Novel salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-n-(thiazol-4-YL)benzenesulfonamide and preparation method thereof

Abstract

The present disclosure provides a novel salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide and a method for preparing the same. The mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide, which may be prepared using methanesulfonic acid and, without wishing to be bound by theory, can exhibit reduced hygroscopicity and improved physicochemical stability and solubility. In some aspects, the present disclosure provides a pharmaceutical composition for preventing or treating a sodium channel blocker-related disease, comprising the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide.

Description

Attorney Docket: NRA-005WONOVEL SALT OF 5-CHLORO-2-FLUORO-4-((4-FLUORO-2-(METHYL(2- (METHYLAMINO)ETHYL)AMINO)PHENYL)AMINO)-N-(THIAZOL-4- YL)BENZENESULFONAMIDE AND PREPARATION METHOD THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of Korean Application No. 10-2024-0188619, filed December 17, 2024, the content of which is herein incorporated by reference in its entirety.BACKGROUND

[0002] 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2- (methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide is a sodium channel blocker, particularly exhibiting inhibitory activity against Nav1.7, and is known to be useful in the treatment of acute pain, chronic pain, neuropathic pain, post-surgical pain, migraine, arthralgia, neuropathy, nerve damage, diabetic neuropathy, neuropathic disease, epilepsy, arrhythmia, myotonia, ataxia, multiple sclerosis, irritable bowel syndrome, urinary incontinence, visceral pain, depression, erythromelalgia, or paroxysmal extreme pain disorder (PEPD).

[0003] There’s thus a need to develop a novel salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide which may provide benefits for developing the compound as therapeutic agent. The present disclosure addresses this need.SUMMARY

[0004] In some aspects, the present disclosure provides a mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide.

[0005] In some aspects, the present disclosure provides a method for preparing the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide disclosed herein.

[0006] In some aspects, the present disclosure provides a method of inhibiting Nav1.7 in a subject, comprising administering the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide disclosed herein to the subject.

[0007] In some aspects, the present disclosure provides the mesylate salt of 5-chloro-2-fluoro-Attorney Docket: NRA-005WO 4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide disclosed herein for use in inhibiting Nav1.7 in a subject.

[0008] In some aspects, the present disclosure provides use of the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yljbenzenesulfonamide disclosed herein in the manufacture of a medicament for use in inhibiting Nav1.7 in a subject.

[0009] In some aspects, the present disclosure provides a method of preventing or treating a disease in a subject in need thereof, comprising administering a therapeutically effective amount of the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide disclosed herein to the subject.

[0010] In some aspects, the present disclosure provides the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide disclosed herein for use in preventing or treating a disease in a subject in need thereof.

[0011] In some aspects, the present disclosure provides use of the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide disclosed herein in the manufacture of a medicament for use in preventing or treating a disease in a subject in need thereof.

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

[0013] Other features and advantages of the disclosure will be apparent from the following detailed description and claims.Attorney Docket: NRA-005WO DESCRIPTION OF DRAWINGS

[0014] FIG. 1 shows1H-NMR data indicating the structure of the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide according to the present disclosure.

[0015] FIGS. 2 A and 2B show dynamic water vapor sorption (DVS) curves of the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide according to the present disclosure.DETAILED DESCRIPTION

[0016] The present disclosure relates to a novel salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide and a method for preparing the same.

[0017] It is understood that 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide is a compound represented by Chemical Formula 1.[Chemical Formula 1]

[0018] For this compound represented by Chemical Formula 1, only a hydrochloride salt, which is the initial form obtained during the synthesis of the compound, has been first disclosed in Korean Patent No. 10-2245930 (incorporated by reference).

[0019] Meanwhile, the reason why the salt conversion step is important in pharmaceutical development is that high bioavailability may be achieved by easily improving the physical properties of the drug through salt conversion, and that the step plays an important role in improving the stability of the drug. In many pharmaceutical development markets, salt conversion is used to improve the properties of drugs and select new candidates, and is considered as an important factor in the drug synthesis and formulation stages for the following reasons. First, when assessing drug stability, appropriate drug stability may be achieved depending on the salt form, and screening for salts may identify the most stable form. Second,Attorney Docket: NRA-005WO converting the salt form to improve drug solubility may increase drug absorption and bioavailability. Third, an appropriate salt form may improve the manufacturing and storage characteristics of the drug, thereby enhancing the physical stability of the drug and reducing the hygroscopic properties.

[0020] The compound represented by Chemical Formula 1 has limited stability to heat and moisture. Although the compound showed stable results up to 4 weeks in long-term and accelerated tests, it showed unstable results up to 4 weeks in stress testing due to an increase in related substances.

[0021] The present disclosure provides a novel mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide, which may be prepared using methanesulfonic acid and, without wishing to be bound by theory, can exhibit reduced hygroscopicity and improved physicochemical stability and solubility.

