Salt of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one, method for producing the same, and use as an ERK kinase inhibitor

Abstract

The present invention relates to the following formula (I) With respect to pharmaceutically acceptable salts of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one represented by TIFF2026525238000064.tif49170, the salt is selected from hydrochloride, maleate, esylate, oxoglutarate, malonate and oxalate.

Description

[Technical Field]

[0001] The present invention relates to a novel salt of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one, an inhibitor of ERK kinase (ERK1 and ERK2), its preparation, and its use for therapeutic purposes. [Background technology]

[0002] The ERK protein belongs to the RAS / RAF / MEK / ERK pathway, which plays a crucial role in the cell cycle, proliferation, growth, and survival. The RAS / RAF / MEK / ERK pathway is activated by growth factors via a receptor tyrosine kinase that enables the activation of the GTPase RAS. RAS then activates the RAF protein. RAF then activates MEK, which in turn activates ERK. Ultimately, this process enables the phosphorylation of numerous substrates that play vital roles in metabolism, protein synthesis, cell proliferation, and survival.

[0003] RAF mutations, in particular, cause overactivation of the 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).

[0004] In fact, RAF mutations are frequently observed in melanoma (27%–70%), thyroid cancer (36%–53%), colorectal cancer (5%–22%), and ovarian cancer (30%). Similarly, RAS mutations are found in approximately 30% of cancers, including pancreatic cancer (90%), lung cancer (35%), colorectal cancer (45%), and liver cancer (30%) (Downward, Nat. Rev. Cancer. 2003).

[0005] Therefore, proteins in the RAS / RAF / MEK / ERK pathway are the subject of research in cancer treatment. In fact, pharmaceutical companies are focusing on the upstream kinases (RAF, MEK).

[0006] However, current treatments using RAF inhibitors and MEK inhibitors eventually lead to resistance (Lito et al., Nat. Med. 2013; Caunt et al., Nat. Rev. Cancer, 2015).

[0007] Furthermore, most resistance to MEK inhibitors or RAF inhibitors induces ERK reactivation through various mechanisms such as MEK mutations, B-RAF amplification, and C-RAF mutations (Little et al., Oncogene, 2013).

[0008] Furthermore, RAF or MEK inhibition suppresses negative feedback of ERK, which restores upward signaling and ultimately restores ERK activity (Lito et al., Nat. Med., 2013).

[0009] Considering the resistance phenomena that have emerged after current treatments with RAF inhibitors and MEK inhibitors, it is essential to develop new treatment options.

[0010] ERK signaling has been shown to play a crucial role in hyperproliferative diseases, as well as in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Huntington's disease (Cheung et al., Sci.STKE.2004; Bodai et al., Bioessays., 2012), and inflammation such as in the pathogenesis of rheumatoid arthritis (Thalhamer et al., Rheumatology.2008). Therefore, the present invention relates to the development of ERK inhibitors for treating a wide range of diseases.

[0011] Some ERK inhibitors have already been described in the prior art. For example, US8,697,697B2 describes substituted pyrazole derivatives as ERK2 kinase activity inhibitors. Pyrrolo[2,3-b]pyrazine derivatives have been reported as ERK inhibitors in international patent application WO2014 / 060395A1, and azaindole derivatives have been reported as ERK inhibitors in international patent application WO2017 / 085230A1.

Summary of the Invention

Means for Solving the Problems

[0012] (S)-1-(1-(3-Chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one of chemical formula (I) described below is an inhibitor of ERK kinase (ERK1 and ERK2). This can be used particularly as an anticancer agent. TIFF2026525238000002.tif49170 Such compounds have been developed in the form of free bases that can improve solubility. In fact, such ERK inhibitors are desired to exhibit high solubility when used in pharmaceutical formulations, particularly pharmaceutical formulations for oral administration.

[0013] Furthermore, it is desirable that the solubility profile of such ERK inhibitors does not depend on pH conditions. In fact, the free base of such ERK inhibitors has a solubility profile that strongly depends on pH. Thus, at acidic pH, the free base dissolves slightly, but when the pH exceeds 3, the solubility significantly decreases, which is disadvantageous for oral administration. Therefore, there is a need to provide new means for improving the solubility profile of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one with respect to pH.

[0014] The present invention relates to novel salts of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one, a method for producing the same, and its use as an ERK kinase activity inhibitor. The compounds of the present invention are novel salts having at least enhanced anti-proliferative activity and good solubility in an aqueous solution. The salts according to the present invention are characterized by their low toxicity, high permeability, and kinase inhibition selectivity. Overall, the salts according to the present invention are remarkable in their drug-like properties.

[0015] The first subject of the present invention relates to pharmaceutically acceptable salts of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one of the following formula (I), and solvates thereof. TIFF2026525238000003.tif49170 Here, the salt is selected from hydrochloride, maleate, esylate, oxoglutarate, malonate, and oxalate.

[0016] As a result of extensive searches and screening tests, the inventors of the present application have determined that these novel salts of the compound of formula (I) selectively target the active site of ERK kinase, act as effective inhibitors of ERK kinase activity, and have good solubility, as demonstrated in the following examples.

[0017] Advantageously, the salts of the present invention have higher solubility in water compared to free bases. Furthermore, the pH dependence of the solubility is reduced, enabling good absorption of the compound in the intestinal tract. Moreover, obtaining the salts according to the present invention has the advantage of ensuring the reproducibility of the compound by defining a specific crystal form and thereby controlling its synthesis. Preferably, the salts of the present invention have higher solubility in water compared to free bases. Furthermore, the pH dependence of the solubility is reduced, enabling good absorption of the compound in the intestinal tract. Moreover, obtaining the salts according to the present invention has the advantage of ensuring the reproducibility of the compound by defining a specific crystal form and thereby controlling its synthesis.

[0018] As described later, these salts are useful for the treatment of symptoms or diseases, particularly cancer, in which modification of ERK activity is thought to yield favorable therapeutic effects. Other subjects relate to methods for producing salts of the compound of formula (I). Other subjects relate to salts of the compound of formula (I) for use in pharmaceuticals or pharmaceutical compositions. Further subjects relate to salts according to the present invention for use as inhibitors of ERK kinase activity, particularly for use as inhibitors of ERK1 and / or ERK2 kinase activity.

[0019] Abbreviations and Definitions In the context of this invention, the following abbreviations and common notations are used. ACN Acetonitrile ATP (Adenosine 5'-triphosphate) Brij-35 Polyoxyethylene glycol dodecyl ether Bs Brosyl (parabromophenylsulfonyl) C18 column, reversed-phase C18 column CaCl2 calcium chloride CMC (Carboxymethylcellulose) DABCO 1,4-Diazabicyclo[2.2.2]octane DCM Dichloromethane DMF Dimethylformamide DMEM Dulbecco's Modified Eagle Medium DMSO (Dimethyl Sulfoxide) DSC (Differential Scanning Calorimetry) DVS Dynamic Water Vapor Adsorption Celsius (℃) ee Enantiomeric excess EGTA (Eggtadic Acid) Eq equivalent Et2O Diethyl ether HCl ethyl acetate EtOH Ethanol FaSSIF (Fasting Simulation of Intestinal Fluid) FaSSGF simulated gastric juice in an empty stomach FBS (Fetal Bovine Serum) FT-IR Fourier Transform Infrared Spectroscopy g grams h time HBSS Hanks' equilibrium salt solution HCl (hydrochloric acid) HEPES 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid hERG Human Delayed Rectification Potassium Ion Channel Gene HPLC (High-Performance Liquid Chromatography) IR infrared spectroscopy K2CO3 potassium carbonate KCl Potassium Chloride KF Potassium Fluoride KOH (Potassium Hydroxide) LC / MS Liquid Chromatography / Mass Spectrometry LiAlH4 Lithium Aluminum Hydride LiHMDS (Lithium Bis(Trimethylsilyl)amide) M = Number of moles per liter MeCN acetonitrile MeOH methanol mg milligrams MH + Pseudo-molecular ions (cationic modes in mass spectrometry) MHz (megahertz) MS mass spectrometry μl (microliter) MgCl2 (magnesium chloride) ml (milliliter) mmol millimol mole MPA mobile phase A MPB mobile phase B NaCl (Sodium Chloride) Na2CO3 (sodium carbonate) NaHCO3 (sodium bicarbonate) NaOH (Sodium Hydroxide) Sodium sulfate (Na2SO4) NH4Cl (Ammonium Chloride) NMR nuclear magnetic resonance PLM Polarizing Microscope PSD Particle Size Distribution RH (Relative Humidity) RuPhos 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl RuPhos Pd G2 Chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) SDS Sodium Dodecyl Sulfate TBAF Tetrabutylammonium Fluoride TEA (Triethylamine) TG thermogravimetry TGA thermogravimetric analysis THF (Tetrahydrofuran) U(H)PLC Ultra-High-Speed ​​Liquid Chromatography UV ultraviolet light XRPD (X-ray Powder Diffraction)

[0020] In the sense of the present invention, “kinase inhibitor” means a compound that reduces or inhibits the activity of a target kinase compared to the activity measured without the inhibitor. In the sense of the present invention, the terms “prevent” or “prevent” an event mean reducing the risk of the event occurring. In this specification, the terms “ambient temperature” or “room temperature” refer to a temperature range of 15°C to 30°C, more specifically, a temperature range of 18°C ​​to 25°C. Hydrochloride is a salt of hydrochloric acid. Maleate is a salt of maleic acid. Esylate (esylate) is a salt of ethanesulfonic acid (also called ethylic acid). Oxoglutarate is a salt of oxoglutarate (also called 2-oxoglutarate or α-ketoglutarate). Malonate is a salt of malic acid (also called 2-hydroxybutanediic acid). In the sense of the present invention, oxalate is a salt of oxalic acid (also called ethanediic acid). In the sense of the present invention, a besilate is a salt of benzenesulfonic acid (also called besilicic acid). In the sense of the present invention, a napsilate is a salt of naphthalenesulfonic acid. Other features, properties, and advantages of the present invention will become clearer from the following description and examples. [Brief explanation of the drawing]

[0021] [Figure 1] Figure 1 is an X-ray powder diagram of the monohydrochloride anhydrous salt of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one (see Example 12). [Figure 2] Figure 2 is an X-ray powder image of the hydrochloride hydrate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one (see Example 13). [Figure 3]Figure 3 is an X-ray powder map of the maleate anhydride salt of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one (see Example 14). [Figure 4] Figure 4 is an X-ray powder diagram of the esylate anhydrous salt of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one (see Example 15). [Figure 5] Figure 5 is an X-ray powder map of the oxoglutarate anhydrous salt of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one (see Example 16). [Figure 6] Figure 6 is an X-ray powder diagram of the malonate anhydrous salt of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one (see Example 17). [Figure 7] Figure 7 is an X-ray powder diagram of the oxalate anhydrous salt of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one (see Example 18). [Figure 8] Figure 8 is an X-ray powder diagram of the besylate anhydride salt of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one (see Example 19). [Figure 9] Figure 9 is an X-ray powder diagram of the napsylate anhydrous salt of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one (see Example 20). [Modes for carrying out the invention]

[0022] As described above, the salts according to this disclosure exhibit improved solubility compared to the solubility of the free base form.

[0023] The salt of the present invention As described above, the object of the present invention is the following formula (I) A pharmaceutically acceptable salt of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one, represented by TIFF2026525238000004.tif49170, and its solvate, The salt is selected from hydrochloride, maleate, esylate, oxoglutarate, malonate, and oxalate.

[0024] According to a preferred embodiment, the salt is the hydrochloride salt of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one.

[0025] According to a preferred embodiment, the salt is (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one monohydrochloride anhydrous salt or hydrochloride hydrate salt.

[0026] According to a preferred embodiment, the salt is the maleate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one.

[0027] According to a preferred embodiment, the salt of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one is selected from hydrochloride and maleate salts.

[0028] According to a preferred embodiment, the salt is the esylate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one.

[0029] According to a preferred embodiment, the salt is the oxoglutarate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one.

[0030] According to a preferred embodiment, the salt is the malonate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one.

[0031] According to a preferred embodiment, the salt is the oxalate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one.

[0032] According to a preferred embodiment, the pharmaceutically acceptable salt is anhydrous and selected from anhydrous crystalline (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one hydrochloride, maleate, esylate, oxoglutarate, malonate, and oxalate.

[0033] According to a preferred embodiment, pharmaceutically acceptable salts of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one as defined in the present invention are selected from anhydrous crystalline hydrochloride, anhydrous crystalline maleate, anhydrous crystalline esylate, anhydrous crystalline oxoglutarate, anhydrous crystalline malonate, and anhydrous crystalline oxalate.

[0034] According to a preferred embodiment, the pharmaceutically acceptable salt is crystalline (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one hydrochloride hydrate.

[0035] According to a preferred embodiment, pharmaceutically acceptable salts of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one as defined in the present invention are selected from anhydrous crystalline hydrochloride, crystalline hydrochloride hydrate, anhydrous crystalline maleate, anhydrous crystalline esylate, anhydrous crystalline oxoglutarate, anhydrous crystalline malonate, and anhydrous crystalline oxalate.

[0036] According to a preferred embodiment, pharmaceutically acceptable salts of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one as defined in the present invention are selected from anhydrous crystalline hydrochloride and anhydrous crystalline maleate.

[0037] pharmaceutically acceptable salts of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one can be characterized, for example, by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC).

[0038] According to a preferred embodiment, the pharmaceutically acceptable salt of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one as defined in the present invention is an anhydrous crystalline hydrochloride, preferably an anhydrous crystalline monohydrochloride.

[0039] More specifically, the anhydrous crystalline hydrochloride of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one exhibits an X-ray powder diffraction pattern showing peaks at 2θ angles of 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 ±0.2°), as shown in Figure 1 (X-ray powder diffraction pattern), and / or exhibits a single endothermic reaction with an onset temperature of 258.0°C (±2°C).

[0040] The characteristic X-ray powder diffraction pattern of the anhydrous crystalline hydrochloride salt of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one is shown in Figure 1, and its characteristic signals are summarized in the table below. [Table 1]

[0041] According to a preferred embodiment, the anhydrous crystalline hydrochloride of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one exhibits an X-ray powder diffraction pattern showing at least one peak, particularly at least two peaks, preferably at least five peaks, and more preferably at least ten peaks, selected from 2θ angles of 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 ±0.2°).

[0042] According to a preferred embodiment, the anhydrous crystalline hydrochloride of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one of the present invention has XRPD properties substantially similar to those shown in Figure 1.

[0043] According to a preferred embodiment, the pharmaceutically acceptable salt of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one as defined in the present invention is a crystalline hydrochloride hydrate salt.

[0044] More specifically, the crystalline hydrochloride hydrate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one has 2θ angles of 8.71°, 12.14°, 13.15°, 17.66°, and 18. The X-ray powder diffraction pattern shows peaks at 22°, 18.73°, 20.64°, 22.16°, 23.19°, 23.74°, 24.39°, 25.18°, 25.71°, 26.90°, and 27.49° (each within ±0.2°), and / or exhibits an endothermic reaction with starting temperatures of 85.3°C, 194.5°C, and 255.5°C (±2°C).

[0045] The characteristic X-ray powder diffraction pattern of the crystalline hydrochloride hydrate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one is shown in Figure 2, and its characteristic signals are summarized in the table below. [Table 2]

[0046] According to a preferred embodiment, the crystalline hydrochloride hydrate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one exhibits an X-ray powder diffraction pattern showing at least one peak, particularly at least two peaks, preferably at least five peaks, and more preferably at least ten peaks, selected from 2θ angles of 8.71°, 12.14°, 13.15°, 17.66°, 18.22°, 18.73°, 20.64°, 22.16°, 23.19°, 23.74°, 24.39°, 25.18°, 25.71°, 26.90°, and 27.49° (each ±0.2°).

[0047] According to a preferred embodiment, the crystalline hydrochloride hydrate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one of the present invention has XRPD properties substantially similar to those shown in Figure 2.

[0048] According to a preferred embodiment, the pharmaceutically acceptable salt of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one as defined in the present invention is an anhydrous crystalline maleate.

[0049] More specifically, the anhydrous crystalline maleate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one exhibits an X-ray powder diffraction pattern showing peaks at 2θ angles of 3.80°, 10.21°, 15.42°, 15.89°, 16.55°, 16.72°, 17.42°, 19.69°, 19.91°, 20.47°, 21.98°, 22.93°, 24.65°, and 25.26° (each ±0.2°), as shown in Figure 3 (X-ray powder diffraction pattern), and / or exhibits a single endothermic reaction with an onset temperature of 185.0°C (±2°C).

