 mL) as anti-solvent, then dried on a sinter funnel prior to drying under vacuum at 45 °C overnight.

[0231] XRPD analysis was carried out on the dried solid. The solid was also characterized by PLM, TG / DTA, DSC, and1H NMR.

[0232] The following results were obtained:

[0233] - XRPD analysis (Figure 4) showed a crystalline material (Form 3).

[0234] - PLM showed birefringence under crossed polarized light. Crystals were fine agglomerating uniform particles under 40 pm in size. - The TGA trace of the TG / DTA (Figure 11) showed a 2.1 wt.% loss over the 37-122 °C temperature range (equivalent to 1.0 eq. water) and a 5.5 wt.% loss over the 123-239 °C temperature range (equivalent to 2.6 eq. water), suggesting a hydrate potassium salt.

[0235] - The DSC trace (Figure 18) showed an endothermic event at onset: 75 °C; peak: 95 °C.

[0236] -!H NMR analysis was consistent with compound N°1 potassium salt with trace THF (ca. 0.344 eq.), and / -heptane (ca. 0.045 eq.).

[0237] Thermodynamic solubility

[0238] The thermodynamic solubility assessment carried out on the salt showed:

[0239] A very slight solubility was observed for the potassium salt in unbuffered water and FaSSIF, where a solubility between 0.1 and 1 mg / mL was obtained. The solubility of the salt in FaSSIF is significantly improved (155 times).

[0240] Example 5: Calcium salt

[0241] Calcium salt of compound N°1 was prepared as follows:

[0242] Compound N° 1 (1 g) was mixed with 2-MeTHF / DMSO (20: 1 v / v, 14 mL), then Ca(OH)2 (0.97 eq.) was charged, and the slurry was heated to 60 °C under agitation (1000 rpm), held at 60 °C for 24 h, then cooled to room temperature, stirred at room temperature for 72 h, then concentrated under an N2 flow. Acetone / water (20: 1) (5 mL) was charged, and the mixture was heated overnight at 50 °C under agitation, then cooled to room temperature, seeded and aged overnight. / / -Heptane (10 mL) was charged on the slurry obtained, and the resulting material was dried in a rotary evaporator. Acetone (5 mL) was charged, and the resulting material was held overnight. The resulting solids were isolated by vacuum filtration, washed with acetone (5 mL), and dried under vacuum at 45 °C overnight.

[0243] XRPD analysis was carried out on the dried solid. The solid was also characterized by PLM,

[0244] The following results were obtained:

[0245] - XRPD analysis (Figure 5) showed a crystalline material (Form 4). - PLM showed birefringence under crossed polarized light. Crystals were mostly plate-like particles under 40 pm in size.

[0246] - The TGA trace of the TG / DTA (Figure 12) showed a 2.4 wt.% loss over the 40-222 °C temperature range (equivalent to 1.1 eq. water), suggesting a hydrate calcium salt.

[0247] - The DSC trace (Figure 19) showed an endothermic event at onset: 214 °C; peak: 220 °C.

[0248] -!H NMR analysis was consistent with compound N°1 calcium salt with trace acetone (ca. 0.007 eq.) and / -heptane (ca. 0.054-0.246 eq.) present.

[0249] Thermodynamic solubility

[0250] The thermodynamic solubility assessment carried out on the salt showed:

[0251] The calcium salt was practically insoluble in unbuffered water and FaSSGF. The solubility of the salt in FaSSIF is significantly improved (about 60 times)..

[0252] Example 6: Hydrochloride salt (Counter-example)

[0253] Hydrochloride salt of compound N°1 was prepared as follows:

[0254] Compound N°1 (1 g) was mixed with ACN (5 mL), then HC1 in 1,4-dioxane (4M, 2 eq.) was charged on the suspension, and the mixture was held at 50 °C under agitation (300 rpm). Additional ACN (5 mL) was charged on the mixture, which was then cooled to room temperature and stirred overnight. The resulting solids were worked up with / / -heptane (5 mL) as anti-solvent, then dried on a sinter funnel prior to drying under vacuum at 45 °C overnight. XRPD analysis was carried out on the dried solid. The solid was also characterized by PLM, TG / DTA, and1H NMR.