[0022] In some aspects, the present disclosure provides a mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide represented by Chemical Formula 2 below:[Chemical Formula 2]

[0023] In some aspects, the present disclosure provides a method for preparing the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide represented by Chemical Formula 2, comprising step (a) of reacting 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2- (methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide with methanesulfonic acid in an organic solvent.

[0024] Without wishing to be bound by theory, the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide disclosed herein exhibits enhanced stability and solubility in consideration of the total amount of related substances and hygroscopicity.Attorney Docket: NRA-005WO

[0025] The effects of the present disclosure are not limited to the effects mentioned above, and include various effects within a range obvious to those skilled in the art from the following description.

[0026] The present disclosure is based on a discovery of a novel salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide. Without wishing to be bound by theory, the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide, which is in the form of a methanesulfonic acid addition salt, has lower hygroscopicity than other acid addition salts, may have improved stability by minimizing the generation of related substances under accelerated and stress conditions, and may have improved solubility.

[0027] The present specification is described in more detail as follows. The terms used herein are selected as general terms that are currently widely used as much as possible while considering the functions in the present disclosure, but they may vary depending on the intention or precedent of those of ordinary skill in the art, the emergence of new technology, or the like. In addition, in certain cases, there are terms arbitrarily selected by the applicant, and in this case, the meaning will be described in the corresponding part of the detailed description of the invention. Therefore, the terms used in the present disclosure should be defined based on the meaning of the terms and the overall content of the present disclosure, rather than simply the names of the terms.Mesylate Salt of the Present Disclosure

[0028] In some aspects, the present disclosure provides a mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide.

[0029] In some embodiments, the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide is a compound represented by Chemical Formula 2 below:Attorney Docket: NRA-005WO[Chemical Formula 2]

[0030] In some embodiments, the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide may be a mesylate salt wherein the molar ratio of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide to methanesulfonic acid is 1:1.

[0031] In some embodiments the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide exhibits a solubility of about 10 mg / mL or higher, about 11 mg / mL or higher, about 12 mg / mL or higher, about 13 mg / mL or higher, about 14 mg / mL or higher, about 15 mg / mL or higher, about 16 mg / mL or higher, about 17 mg / mL or higher, about 18 mg / mL or higher, about 19 mg / mL or higher, or about 20 mg / mL or higher in water at a pH value of about 7.0.

[0032] In some embodiments the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide exhibits a solubility of about 17.9±5.0 mg / mL, about 17.9±4.0 mg / mL, about 17.9±3.0 mg / mL, about 17.9±2.0 mg / mL, about 17.9±1.5 mg / mL, about 17.9±1.0 mg / mL, about 17.9±0.5 mg / mL, about 17.9±0.4 mg / mL, about 17.9±0.3 mg / mL, about 17.9±0.2 mg / mL, or about 17.9±0.1 mg / mL (e.g., about 17.9 mg / mL), in water at a pH value of about 7.0.

[0033] In some embodiments, the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide exhibits no substantial impurity increase (e.g., as measured by HPLC) upon storage at about 25 °C and about 60% humidity for 2 weeks.

[0034] In some embodiments, the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide exhibits an increase of impurity concentration of about 0.5% or less, about 0.4% or less, about 0.3% or less, about 0.2% or less, about 0.1% or less, about 0.05% or less, about 0.04% or less, about 0.03% or less, about 0.02% or less, or about 0.01% or less (e.g., as measured by HPLC)Attorney Docket: NRA-005WO upon storage at about 25 °C and about 60% humidity for 2 weeks.

[0035] In some embodiments, the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide exhibits no substantial impurity increase (e.g., as measured by HPLC) upon storage at about 25 °C and about 60% humidity for 4 weeks.

[0036] In some embodiments, the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide exhibits an increase of impurity concentration of about 0.5% or less, about 0.4% or less, about 0.3% or less, about 0.2% or less, about 0.1% or less, about 0.05% or less, about 0.04% or less, about 0.03% or less, about 0.02% or less, or about 0.01% or less (e.g., as measured by HPLC) upon storage at about 25 °C and about 60% humidity for 4 weeks.

[0037] In some embodiments, the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide exhibits no substantial impurity increase (e.g., as measured by HPLC) upon storage at about 25 °C and about 60% humidity for 6 weeks.

[0038] In some embodiments, the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide exhibits an increase of impurity concentration of about 0.5% or less, about 0.4% or less, about 0.3% or less, about 0.2% or less, about 0.1% or less, about 0.05% or less, about 0.04% or less, about 0.03% or less, about 0.02% or less, or about 0.01% or less (e.g., as measured by HPLC) upon storage at about 25 °C and about 60% humidity for 6 weeks.

[0039] In some embodiments, the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide exhibits no substantial impurity increase (e.g., as measured by HPLC) upon storage at about 40 °C and about 75% humidity for 2 weeks.