[0050] The characteristic X-ray powder diffraction pattern of the anhydrous crystalline maleate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one is shown in Figure 3, and its characteristic signals are summarized in the table below. [Table 3]

[0051] According to a preferred embodiment, the anhydrous crystalline maleate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one exhibits an X-ray powder diffraction pattern showing at least one peak, particularly at least two peaks, preferably at least five peaks, and more preferably at least ten peaks, selected from 2θ angles of 3.80°, 10.21°, 15.42°, 15.89°, 16.55°, 16.72°, 17.42°, 19.69°, 19.91°, 20.47°, 21.98°, 22.93°, 24.65°, and 25.26° (each ±0.2°).

[0052] According to a preferred embodiment, the anhydrous crystalline maleate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one of the present invention has XRPD properties substantially similar to those shown in Figure 3.

[0053] According to a preferred embodiment, the pharmaceutically acceptable salt of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one as defined in the present invention is an anhydrous crystalline ethylate.

[0054] More specifically, the anhydrous crystalline esylate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one has 2θ angles of 3.37°, 11.43°, 12.06°, and 12.51°, as shown in Figure 4 (X-ray powder diffraction diagram). The X-ray powder diffraction pattern shows peaks at 14.69°, 15.31°, 15.69°, 17.18°, 17.46°, 17.69°, 22.11°, 22.88°, 24.00°, 25.08°, and 25.91° (each within ±0.2°), and / or exhibits an endothermic reaction with starting temperatures of 197.0°C and 247°C (±2°C).

[0055] The characteristic X-ray powder diffraction pattern of the anhydrous crystalline esylate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one is shown in Figure 4, and its characteristic signals are summarized in the table below. [Table 4]

[0056] According to a preferred embodiment, the anhydrous crystalline esylate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one exhibits an X-ray powder diffraction pattern showing at least one peak, particularly at least two peaks, preferably at least five peaks, and more preferably at least ten peaks, selected from 2θ angles of 3.37°, 11.43°, 12.06°, 12.51°, 14.69°, 15.31°, 15.69°, 17.18°, 17.46°, 17.69°, 22.11°, 22.88°, 24.00°, 25.08°, and 25.91° (each ±0.2°).

[0057] According to a preferred embodiment, the anhydrous crystalline esylate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one of the present invention has XRPD properties substantially similar to those shown in Figure 4.

[0058] According to a preferred embodiment, the pharmaceutically acceptable salt of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one as defined in the present invention is an anhydrous crystalline oxoglutarate.

[0059] More specifically, the anhydrous crystalline oxoglutarate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one has 2θ angles of 9.90°, 10.97°, 11.62°, 12.87°, and 14. The X-ray powder diffraction pattern shows peaks at 91°, 15.37°, 16.42°, 18.21°, 18.77°, 19.38°, 18.89°, 21.31°, 22.03°, 22.29°, 23.35°, 23.80°, and 24.26° (each within ±0.2°), and / or exhibits an endothermic reaction with starting temperatures of 177.0°C and 250°C (±2°C).

[0060] The characteristic X-ray powder diffraction pattern of the anhydrous crystalline oxoglutarate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one is shown in Figure 5, and its characteristic signals are summarized in the table below. [Table 5]

[0061] According to a preferred embodiment, the anhydrous crystalline oxoglutarate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one has 2θ angles of 9.90°, 10.97°, 11.62°, 12.87°, 14.91°, 15.37°, 16.42°, and 1 The X-ray powder diffraction pattern exhibits at least one peak, particularly at least two peaks, preferably at least five peaks, and more preferably at least ten peaks, selected from 8.21°, 18.77°, 19.38°, 18.89°, 21.31°, 22.03°, 22.29°, 23.35°, 23.80°, and 24.26° (each within ±0.2°).

[0062] According to a preferred embodiment, the anhydrous crystalline oxoglutarate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one of the present invention has XRPD properties substantially similar to those shown in Figure 5.

[0063] According to a preferred embodiment, the pharmaceutically acceptable salt of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one as defined in the present invention is an anhydrous crystalline malonate.

[0064] More specifically, the anhydrous crystalline malonate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one exhibits an X-ray powder diffraction pattern showing peaks at 2θ angles of 8.51°, 12.48°, 14.96°, 15.30°, 17.04°, 18.69°, 19.61°, 23.07°, 23.93°, 24.54°, and 26.80° (each ±0.2°), as shown in Figure 6 (X-ray powder diffraction pattern), and / or exhibits an endothermic reaction with starting temperatures of 125.0°C and 259°C (±2°C).

[0065] The characteristic X-ray powder diffraction pattern of the anhydrous crystalline malonate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one is shown in Figure 6, and its characteristic signals are summarized in the table below. [Table 6]

[0066] According to a preferred embodiment, the anhydrous crystalline malonate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one exhibits an X-ray powder diffraction pattern showing at least one peak, particularly at least two peaks, preferably at least five peaks, and more preferably at least ten peaks, with 2θ angles selected from 8.51°, 12.48°, 14.96°, 15.30°, 17.04°, 18.69°, 19.61°, 23.07°, 23.93°, 24.54°, and 26.80° (each ±0.2°).

[0067] According to a preferred embodiment, the anhydrous crystalline malonate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one of the present invention has XRPD properties substantially similar to those shown in Figure 6.

[0068] According to a preferred embodiment, a pharmaceutically acceptable salt of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one as defined in the present invention is an anhydrous crystalline oxalate.

[0069] More specifically, the anhydrous crystalline oxalate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one has 2θ angles of 9.44°, 11.14°, 12.03°, and 12.48°, as shown in Figure 7 (X-ray powder diffraction diagram). The X-ray powder diffraction pattern shows peaks at 14.67°, 15.28°, 15.62°, 17.17°, 18.99°, 19.36°, 22.88°, 23.13°, 25.04°, 26.25°, and 29.92° (each ±0.2°), and / or exhibits an endothermic reaction with starting temperatures of 204.0°C and 251°C (±2°C).

[0070] The characteristic X-ray powder diffraction pattern of the anhydrous crystalline oxalate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one is shown in Figure 7, and its characteristic signals are summarized in the table below. [Table 7]

[0071] According to a preferred embodiment, the anhydrous crystalline oxalate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one exhibits an X-ray powder diffraction pattern showing at least one peak, particularly at least two peaks, preferably at least five peaks, and more preferably at least ten peaks, selected from 2θ angles of 9.44°, 11.14°, 12.03°, 12.48°, 14.67°, 15.28°, 15.62°, 17.17°, 18.99°, 19.36°, 22.88°, 23.13°, 25.04°, 26.25°, and 29.92° (each ±0.2°).

[0072] According to a preferred embodiment, the anhydrous crystalline oxalate of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one of the present invention has XRPD properties substantially similar to those shown in Figure 7. Salt production

[0073] First, the compound of formula (I) can be produced according to methods well known to those skilled in the art, as shown in the following examples.

[0074] Preferably, the compound of formula (I) can be produced according to the method shown in Example 1.

[0075] This specification further provides a method for producing a pharmaceutically acceptable salt of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one, the method comprising the following steps:

[0076] (a)(S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one is dissolved in a solvent or a mixture of solvents.

[0077] (b) Add a counterion in the form of an acid that may already be dissolved in the solvent or solvent mixture to the mixture obtained in step (a) to obtain (a)(S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one. The molar ratio of the counterions is 3:1 to 1:2, in particular 5:2 to 1:2, more specifically 2:1 to 1:2, and even more specifically 2:1 or 1:1.

[0078] (c) Optionally, the solvent(s) are evaporated from 0°C to the boiling point of the selected solvent(s) or mixture of solvents(s) from step (a) and step (b), particularly from room temperature to 60°C, and more specifically from room temperature to 50°C.

[0079] (d) Optionally, a solvent or solvent mixture may be added.

[0080] (e) Apply the temperature program.

[0081] (f) Optionally, filter the solution.

[0082] (g) Next, optionally, dry at temperatures ranging from room temperature to 60°C to obtain the desired salt of (a)(S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one.

[0083] The solvent(s) used in steps (a), (b), and (d) are any solvents conventionally used in the crystallization step, particularly organic solvents, and can 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, acetic acid solvents such as ethyl acetate and isopropyl acetate, aromatic solvents such as toluene, hydrocarbon solvents such as N-heptane, chlorinated solvents such as dichloromethane and chloroform, organic sulfur solvents such as dimethyl sulfoxide (DMSO), amine and amide solvents such as N-methyl-2-pyrrolidone (NMP), dimethylacetamide, and acetonitrile, and mixtures thereof.

[0084] According to a preferred embodiment, the solvent(s) used in step (a), step (b), and step (d) are selected from 2-propanol, acetone, acetonitrile, ethanol, ethyl acetate, tetrahydrofuran, dichloromethane, methanol, 1,4-dioxane, and mixtures thereof.

[0085] According to a preferred embodiment, the solvents used in steps (a), (b), and (d) are 2-propanol, acetone, acetonitrile, ethanol, ethyl acetate, tetrahydrofuran, dichloromethane, methanol, and mixtures thereof.

[0086] According to a preferred embodiment, the solvent used in step (a), step (b), and / or step (d) is 2-propanol.

[0087] According to a preferred embodiment, the solvent used in step (a), step (b), and / or step (d) is acetone.

[0088] According to a preferred embodiment, the solvent used in step (a), step (b), and / or step (d) is acetonitrile.

[0089] In a preferred embodiment, the solvent used in step (a), step (b), and / or step (d) is ethanol.

[0090] In a preferred embodiment, the solvent used in step (a), step (b), and / or step (d) is ethyl acetate.

[0091] In a preferred embodiment, the solvent used in step (a), step (b), and / or step (d) is tetrahydrofuran.

[0092] In a preferred embodiment, the solvent used in step (a), step (b), and / or step (d) is dichloromethane.

[0093] In a preferred embodiment, the solvent used in step (a), step (b), and / or step (d) is DCM / methanol.

[0094] According to a preferred embodiment, the solvent used in step (a), step (b), and / or step (d) is 1,4-dioxane.

[0095] Those skilled in the art will know how to determine the most suitable solvent in each step (a), step (b), and step (d) in order to obtain the desired pharmaceutically acceptable salt.

[0096] According to one embodiment, the solvent(s) used in step (a), step (b), and / or step (d) are the same.

[0097] According to one embodiment, the solvents(s) used in step (a), step (b), and / or step (d) are different from each other.

[0098] According to a preferred embodiment, the counterion of the form of the acid in step (b) is selected from hydrochloric acid, maleic acid, ethanesulfonic acid, ketoglutaric acid, malonic acid, and oxalic acid.

[0099] According to a preferred embodiment, the counterion of the form of the acid in step (b) is hydrochloric acid.

[0100] According to a preferred embodiment, the counterion of the acid form in step (b) is maleic acid.

[0101] According to a preferred embodiment, the counterion of the acid form in step (b) is ethanesulfonic acid.

[0102] According to a preferred embodiment, the counterion of the acid form in step (b) is ketoglutaric acid.

[0103] According to a preferred embodiment, the counterion of the acid form in step (b) is malonic acid.

[0104] According to a preferred embodiment, the counterion of the acid form in step (b) is oxalic acid.

[0105] According to a preferred embodiment, the method for producing a hydrochloride salt according to the present invention includes the step of adding hydrochloric acid to a compound of formula (I) in a solvent selected from 2-propanol, acetone, acetonitrile, ethanol, ethyl acetate, 1,4-dioxane, and tetrahydrofuran, particularly in a solvent selected from 2-propanol, acetone, acetonitrile, and ethanol, preferably in a solvent selected from 2-propanol and acetone.

[0106] According to a preferred embodiment, the method for producing an anhydrous monohydrochloride salt according to the present invention includes the step of adding hydrochloric acid to a compound of formula (I) in a solvent selected from 2-propanol, acetone, acetonitrile, ethanol, ethyl acetate, and tetrahydrofuran, particularly in a solvent selected from 2-propanol, acetone, acetonitrile, and ethanol, preferably in a solvent selected from 2-propanol and acetone.

[0107] According to a preferred embodiment, the method for producing a hydrochloride hydrate salt according to the present invention comprises the step of adding hydrochloric acid to a compound of formula (I) in a solvent selected from 2-propanol, acetone, ethanol, 1,4-dioxane, and tetrahydrofuran.

[0108] According to a preferred embodiment, the method for producing a hydrochloride salt according to the present invention includes the step of adding hydrochloric acid to a compound of formula (I) in a solvent selected from 2-propanol, acetone, acetonitrile, ethanol, ethyl acetate, 1,4-dioxane, and tetrahydrofuran, particularly in a solvent selected from 2-propanol, acetone, acetonitrile, and ethanol, preferably in a solvent selected from 2-propanol and acetone.

[0109] According to a preferred embodiment, the method for producing a maleate salt according to the present invention includes the step of adding maleic acid to a compound of formula (I) in a solvent selected from 2-propanol, acetone, acetonitrile, and ethyl acetate, particularly in a solvent selected from 2-propanol, acetone, and acetonitrile, preferably in 2-propanol.

[0110] According to a preferred embodiment, the method for producing an ethylate salt according to the present invention includes the step of adding ethanesulfonic acid to a compound of formula (I) in a solvent selected from acetone, acetonitrile, ethyl acetate, and tetrahydrofuran, particularly in a solvent selected from acetone and ethyl acetate, preferably in acetone.

[0111] According to a preferred embodiment, the method for producing an oxoglutarate according to the present invention includes the step of adding ketoglutaric acid to a compound of formula (I) in a solvent selected from 2-propanol, acetone, acetonitrile, ethanol, ethyl acetate, dichloromethane, methanol, and a mixture of dichloromethane and methanol, particularly in a solvent selected from ethanol, 2-propanol, acetonitrile, dichloromethane, and a mixture of dichloromethane and methanol, preferably in a solvent selected from dichloromethane and a mixture of dichloromethane and methanol.

[0112] According to a preferred embodiment, the method for producing a malonic acid salt according to the present invention includes the step of adding malonic acid to a compound of formula (I) in a solvent selected from dichloromethane, a mixture of dichloromethane and methanol, and 2-propanol, preferably in a solvent selected from dichloromethane and a mixture of dichloromethane and methanol.

[0113] According to a preferred embodiment, the method for producing an oxalate according to the present invention includes the step of adding oxalic acid to a compound of formula (I) in methanol.

[0114] According to a preferred embodiment, the salt production method according to the present invention is carried out at a temperature in the range of 40°C to 80°C, more specifically at a temperature in the range of 45°C to 60°C.

[0115] According to a preferred embodiment, the method for producing a salt according to the present invention includes the step of cooling to a temperature in the range of -5°C to 30°C, more specifically to a temperature in the range of 5°C to room temperature.

[0116] Purpose As described above and as clearly explained in the following examples, the salt according to the present invention is useful as an inhibitor of ERK kinase activity.

[0117] According to the first aspect, the salt of the present invention is used as an inhibitor of ERK2 kinase activity, preferably as a selective inhibitor of ERK2 kinase activity.

[0118] More specifically, the salts of the present invention are used to prevent and / or inhibit and / or treat diseases or conditions mediated by ERK kinase activity, particularly by ERK2 kinase activity.

[0119] Accordingly, the present invention provides a method for preventing and / or treating a disease or condition mediated by ERK kinase activity, the method comprising at least the step of administering at least an effective amount of at least one salt according to the present invention to an individual in need.

[0120] The present invention also provides salts of the present invention used to prevent and / or inhibit and / or treat, preferably prevent and / or treat, more preferably treat, diseases or conditions mediated by ERK kinase activity, preferably ERK2 kinase activity.

[0121] The present invention also provides the use of salts of the present invention for preventing and / or inhibiting and / or treating, preferably for preventing and / or treating, more preferably for treating, diseases or conditions mediated by ERK kinase activity, preferably ERK2 kinase activity.

[0122] According to one embodiment, the above-mentioned disease or symptom can be selected from cancer, metastasis, and human immunodeficiency virus (HIV), and preferably from cancer and metastasis.

[0123] More specifically, the above diseases or symptoms may be selected from glioblastoma, multiple myeloma, cancer, leukemia, especially myeloid leukemia (AML), lymphocytic leukemia, myeloid leukemia (CML), or lymphoblastic leukemia, myelodysplastic syndrome, Kaposi's sarcoma, cutaneous angiosarcoma, solid tumors, lymphoma, especially non-Hodgkin lymphoma, melanoma, especially malignant melanoma, bladder cancer, breast cancer, gastric cancer, colon cancer, colorectal cancer, endometrial cancer, lung cancer including non-small cell carcinoma, pancreatic cancer, prostate cancer, rectal cancer, kidney cancer, head and neck cancer, liver cancer, ovarian cancer, especially serous ovarian cancer, seminomastoma, respiratory and thoracic cancers, thyroid cancer, especially papillary thyroid carcinoma or follicular thyroid carcinoma, or other tumors that express ERK.