[0255] The following results were obtained:

[0256] - XRPD analysis (Figure 6) showed a disordered pattern suggesting an amorphous structure.

[0257] - PLM showed agglomerating irregular particles with little birefringence under crossed polarized light, suggesting an amorphous structure.

[0258] - The TGA trace of the TG / DTA (Figure 13) showed a 3.3 wt.% loss over the 39-169 °C temperature range (equivalent to 0.3 eq. dioxane), a 3.4 wt.% loss over the 170-243 °C temperature range (equivalent to 1.5 eq. water), and a 3.8 wt.% loss over the 244-263 °C temperature range (equivalent to 1.7 eq. water), suggesting a hydrate hydrochloride salt.

[0259] -!H NMR analysis was consistent with compound N° 1 hydrochloride salt with trace dioxane (ca. 0.301 eq.), acetonitrile (ca. 0.091 eq.), and / / -heptane (ca. 0.0031-0.0035 eq.) present.

[0260] Thermodynamic solubility

[0261] The thermodynamic solubility assessment carried out on the salt showed:

[0262] The hydrochloride salt was practically insoluble in unbuffered water, FaSSIF, and FaSSGF. The solubility of the salt in FaSSIF is only slightly improved (2 times)..

[0263] Example 7: Napadisylate salt (Counter-example)

[0264] Napadisylate salt of compound N°1 was prepared as follows:

[0265] Compound N°1 (1 g) was mixed in acetone (10 mL), and the mixture heated to 50 °C under agitation (1000 rpm). 1,5 -Naphthalenedisulfonic acid (NDSA, 1.1 eq.) was charged, and the mixture held at 50 °C. Further acetone (8 mL) was added, and the mixture was held 2 h at 50 °C, then cooled to room temperature, seeded with 1% w / w napadisylate salt crystalline material, and aged for 1.25 h. DMSO (200 pL) was charged, the mixture was seeded with an additional 1% w / w napadisylate salt crystalline material and held 1 h at 50 °C, then cooled to room temperature, and aged for 22 h. / / -Heptane (6 mL) was charged, and the mixture was aged 2 h then filtered and air dried prior to drying under vacuum at 45 °C overnight.

[0266] XRPD analysis was carried out on the dried solid. The solid was also characterized by PLM,

[0267] The following results were obtained:

[0268] - XRPD analysis (Figure 7) showed a crystalline material (Form 5).

[0269] - PLM showed birefringence under crossed polarized light. Crystals were mostly fine agglomerating particles under 40 pm in size. - The TGA trace of the TG / DTA (Figure 14) showed a 2.9 wt.% loss over the 40-189 °C temperature range (equivalent to 1.7 eq. water) and a 1.9 wt.% loss over the 190-227 °C temperature range (equivalent to 1.1 eq. water), suggesting a hydrate napadisylate salt.

[0270] -!H NMR analysis was consistent with compound N°1 mononapadisylate salt (ca. 1.10 eq. napadisylate) with trace acetone (ca. 0.02 eq.) and / / -heptane (ca. 0.023-0.026 eq.) present.

[0271] Thermodynamic solubility

[0272] The thermodynamic solubility assessment carried out on the salt showed:

[0273] The napadisylate salt was practically insoluble in unbuffered water, FaSSIF, and FaSSGF. The solubility of the salt in FaSSIF is not improved.

Claims

CLAIMS1. A pharmaceutically acceptable salt, or solvate thereof, of ((2,3- dichlorophenyl)sulfonyl)(2,4-difluoro-3-((6-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-l-yl)- lH-benzo[d]imidazol-l-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)amide of the formula (I) below:wherein said salt is selected from a sodium salt, a choline salt, a potassium salt, and a calcium salt.