[0040] In some embodiments, the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide exhibits an increase of impurity concentration of about 0.5% or less, about 0.4% or less, about 0.3% or less, about 0.2% or less, about 0.1% or less, about 0.05% or less, about 0.04% or less, about 0.03% or less, about 0.02% or less, or about 0.01% or less (e.g., as measured by HPLC) upon storage at about 40 °C and about 75% humidity for 2 weeks.

[0041] In some embodiments, the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide exhibits no substantial impurity increase (e.g., as measured by HPLC) upon storage at aboutAttorney Docket: NRA-005WO 40 °C and about 75% humidity for 4 weeks.

[0042] In some embodiments, the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide exhibits an increase of impurity concentration of about 0.5% or less, about 0.4% or less, about 0.3% or less, about 0.2% or less, about 0.1% or less, about 0.05% or less, about 0.04% or less, about 0.03% or less, about 0.02% or less, or about 0.01% or less (e.g., as measured by HPLC) upon storage at about 40 °C and about 75% humidity for 4 weeks.

[0043] In some embodiments, the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide exhibits no substantial impurity increase (e.g., as measured by HPLC) upon storage at about 40 °C and about 75% humidity for 6 weeks.

[0044] In some embodiments, the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide exhibits an increase of impurity concentration of about 0.5% or less, about 0.4% or less, about 0.3% or less, about 0.2% or less, about 0.1% or less, about 0.05% or less, about 0.04% or less, about 0.03% or less, about 0.02% or less, or about 0.01% or less (e.g., as measured by HPLC) upon storage at about 40 °C and about 75% humidity for 6 weeks.

[0045] In some embodiments, the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide exhibits a moisture absorption of about 3.0% w / w or less, about 2.5% w / w or less, about 2.0% w / w or less, about 1.5% w / w or less, about 1.4% w / w or less, about 1.3% w / w or less, about 1.2% w / w or less, about 1.1% w / w or less, or about 1.0% w / w or less, at 60% RH (e.g., as determined by DVS).

[0046] In some embodiments, the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide exhibits a moisture absorption of about 5.0% w / w or less, about 4.5% w / w or less, about 4.0% w / w or less, about 3.5% w / w or less, about 3.0% w / w or less, about 2.5% w / w or less, or about 2.0% w / w or less, at 80% RH (e.g., as determined by DVS).

[0047] In some embodiments, the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide exhibits a moisture absorption of about 10% w / w or less, about 9% w / w or less, about 8% w / w or less, about 7% w / w or less, about 6% w / w or less, or about 5% w / w or less, at 95% RH (e.g., as determined by DVS).

[0048] In some embodiments, the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-Attorney Docket: NRA-005WO (methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide demonstrates a reversible sorption-desorption profile with hysteresis of about 1.0% or less, about 0.9% or less, about 0.8% or less, about 0.7% or less, about 0.6% or less, about 0.5% or less, about 0.4% or less, about 0.3% or less, about 0.2% or less, about 0.1% or less mass difference between the sorption and desorption curves.

[0049] It is understood that the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide disclosed herein intends to encompass all stereoisomers.

[0050] As used herein, the term “stereoisomer” means a compound having one or more chiral centers (*), each of which may exist in the R or S configuration. Stereoisomers include not only diastereoisomers, enantiomers, and epimers, but also racemates and mixtures thereof.

[0051] In addition, although it is known that the preparation of salt forms can improve the physical or pharmaceutical properties of a pharmaceutical active compound, it is not possible to predict which salt forms may possess advantages for a particular purpose prior to the actual preparation and characterization of the salt form. Because salt formation may alter the physicochemical properties of a drug without altering the chemical structure of the drug, selecting an appropriate salt is an important consideration for solubility and stability. Solubility, in particular, is a critical property that may influence the drug's suitability for use.

[0052] Without wishing to be bound by theory, the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide disclosed herein may possess enhanced physicochemical properties as compared to 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2- (methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide or other salts of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide.

[0053] In some embodiments, the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide disclosed herein may have improved stability by minimizing the generation of related substances under long-term, accelerated, and stress conditions while exhibiting low hygroscopicity. Therefore, even when a formulation containing the mesylate is prepared and then stored for a long period of time, it may be maintained in the same state, so that the content uniformity of the formulation may be stably maintained, and thus the formulation may be easily applied to mass production.

[0054] Without wishing to be bound by theory, the mesylate salt of 5-chloro-2-fluoro-4-((4-Attorney Docket: NRA-005WO fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide disclosed herein may be usefully applied as a drug for diseases treatable with sodium channel blockers, etc., by using pharmaceutically acceptable methanesulfonic acid.Methods of Preparation

[0055] In some aspects, the present disclosure provides a method for preparing a mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide represented by Chemical Formula 2.

[0056] In some embodiments, the method comprises step (a) of reacting 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide with methanesulfonic acid in an organic solvent.

[0057] In some embodiments, the method comprises one or more of the following steps, without being limited thereto:step (b) of further stirring the solution from step (a), followed by concentration under reduced pressure to obtain a solid; andstep (c) of washing and drying the obtained solid.