[0124] According to another embodiment, the above-mentioned disease or symptom can be selected from neoplastic diseases, allergic diseases, inflammatory diseases, autoimmune diseases, malaria-related diseases, mast cell-related diseases, graft-versus-host diseases, metabolic syndrome, central nervous system-related diseases, neurodegenerative diseases, pain disorders, substance abuse disorders, prion diseases, heart diseases, fibrous diseases, idiopathic arterial hypertension (IPAH), and primary pulmonary hypertension (PPH).

[0125] According to yet another embodiment, the salts of the present invention can be used to prevent and / or inhibit and / or treat human immunodeficiency virus (HIV).

[0126] The salt of the present invention may be used alone or in combination with a chemotherapy agent or a radiotherapy regimen.

[0127] Therefore, according to one embodiment, the method of the present invention may include the step of administering the salt according to the present invention separately, sequentially, or simultaneously with a chemotherapeutic agent.

[0128] Examples of chemotherapeutic agents suitable for the present invention include chemotherapeutic agents selected from alkylating agents, insertants, microtubule inhibitors, mitotic inhibitors, antimetabolites, antiproliferative agents, antibiotics, immunomodulators, anti-inflammatory agents, kinase inhibitors, angiogenesis inhibitors, antivascular agents, estrogens, and androgenic hormones.

[0129] A radiation therapy regimen can be administered by exposing the individual requiring it to a source of ionizing radiation, such as X-rays, gamma rays, or beta rays.

[0130] In another aspect of the present invention, the present invention relates to a pharmaceutical composition comprising at least one salt according to the present invention and at least one pharmaceutically acceptable excipient.

[0131] The salt according to the present invention can be used for the manufacture of pharmaceuticals, particularly for the manufacture of pharmaceuticals to inhibit the activity of ERK kinase, preferably the activity of ERK2 kinase.

[0132] Therefore, according to yet another aspect of the present invention, the present invention relates to a pharmaceutical comprising at least one salt according to the present invention.

[0133] The term "pharmaceutically acceptable" generally refers to a pharmaceutical composition that is safe, non-toxic, and not biologically or otherwise undesirable, and is useful for manufacturing such compositions, encompassing not only human pharmaceutical use but also veterinary use.

[0134] More specifically, the above pharmaceutical composition may contain an effective amount of at least one salt according to the present invention.

[0135] "Effective dose" means an amount sufficient to induce a favorable change in the symptom to be regulated or treated, but low enough to avoid serious side effects. The effective dose may vary depending on the pharmacological effect obtained, the specific symptom being treated, the age and physical condition of the end user, the severity of the symptom being treated / prevented, the duration of treatment, the nature of other treatments, the specific compound or composition used, the route of administration, and similar factors.

[0136] The salt according to the present invention can be administered in an effective amount by any of the administration methods recognized in the art.

[0137] In some embodiments, the salts of the present invention can be used in compositions intended to be administered orally, nasally, sublingually, ocularly, topically, rectally, vaginally, urethrally, or parenterally by injection.

[0138] The route of administration and the herbal preparation will be adapted by those skilled in the art according to the desired pharmacological effect.

[0139] In preferred embodiments, the salt of the present invention may be used in compositions intended for oral administration.

[0140] Those skilled in the field of therapeutic formulations will be able to determine the therapeutically effective dosage of the salt of the present invention for a given indication by relying on their personal knowledge, without conducting excessive experiments.

[0141] The pharmaceutical composition of the present invention can be formulated with any known and appropriate pharmaceutically acceptable excipient, depending on the dosage, formulation form, route of administration, etc.

[0142] In this specification, “pharmaceutically acceptable excipients” include all solvents, dispersions, coatings, antimicrobial and antifungal agents, isotonic agents and absorption retarders, etc. Their use in the pharmaceutical or pharmaceutical composition of the present invention is envisioned unless conventional excipients are incompatible with the active compound.

[0143] The pharmaceutical or pharmaceutical composition of the present invention may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, sprays, ointments, gels, creams, sticks, lotions, pastes, soft and hard gelatin capsules, suppositories, sterile injection solutions, sterile packaged powders, and the like.

[0144] According to one embodiment, the pharmaceutical composition of the present invention may be intended to be administered separately, sequentially, or simultaneously with a pharmaceutical useful for the prevention and / or treatment of disease symptoms, particularly cancerous conditions, wherein the pharmaceutical is different from the compound of formula (I) of the present invention.

[0145] The above applications also include kits of novel components suitable for cancer treatment.

[0146] A kit of components according to the present invention may include (i) a salt according to the present invention, and (ii) at least one pharmaceutical product useful for the prevention and / or treatment of cancer (the pharmaceutical product being different from the salt). The pharmaceutical product useful for the prevention and / or treatment of cancer may be a chemotherapeutic agent or a radiotherapy agent.

[0147] The present invention will be better understood by referring to the following embodiments, which are provided for illustrative purposes only and should not be construed as limiting the invention in any way. Examples

[0148] Equipment and analytical methods used in the synthesis of the examples. Unless otherwise specified, the following instruments and analytical methods are used in the examples.

[0149] 1. X-ray powder diffraction (XRPD) XRPD analysis was performed using a PANalytical Xpert pro and a PIXcel detector (128 channels), scanning the sample in the range of 3° to 35° (2θ). The sample was lightly ground using a mortar and pestle to release agglomerates, and then placed on a multiwell plate fixed with Mylar polymer film. Next, the multiwell plate was set in a diffractometer, and analysis was performed using Cu's K radiation (wavelength λ α1=1.54060Å, α2=1.54443Å, β=1.39225Å, α1:α2 ratio=0.5) in transmission mode (2θ step size 0.0130°, step time 18.87s), with a 40kV / 40mA generator setting. The data was visualized and images were generated using the HighScore Plus 4.9 desktop application (PANalytical, 2020).

[0150] 2. Polarizing Microscope (PLM) The presence or absence of crystalline (birefringence) properties was determined using an Olympus BX53 microscope equipped with cross-polarizing lenses and a Motic camera. Images were acquired using Motic Images Plus 3.0. Unless otherwise specified, all images were recorded using a 20x objective lens.

[0151] 3. Thermogravimetric Analysis / Differential Scanning Calorimetry (TGA / DSC) Approximately 5 mg to 10 mg of sample was placed in a pre-tareed open aluminum pan and set in a TA Instruments Discovery SDT 650, an automated instrument capable of simultaneous DSC, and kept at room temperature. The sample was then heated from 30°C to 400°C at a rate of 10°C / min, and the change in sample weight during this process was recorded along with the heat flow response (DSC). Nitrogen was used as the sample purging gas at a flow rate of 200 cm³. 3 It was set to / minutes.

[0152] 4. Differential Scanning Calorimetry (DSC) Approximately 1 mg to 5 mg of sample was weighed into an aluminum DSC pan and sealed airtight with an aluminum 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 material were heated to a maximum of 300°C at a scanning rate of 10°C / min, and the resulting heat flow response was monitored. The sample was recooled to 20°C and then reheated to a maximum of 300°C at a continuous rate of 10°C / min. Nitrogen was used as the purging gas at a flow rate of 50 cm³. 3 It was set to / minutes.

[0153] 5. Infrared spectroscopy (IR) Infrared spectroscopy was performed using a Bruker ALPHA P spectrometer. A sufficient amount of sample was placed in the center of the spectrometer plate, and the spectrum was measured using the following parameters. ·Resolution: 4cm -1 • Background scan time: 16 scans • Sample scanning time: 16 scans • Data collection range: 4000cm -1~400cm -1 • Resulting spectrum: transmittance • Software: OPUS Version 6

[0154] 6.Nuclear magnetic resonance (NMR) NMR experiments were performed using a Bruker AVIIIHD spectrometer equipped with a DCH cryoprobe operating at 500.12 MHz for protons. The experiments were conducted in deuterated dimethyl sulfoxide, with each sample prepared to a concentration of approximately 10 mM. Chemical shifts are expressed in parts per million (ppm), and signals are 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.

[0155] 7. Dynamic water vapor adsorption (DVS) Approximately 10 mg to 20 mg of sample was placed in a mesh pan for a water vapor adsorption analyzer and loaded into a Surface Measurement Systems DVS Intrinsic or Advantage dynamic water vapor adsorption analyzer. The sample was subjected to a profile where the relative humidity (RH) was increased by 10% increments from 40% to 90%, while holding the sample at each step, until a stable weight (dm / dt 0.004%, minimum step length 30 minutes, maximum step length 500 minutes) was achieved at 25°C. After the adsorption cycle was completed, the sample was dried to 0% RH using the same procedure, and then a second adsorption cycle was performed, returning it to 40% RH. This cycle was performed twice. The hygroscopicity of the sample could be determined by plotting the weight change during the adsorption / desorption cycle. Next, XRPD analysis was performed on the held solid.

[0156] 8. High-performance liquid chromatography-ultraviolet detection (HPLC-UV) Column: Halo C18 100x3.0mm, 2.7μm Column temperature: 40℃ Flow rate: 1.0mL / min Column pressure at the start of analysis: 400 Bar Injection volume: 2μL Autosampler temperature: Room temperature (°C) Detection parameter: UV (219nm) Sampling rate: 10Hz Mobile phase A: 0.1% formic acid aqueous solution Mobile phase B: 0.1% acetonitrile formate solution Dilution: 50:50 MPA:MPB Needle cleaning solution: MPB Gradient: [Table 8]

[0157] 9.Mass spectrometry Column: X-Bridge C18, 50mm x 3mm, 3.5μm Column temperature: 40℃ Flow rate: 1.0mL / min Injection volume: 1μL Autosampler temperature: Room temperature (°C) Detection parameters: UV 210nm (monitor only), UV scan 190nm~900nm; MS+ / - ESI Fragmentor 135V Mobile phase A: 0.1% formic acid aqueous solution (v / v) Mobile phase B: 0.1% acetonitrile formate aqueous solution (v / v) Diluent: Acetonitrile:Water (50:50 %v / v) Gradient: Time (minutes) MP A % MP B % [Table 9] Sample preparation: Working concentration: 0.1 mg / mL

[0158] 10. Determining the pKa The automated titration system includes a UV-Vis spectrometer (Sirius T3). TMA Pion Inc.-made spectroscopy system was incorporated and used for acquiring spectroscopic and / or potentiometric data. The optics consisted of a photodiode array detector with a deuterium lamp and a fiber optic dip probe. The titration module consisted of a temperature controller (using a Peltier element and in-situ thermocouple), a pH electrode, an overhead stirrer, and an electric dispenser for automatic supply of titrant and reagents via a capillary. SiriusT3Control software (V2.0) was used to operate the instrument. SiriusT3Refine software (V2.0) was used for data processing and pKa value generation.

[0159] All experiments are performed at a controlled temperature of 25.0 ± 0.2°C. The pH range of the titration assay is set to pH 2.0 to pH 12.0 unless otherwise specified. Before use, the 0.5 M KOH base titration is standardized by titrating approximately 15 mg of potassium bitrate three times. Subsequently, the 0.5 M HCl titration is standardized relative to the base titration. The assay medium for pKa measurement is maintained under a constant ionic strength of 0.15 M KCl and an argon atmosphere. The pH electrode is calibrated daily using the Avdeef-Bucher four-parameter equation. Both pH and UV methods are used to measure pKa values. The pKa results are recorded for compounds from data obtained using the UV method, where pKa indicates UV activity and pH titration is performed to supplement the UV data. If the pKa value cannot be determined using the UV assay, the pKa value measured by the pH method is provided. The pKa values ​​obtained from spectrophotometer experiments show very good agreement with those obtained by potentiometric titration.

[0160] When incorporating a cosolvent into the assay design, the aqueous pKa value is extrapolated from the apparent pKa value (psKa) measured in the presence of the cosolvent using the Yasuda-Schedrowski extrapolation formula. This formula expresses the reciprocal relationship between psKa and dielectric constant (ε) in different cosolvent mixtures. To determine the aqueous pKa value, titrate at least three different water / cosolvent ratios.

[0161] 11. Particle Size Distribution (PSD) Particle size distribution analysis was performed using a Malvern Mastersizer 2000 stirring unit that had been washed with 2-propanol before use. The following parameters were used. PSD parameters: • Dispersant: Span-85 0.05 w / v% in heptane • Dispersant amount: 10 mL • Sample weight: 150±3mg • Analysis model: General purpose ·Particle shape: irregular • Sensitivity: Standard • Particle refractive index: Fraunhofer • Particle absorbance: Fraunhofer • Dispersant refractive index: 1.39 • Number of measurements: 3 • Background / measurement time: 10 seconds ·Circulation time before measurement: 3 minutes ·Circulation speed: 2800rpm • Ultrasonic treatment time: Not applicable • Shielding limit: 9%~15% Sample preparation: The bulk sample was gently inverted and rotated to ensure homogenization. Approximately 150 mg of the sample was weighed into a 20 mL scintillation vial, and 10 mL of dispersant was added.

[0162] 12. Flash chromatography Equipment: Biotage SP with auto-collector and UV detector (2 wavelengths) Normal-phase column: Biotage external dry-load cartridge kit, 10g, 25g, or 120g, packed with Sigma-Aldrich 40-63μm silica gel. Reverse-phase column: 30g Biotage SNAP cartridge, KP-C18-HS Chiral column: Daicel ChiralFlash IG 100x30mm 20μM

[0163] 13. Thermodynamic Solubility Test 1 The thermodynamic solubility test of the salts was performed as follows: Before starting the solubility test, the purity of the salts was analyzed by HPLC. Approximately 15 mg to 20 mg of each sample was weighed into a 2 mL vial. A stirrer bar was added, and the samples were kept at 37°C. While stirring the samples, 50 μL of water / buffer was added until the salt was dissolved or a total of 1 mL was added. The media used were unbuffered water, FaSSIF (pH 6.5), and FaSSGF (pH 1.6). If a clear solution was observed, the corresponding salt was added until a slurry was obtained. At T=0 and T=4 hours, the slurry was filtered, and the filtrate was analyzed by HPLC to determine the concentration. pH was measured at each time point whenever sufficient liquid volume allowed. Solids were analyzed by XRPD wherever the material allowed.

[0164] 14. Thermodynamic Solubility Test 2 The thermodynamic solubility test of the salt was performed as follows: Before starting the solubility test, the purity of the salt was analyzed by HPLC. One sample per buffer, approximately 25 mg to 30 mg of each sample, was weighed into a 2 mL vial. A stirrer bar was added and the sample was kept at approximately 37°C. While stirring the sample, 75 μL of water / buffer was added until the salt dissolved or a total of 1.5 mL was added. Once complete dissolution was observed, further solid material was added until a slurry was obtained. Mediums used: unbuffered water, FaSSIF (pH 6.5), FaSSGF (pH 1.6). Aliquots of the slurry were filtered at T=0, T=4, and T=24 hours. The filtrate was analyzed by HPLC and the concentration was measured. The solid was analyzed by XRPD.

[0165] 15.7-day stability test The 7-day stability assessment was performed as follows: Approximately 10 mg of the corresponding salt was exposed to the following conditions for 7 days: 40°C / 75%RH, 80°C, room temperature, humidity, light, and a slurry in migliol (15 mg suspended in 1 mL of migliol (caprylic / capric triglyceride)). After 7 days, the solid substance was analyzed by XRPD, and its purity was analyzed by HPLC.

[0166] 16. Hydration Test The salt hydration reaction test was performed using the following procedure. 400 μL of the appropriate ethanol-water mixture was added to approximately 10 mg of the corresponding salt according to the table below. The mixture was stirred at room temperature for 24 hours. The solid was separated by centrifugal filtration and analyzed by XRPD. [Table 10]

[0167] 17. Salt disproportionation test The salt disproportionation test was performed using the following procedure: Approximately 10 mg of each salt was weighed into a 2 mL vial, and 500 μL of water was added to prepare a slurry. The vial was stirred at room temperature for 24 hours. The solid was separated by centrifugal filtration and analyzed by XRPD.

[0168] 18.3-month stability test The compounds were subjected to stability tests to investigate their chemical and physical stability over a total of three months. The conditions evaluated were as follows: • Ambient light and temperature (sealed vial) after 2 weeks, 1 month, and 3 months. • 80°C (sealed vial) 2 weeks, 1 month, 3 months later • 25℃ / 60%RH (opened vial) 2 weeks, 1 month, 3 months • 40℃ / 75%RH (opened vial) 2 weeks, 1 month, 3 months later Samples were analyzed by XRPD and HPLC at each time point.