2. A salt, or solvate thereof, according to claim 1, wherein said salt is a sodium salt.

3. A salt, or solvate thereof, according to claim 1, wherein said salt is a choline salt.

4. A salt, or solvate thereof, according to claim 1, wherein said salt is a potassium salt.

5. A salt, or solvate thereof, according to claim 1, wherein said salt is a calcium salt.

6. A process for the preparation of a sodium salt according to claim 1 or 2, comprising the step of adding sodium hydroxide to a compound of formula (I) in a solvent chosen from water, 2-propanol, acetone, acetonitrile, ethanol, ethyl acetate, tetrahydrofuran, 2- methyltetrahydrofuran, dichloromethane, DMSO, / / -heptane, methanol, 1,4-dioxane, and mixtures thereof, in particular chosen from water, acetone, acetonitrile, ethanol, tetrahydro furan, 2 -methyltetrahydro furan, DMSO, / / -heptane, 1,4-dioxane, and mixtures thereof, and preferably chosen from water ethanol, and mixtures thereof.

7. A process for the preparation of a choline salt according to claim 1 or 3, comprising the step of adding choline hydroxide to a compound of formula (I) in a solvent chosen water, 2-propanol, acetone, acetonitrile, ethanol, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, DMSO, / / -heptane, methanol, 1,4-dioxane, and mixtures thereof, in particular chosen from water, acetone, acetonitrile, ethanol, tetrahydro furan, 2 -methyltetrahydro furan, DMSO, / / -heptane, 1,4-dioxane, and mixtures thereof, and preferably chosen from tetrahydrofuran, / / -heptane, and mixtures thereof.

8. A process for the preparation of a potassium salt according to claim 1 or 4, comprising the step of adding potassium hydroxide to a compound of formula (I) in a solvent chosen from water, 2-propanol, acetone, acetonitrile, ethanol, ethyl acetate, tetrahydrofuran, 2- methyltetrahydrofuran, dichloromethane, DMSO, / / -heptane, methanol, 1,4-dioxane, and mixtures thereof, in particular chosen from water, acetone, acetonitrile, ethanol, tetrahydro furan, 2 -methyltetrahydro furan, DMSO, / / -heptane, 1,4-dioxane, and mixtures thereof, and preferably chosen from water, acetone, tetrahydrofuran, / / -heptane, and mixtures thereof.

9. A process for the preparation of a calcium salt according to claim 1 or 5, comprising the step of adding calcium hydroxide to a compound of formula (I) in a solvent chosen from water, 2-propanol, acetone, acetonitrile, ethanol, ethyl acetate, tetrahydrofuran, 2- methyltetrahydrofuran, dichloromethane, DMSO, / / -heptane, methanol, 1,4-dioxane, and mixtures thereof, in particular chosen from water, acetone, acetonitrile, ethanol, tetrahydro furan, 2 -methyltetrahydro furan, DMSO, / / -heptane, 1,4-dioxane, and mixtures thereof, and preferably chosen from water, acetone, 2-methyltetrahydrofuran, DMSO, n- heptane, and mixtures thereof.

10. A salt, or solvate thereof, according to any one of claims 1 to 5, for use in medicine.

11. A salt, or solvate thereof, according to any one of claims 1-5, for use in the treatment of a disease or disorder selected from a proliferative disease or disorder, a developmental anomaly caused by dysregulation of the RAS-ERK signaling cascade (RASopathies), an inflammatory disease, and an immune system disorder.

12. The salt, or solvate thereof, for use according to claim 11, wherein said treatment comprises inhibiting the RAS-ERK signaling pathway without substantial induction of a paradoxical pathway.

13. Medicament comprising at least one salt, or solvate thereof, according to any one of claims 1 to 5.

14. A pharmaceutical composition comprising at least one salt, or solvate thereof, according to any one of claims 1 to 5, and at least one pharmaceutically acceptable excipient.

Images