[0058] In some embodiments, the organic solvent in step (a) comprises ethyl acetate.

[0059] In some embodiments, the organic solvent in step (a) comprises water.

[0060] In some embodiments, the organic solvent in step (a) comprises ethyl acetate and water.

[0061] In some embodiments, the organic solvent in step (a) is ethyl acetate or a mixed solution of ethyl acetate and water, without being limited thereto.

[0062] In some embodiments, the organic solvent in step (a) is added in an amount ranging from 10 times to 30 times (volume / weight) to the amount of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide, without being limited thereto.

[0063] In some embodiments, the methanesulfonic acid in step (a) is added at a molar ratio ranging from 0.8 equivalents to 1.5 equivalents relative to 1.0 equivalent of a free base of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide, without being limited thereto.

[0064] In some embodiments, step (b) comprises further stirring the solution from the step (a) under a room temperature (e.g., ranging from 20 °C to 25 °C) for a time ranging from 20 hours to 30 hours, followed by concentration under reduced pressure to obtain a solid, without being limited thereto.Attorney Docket: NRA-005WO

[0065] In some embodiments, step (c) comprises washing the obtained solid with a solvent selected from the group consisting of methanol, ethanol, acetone, isopropanol, ethyl acetate, and mixed solvents thereof, without being limited thereto.

[0066] In some embodiments, the drying in step (c) is performed under vacuum conditions for a time ranging from 15 hours to 35 hours, without being limited thereto.

[0067] The mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide prepared according to the present disclosure is applied in the same manner as the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide prepared above, unless they are mutually contradictory.

[0068] Pharmaceutical Compositions

[0069] In some aspects, the present disclosure provides a pharmaceutical composition for preventing or treating a sodium channel blockers-related disease, comprising the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide.

[0070] In some aspects, the present disclosure provides a pharmaceutical composition for preventing or treating a sodium channel blockers-related disease, comprising the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide as an active ingredient.

[0071] As used herein, the term “active ingredient” means a substance or group of substances that are expected to directly or indirectly exhibit the efficacy and effect of the composition through inherent pharmacological action, and is meant to include a main ingredient.

[0072] In some embodiments, the pharmaceutical composition is prepared in a unit dose form or prepared to be contained in a multi-dose container by formulating with a pharmaceutically acceptable carrier, according to a method that a person skilled in the art can easily perform.

[0073] As used herein, the term “pharmaceutically acceptable” refers to a composition which is physiologically acceptable and, when administered to the human beings, does not cause allergic reactions such as gastrointestinal disorders and dizziness, or similar reactions.

[0074] As used herein, the term "pharmaceutically acceptable carrier" typically includes the liquid or non-liquid basis of the pharmaceutical composition. If the pharmaceutical composition is provided in liquid form, the carrier will typically be pyrogen-free water; isotonic saline or buffered (aqueous) solutions, e.g., phosphate, citrate etc. buffered solutions. The injection buffer may be hypertonic, isotonic or hypotonic with reference to the specificAttorney Docket: NRA-005WO reference medium, i.e., the buffer may have a higher, identical or lower salt content with reference to the specific reference medium, wherein preferably such concentrations of the afore mentioned salts may be used, which do not lead to damage of cells due to osmosis or other concentration effects. Reference media are, for example, liquids occurring in “in vivo” methods, such as blood, lymph, cytosolic liquids, or other body liquids, or e.g., liquids, which may be used as reference media in “in vitro” methods, such as common buffers or liquids. Such common buffers or liquids are known to those skilled in the art.

[0075] In some embodiments, the pharmaceutically acceptable carriers include, but are not limited to, those commonly used in the art, such as lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0076] In some embodiments, the pharmaceutical composition may comprise diluents or excipients such as a filler, a bulking agent, a binder, a wetting agent, a disintegrating agent, or a surfactant, and other pharmaceutically acceptable additives.

[0077] In some embodiments, the pharmaceutical composition can be prepared in the form of a liquid, suspension, powder, granule, tablet, capsule, pill, or extract.

[0078] In some embodiments, the pharmaceutical composition can be administered orally or parenterally (e.g., by application or intravenous, subcutaneous, or intraperitoneal injection).

[0079] As used herein, the term “oral administration” refers to a method of administering a drug through the mouth for the alleviation of pathological symptoms, the term “parenteral administration” refers to a method of administering a drug subcutaneously, intramuscularly, intravenously, or intraperitoneally, excluding oral administration.

[0080] Solid preparations for oral administration include powders, granules, tablets, capsules, soft capsules, and pills. Liquid preparations for oral administration include suspensions, internal use solutions, emulsions, syrups, and aerosols, and may contain, in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives.