[0169] Example 1: Synthesis of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one (Compound No. 1) TIFF2026525238000015.tif45170

[0170] Step 1: 1-Chloro-3-vinylbenzene TIFF2026525238000016.tif211703- Dissolve 10 g (71.1 mmol) of chlorobenzaldehyde in 50 ml of anhydrous THF and cool the solution to -10°C in a dry ice / acetone bath. Add 17.3 g (48.4 mmol, 1.2 equivalents) of methyltriphenylphosphonium bromide, followed by 2.1 g (52.4 mmol, 1.3 equivalents) of sodium hydride (60% in paraffin oil). Next, stir the suspension overnight at room temperature under an argon atmosphere. Dilute the mixture with 100 ml of Et2O and filter the precipitate through Celite. Concentrate the filtrate under reduced pressure to obtain an orange residue. Finally, purify the crude mixture by flash chromatography using a silica gel column and Et2O / pentane mixture (3 / 97) as the eluent. 4.05 g of the title compound is obtained.

[0171] Step 2: 2-(3-chlorophenyl)oxiran Dissolve 4.05 g (29.2 mmol) of 1-chloro-3-vinylbenzene (as described in the previous step) in 6 ml of 1,4-dioxane and 18 ml of water. Cool the solution to 0°C, add 584 μl (10.2 mmol, 1 equivalent) of acetic acid, followed by 1.99 g (11.2 mmol, 1.1 equivalent) of N-bromosuccinimide. Stir the reaction mixture at 0°C for 5 minutes, then stir at room temperature for 2 hours. Cool the mixture again to 0°C, and slowly add 2N NaOH aqueous solution (35.7 mmol, 3.5 equivalents). Stir the solution at room temperature for 1 hour. Concentrate the reaction mixture under reduced pressure, and extract the resulting aqueous phase three times with DCM. Dry the collected organic layer over Na2SO4, filter, and concentrate under reduced pressure. The crude mixture was purified by flash chromatography using a silica gel column and a DCM / hexane mixture (2 / 98) as the eluent. 3.85 g of the title compound was obtained.

[0172] Step 3: 1-(3-chlorophenyl)-2-(dimethylamino)ethane-1-ol Dissolve 4.15 g (26.9 mmol) of 2-(3-chlorophenyl)oxirane (as described in the previous step) in 14 ml of 96% ethanol, and add 7.38 ml (14.76 mmol, 2 equivalents) of dimethylamine (2 M in THF) solution. Heat the resulting clear solution under microwave irradiation at 80°C for 30 minutes. Concentrate the reaction mixture under reduced pressure and dilute with water. Extract the solution three times using DCM. Dry the collected organic phase over Na2SO4, filter, and concentrate under reduced pressure. Purify the crude mixture by flash chromatography using a silica gel column and a DCM / MeOH mixture as the eluent. 4.06 g of the title compound is obtained.

[0173] Step 4: 2-Chloro-2-(3-chlorophenyl)-N,N-dimethylethane-1-amine TIFF2026525238000019.tif181701-(3-chlorophenyl)-2-(dimethylamino)ethane-1-ol (as described in the previous step) was dissolved in 15 ml of DCM and left at 0°C. 2.1 ml of triethylamine (15.1 mmol, 3 equivalents) was added, followed by 0.781 ml of mesylchloride (10.1 mmol, 2 equivalents). The reaction mixture was stirred under an argon atmosphere at 0°C for 2 hours. Water was then added and decanted. The aqueous layer was extracted twice with DCM. The collected organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was used directly in the next step without further purification. 4.41 g of the title compound was obtained.

[0174] Step 5: 4-Bromo-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)pyridine-2(1H)-one To a mixture of 0.744 g (4.28 mmol, 1 equivalent) of 4-bromopyridine-2-(1H)-one and 1.39 g (4.28 mmol, 1 equivalent) of cesium carbonate in 10 ml of anhydrous DMF, add a solution of 4.41 g (20.3 mmol) of 2-chloro-2-(3-chlorophenyl)-N,N-dimethylethane-1-amine (described in the previous step) in 5 ml of anhydrous DMF. Next, stir the solution at room temperature for 2 hours. Add siRNA and wash the mixture four times with water and once with saturated brine. Dry the organic layer over Na2SO4, filter, and concentrate under reduced pressure. Purify the crude mixture by flash chromatography using an inactivated silica gel column and a hexane / siRNA mixture as the eluent. 5.02 g of the title compound is obtained.

[0175] Step 6: 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one Dissolve 2 g (5.6 mmol) of 4-bromo-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)pyridine-2(1H)-one (as described in the previous step) and 2.45 g (5.01 mmol, 1.3 equivalents) of 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-yl)morpholine (as described in step 3) in 13 ml of MeCN under an argon atmosphere. Then, add 13 ml of 2 M Na2CO3 solution to make a two-phase mixture and bubble with argon for 15 minutes. Add 135 mg (0.19 mmol, 0.05 equivalents) of bis(triphenylphosphine)palladium dichloride and bubble with argon for a further 15 minutes. Stir the reaction mixture under an argon atmosphere at 70°C for 2 hours. Dilute the reaction mixture with water and ethyl acetate and decant. Extract the aqueous layer twice with ethyl acetate. Dry the collected organic layer over Na2SO4, filter, and concentrate under reduced pressure. Purify the crude mixture by flash chromatography using a silica gel column and a DCM / MeOH mixture as the eluent. 2.68 g of the title compound is obtained.

[0176] Step 7: 1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one TIFF2026525238000022.tif431701-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (described in the previous step), 2.68 g (4.2 mmol), is dissolved in 15 mL of anhydrous THF under an argon atmosphere. Next, 10 mL (10 mmol, 3 equivalents) of a TBAF solution (1 M in THF) is added, and the reaction mixture is stirred at 66 °C for 1 hour under an argon atmosphere. The solvent is removed under reduced pressure, and 100 mL of saturated NaHCO₃ solution is added. The mixture is extracted three times with EtOAc. The collected organic phase is dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude mixture is purified by flash chromatography using a silica gel column and a DCM / MeOH mixture as the eluent. 617 mg of the racemate is obtained.

[0177] Step 8: (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one TIFF2026525238000023.tif43170The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a hexane / ethanol / DCM / 0.1% TEA mixture as the mobile phase. The first eluted is the (-)(R)-enantiomer, followed by the (+)(S)-enantiomer with ee > 98%. 227 mg of the title compound is obtained from 617 mg of the racemate. MH + : 478.5; 480.6 (M; M+2) 1 ¹H NMR (DMSO-d₆, 400 MHz): δ 12.06 (br s, 1H); 8.17 (d, J = 2.4 Hz, 1H); 8.10 (d, J = 2.3 Hz, 1H); 7.76 (d, J = 8.0 Hz, 1H); 7.70 (d, J = 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)

[0178] Example 2: Synthesis of comparative compound (S)-1-(2-amino-1-(3-chlorophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one (compound A) TIFF2026525238000024.tif43170

[0179] Step 1: 2-(3-chlorophenyl)-2-((trimethylsilyl)oxy)acetonitrile Under an argon atmosphere, 5 g (36 mmol, 1 equivalent) of 3-chlorobenzaldehyde is dissolved in 50 ml of anhydrous DCM. 399 mg (36 mmol, 1 equivalent) of DABCO is added, followed by 4.45 ml (36 mmol, 1 equivalent) of trimethylsilyl cyanide. The resulting mixture is stirred at 40°C for 2 hours. The reaction mixture is diluted with DCM and washed twice with water and once with saturated brine. The organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is used in the next step without purification. 7.80 g of the title compound is obtained.

[0180] Step 2: 2-amino-1-(3-chlorophenyl)ethane-1-ol TIFF2026525238000026.tif18170 Add 1.85 g (49 mmol, 1.5 equivalent) of LiAlH4 to a solution of 7.80 g (33 mmol, 1 equivalent) of 2-(3-chlorophenyl)-2-((trimethylsilyl)oxy)acetonitrile (as described in the previous step) in 80 ml of anhydrous Et2O cooled to 0°C in an ice bath. Stir the resulting mixture at 0°C for 1 hour. Next, slowly add ice to the reaction mixture at 0°C until no more gas is produced, and finally add 100 ml of water. Stir the mixture at room temperature for 30 minutes, filter the precipitate through Celite, and wash twice with Et2O. Decant the filtrate and extract the aqueous layer twice with Et2O. Dry the collected organic layer over Na2SO4, filter, and concentrate under reduced pressure. Use the crude product in the next step without purification. 5.95 g of the title compound is obtained.

[0181] Step 3: tert-butyl(2-(3-chlorophenyl)-2-hydroxyethyl)carbamate Dissolve 5.95 g (35 mmol, 1 equivalent) of 2-amino-1-(3-chlorophenyl)ethane-1-ol (as described in the previous step) in 60 ml of THF, add 8.32 g (38 mmol, 1.1 equivalents) of di-tert-butyl dicarbonate, and stir the resulting mixture at room temperature for 1 hour. Remove the solvent under reduced pressure and dilute the mixture with 100 ml of siRNA. Wash the organic layer twice with water and once with saturated brine, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the crude mixture by flash chromatography using a silica gel column and a DCM / MeOH mixture as the eluent. 6.78 g of the title compound is obtained.

[0182] Step 4: 2-((tert-butoxycarbonyl)amino)-1-(3-chlorophenyl)ethylmethanesulfonate TIFF2026525238000028.tif20170 Dissolve 6.78 g (25 mmol) of tert-butyl(2-(3-chlorophenyl)-2-hydroxyethyl) carbamate (as described in the previous step) in 15 ml of DCM and cool to 0°C. Add 2.1 ml (15.1 mmol, 3 equivalents) of triethylamine, followed by 0.781 ml (10.1 mmol, 2 equivalents) of mesyl chloride. Stir the reaction mixture under an argon atmosphere at 0°C for 2 hours. Then add water and decant the mixture. Extract the aqueous layer twice with DCM. Dry the collected organic layer over Na2SO4, filter, and concentrate under reduced pressure. The crude compound is used directly in the next step without further purification. 9.28 g of the title compound is obtained.

[0183] Step 5: tert-butyl(2-(4-bromo-2-oxopyridine-1(2H)-yl)-2-(3-chlorophenyl)ethyl) carbamate To a mixture of 0.744 g (4.28 mmol, 1 equivalent) of 4-bromopyridine-2-(1H)-one and 1.39 g (4.28 mmol, 1 equivalent) of cesium carbonate in 10 ml of anhydrous DMF, add a solution of 8.73 g (25 mmol) of 2-((tert-butoxycarbonyl)amino)-1-(3-chlorophenyl)ethylmethanesulfonate (described in the previous step) in 5 ml of anhydrous DMF. Next, stir the solution at room temperature for 2 hours. Add siRNA and wash the mixture four times with water and once with saturated brine. Dry the organic layer over Na2SO4, filter, and concentrate under reduced pressure. Purify the crude mixture by flash chromatography using an inactivated silica gel column and a hexane / siRNA mixture as the eluent. 5.56 g of the title compound is obtained.

[0184] Step 6: 4-(1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine Dissolve 947 mg of RuPhos (2.03 mmol, 0.01 equivalent) and 1.58 g of RuPhos Pd G2 (2.03 mmol, 0.01 equivalent) in 487 ml of LiHMDS (1 M in THF, 487 mmol, 2.4 equivalents). Next, add 40 g of 5-bromo-1H-pyrrolo[2,3-b]pyridine (203 mmol, 1 equivalent) and 21.1 ml of morpholine (244 mmol, 1.2 equivalents) under an argon atmosphere, and heat the solution at 66°C for 1 hour and 30 minutes. Next, cool the reaction mixture to room temperature, and add it dropwise to 1.2 L of saturated NH4Cl solution while maintaining the temperature below 10°C in an ice bath. Decant the mixture by stirring at this temperature for 10 minutes. The aqueous layer is extracted three times using DCM. The collected organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 44.4 g of brown solid. The crude product is ground in 200 ml of a mixed solvent of SiO2 and hexane(3 / 7) for 1 hour. The solid is filtered, washed with 200 ml of a mixed solvent of SiO2 and hexane(1 / 9), and dried under vacuum to obtain 38.98 g of a slightly brown powder.

[0185] Step 7: 4-(1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-yl)morpholine Dissolve 38.98 g (192 mmol, 1 equivalent) of TIFF2026525238000031.tif341704-(1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine (as described in the previous step) in 390 ml of anhydrous DMF under an argon atmosphere. Cool the solution to 0°C and slowly add 11.5 g (288 mmol, 1.5 equivalent) of sodium hydride (60% in paraffin oil). Stir the mixture at this temperature for 10 minutes, then stir at room temperature for 40 minutes. Cool the mixture again to 0°C and slowly add 47.5 g (249 mmol, 1.3 equivalent) of tosyl chloride under an argon atmosphere. Stir the reaction mixture at 0°C for 1 hour, then stir at room temperature for 1 hour. Drop the mixture into 800 g of ice / water and stir for 1 hour. Filter the resulting precipitate and rinse several times with cold water. The precipitate is dissolved in 1.2 liters of DCM and washed twice with saturated NaHCO3 solution, twice with water, and once with saturated brine. The organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is ground in a mixture of 500 ml of siRNA and hexane (5 / 95) for 3 hours. The resulting solid is filtered, rinsed with hexane, and dried under vacuum to obtain 62.56 g of an off-white solid.

[0186] Step 8: 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-yl)morpholine TIFF2026525238000032.tif431704 - (1 - Tosyl - 1H - pyrrolo[2,3 - b]pyridin - 5 - yl)morpholine (described in the previous step), 62.56 g (175 mmol, 1 equivalent), is suspended in 512 ml of Me - THF under an argon atmosphere. Next, 48.9 g (193 mmol, 1.1 equivalents) of bis(pinacolato)diboron, 1.88 g (7 mmol, 0.036 equivalents) of 4,4’ - di - tert - butylbiphenyl, and 2.32 g (3.5 mmol, 0.018 equivalents) of (1,5 - cyclooctadiene)(methoxy)iridium(I) dimer are added. The reaction solution is heated to reflux for 45 minutes under an argon atmosphere. The reaction mixture is cooled to - 10 °C in a dry ice / acetone bath and carefully quenched with MeOH (350 ml). The solution is stirred at room temperature for 15 minutes and concentrated under reduced pressure to obtain a brown oily substance. Next, the dark oily substance is dissolved in 1 L of DCM and washed 3 times with water and once with saturated brine. The organic layer is concentrated under reduced pressure to obtain a brown oily substance. 2 L of Et2O is added, the mixture is stirred at room temperature for 15 minutes, filtered through celite, and concentrated under reduced pressure to obtain 95 g of a brown porous solid. Finally, the crude mixture is purified by flash chromatography using a silica gel column and an EtOAc / hexane mixture as the eluent. 75.5 g of the title compound is obtained.

[0187] Step 9: tert-butyl(2-(3-chlorophenyl)-2-(4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-2-oxopyridine-1(2H)-yl)ethyl)carbamate TIFF2026525238000033.tif45170tert-butyl (2-(4-bromo-2-oxopyridin-1(2H)-yl)-2-(3-chlorophenyl)ethyl)carbamate (described in Step 5) 2.8 g (6.50 mmol, 1 equivalent), 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine (described in the previous step) 3.16 g (6.50 mmol, 1 equivalent), and K2CO3 905 mg (6.50 mmol, 1 equivalent) are placed in 140 ml of MeCN under an argon atmosphere. After bubbling the mixture with argon for 15 minutes, 459 mg (0.65 mmol, 0.1 equivalent) of bis(triphenylphosphine)palladium dichloride is added. After further bubbling for 15 minutes, the reaction solution is stirred at 80 °C for 1 hour under an argon atmosphere. The reaction mixture is diluted with 140 ml of EtOAc and washed three times with water. The organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture is purified by flash chromatography using a silica gel column and a DCM / MeOH mixture as the eluent. 4.79 g of the title compound is obtained.

[0188] Step 10: tert-butyl(2-(3-chlorophenyl)-2-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)-2-oxopyridine-1(2H)-yl)ethyl)carbamate TIFF2026525238000034.tif42170tert-butyl (2-(3-chlorophenyl)-2-(4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)carbamate (described in the previous step) 1.0 g (1.4 mmol) is suspended in 5 ml of MeCN and 2.5 ml of 2M Na2CO3 solution. The mixture is stirred at 120 °C for 1 hour under microwave irradiation (150 W) in a sealed tube. The mixture is cooled to room temperature, diluted with EtOAc, and washed three times with water. The organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. Finally, the crude product is purified by flash chromatography using a silica gel column and a DCM / MeOH mixture as the eluent. 644 mg of the racemate is obtained.

[0189] Step 11: 1-(2-amino-1-(3-chlorophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one TIFF2026525238000035.tif42170 Add 3 ml of trifluoroacetic acid to 6 ml of DCM solution of 644 mg (1.17 mmol, 1 equivalent) of tert-butyl(2-(3-chlorophenyl)-2-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)-2-oxopyridine-1(2H)-yl)ethyl) carbamate (as described in the previous step) cooled to 0°C in an ice bath. Stir the solution at 0°C for 1 hour and 30 minutes, then remove the solvent under reduced pressure and dilute the mixture with 100 ml of saturated NaHCO3 solution. Extract the solution three times with DCM. Dry the collected organic layer over Na2SO4, filter, and concentrate under reduced pressure. Purify the crude mixture by flash chromatography using a C18 column and a water / MeOH mixture as the eluent. 340 mg of the title compound is obtained.

[0190] Step 12: (S)-1-(2-amino-1-(3-chlorophenyl)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one The enantiomers obtained in the previous step were separated by flash chromatography using a Chiralflash IG column and a hexane / ethanol / DCM / 0.1% TEA mixture as the mobile phase. The (-)(R)-enantiomer was eluted first, followed by the (+)(S)-enantiomer with ee > 98%. 33 mg of the title compound was obtained from 120 mg of the racemic mixture. MH + :450.7;452.7(M;M+2) 1 H NMR(DMSO-d6,400MHz):δ 12.06(br s,1H);8.17(d,J=2.5Hz,1H);8.09(s,1H);7.75(d,J=8.1Hz,1H);7.70(d,J=2.6Hz,1H);7.44-7.29(m,4H); 6.74-6.67(m,2H);5.90(t,J=7.5Hz,1H);3.84-3.72(m,4H);3.34-3.25(m,2H);3.18-3.09(m,4H);1.60(br s,2H)

[0191] Example 3: Synthesis of comparative compound (S)-1-(1-(3,4-dichlorophenyl)-2-(methylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one (compound B) TIFF2026525238000037.tif42170

[0192] Step 1: 2-(3,4-dichlorophenyl)-2-((trimethylsilyl)oxy)acetonitrile Under an argon atmosphere, 2.5 g (14.3 mmol) of 3,4-dichlorobenzaldehyde is dissolved in 50 ml of anhydrous DCM, 399 mg (36 mmol, 1 equivalent) of DABCO is added, followed by 4.45 ml (36 mmol, 1 equivalent) of trimethylsilyl cyanide, and the resulting mixture is stirred at 40°C for 2 hours. The reaction mixture is diluted with DCM and washed twice with water and once with saturated saline. The organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is used in the next step without purification. 3.70 g of the title compound is obtained.

[0193] Step 2: 2-amino-1-(3,4-dichlorophenyl)ethane-1-ol TIFF2026525238000039.tif18170 Add 1.85 g (49 mmol, 1.5 equivalents) of LiAlH4 to a solution of 3.70 g (13.5 mmol) of 2-(3,4-dichlorophenyl)-2-((trimethylsilyl)oxy)acetonitrile (as described in the previous step) in 80 ml of anhydrous Et2O cooled to 0°C in an ice bath. Stir the resulting mixture at 0°C for 1 hour. Next, slowly add ice to the reaction mixture at 0°C until no more gas is produced, and finally add 100 ml of water. Stir the mixture at room temperature for 30 minutes, filter the precipitate on Celite and wash twice with Et2O. Decant the filtrate and extract the aqueous layer twice with Et2O. Dry the collected organic layer over Na2SO4, filter, and concentrate under reduced pressure. The crude compound is used in the next step without further purification. 1.66 g of the title compound is obtained.

[0194] Step 3: tert-butyl(2-(3,4-dichlorophenyl)-2-hydroxyethyl)carbamate Dissolve 1.66 g (8.03 mmol) of 2-amino-1-(3,4-dichlorophenyl)ethane-1-ol (as described in the previous step) in 60 ml of THF, add 8.32 g (38 mmol, 1.1 equivalents) of di-tert-butyl dicarbonate, and stir the resulting mixture at room temperature for 1 hour. Remove the solvent under reduced pressure and dilute the mixture with 100 ml of siRNA. Wash the organic layer twice with water and once with saturated brine, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the crude mixture by flash chromatography using a silica gel column and a DCM / MeOH mixture as the eluent. 2.55 g of the title compound is obtained.

[0195] Step 4: 2-((tert-butoxycarbonyl)amino)-1-(3,4-dichlorophenyl)ethylmethanesulfonate TIFF2026525238000041.tif19170 Dissolve 2.46 g (8.03 mmol) of tert-butyl(2-(3,4-dichlorophenyl)-2-hydroxyethyl) carbamate (as described in the previous step) in 15 ml of DCM and cool to 0°C. Add 2.1 ml (15.1 mmol, 3 equivalents) of triethylamine, followed by 0.781 ml (10.1 mmol, 2 equivalents) of mesyl chloride. Stir the reaction mixture under an argon atmosphere at 0°C for 2 hours. Then add water and decant the mixture. Extract the aqueous layer twice with DCM. Dry the collected organic layer over Na2SO4, filter, and concentrate under reduced pressure. The crude compound was used directly in the next step without further purification. 3.23 g of the title compound was obtained.

[0196] Step 5: tert-butyl(2-(4-bromo-2-oxopyridine-1(2H)-yl)-2-(3,4-dichlorophenyl)ethyl)carbamate To a mixture of 0.744 g (4.28 mmol, 1 equivalent) of 4-bromopyridine-2-(1H)-one and 1.39 g (4.28 mmol, 1 equivalent) of cesium carbonate in 10 ml of anhydrous DMF, add a solution of 3.09 g (8.03 mmol) of 2-((tert-butoxycarbonyl)amino)-1-(3,4-dichlorophenyl)ethylmethanesulfonate (described in the previous step) in 5 ml of anhydrous DMF at 0°C. Then, stir the solution at room temperature for 2 hours. Add SiO4 and wash the mixture four times with water and once with saturated brine. Dry the organic layer over Na2SO4, filter, and concentrate under reduced pressure. Purify the crude mixture by flash chromatography using an inactivated silica gel column and a hexane / SiO4 mixture as the eluent. 1.74 g of the title compound is obtained.

[0197] Step 6: tert-butyl(2-(4-bromo-2-oxopyridine-1(2H)-yl)-2-(3,4-dichlorophenyl)ethyl)(methyl)carbamate Dissolve 840 mg (1.82 mmol, 1 equivalent) of tert-butyl(2-(4-bromo-2-oxopyridine-1(2H)-yl)-2-(3,4-dichlorophenyl)ethyl) carbamate (as described in the previous step) in 9 ml of anhydrous DMF, maintain at 0°C in an ice bath, then add 87 mg (2.18 mmol, 1.2 equivalents) of sodium hydride (60% in paraffin oil) under an argon atmosphere, followed by 170 μl (2.73 mmol, 1.5 equivalents) of methyl iodide. Stir the solution at 0°C for 1 hour and 30 minutes, then dilute the mixture with 100 ml of siRNA. Wash the solution four times with water and once with saturated saline. Dry the organic layer over Na2SO4, filter, and concentrate under reduced pressure. The crude mixture is purified by flash chromatography using a silica gel column and a ¼ / hexane mixture as the eluent. 750 mg of the title compound is obtained.

[0198] Step 7: tert-butyl(2-(3,4-dichlorophenyl)-2-(4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-2-oxopyridine-1(2H)-yl)ethyl)(methyl)carbamate Dissolve 750 mg (1.57 mmol) of tert-butyl(2-(4-bromo-2-oxopyridine-1(2H)-yl)-2-(3,4-dichlorophenyl)ethyl)(methyl)carbamate (as described in the previous step) and 2.45 g (5.01 mmol, 1.3 equivalents) of 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-yl)morpholine (as described in step 3) in 13 ml of MeCN under an argon atmosphere. Then add 13 ml of 2 M Na2CO3 solution to obtain a two-phase mixture and bubble with argon for 15 minutes. 135 mg (0.19 mmol, 0.05 equivalents) of bis(triphenylphosphine)palladium dichloride was added, and the mixture was bubbling with argon for a further 15 minutes. The reaction mixture was stirred under an argon atmosphere at 70°C for 2 hours. The reaction mixture was diluted with water and ethyl acetate and then decanted. The aqueous layer was extracted twice with ethyl acetate. The collected organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by flash chromatography using a silica gel column and a DCM / MeOH mixture as the eluent. 1.27 g of the title compound was obtained.

[0199] Step 8: tert-butyl(2-(3,4-dichlorophenyl)-2-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)-2-oxopyridine-1(2H)-yl)ethyl)(methyl)carbamate TIFF2026525238000045.tif42170 1.27 g (1.69 mmol) of tert-butyl(2-(3,4-dichlorophenyl)-2-(4-(5-morpholino-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-2-oxopyridine-1(2H)-yl)ethyl)(methyl)carbamate (as described in the previous step) is suspended in 5 ml of MeCN and 2.5 ml of 2 M Na2CO3 solution. The mixture is stirred in a sealed tube under microwave irradiation (150 W) at 120°C for 1 hour. The mixture is cooled to room temperature, diluted with ethyl acetate, and washed three times with water. The organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is finally purified by flash chromatography using a silica gel column and a DCM / MeOH mixture as the eluent. A racemic mixture of 730 mg is obtained.

[0200] Step 9: 1-(1-(3,4-dichlorophenyl)-2-(methylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one TIFF2026525238000046.tif41170 A solution of 730 mg (1.20 mmol) of tert-butyl (2-(3,4-dichlorophenyl)-2-(4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxopyridin-1(2H)-yl)ethyl)(methyl)carbamate (described in the previous step) in 6 ml of DCM cooled to 0 °C in an ice bath is added with 3 ml of trifluoroacetic acid. The solution is stirred at 0 °C for 1 hour 30 minutes, then the solvent is removed under reduced pressure, and the mixture is diluted with 100 ml of saturated NaHCO3 solution. The solution is extracted 3 times with DCM. The collected organic layers are dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture is purified by flash chromatography using a C18 column and a water / MeOH mixture as the eluent. 543 mg of the racemate is obtained.

[0201] Step 10: (S)-1-(1-(3,4-dichlorophenyl)-2-(methylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one TIFF2026525238000047.tif43170 The enantiomers obtained in the previous step are separated by flash chromatography using a Chiralflash IG column and a hexane / ethanol / DCM / 0.1% TEA mixture as the mobile phase. The first eluted is the (-)(R)-enantiomer, followed by the (+)(S)-enantiomer eluting with ee>98%. 54 mg of the title compound is obtained from 150 mg of the racemate. MH + :498.6;500.5(M;M+2) 1H NMR(DMSO-d6,400MHz):δ 12.08(br s,1H);8.17(d,J=2.5Hz,1H);8.10(d,J=2.6Hz,1H);7.76(d,J=7.3Hz,1H);7.69(d,J=2.5Hz,1H);7.66-7.61(m,2H);7.37-7.30(m,1H); 6.74-6.66(m,2H);6.08-5.98(m,1H);3.84-3.73(m,4H);3.34-3.24(m,1H);3.22-3.14(m,1H);3.14-3.09(m,4H);2.30(s,3H);1.94(br s,1H)

[0202] Example 4: ERK2 (MAPK1) Enzyme Assay To evaluate the ERK2 enzyme activity inhibitory ability of compound number 1 according to Example 1, the Z'-Lyte biochemical assay from Life Technologies was used according to the manufacturer's instructions. Briefly, a black 384-well plate containing 100 nl of 100x compound solution in 100% DMSO, 2.4 μl of kinase buffer, 5 μl of 2x MAPK1(ERK2) / Ser / Thr O3 mixture, and 2.5 μl of 4x ATP solution was used. The plate was shaken for 30 seconds and incubated at room temperature for 60 minutes. Next, 5 μl of a 1:1024 dilution of developer reagent A was added. The plate was shaken for 30 seconds and incubated at room temperature for 60 minutes. A plate reader was used to read the fluorescence. In this assay, the ERK2 enzyme was used at a concentration of 0.4 μg / ml (5.74 nM) with ATP Km (100 μM). The kinase buffer consisted of HEPES 50 mM (pH 7.5), BRIJ-35 0.01%, MgCl2 10 mM, and EGTA 1 mM. IC of the compound... 50 The values ​​were measured using a 3-fold serial dilution (two 10-point titrations).

[0203] Compound No. 1 in Example 1 exhibits ERK2 inhibitory activity (IC2). 50 The concentration is 2.1 nM. Therefore, it exhibits the ability to inhibit ERK2 enzyme activity.

[0204] Example 5: Cell line proliferation assay The cell proliferation inhibitory activity of compound number 1 according to Example 1 was measured using a cell line assay. A375 cells (malignant melanoma) were grown to nearly 80% confluence and seeded at a rate of 3000 cells per well in 10% FBS-containing DMEM medium in a 96-well flat-bottom plate, with 100 μl of compound per well. The cells were incubated at 37°C for 24 hours under a 5% CO2 atmosphere. 100 μl of compound solution was added to the cells and incubated at 37°C for 72 hours. The total volume of medium was 200 μl per well. The compound was screened twice at each concentration using 10 titration points with a final DMSO concentration of 0.15%. The negative control well consisted of the vehicle only (DMEM medium containing 10% FBS with 0.15% DMSO added). 72 hours after compound treatment, 1% SDS (final) was added to the positive control well and incubated at 37°C for 15 minutes. Subsequently, the culture medium was discarded, and 100 μl of MTT solution (3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide) (Sigma, catalog number M5655) at 0.5 mg / ml per well was added to DMEM containing 10% FBS. Cells were incubated at 37°C for 4 hours. The MTT reaction was stopped by adding 100 μl of 10% SDS, 0.01 M HCl per well, and the cells were homogenized. After 16 hours at 37°C, the absorbance at 570 nm was measured using a Bio-Tek plate reader (PowerWave HT). Growth inhibition rates were calculated with the negative control (DMSO 0.15%) as 0% growth inhibition and the positive control (SDS 1%) as 100% growth inhibition. IC 50 The value (the concentration that induces half of the maximum growth inhibition) was determined by nonlinear regression analysis of the inhibition curve created from the mean repeated values ​​(using a sigmoid dose-response curve with a variable Hill slope, a constant upper limit of 100, and a lower limit of 0-50). The analysis was performed using GraphPad Prism software.

[0205] Cell proliferation inhibitory activity of compound number 1 according to Example 1 ("MTT A375 IC 50 The concentration is 35 nM. Therefore, compound number 1 exhibits the ability to inhibit the proliferation of A375 cells.

[0206] Example 6: hERG channel inhibition assay The hERG channel inhibitory effect of compound number 1 according to Example 1 was evaluated. The compound was used as a 10 mM stock in DMSO and then diluted to 30 μM with HEPES-buffered saline. A 6-point concentration-response curve was created by serial dilutions of 3.16 times from the highest test concentration. Electrophysiological recordings were performed using a Chinese hamster ovary cell line that stably expresses full-length ion channels. Single-cell ion currents were measured using a Patchliner (Nanion Technologies) at room temperature (21°C to 23°C) in all cell compositions. The internal solution for hERG contained KF 120 mM, KCl 20 mM, EGTA 10 mM, and HEPES 10 mM, buffered to pH 7.3. The external solution (HEPES-buffered saline) contained 138 mM NaCl, 4.5 mM KCl, 21.8 mM CaCl, 21.0 mM MgCl, 10 mM HEPES, and 10 mM glucose, and was buffered to pH 7.4. The voltage application protocol is shown below. The current was measured from the step and referenced to the holding current. The compound was then incubated for 2 minutes until a steady state was reached, after which the next concentration of the compound was added. [Table 11] hERG channel inhibition properties of compound number 1 according to Example 1 ("hERG IC 50 The concentration was 10.9 μM. Therefore, the patch-clamp assay showed a safe hERG profile.

[0207] Example 7: CYP3A4 Inhibition Assay To evaluate the ability of compound number 1 according to Example 1 to inhibit CYP3A4 enzyme activity, test compounds (0.1 μM to 25 μM) were incubated with cryopreserved human hepatocytes for 10 minutes in the presence of midazolam, a specific CYP3A4 probe substrate.

[0208] 1-hydroxymidazolam was monitored by LC-MS / MS, and the decrease in metabolite production compared to the vehicle control was used to determine IC50.50 The value was calculated. The CYP3A4 inhibitory activity of the compound ("CYP3A4 IC") 50 The table below shows the results. [Table 12] Compound number 1 from Example 1 exhibits low inhibitory activity against CYP3A4. In fact, its IC 50 The value exceeds 5 μM. In contrast, the IC of comparative compound A... 50 The value is 0.74 μM. Therefore, comparative compound A is a very potent inhibitor of CYP3A4.