[0081] Preparations for parenteral administration may be formulated and used in the form of external preparations such as sterilized aqueous solutions, liquids, non-aqueous solutions, suspensions, emulsions, eye drops, eye ointments, syrups, suppositories, aerosols, etc., and sterile injectable preparations, according to conventional methods. Preferably, pharmaceutical compositions such as creams, gels, patches, sprays, ointments, ointments, lotions, liniments, eye ointments, eye drops, pastes, or cataplasmas may be prepared and used, without beingAttorney Docket: NRA-005WO limited thereto. Compositions for topical administration may be anhydrous or aqueous depending on the clinical prescription. As non-aqueous solvents or suspending agents, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, or injectable esters such as ethyl oleate may be used. As a suppository base, witepsol, macrogol, tween 61, cocoa butter, laurin fat, glycerogelatin, etc. may be used.

[0082] The pharmaceutically acceptable additive according to the present disclosure may be contained in the pharmaceutical composition in an amount of 0.1 to 99.9 parts by weight, specifically 0.1 to 50 parts by weight, without being limited thereto.

[0083] In some embodiments, the sodium channel blockers-related disease may be any one selected from the group consisting of acute pain, chronic pain, neuropathic pain, post-surgical pain, migraine, arthralgia, neuropathy, nerve damage, diabetic neuropathy, neuropathic disease, epilepsy, arrhythmia, myotonia, ataxia, multiple sclerosis, irritable bowel syndrome, urinary incontinence, visceral pain, depression, erythromelalgia, or paroxysmal extreme pain disorder (PEPD), without being limited thereto.

[0084] In some aspects, the present disclosure provides a pharmaceutical composition for preventing or treating a sodium channel blockers-related disease, comprising the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide in an amount of 1 mg to 100 mg as 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yljbenzenesulfonamide and is administered once to three times a day.Methods for Use

[0085] In some aspects, the present disclosure provides a method of inhibiting Nav1.7 in a subject, comprising administering the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide disclosed herein to the subject.

[0086] In some aspects, the present disclosure provides the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yljbenzenesulfonamide disclosed herein for use in inhibiting Nav1.7 in a subject.

[0087] In some aspects, the present disclosure provides use of the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yljbenzenesulfonamide disclosed herein in the manufacture of a medicament for use in inhibiting Nav1.7 in a subject.

[0088] In some aspects, the present disclosure provides a method of preventing or treating aAttorney Docket: NRA-005WO disease in a subject in need thereof, comprising administering a therapeutically effective amount of the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide disclosed herein to the subject.

[0089] In some aspects, the present disclosure provides the mesylate salt of 5-chloro-2-fluoro-4-((4-fhioro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide disclosed herein for use in preventing or treating a disease in a subject in need thereof.

[0090] In some aspects, the present disclosure provides use of the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide disclosed herein in the manufacture of a medicament for use in preventing or treating a disease in a subject in need thereof.

[0091] In some embodiments a pharmaceutical composition comprising the the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide disclosed herein is administered to the subject.

[0092] In some embodiments, the subject is human.

[0093] In some embodiments, the disease is a sodium channel blocker-related disease.

[0094] In some embodiments, the disease is a pain or a neuroendocrine disorder.

[0095] In some embodiments, the disease is a pain.

[0096] In some embodiments, the disease is a neuroendocrine disorder.

[0097] In some embodiments, the disease is acute pain, chronic pain, neuropathic pain, postoperative pain, visceral pain, nerve damage, migraine, epilepsy, depression, anthralgia, erythralgia, arrhythmia, myotonia, ataxia, neuropathy, multiple sclerosis, irritable bowel syndrome, urinary incontinence, or paroxysmal extreme pain disorder.

[0098] In some embodiments, the disease is acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy or epilepsy conditions, neurodegenerative diseases, psychiatric disorders such as anxiety and depression, bipolar disorder, muscular rigidity, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritic pain, postherpetic neuralgia, diabetic neuropathy, radiculalgia, sciatica, back pain, headache, neck pain, severe or intractable pain, nociceptive pain, penetrating pain, postoperative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress- or exercise-induced angina, heart palpitation, hypertension, migraine, or abnormal gastrointestinal activity.Attorney Docket: NRA-005WO

[0099] In some embodiments, the disease is radiculalgia, sciatica, back pain, headache, neck pain, intractable pain, acute pain, postoperative pain, back pain, tinnitus, or cancer pain.

[0100] As used herein, the term “therapeutically effective amount” refers to an amount of the active ingredient or the composition (which is sought by researchers, veterinarians, physicians, or other clinicians) that induces a biological or medical response in a tissue system, an animal or a human, including an amount that induces alleviation of symptoms of the disease or disorder which is being treated. It is obvious to those skilled in the art that the therapeutically effective dosage and frequency of administration of the active ingredient disclosed herein will vary depending on the desired effect. Therefore, the optimal dosage to be administered may be readily determined by those skilled in the art, and may be adjusted depending on various factors including the type of disease, the severity of the disease, the contents of the active ingredient and other ingredients in the composition, the type of formulation, and the patient's age, weight, general health, sex, and diet, the time of administration, the route of administration, and the excretion rate of the composition, the treatment period, and concurrently used drugs.

[0101] Specifically, the therapeutically effective amount is the amount of the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide according to the present disclosure, which is effective for the prevention or treatment of a sodium channel blockers-related disease. Preferably, the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2- (methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide may be administered once to three times a day in an amount of 1 mg to 100 mg as 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yljbenzenesulfonamide. However, the therapeutically effective amount may be interpreted to encompass all doses at which the symptoms of a sodium channel blockers-related disease are alleviated or completely cured by the pharmaceutical composition.

[0102] The method for prevention or treatment according to the present disclosure includes treating the disease itself before the onset of symptoms thereof, and inhibiting or avoiding the symptoms by administering the pharmaceutical composition.

[0103] In some embodiments, the method further comprises administering a therapeutically effective amount of an additional active agent helpful in treating the disease together with the pharmaceutical composition, wherein the additional active agent may exhibit a synergistic or additive effect together with the pharmaceutical composition.

[0104] The matters mentioned with respect to the pharmaceutical composition, treatment method and use of the present disclosure are applied equally unless they are mutuallyAttorney Docket: NRA-005WO contradictory.Definitions

[0105] Unless otherwise defined, all terms, comprising technical and scientific terms used herein, have the same meaning as generally understood by one of ordinary skill in the art to which the present disclosure pertains. Terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and are not interpreted in an idealized or overly formal sense unless clearly so defined in the present disclosure.

[0106] Numerical ranges are inclusive of the values defined therein. Every maximum numerical limitation given throughout the present specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written. Every minimum numerical limitation given throughout the present specification includes every higher numerical limitation, as if such higher numerical limitations were expressly written. Every numerical limitation given throughout the present specification will include every better numerical range within the broader numerical range, as if the narrower numerical limitations were expressly written.

[0107] Hereinafter, each description and embodiment disclosed in the present disclosure may also be applied to other descriptions and embodiments for each. In other words, all combinations of various elements disclosed in the present disclosure fall within the scope of the present disclosure. In addition, the scope of the present disclosure may not be considered as being limited by the specific description described below.

[0108] Expressions such as "comprising" as used herein should be understood as open-ended terms implying the possibility of including other embodiments.

[0109] As used herein, the term “about” refers to a range covering any normal fluctuations appreciated by one of ordinary skill in the relevant art. In some embodiments, the term “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0110] As used herein, the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl.Attorney Docket: NRA-005WO In some embodiments, the subject is a human.

[0111] As used herein, the term “subject in need thereof’ refers to a subject having a disease or having an increased risk of developing the disease. A subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy.

[0112] As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model. It is to be appreciated that references to “treating” or “treatment” include the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0113] As used herein, the term “preventing” or “prevent” means delaying onset of a disease, disorder, or condition. When onset of a disease, disorder, or condition has been delayed for a predefined period of time, prevention may be considered complete.

[0114] As used herein, the term “subject in need of treatment” means mammals such asAttorney Docket: NRA-005WO monkeys, cows, horses, dogs, cats, rabbits, rats, and mice, and includes, particularly, humans.

[0115] As used herein, the term “administration” means providing a predetermined substance to a patient by any appropriate method. In the method for treatment according to the present disclosure, the pharmaceutical composition for preventing or treating the sodium channel blockers-related disease containing the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide as an active ingredient may be administered in a conventional manner by an oral, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, transdermal, topical, intraocular, or intradermal route.

[0116] Hereinafter, the invention will be described in detail through examples, comparative examples, and experimental examples. However, the following examples, comparative examples, and experimental examples are only intended to illustrate the present disclosure, and the scope of the present disclosure is not limited thereto.EXAMPLES

[0117] It is understood that, unless specified otherwise, values presented in the examples are approximate and are subject to experimental and / or instrumental variations.Example 1. Investigation of Acid Addition Salts

[0118] Acid addition salts of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide were prepared using various acids listed in Table 1 below.Table 1No. Acid used1 Hydrobromic acid2 Glucuronic acid3 Aspartic acid4 Fumaric acid5 Mucic acid6 Methanesulfonic acidExample 2. Preparation of free base of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide

[0119] The starting material, the free base of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide, used in Examples 3 to 7 below, was prepared from 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-Attorney Docket: NRA-005WO (methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide hydrochloride following the method described in Example 92 of Korean Patent No. 10-2245930.