[0209] Example 8: Kinase Panel To evaluate the kinase selectivity of compound number 1 according to Example 1(S), Life Technologies' Z'-Lyte biochemical assay and Adapta / Lanthascreen binding assay were used according to the manufacturer's instructions. The inhibition rate at 500 nM of the test compound was evaluated for 58 kinases: ABL1, ACVR1B (ALK4), AKT2 (PKB beta), AMPK (A1 / B2 / G3), AURKA (Aurora A), AXL, BRAF, BTK, CAMK2B (CaMKII beta), CDK2 / cyclin A, CHEK1 (CHK1), CLK1, CSNK1A1 (CK1 alpha 1), CSNK2A1 (CK2 alpha 1), DAPK3 (ZIPK), DYRK1A, EGFR (ErbB1), EPHB3, ERBB2 (HER2), and F. GFR2, FLT3, FRAP1 (mTOR), GSK3B (GSK3 Beta), IGF1R, IKBKB (IKK Beta), INSR, IRAK4, JAK2, KDR (VEGFR2), KIT, LCK, MAP2K1 (MEK1), MAPK10 (JNK3), MAPK11 (p38 Beta), MAPKAPK2, MARK2, MET (cMet), NEK2, NTRK1 (TRKA), PAK2 (PAK65), PDGFRB (PDGFR Beta), PDK1 These include Direct, PHKG2, PIK3CA / PIK3R1 (p110 alpha / p85 alpha), PIM1, PLK1, PRKACA (PKA), PRKCA (PKC alpha), PTK2 (FAK), RET, ROCK1, RPS6KA1 (RSK1), RPS6KB1 (p70S6K), SRC, STK3 (MST2), SYK, TEK (Tie2), and TYRO3 (RSE). For MAPK10 (JNK3), an ATP concentration of 100 mM was used. Except for BRAF and MAP2K1 (MEK1), which were subjected to binding assays, the apparent Km value was used for all other kinases.

[0210] The results are shown in the table below. [Table 13] Compound No. 1 from Example 1 showed a good kinase selectivity score in a representative kinase panel. In fact, only one kinase was inhibited with an inhibition rate of over 80% out of 58 kinases, and a maximum of 10 kinases were inhibited with an inhibition rate of over 50%.

[0211] In contrast, comparative compounds A and B showed low selectivity scores. In fact, comparative compounds A and B inhibited 15 out of 58 kinases and 10 out of 58 kinases, respectively, with inhibition rates exceeding 80%, and inhibited 26 out of 58 kinases and 20 out of 58 kinases with inhibition rates exceeding 50%.

[0212] Example 9: Permeability assay The Caco-2 cell line was used for in vitro transport studies and was obtained from ATCC. Cells were divided every other day at a division ratio of 1:3 to 1:5 and cultured in Dulbecco's Modified Eagle Medium (GlutaMAX I, D-glucose 4,500 mg / L, sodium pyruvate) supplemented with 10% FBS in the presence of antibiotics. For transport studies, cells were seeded at a density of 60,000 cells / well on polycarbonate Transwell filter membranes (Millipore). The medium was changed 24 hours after seeding and the cells were cultured for a further 21 days before the transport experiment. In transport studies, the donor solution was prepared by diluting the stock solution of the test compound with the transport medium (HBSS buffer containing 10 mM HEPES, pH 7.4). The receptor solution was the same HBSS buffer (pH 7.4) containing 10 mM HEPES. The transport of the test compound (5 μM) was measured twice in two directions (from the apical membrane side to the basement membrane side (A→B) and from the basement membrane side to the apical membrane side (B→A)).

[0213] The permeability coefficient for membrane transport of the test compound was determined using the following formula: Papp (cm / sec) = (Vr / C0)(1 / S)(dC / dt); Papp = apparent permeability coefficient, Vr = volume of the medium in the receiving chamber, C0 = PAR of the test drug in the receiving chamber, S = surface area of ​​the cell membrane monolayer, dC / dt = PAR of the drug in the receiving chamber, which changes over time. The efflux ratio was defined as follows: efflux ratio = Papp BA / Papp AB. Bioanalysis was performed by LC-MS / MS.

[0214] The results are shown in the table below. [Table 14] Compound number 1 from Example 1 exhibits excellent Caco-2 permeability parameters. In fact, the Papp AB value is 10 × 10⁻⁶. -6 The flow rate exceeds cm / s. Furthermore, the outflow ratio is less than 2.

[0215] In contrast, comparative compounds A and B exhibited poor Caco-2 permeability parameters and low Papp AB values ​​(10 × 10⁻¹⁰). -6 It exhibits emissions of less than cm / s and a high emission ratio (greater than 3).

[0216] Example 10: Amorphization of compound number 1 according to Example 1 Before further experiments, the compound was amorphous to obtain a material without crystal nuclei using the following method: The compound was weighed into a 20 mL vial and transferred to a 100 mL round-bottom flask.

[0217] When 15 mL of dichloromethane:methanol (1:2 v / v) was added and gently heated, it became a slurry. When 15 mL of dichloromethane was added, a clear solution was obtained. The solvent was rapidly removed using a rotary evaporator, resulting in a yellow solid. To confirm the morphology of the solid, it was analyzed by XRPD. The solid obtained by rapid evaporation of the dichloromethane-methanol mixture was mainly amorphous.

[0218] Characterization of compounds The following results were obtained from the characterization of the compound. XRPD analysis revealed a crystalline substance named Free Base Pattern 1. PLM analysis revealed extremely small, irregularly shaped particles that exhibited birefringence under cross-polarized light. TGA / DSC demonstrated that the compound was an anhydride with no weight loss until melting decomposition occurred. The DSC plot showed that the melting endothermic reaction occurred simultaneously with the onset of decomposition, with the decomposition onset temperature at 281°C and the peak temperature at 285°C. Standalone DSC analysis was consistent with the initial melting event shown in TGA / DSC analysis. No significant thermal events were observed during the subsequent cooling and heating phases. DVS analysis showed adsorption of 0.6 wt% at 80% RH (relative humidity). Subsequent desorption and adsorption steps showed very similar profiles, indicating slight hygroscopicity of the sample. No clear signs of morphological change were observed. Post-experiment XRPD analysis revealed that the same diffraction pattern was obtained. FTIR analysis, performed for comparison with candidate salts, showed a profile consistent with the functional groups present in the molecule. 1 1H NMR analysis also confirmed that the substance's structure matched the observed properties. Trace amounts of dichloromethane (<0.01 equivalents) were detected in the spectrum. HPLC analysis showed that the compound had a purity of 98.56% by area. LC-MS analysis revealed that the positive ion mode ESI m / z of this substance is 478.1 [M+H]. + This was shown to be the case. This was consistent with the predicted mass of 477.2 g / mol. pKa analysis revealed that the acid had a pKa of 12.62, while the two bases had pKas of 2.85 and 6.81, respectively. Therefore, it is considered that the reaction of the acid with a pKa of less than 4.81 is suitable for salt formation.

[0219] Example 11: Solubility and solubility of the compound according to Example 1 The solubility and dissolution of the compound according to Example 1 were measured in fasting simulated gastric juice (FaSSGF) at pH=1.6, feeding simulated intestinal juice (FeSSIF) at pH=5, and fasting simulated intestinal juice (FaSSIF) at pH=6.5. The data were compared with the solubility values ​​for each pH obtained in the buffer solution.

[0220] I. Preparation of Biomedical Vessels The FaSSGF medium (8.7 mM sodium lauryl sulfate, 34 mM NaCl, 0.03N HCl, pH 1.6) was prepared by mixing 251.57 mg of sodium lauryl sulfate, 200.20 mg of sodium chloride, and 3 mL of 1N HCl, then diluting it with purified water to 100 mL. The pH was measured at 1.53, so it was adjusted to 1.58. The FaSSIF medium was prepared using 8.336 g of concentrated FaSSIF buffer, 192.18 g of purified water, and 0.448 g of FaSSIF powder. The mixture was stirred with a magnetic stirrer until completely dissolved, and then equilibrated at room temperature for 2 hours. The pH was 6.47. The FeSSIF medium was prepared using 20.345 g of concentrated FeSSIF buffer, 229.80 g of purified water, and 2.80 g of FeSSIF powder. The mixture was stirred with a magnetic stirrer until completely dissolved, and the pH was 4.98.

[0221] II. Dissolution Test Microdissolutest μDISS Profiler TM This was used in accordance with the AuPRO Instruction Manual 2018-2019 Pion Inc. PN IM10001 Rev D.

[0222] Stock solution Solution 1 (1) was prepared as follows to a concentration of 5 mg / mL using DMSO. • First test using FaSSIF as the donor medium: 24.28 mg of the compound from Example 1 was weighed into a 5 mL volumetric flask. 4 mL of DMSO was added, and the mixture was stirred until the active ingredient was completely dissolved. 5 mL of DMSO was added up to the graduation mark, and the final mixture was stirred. • Second test using FeSSIF as the donor medium: 25.91 mg of the compound from Example 1 was weighed into a 5 mL volumetric flask. 4 mL of DMSO was added and stirred until the active pharmaceutical component was completely dissolved. An appropriate amount of DMSO was added up to the 5 mL mark, and the final mixture was stirred. The first solution was diluted to 1 / 5 with DMSO in a 5 mL volumetric flask to obtain a 1 mg / mL stock solution (2).

[0223] Collection of standard material 1. In FaSSIF media (donor compartment) To create a calibration curve in the donor compartment, standard substances were collected as follows. The test medium was dispensed into glass vials as follows. 15 mL of the test donor medium (FaSSIF) was dispensed into positions 1, 3, 5, and 7. A cruciform stirring bar was placed in the glass vials and stirred at 150 rpm. A probe fitted with a 20 mm tip was inserted into each medium, taking care to avoid air bubbles. 100% transmittance was read to standardize the detection system. Stock solution (1) was added to each medium in stages, and measurements were taken, yielding a concentration range of 0.97 μg / mL to 19.35 μg / mL. The spectrum (OD versus wavelength) was saved as the "blue standard substance". Calculation parameters were selected from the spectrum of the standard substance to create the best performing calibration curve.

[0224] 2. From FaSSIF media to ASB (Acceptor Sync Buffer) media (Acceptor Compartment) The same procedure as above was used, except for the following items. The test medium was dispensed into glass containers. Specifically, 15 mL of acceptor sink buffer (ASB) was dispensed into positions 2, 4, 6, and 8. A 20 mm tip was attached to the probe. Stock solution (2) was added to each medium in stages, and measurements were taken, yielding a concentration range of 0.19 μg / mL to 5.02 μg / mL.

[0225] 3. In the FeSSIF medium (donor compartment) Except for the following items, the same operating procedure as described for the FaSSIF medium was used. The test medium was dispensed into glass containers; specifically, 15 mL of FeSSIF was dispensed into positions 1, 3, 5, and 7. A 10 mm tip was attached to the probe. Stock solution (1) was added to each medium in stages, and measurements were taken, yielding a concentration range of 5.18 μg / mL to 86.62 μg / mL.

[0226] 4. From FeSSIF media to ASB media (acceptor compartment) Except for the following items, the same operating procedure as above was used. Stock solution (2) was added to each medium in stages, and measurements were taken to obtain a concentration range of 0.21 μg / mL to 5.36 μg / mL.

[0227] 5. Dissolution experiment The experiment was conducted as follows. Probes with the following tips were used: 20mm tips were fitted to the donor compartment and acceptor compartment (ASB) containing FaSSIF. A 10mm tip was fitted to the donor compartment containing FeSSIF. μFlux glassware pairs were assembled. The last μFlux glassware pair was reserved for "blank" measurements. 1.2 mg to 1.6 mg of the compound from Example 1 was weighed into each donor compartment to create a donor concentration of 60 μg / mL to 80 μg / mL. Before connecting the μFlux pairs, 25 μL of GIT lipid solution was applied to the PVDF hydrophobic membrane. 20 mL of ASB was added to the acceptor compartment, and 20 mL of test medium was added to the donor compartment. A cruciform stirring bar was placed in each compartment, the μFlux pairs were placed on the heater block, and the stirring speed was set to 150 rpm. The probes with the tips attached were inserted into each medium, taking care to avoid air bubbles. UV spectra were measured in the donor and acceptor compartments for 24 hours. The maximum dissolution rate and solubility at equilibrium were calculated.

[0228] Solubility test 1. Solubility in FaSSGF 22 mg of the compound from Example 1 was precisely weighed into a glass vial. 2 mL of FaSSGF pH 1.6 was added to achieve a concentration of approximately 11 mg / mL, which was thought to be higher than the actual solubility. The mixture was homogenized using a vortex mixer and kept at 37°C while stirring with a magnetic stirrer. Approximately 500 μL of sample was taken at T30 minutes, T4 hours, and T24 hours and filtered through a GV-PVDF 0.22 μm membrane. Each filtrate was divided into two vials. The final pH was measured in the first vial. The solution in the second vial was diluted with HPLC diluent and analyzed by HPLC. The appearance of the mixture at each time point was recorded.

[0229] 2. Solubility in FeSSIF During the dissolution test, the entire amount of the compound from Example 1 introduced into the donor compartment completely dissolved in the FeSSIF medium. Therefore, an additional solubility test was performed in FeSSIF with the goal of achieving a solubility higher than 73 μg / mL. 7 mg of the compound from Example 1 was precisely weighed into a glass vial. 2 mL of FeSSIF pH 5.0 was added to obtain a concentration of approximately 3.5 mg / mL, which is assumed to be higher than the actual solubility. The solubility was then measured as described above.

[0230] III. Results Solubility in simulated intestinal fluid and simulated gastric fluid 1. Solubility at FaSSIF pH 6.5 The individual and average solubility of the compounds obtained from Example 1 in FaSSIF medium (pH 6.5, 37°C) was measured to determine the solubility data for the compounds from Example 1. The dissolution step lasted approximately 1 hour until a plateau was reached. The compounds from Example 1 (average concentration 61 μg / mL) introduced into the donor compartment did not dissolve completely, allowing the solubility to be determined. At equilibrium, the average solubility at 37°C was measured as 3.44 μg / mL ± 0.17 μg / mL during the plateau from 1 hour to 3.3 hours.

[0231] 2. Solubility at FeSSIF pH 5.0 The individual and average solubility of the compounds obtained from Example 1 in FeSSIF medium (pH 5.0, 37°C) was measured to determine the solubility data for the compounds from Example 1. The dissolution step was continued for approximately 30 minutes until the maximum soluble concentration was reached. Since the compounds from Example 1 (average concentration 73 μg / mL) introduced into the donor compartment were completely dissolved, the actual solubility of the compounds from Example 1 in FeSSIF can be expected to be greater than 73 μg / mL.

[0232] 3. Solubility at FeSSIF pH 5.0 and FaSSGF pH 1.6 The table below shows the solubility data of the compound according to Example 1, and the final pH after 30 minutes, 4 hours, and 24 hours at FeSSIF pH 5.0 and FaSSGF pH 1.6. [Table 15] The compound from Example 1 showed a solubility of 328 μg / mL after 24 hours at 37°C in FeSSIF pH=5.0. This value was already achieved at a maximum of 4 hours, supporting the data obtained in the dissolution test (see >73 μg / mL). In FaSSGF at pH 1.6, a solubility of 6.7 mg / mL was obtained after 24 hours at 37°C. This value is on the same order of magnitude as the solubility obtained after 4 hours (7.0 mg / mL), but lower than the value obtained after 30 minutes (8.9 mg / mL), indicating that the API may reprecipitation at equilibrium, which appears to be consistent with visual observation (change from a milky white suspension at T=30 minutes to a solution containing particles at T=24 hours). At 6.7 mg / mL, the compound from Example 1 exhibits buffering capacity that raises the initial pH of FaSSGF from 1.6 to 2.9. In biomedical media, the solubility of the compound from Example 1 at pH 1.6 is 20 times higher than its solubility at pH 5.0.

[0233] 4. Comparison of solubility data The solubility data obtained for the compounds according to Example 1 in biomedical media and buffer solutions are shown in the table below, along with pH, ​​media composition, and the ionization state of the two pKa values. We determined which of the two sets of data—the experimentally obtained pKa and the calculated pKa—represented the correct evaluation. [Table 16] The solubility of the compound in Example 1 increases with decreasing pH (expected behavior for a base). The solubility profiles better agree with the experimentally obtained pKa values ​​(2.85 and 6.81) than with the overly high calculated values ​​(5.8 and 8.5). In biomedical media, the solubility of FaSSIF at pH 6.5 is approximately three times higher (3.4 μg / mL compared to 1.2 μg / mL at phosphate buffer pH 6.7), and that of FeSSIF at pH 5.1 is approximately eight times higher (328 μg / mL compared to an estimated solubility of approximately 40 μg / mL between 13 μg / mL and 149 μg / mL obtained at acetate buffer pH 5.5 and 4.6, respectively). FeSSIF is three times more concentrated in surfactants than FaSSIF, which may explain this difference in solubility improvement. In FaSSGF, the compound from Example 1 exhibits a high solubility of 6.66 mg / mL and a buffering capacity that raises the initial pH from 1.6 to 2.9. The compound from Example 1 is considered to have "low solubility".