[0120] 30 g of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2- (methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide hydrochloride was added to 500 mL of THF, and then a solution of K2CO3(9.5 g, 1.2 eq.) in 30 mL of purified water was added thereto, followed by stirring at room temperature for 2 hours. After filtering the undissolved solid under reduced pressure, 600 mL of ethyl acetate and 300 mL of purified water were added to the filtrate and stirred. The reaction mixture was transferred to a separatory funnel, and the organic layer was fractionated. The obtained organic layer was washed five times with 600 mL of purified water. After washing, the organic layer was treated with a drying agent (MgSO4) and distilled under reduced pressure to remove the solvent. After concentration, the reaction mixture was dissolved in 200 mL of THF, and then added to 1,200 mL of n-hexane with rapid stirring to solidify. The resulting solid was filtered under reduced pressure and then washed twice with 300 mL of n-hexane. The formed solid was transferred to a 250-mL round bottom flask, shielded from light, and then vacuum-dried for 3 days to obtain 27 g of a free base of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide as a beige powder in a yield of 96.4%.Example 3. Preparation of bromide salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide

[0121] 100 mg of the free base of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide was added to 4 mL of MeOH, and hydrobromic acid (21.7 pL, 1 eq.) was added thereto with stirring. After stirring for 2 hours, MeOH was evaporated at room temperature, and 2 mL of ethyl ether was added to the residue, followed by stirring for 2 hours. Ethyl ether was evaporated at room temperature to obtain 116 mg of the bromide salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide as a white solid.

[0122] Hereinafter, for convenience, the bromide salt of '5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide is also referred to as “the bromide salt”.Attorney Docket: NRA-005WOExample 4. Preparation of glucuronate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide

[0123] 100 mg of the free base of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide was added to 5 mL of MeOH, and glucuronic acid (38.8 mg, 1 eq.) was added thereto with stirring, followed by stirring at room temperature for 2 hours. After evaporating MeOH at room temperature, 2 mL of water was added to the residue, and 1 mL of ethyl acetate was added as an antisolvent with stirring to obtain a precipitate. 139 mg of the glucuronate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide was obtained as a white solid using a powder filter.

[0124] Hereinafter, for convenience, the glucuronate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide is also referred to as “the glucuronate salt”.Example 5. Preparation of aspartate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide

[0125] 100 mg of the free base of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide was added to 4 mL of MeOH, and aspartic acid (26.6 mg, 1 eq.) and 0.5 mL of water were added thereto with stirring, followed by stirring at room temperature for 2 hours. After evaporating the solvent, 2 mL of ethyl acetate was added to the residue, followed by stirring for 2 hours. The solvent was evaporated at room temperature to obtain 127 mg of the aspartate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide as a white solid.

[0126] Hereinafter, for convenience, the aspartate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide is also referred to as “the aspartate salt”.Example 6. Preparation of fumarate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide

[0127] 93.3 mg of the free base of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide was added to 3 mL of MeOH, and fumaric acid (22.2 mg, 1 eq.) was added thereto with stirring, followed by stirring at room temperature for 2 hours. After evaporating MeOH using an evaporator, 3Attorney Docket: NRA-005WO mL of diethyl ether was added to the residue, followed by stirring for 3 hours. After evaporating the solvent at room temperature, 115 mg of the fumarate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide was obtained as a white solid.

[0128] Hereinafter, for convenience, the fumarate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide is also referred to as “the fumarate salt”.Example 7. Preparation of mucate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide

[0129] 140.3 mg of the free base of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide was added to 4 mL of MeOH, and mucic acid (60.42 mg, 1 eq.) was added thereto with stirring, and 100 pL of water was added thereto. After stirring for 1 hour at about 60°C using a hot plate and further stirring for 15 hours at room temperature, 200 mg of a mucate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide was obtained as a white solid using a powder filter.

[0130] Hereinafter, for convenience, the mucate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide is also referred to as “the mucate salt”.Example 8. Preparation of mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide

[0131] The free base of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide (compound (2) in Reaction Scheme 1 below, 10 g, 20.5 mmol) and EtOAc (EA, 200 mL, 20 (volume / weight) times the amount of compound (2)) were added and stirred. Methanesulfonic acid (compound (5) in Reaction Scheme 1 below, 1.3 mL, 20.5 mmol) was added thereto, the flask was closed using a yellow cap, and then the mixture was stirred at 50°C for 2 hours until a clear solution was obtained. Next, the mixture was further stirred at room temperature for 24 hours. The reaction mixture was filtered under reduced pressure using a membrane filter (Durapore® 0.45 pm, PVDF, hydrophobic). The solid was washed with EtOAc (250 mL) and dried under vacuum for 24 hours to obtain the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamideAttorney Docket: NRA-005WO (compound (6) in Reaction Scheme 1 below) as a beige powder (11 g, yield: 92.8%).

[0132] FIG. 1 shows1H-NMR data indicating the structure of the mesylate salt of 5-chloro- 2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide according to the present disclosure.EA50 °C (2hr) to RT (24hr)H[Reaction Scheme 1]

[0133] Hereinafter, for convenience, the mesylate salt of '5-chloro-2-fluoro-4-((4-fluoro-2- (methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide is also referred to as “the mesylate salt”.Example 9. Hygroscopicity Test

[0134] Test Method

[0135] A hygroscopicity test for the acid addition salts of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide prepared according to Examples 3 to 7 was conducted using a dynamic vapor sorption (DVS) analyzer according to the European Pharmacopoeia Technical Guidelines, and the results are shown in Table 2 below.