[0234] Example 12: Monohydrochloride anhydrous salt The monohydrochloride salt of compound number 1 was prepared as follows: 800 mg of the compound from Example 10 was weighed into a 20 mL vial and suspended in 15 mL of 2-propanol. 1.05 equivalents of hydrochloric acid were added to the system in stock form. The experiment then involved a temperature cycle from 50°C to 20°C at 0.1°C / min, holding at each temperature for 1 hour, followed by stirring for 48 hours. After this, mainly amorphous diffraction patterns were observed. The solid was isolated under vacuum by Buchner filtration. 15 mL of acetone was added to the solid, and the slurry was circulated for a further 48 hours. After this, the diffraction pattern indicated the formation of the hydrochloride salt. The solid was isolated and dried under vacuum at 40°C for approximately 24 hours. After drying, no changes were observed in the diffraction pattern.

[0235] This salt was well characterized as hydrochloride pattern 1. The following observations and results were obtained. The solid isolated from 2-propanol after 48 hours was mostly amorphous. The solubility of the hydrochloride was not sufficiently high at 50°C, and efficient Ostwald aging did not occur, resulting in the failure to obtain a highly crystalline substance. However, a crystalline substance was obtained when the mixture was re-slurried with acetone. XRPD analysis (Figure 1) showed that this substance was consistent with hydrochloride pattern 1. No morphological changes occurred upon drying. PLM analysis revealed very small, birefringent needle-shaped crystals. TGA analysis showed no weight loss up to the melting point, indicating that it is an anhydrous salt. The melting point occurred at the onset of molecular decomposition / disproportionation. Simultaneous DSC analysis revealed an endothermic reaction that began at 256°C (peak at 267°C). • DSC analysis was performed with the material sealed airtight with a perforated lid. In the initial heating phase of the DSC analysis, an endothermic reaction was observed, starting at 273°C and peaking at 275°C. Vitrification, which was expected after the initial melting, was not observed during the cooling cycle. Similarly, no clear thermal phenomena were observed in the second heating phase. DVS analysis revealed that hydrochloride pattern 1 was slightly hygroscopic, absorbing 0.97% by weight of water at a relative humidity of 80% (0.4 molar equivalents of water). No signs of morphological change were observed during the DVS experiment, and equilibration was rapid at each step. XRPD analysis showed no morphological changes in hydrochloride pattern 1 after the completion of the DVS experiment. HPLC analysis revealed that the hydrochloride salt had a purity of 98.39%. HPLC-CAD analysis revealed a chloride content of 7.0 w / w% (average of two repeated measurements), which is consistent with the presence of a monohydrochloride salt. • FT-IR analysis was consistent with expectations. No signs of hydration were observed in the crystal structure. • Hydrochloride pattern 1 1 ¹H NMR analysis revealed the presence of 0.06 molar equivalents (trace amount) of 2-propanol, and the chemical shift was consistent with salt formation. The following values ​​were obtained from the PSD analysis of hydrochloride pattern 1. D10-0.824μm • D50 - 2.705 μm • D90-11.635μm

[0236] Thermodynamic solubility (according to Test 2) The results of the thermodynamic solubility test of salt are as follows: [Table 17] Thermodynamic solubility evaluation of hydrochloride pattern 1 showed a solubility of approximately 20 mg / mL in water and FaSSGF throughout the test period. In FaSSIF, the solubility at each time point was less than approximately 3 mg / mL. Furthermore, analysis of XRPD diffraction patterns 24 hours after extraction from water and FaSSGF showed that hydrochloride pattern 1 was recovered unchanged in water after 24 hours, although its crystallinity was poor. In FaSSIF, several small peaks that could be attributed to free base were observed throughout the test period.

[0237] 7-day stability test Seven-day stability tests of the salt showed no morphological changes under ambient light, 40°C / 75%RH, 80°C, or migliol, indicating that purity was maintained under all conditions. These data highlight the morphological stability of the salt under these conditions.

[0238] Hydration test At each water activity level investigated, hydrochloride pattern 1 was observed, and hydrochloride pattern 1 was shown to be stable at least up to a water activity of 0.8. These data provide detailed evidence that the hydrochloride is stable against hydration.

[0239] 3-month stability test After storage for two weeks under each condition, the purity of both hydrochloride pattern 1 and free base remained unchanged from the purity at the time of introduction (hydrochloride pattern 1: 98.39, free base: 98.56). Chemical stability also remained unchanged, and the XRPD diffraction patterns showed free base pattern 1 and hydrochloride pattern 1, respectively. The absence of changes in the diffraction patterns indicates that the physical and chemical purity remained stable even after one month. After three months, the purity of each sample remained unchanged relative to the input substance. No changes were observed in the diffraction patterns, indicating that the physical and chemical purity remained stable under the test conditions even after three months.

[0240] conclusion Hydrochloride pattern 1 is an anhydrous monohydrochloride with good thermal properties, maintaining its form and crystallinity under dry conditions, storage at 40°C / 75%RH, and storage at high temperatures. This salt exhibited a good chemical and physical stability profile in solid state, maintaining its form and purity after one week under each accelerated degradation condition (80°C, 40°C / 75%RH, and in migliol). The hydrochloride remained substantially unchanged after 24 hours, indicating improved robustness in biocompatible media. A 3-month stability test demonstrated that the compound maintained high purity and crystalline form.

[0241] Example 13: Hydrochloride hydrate salt The hydrochloride hydrate of compound number 1 was prepared as follows: The compound from Example 10 was added to 3.33 times the volume of ethanol for crystallization under nitrogen protection. The slurry was heated to 70°C to 75°C and held for 0.5 to 1 hour. 1.1 equivalents of hydrochloric acid were diluted with 1.67 times the volume of water. The resulting hydrochloric acid solution was added to the slurry. A clear solution was obtained. This solution was cooled to 65°C to 70°C, 0.5% by weight of seed crystals were added, and it was aged for 2 to 4 hours. Next, the solution was cooled to 20°C to 25°C over 4.5 to 9 hours and aged for 1 to 2 hours. 20 times the volume of acetone was added over 5 to 10 hours and aged for 2 to 4 hours. The solution was cooled to -5°C to 0°C over 2.5 to 5 hours and held at -5°C to 0°C for 4 to 8 hours. The slurry was filtered, and the wet cake was washed twice with 1 times the volume of acetone. The solid material is separated and dried under vacuum at 40°C to 45°C until a constant weight is reached.

[0242] This salt was well characterized as hydrochloride pattern 2. Based on the following data, pattern 2 was shown to be a hydrate. The following observations and results were obtained. XRPD analysis (Figure 2) showed that the sample was consistent with hydrochloride pattern 2. No morphological changes occurred due to drying. X-ray powder diffraction data were collected at room temperature and atmospheric pressure using a Bruker D2 PHASER diffractometer equipped with a 300 W low-power X-ray generator. Powder patterns were collected at 30 kV and 10 mA using a zero-background sample holder, at 0.15 seconds / step, a total of 1837 steps, and a 2θ of 0.02° per step. A Cu(Kα) X-ray tube was used, and the Kα2 / Kα1 intensity ratio was 0.50 (1.54439 Å / 1.5406 Å). According to TGA analysis, a weight loss of 11.4% was observed up to 150°C (approximately 3.4% per equivalent of water), and a weight loss of 2.7% was observed from 150°C to 205°C. Thermogravimetric analysis data was collected using a TA Discovery 550 series TGA. A few milligrams of sample were heated from room temperature to the target temperature at a heating rate of 10°C per minute under nitrogen protection. The DSC results showed three endothermic reactions at 85.3°C, 194.5°C, and 255.5°C (peak temperature). Differential scanning calorimetry was performed using a TA Discovery 2500 series DSC with approximately several mg of sample placed in a Tzero aluminum pan sealed with a Tzero airtight lid. The sample was analyzed under a nitrogen flow of 50 mL / min at a heating rate of 10°C / min. • Hydrochloride pattern 2 1 ¹H NMR analysis revealed that the molar ratio of residual 1,4-dioxane to free base was 0.05 (0.8 wt%). 1 ¹H NMR data were acquired using a Bruker AVANCE NEO 400MHz in DMSO-d6 solvent. For pattern 2, ultra-high performance liquid chromatography (UPLC) and IC were tested. As a result, the purity by UPLC was 99.55% area, and Cl - The content was 5.9%, and the acid / base stoichiometric ratio was shown to be 1.0.

[0243] UPLC was used in the manner shown in the table below. [Table 18]

[0244] The chloride ion content data was collected using a DIONEX ICS-6000+ DP (Chromeleon 7.2 system) ion chromatography system, and the method is shown in the table below. [Table 19]

[0245] Example 14: Maleate The maleate of compound number 1 was prepared as follows: The compound from Example 10 (800 mg) was weighed into a 20 mL vial and suspended in 2-propanol (16 mL). 1.05 equivalents of maleic acid were added to the system in stock solution. Next, a temperature cycle was performed from 20 °C to 50 °C at 0.1 °C / min, and the mixture was held and stirred at each temperature for 1 hour. After one cycle, a certain amount was taken and examined by XRPD, confirming that it was in the correct form. The solid was isolated, dried under vacuum at 40 °C for 16 hours, and then re-analyzed by XRPD.

[0246] This salt was well characterized as maleate pattern 1. The following observations and results were obtained. XRPD analysis (Figure 3) showed that the substance was in the correct form after one thermal cycle. XRPD analysis of the wet cake after separation showed that the substance was consistent with maleate pattern 1. There was no change in morphology due to drying. PLM analysis revealed very small, birefringent, irregularly shaped crystals. TGA analysis showed no weight loss until the simultaneous melting / disproportionation reaction at approximately 170°C. At this point, there was a loss of 18.8 wt%, which corresponds to 1.2 equivalents of maleic acid. Simultaneous DSC analysis showed that an endothermic reaction initiated at 177°C (peak 184°C). A second endothermic reaction initiated at 269°C (peak 276°C), which was associated with the melting of the free base. • DSC analysis was performed with the material sealed airtight with a perforated lid. In the initial heating phase of the DSC analysis, an endothermic reaction was observed, starting at 172°C and peaking at 178°C. This was immediately followed by an exothermic reaction indicating the possibility of recrystallization. This exothermic reaction is likely due to the recrystallization of free bases generated during the disproportionation reaction. During the cooling cycle, the vitrification reaction expected after the initial melt was not observed. In the second heating phase, a glass transition was observed with an intermediate point at 128°C. DVS analysis showed that maleate pattern 1 is slightly hygroscopic, absorbing 1.6 wt% of water at 80% RH (0.5 molar equivalents of water). In the first cycle (humidity 70% RH to 80% RH), a weight loss (0.5 wt%, i.e., 0.16 equivalents of water) was observed, which is likely due to some crystallization phenomenon induced under high humidity conditions. According to XRPD analysis, there was no change in the morphology of maleate pattern 1 after the completion of the DVS experiment. HPLC analysis showed that the purity of the maleate was 98.32% area. • FT-IR analysis was consistent with expectations. No hydration of the crystalline form was observed. • Maleate pattern 1 1 ¹H NMR analysis revealed the presence of 0.07 molar equivalents (trace amount) of 2-propanol, and the chemical shift was consistent with salt formation. Furthermore, it contained 0.93 equivalents of maleic acid, which was consistent with the presence of a monosalt. The following values ​​were obtained from the PSD analysis of maleate ester pattern 1. D10-2,470μm • D50-11.677μm • D90-34.125μm

[0247] Thermodynamic solubility (according to Test 2) The results of the thermodynamic solubility test of salt are as follows: [Table 20] Maleate pattern 1 showed a solubility of approximately 8 mg / mL in FaSSIF, but XRPD analysis at each time point confirmed the diffraction pattern of free bases. Solubility in water was approximately 30 mg / mL. In this example, XRPD analysis revealed two new patterns during the experimental period. A new pattern (pattern 2) was observed at T=0 and T=4 hours, and a second new pattern (pattern 3) was observed at T=24 hours. These patterns may represent hydrated forms. Solubility was much higher in FaSSGF (approximately 80 mg / mL), and new patterns were observed again. Pattern 2 was observed at T=0 hours, and pattern 3 was observed at T=4 hours and T=24 hours.

[0248] 7-day stability test Seven-day stability tests of the salt showed no morphological changes under ambient light, 40°C / 75%RH, 80°C, or in migliol, indicating that purity was maintained under all conditions. These data highlight the morphological stability of the salt under these conditions.

[0249] Salt disproportionation test Based on observations of the solution, no disproportionation occurred during the test.

[0250] conclusion Maleate pattern 1 was an anhydrous monomaleate with good thermal properties. This maleate was physically and chemically stable under dry conditions, storage at 40°C / 75%RH, and storage at high temperatures. This salt exhibited a good chemical and physical stability profile in solid state and maintained its shape and purity after one week under each accelerated degradation condition (80°C, 40°C / 75%RH, in migliol). This maleate showed high thermodynamic solubility.

[0251] Example 15: Esilate The esylate of compound number 1 was prepared as follows: Approximately 250 mg of the compound from Example 10 was weighed into a 20 mL vial. 8.5 mL of acetone was added, followed by the addition of a magnetic stirrer bar. 46 μL (1.05 equivalents) of ethanesulfonic acid was added in stock. The solution was stirred at 40°C for 5 minutes. The experiment involved a thermal cycle between 20°C and 50°C at a rate of 0.1°C / min, with the mixture held at 20°C and 50°C for 1 hour. After 72 hours, a portion of the mixture was taken, isolated by centrifugal filtration, and analyzed by XRPD. The XRPD analysis showed that esylate pattern 1 was obtained. The solid was separated by Buchner filtration (42.5 mm diameter, grade 1, Whatman), washed with cold acetone, and dried under vacuum at 40°C for 16 hours. XRPD analysis was performed on the dried solid. The purity of the esylate was determined by PLM, TG / DSC, DSC, 1 Measurements were taken by 1H NMR and HPLC.

[0252] The following results were obtained for esylate pattern 1. XRPD analysis of the substance isolated from acetone (Figure 4) revealed a crystalline substance consistent with ethylate pattern 1. PLM exhibited birefringence under cross-polarization. However, the crystals were small and had an irregular morphology. The TGA plot showed a loss of 1.3 wt% (equivalent to 0.43 equivalents of surface moisture), which is consistent with the anhydrous esylate. The DSC plot showed two endothermic reactions with an initiation temperature of 190°C and peak temperatures of 197°C and 247°C. DSC analysis revealed melting during the first heating phase at an initiation temperature of 189°C and a peak temperature of 197°C. Vitrification was observed at approximately 63°C during the first cooling phase. A glass transition was observed during the second heating phase with an intermediate temperature of approximately 70°C. · 1 ¹H NMR analysis revealed only trace amounts of solvent, which is consistent with ethylate pattern 1. The spectrum showed approximately 0.5 equivalents of ethanesulfonic acid, indicating that it is a hemi salt. HPLC analysis showed that the purity of ethylate pattern 1 was 99.44% area.

[0253] Thermodynamic solubility (according to Test 1) Esilates showed moderate to low solubility in unbuffered water and FaSSGF, with solubility ranging from 7 mg / mL to 13 mg / mL. In FaSSIF, high solubility exceeding 86 mg / mL was observed.

[0254] Example 16: Oxoglutarate Oxoglutarate of compound number 1 was prepared as follows: Approximately 250 mg of the compound from Example 10 was weighed into a 20 mL vial. 3 mL of dichloromethane was added, followed by the addition of a magnetic stirrer bar. 81.2 mg (1.05 equivalents) of ketoglutarate was added in stock. The experiment involved performing a temperature cycle at a rate of 0.1 °C / min between 5 °C and 20 °C, and holding at 5 °C and 20 °C for 1 hour. After 48 hours, a portion of the mixture was taken, isolated by centrifugation, and analyzed by XRPD. Since an erroneous morphology was observed, the heating cycle was performed for a further 24 hours. XRPD analysis after a total of 72 hours showed that oxoglutarate of pattern 1 was obtained. The solid was separated by Buchner filtration (42.5 mm diameter grade 1, Whatman) and dried under vacuum at 40 °C for 16 hours. XRPD analysis was performed on the dried solid. The purity and organic acid content of oxoglutarate are determined by PLM, TG / DSC, DSC, 1 Measurements were taken by 1H NMR and HPLC.

[0255] The following results were obtained for oxoglutaric acid pattern 1. XRPD analysis of the sample isolated from dichloromethane (Figure 5) showed a crystalline substance consistent with oxoglutaric acid pattern 1. PLM exhibited birefringence under cross-polarization. The crystals were small and had an irregular shape. The TGA plot showed a loss of 11.7% by weight (equivalent to 0.57 equivalents of ketoglutaric acid) between 170°C and 220°C. However, since the mass loss of TGA above this temperature was continuous, the true stoichiometric value of the salt was obtained from the measurement of organic acid content by HPLC (see below). The DSC plot showed an endothermic reaction at an initiation temperature of 177°C and a peak temperature of 182°C, and a second endothermic reaction was observed during molecular decomposition at an initiation temperature of 245°C and a peak temperature of 257°C. DSC analysis captured endothermic events at an initiation temperature of 177°C and a peak temperature of 183°C, and at an initiation temperature of 250°C and a peak temperature of 260°C. The first event is likely part of a simultaneous melting / disproportionation reaction, and the second event is thought to be the melting of free base. · 1 ¹H NMR analysis was consistent with salt formation, and the presence of only trace amounts of DCM confirmed that pattern 1 is an anhydrous salt. HPLC analysis of the organic acid content revealed that ketoglutaric acid was present at 23.3 w / w%, which corresponds to 1.0 molar equivalent and is consistent with its monosalte form. HPLC analysis showed that the purity of oxoglutarate pattern 1 was 98.52% area.

[0256] Thermodynamic solubility (according to Test 1) The results of the thermodynamic solubility test of salt are as follows: [Table 21] Oxoglutarate showed moderate solubility in all media, with solubility of 7 mg / mL to 11 mg / mL in unbuffered water and FaSSIF, and 20 mg / mL to 26 mg / mL in FaSSGF.

[0257] Example 17: Malonate Malonic acid salt of compound number 1 was prepared as follows: Approximately 250 mg of the compound from Example 10 was weighed into a 20 mL vial. 3 mL of dichloromethane was added, followed by the addition of a magnetic stirrer bar. 57.8 mg (1.05 equivalents) of malonic acid was added in stock. The experiment involved performing a temperature cycle at a rate of 0.1 °C / min between 5 °C and 20 °C, holding at 5 °C and 20 °C for 1 hour. After 24 hours, a portion of the mixture was taken, isolated by centrifugation, and analyzed by XRPD. The XRPD analysis showed that a malonic acid salt of pattern 2 was obtained. The solid was separated by Buchner filtration (42.5 mm diameter, grade 1, Whatman) and dried under vacuum at 40 °C for 16 hours. XRPD analysis was performed on the dried solid. The purity of the malonic acid salt was determined by PLM, TG / DSC, DSC, 1 Measurements were taken by 1H NMR and HPLC.

[0258] The following results were obtained for malonate pattern 2. XRPD analysis of the substance isolated from dichloromethane (Figure 6) revealed a crystalline substance consistent with malonate pattern 2. PLM exhibited birefringence under cross-polarization. The crystals were small and had an irregular shape. TGA / DSC analysis showed a weight loss of 3.7% by weight (0.3 equivalents of dichloromethane) from 35°C to 77°C. Subsequently, a gradual weight loss of 12.4% was observed from 150°C to 250°C (0.8 equivalents of malonic acid, consistent with the monosalt). • In the DSC plot, an endothermic reaction was observed at an initiation temperature of 254°C and a peak temperature of 263°C. DSC analysis revealed a small endothermic reaction at an initiation temperature of 125°C and a peak temperature of 128°C. A second endothermic reaction occurred at an initiation temperature of 259°C and a peak temperature of 267°C. The first reaction is likely part of a concurrent melting / disproportionation reaction, while the second reaction may be the melting of a free base. · 1 1H NMR analysis was consistent with salt formation, and only trace amounts of DCM were present. The counterion signal may have been obscured by the water peak in the spectrum. HPLC analysis showed that the purity of malonate pattern 2 was 98.43% area.

[0259] Thermodynamic solubility (according to Test 1) The results of the thermodynamic solubility test of salt are as follows: [Table 22] The solubility of malonate was observed to be low in FaSSIF (approximately 3 mg / mL), moderate / low in unbuffered water (approximately 9 mg / mL), and moderate in FaSSGF (approximately 25 mg / mL).

[0260] Example 18: Oxalate The oxalate of compound number 1 was prepared as follows: Approximately 250 mg of the compound from Example 10 was weighed into a 20 mL vial. 5 mL of methanol was added, followed by the addition of a magnetic stirrer bar. 75.1 mg (1.5 equivalents) of oxalic acid was added in stock form. The experiment involved performing a temperature cycle at a rate of 0.1 °C / min between 5 °C and 20 °C, holding at 5 °C and 20 °C for 1 hour. After 4 days, a portion of the mixture was taken, isolated by centrifugation, and analyzed by XRPD. XRPD analysis showed that a mixture of oxalate pattern 2 and the free base of compound number 1 from Example 1 was obtained. Further 0.5 equivalents (24.5 mg) of oxalic acid were added in stock form with 2 mL of methanol to prepare a fluid slurry. The experiment involved performing a temperature cycle for a further 24 hours. The solids were separated by Buchner filtration (42.5 mm diameter, Grade 1, Whatman) and dried under vacuum at 40°C for 16 hours to obtain Pattern 2. XRPD analysis was performed on the dried solids. The purity of oxalates and organic acid content were determined by PLM, TG / DSC, DSC, 1 Measurements were taken by 1H NMR and HPLC.

[0261] The following results were obtained for oxalate pattern 2. XRPD analysis of the substance isolated from methanol (Figure 7) showed a crystalline substance consistent with oxalate pattern 2. PLM analysis showed birefringence under cross-polarized light. The crystals were small and had an irregular shape. • In the TGA plot, no mass loss was observed up to 180°C, but 32.3% by weight was lost at 180°C, which corresponds to 2 molar equivalents of oxalic acid, indicating that oxalate pattern 2 is bisoxalate. • DSC plots showed an endothermic reaction at an initial temperature of 204°C and a peak temperature of 209°C. After the loss of oxalic acid, a second endothermic reaction was observed at an initial temperature of 251°C and a peak temperature of 267°C, which is related to the melting of free base material. DSC analysis showed a small endothermic reaction at an initial temperature of 209°C and a peak temperature of 212°C. No clear vitrification was observed during the cooling phase, but a glass transition was observed at 123°C during the second heating phase, which is consistent with melting and formation of amorphous material during the first heating phase. · 1 ¹H NMR analysis confirmed that pattern 2 is an anhydrous salt, consistent with salt formation and showing only trace amounts of methanol. HPLC measurement of organic acid content revealed oxalic acid at 32.6 w / w%, which corresponds to 2 molar equivalents and is consistent with the presence of a bis(b) salt. HPLC analysis revealed that the purity of oxalate pattern 2 was 98.72% area.

[0262] Thermodynamic solubility (according to Test 1) The results of the thermodynamic solubility test of salt are as follows: [Table 23] In all media, oxalates exhibited moderate to high solubility, with solubility ranging from 20 mg / mL to 45 mg / mL.

[0263] Example 19: Besylate (counterexample) The besilate of compound number 1 was prepared as follows: Approximately 250 mg of the compound from Example 10 was weighed into a 20 mL vial. 5 mL of 2-propanol was added, followed by the addition of a magnetic stirrer bar. 88.8 mg (1.05 equivalents) of benzenesulfonic acid was added in stock. The vial was washed with 3.5 mL of 2-propanol, and the washing solution was added to the reaction mixture. The solution was stirred at 40°C for 5 minutes. The experiment was performed by cycling the temperature between 20°C and 50°C at a rate of 0.1°C / min, holding at 20°C and 50°C for 1 hour. After 72 hours, a portion of the mixture was taken, isolated by centrifugation, and analyzed by XRPD. XRPD analysis showed that besilate pattern 1 was obtained. The solid was separated by Buchner filtration (42.5 mm diameter grade 1, Whatman), washed with cold 2-propanol, and dried under vacuum at 40°C for 16 hours. XRPD analysis was performed on the dried solid. The purity of the besylate was determined by PLM, TG / DSC, DSC, 1 Measurements were taken by 1H NMR and HPLC.

[0264] The following results were obtained for besylate pattern 1. XRPD analysis of the substance isolated from 2-propanol (Figure 8) showed a crystalline substance consistent with besylate pattern 1. PLM exhibited birefringence under cross-polarized light. However, the crystals were small and had an irregular shape. The TGA plot showed a loss of 1.2 wt% (equivalent to 0.43 equivalents of surface moisture), which is consistent with the anhydrous besilate. The DSC plot showed endothermic melting at an initiation temperature of 221°C and a peak temperature of 224°C before decomposition began. DSC analysis revealed melting during the first heating phase at an initiation temperature of 221°C and a peak temperature of 224°C. During the first cooling phase, vitrification was observed at approximately 54°C, indicating an amorphous material. In the second heating phase, a glass transition was observed with an intermediate temperature of approximately 62°C, and no recrystallization from the amorphous material was observed. · 11H NMR analysis revealed that only trace amounts of solvent were present, consistent with besylate pattern 1. The spectrum showed approximately 1 equivalent of benzenesulfonic acid, indicating that it is a monosalt. HPLC analysis showed that the purity of besylate pattern 1 was 98.95% area.

[0265] Thermodynamic solubility (according to Test 1) The results of the thermodynamic solubility test of salt are as follows: [Table 24] The solubility of besilates was low in all media, with solubility levels below 10 mg / mL being achieved.

[0266] Example 20: Napsylate (counterexample) The napsylate of compound number 1 was prepared as follows: Approximately 250 mg of the compound from Example 10 was weighed into a 20 mL vial. 5 mL of ethyl acetate was added, followed by the addition of a magnetic stirrer bar. 117 mg (1.05 equivalents) of naphthalene-2-sulfonic acid was added in stock. The vial was washed with 3.5 mL of ethyl acetate, and the washing solution was added to the reaction mixture. The solution was stirred at 40°C for 5 minutes. The experiment involved performing a temperature cycle between 20°C and 50°C at a rate of 0.1°C / min, holding at 20°C and 50°C for 1 hour. After 72 hours, a portion of the mixture was taken, isolated by centrifugation, and analyzed by XRPD. XRPD analysis showed that pattern 1 of the napsylate was obtained. The solid was separated by Buchner filtration (42.5 mm diameter grade 1, Whatman), washed with cold ethyl acetate, and dried under vacuum at 40°C for 16 hours. XRPD analysis was performed on the dried solid. The purity of napsylate is PLM, TG / DSC, DSC, 1 Measurements were taken by 1H NMR and HPLC.

[0267] The following results were obtained for napsylate pattern 1. XRPD analysis of the substance isolated from ethyl acetate (Figure 9) showed a crystalline substance consistent with pattern 1. PLM exhibited birefringence under cross-polarization. Its morphology consisted of small, fragmented, plate-like particles. The TGA plot showed a loss of 1.4% by weight (equivalent to 0.54 equivalents of surface water), which is consistent with anhydrous mononapsylate. The DSC plot showed endothermic melting during the first heating phase, with an initial temperature of 201°C and a peak temperature of 207°C. DSC analysis showed a melting event during the first heating phase, with an initial temperature of 199°C and a peak temperature of 206°C. Vitrification was observed at approximately 78°C during the first cooling phase. A glass transition was shown during the second heating phase, with an intermediate temperature of approximately 94°C. · 1 ¹H NMR analysis revealed only trace amounts of solvent, consistent with napsylate pattern 1. The spectrum showed naphthalene sulfonic acid, approximately 0.8 equivalents. Combined with the TGA data, napsylate pattern 1 is likely a monosalt. HPLC analysis showed that the purity of napsylate pattern 1 was 98.44% area.

[0268] Thermodynamic solubility (according to Test 1) The results of the thermodynamic solubility test of salt are as follows: [Table 25] The solubility of napsylate was very low in all media, with solubility of less than 3 mg / mL being achieved.

Claims

1. The following formula (I) A pharmaceutically acceptable salt of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2(1H)-one, and its solvate, The salt is selected from hydrochloride, maleate, esylate, oxoglutarate, malonate, and oxalate. salt.

2. The salt is selected from hydrochloride salts, The salt is preferably selected from monohydrochloride anhydrous salt, hydrochloride hydrate salt, and maleate salt. The salt according to claim 1.

3. A solvent selected from 2-propanol, acetone, acetonitrile, ethanol, ethyl acetate, 1,4-dioxane, and tetrahydrofuran. In particular, a solvent selected from 2-propanol, acetone, acetonitrile, and ethanol, Preferably, a solvent selected from 2-propanol and acetone. Among these, the step of adding hydrochloric acid to the compound of formula (I) is included. A method for producing the hydrochloride salt according to claim 1 or 2.

4. A solvent selected from 2-propanol, acetone, acetonitrile, and ethyl acetate, In particular, a solvent selected from 2-propanol, acetone, and acetonitrile, Preferably 2-propanol Among these, the step of adding maleic acid to the compound of formula (I) is included. A method for producing maleate salt according to claim 1 or 2.

5. A solvent selected from acetone, acetonitrile, ethyl acetate, and tetrahydrofuran, In particular, a solvent selected from acetone and ethyl acetate, Preferably acetone Among these, the step of adding ethanesulfonic acid to the compound of formula (I) is included. A method for producing esylate salt according to claim 1.

6. A solvent selected from 2-propanol, acetone, acetonitrile, ethanol, ethyl acetate, dichloromethane, methanol, and a mixture of dichloromethane and methanol. In particular, a solvent selected from ethanol, 2-propanol, acetonitrile, dichloromethane, and a mixture of dichloromethane and methanol, Preferably, the solvent is selected from dichloromethane and a mixture of dichloromethane and methanol. Among these, the step of adding ketoglutaric acid to the compound of formula (I) is included. A method for producing oxoglutarate according to claim 1.

7. A solvent selected from dichloromethane, a mixture of dichloromethane and methanol, and 2-propanol. Preferably, the solvent is selected from dichloromethane and a mixture of dichloromethane and methanol. Among these, the step of adding malonic acid to the compound of formula (I) is included. A method for producing malonate according to claim 1.

8. The process includes the step of adding oxalic acid to the compound of formula (I) in methanol. A method for producing oxalate according to claim 1.

9. Used to prevent and / or inhibit and / or treat diseases or symptoms mediated by ERK kinase activity, particularly ERK2 kinase activity. The salt according to claim 1 or 2.

10. The aforementioned disease or symptoms are selected from cancer and metastasis. A salt for use according to claim 9.

11. The disease or symptoms described above are selected from glioblastoma, multiple myeloma, cancer, leukemia, especially myeloid leukemia (AML), lymphocytic leukemia, myeloid leukemia, myeloid leukemia (CML), or lymphoblastic leukemia, myelodysplastic syndrome, Kaposi's sarcoma, cutaneous angiosarcoma, solid tumors, lymphoma, especially non-Hodgkin lymphoma, melanoma, especially malignant melanoma, bladder cancer, breast cancer, gastric cancer, colon cancer, colorectal cancer, endometrial cancer, lung cancer including non-small cell carcinoma, pancreatic cancer, prostate cancer, rectal cancer, kidney cancer, head and neck cancer, liver cancer, ovarian cancer, especially serous ovarian cancer, seminomastoma, respiratory and thoracic cancers, thyroid cancer, especially papillary or follicular thyroid cancer, and other tumors that express ERK. A salt for use according to claim 9 or 10.

12. The disease or symptoms described above are selected from neoplastic diseases, allergic diseases, inflammatory diseases, autoimmune diseases, malaria-related diseases, mast cell-related diseases, graft-versus-host diseases, metabolic syndrome, central nervous system-related diseases, neurodegenerative diseases, pain disorders, substance abuse disorders, prion diseases, heart diseases, fibrous diseases, idiopathic arterial hypertension (IPAH), and primary pulmonary hypertension (PPH). A salt for use according to claim 9.

13. Used to prevent and / or inhibit and / or treat human immunodeficiency virus (HIV), A salt for use according to claim 9.

14. For preventing and / or inhibiting and / or treating diseases or symptoms mediated by ERK kinase activity, preferably ERK2 kinase activity, Use of the salt according to claim 1 or 2.

15. A pharmaceutical product comprising at least one salt according to claim 1 or 2.

16. A pharmaceutical composition comprising at least one salt according to claim 1 or 2 and at least one pharmaceutically acceptable excipient.

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