[0136] The evaluation criteria in the guidelines are as follows: “Slightly absorbs moisture” means that the mass of the material increases by 0.2% to 2.0%, and “significantly absorbs moisture” means that the mass of the material increases by 2% to 15%.

[0137] The hygroscopicity test method is as follows. 30 to 40 mg of each of the acid addition salts of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2- (methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide prepared according to Examples 3 to 7 was placed in a 10-mL beaker which was then placed in a roomtemperature desiccator whose relative humidity had been adjusted in advance. After one day, the weight change was measured, and the sample was transferred to another desiccator and the previous experiment was repeated. The desiccator was kept at 23 °C with oversaturated solutions of LiCl2(11% RH), MgCl2(33% RH), Mg(NO3)26H2O (54% RH), NaCl (75% RH), and KNO3(93% RH) to adjust the humidity. For sorption analysis, the weight change was measured while transferring the sample from a desiccator with low humidity to a desiccatorAttorney Docket: NRA-005WO with high humidity, and for desorption analysis, the weight change was measured while transferring the sample from a desiccator with high humidity to a desiccator with low humidity.

[0138] Test Results

[0139] Referring to Table 2 below, it was confirmed that the mucate salt had very low hygroscopicity with a weight increase of about 2% at 93% RH. However, as a result of the hygroscopicity test for the glucuronate salt, aspartate salt, bromide salt, and fumarate salt, it could be confirmed that they all showed very high hygroscopicity with a weight increase of 20% or more at 93% RH, suggesting that they are unstable for use as candidates. Specifically, the bromide salt showed very high hygroscopicity with a weight increase of 22% even at 75% RH, while the aspartate salt and the glucuronate salt showed weight increases of 14% and 6%, respectively, at 75% RH. In addition, it was confirmed that the fumarate salt absorbed about 4% of moisture at 93% RH, and when the relative humidity dropped to 11% RH in the desorption curve, the weight dropped to 98% and at the same time, the powder changed to brown. The weight reduction on the desorption curve and the powder color change suggest that the powder may have been decomposed when the humidity was high, and the results of the moisture stress test for stability confirmed that the stability against humidity was low.Table 2LOD %RH %glucuronate aspartate bromide fumarate mucate 11% 100 100 100 100 100 33% 101.2 102 108 100.8 100.5 sorption 54% 102.8 106.5 116 101.3 101.675% 106.2 113.7 121.8 101.5 101.6 93% 121.5 155.3 174.1 104.1 101.6 75% 106.2 113.7 121.8 100.3 101.6 54% 102.8 107.8 117.6 98.7 100.9 desorption33% 101.2 103.4 109.1 98.5 100.511% 99.6 99.7 100 98 100Example 10. Stress Test for Stability (Content Stability under Stress Conditions)

[0140] Test Method

[0141] A stress stability test for the acid addition salts of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide prepared according to Examples 3 to 7 was conducted in the following manner, and the results are shown in Table 4 below (in Table 4, the generation of 2% or more related substances is marked in gray shading).

[0142] For the temperature stress test for stability, 20 mg of each of the acid addition salts ofAttorney Docket: NRA-005WO 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl) benzenesulfonamide prepared according to Examples 3 to 7 were placed in a 10 mL-vial which was then closed with a lid and stored in a chamber at 60°C. For the humidity stress test for stability, 20 mg of each of the acid addition salts was placed in a 10-mL beaker which was then stored in a 93% RH desiccator without closing the lid. After 2, 4, and 8 weeks, the area% was measured using HPLC (Azura, KNAUER, P6.1 IL, DAD 6. IL). The HPLC analysis conditions are as follows. At this time, the instrument operating conditions are as follows, and the stress stability test was conducted in an environment with 60°C or 93% RH.

[0143] instrument operating conditions>

[0144] Column: Capcell Pak MG Cl 8 (4.6 mm x 250 mm, 5 pm)

[0145] Mobile phase: A= 0.1 % TFA in water / B= acetonitrile

[0146] Flow rate: l. O ml / min.

[0147] Column temp.: 25 °C

[0148] Detector: UV 254 nm

[0149] Injection volume: 10 pL

[0150] Gradient:Table 3Time %A %B0 65 3510 65 3520 55 4525 55 4530 30 7035 30 7038 65 3545 65 35

[0151] Test Results

[0152] Referring to Table 4, it could be confirmed through the temperature and humidity stress tests for stability that, in the case of the glucuronate salt, aspartate salt, bromide salt, fumarate salt, and mucate salt, the glucuronate salt, bromide salt, fumarate salt, and mucate salt were not stable under temperature and humidity stress conditions, and the aspartate salt was not stable under temperature stress conditions.Table 4HPLC area %condition time glucuronate aspartate bromide fumarate mucate(week) (%) (%) (%) (%) (%)Attorney Docket: NRA-005WO0 94.6 98.8 99.4 92.4 99.6 2 91.7 96.8 97.0 81.4 94.9 60 °C4 92.0 96.5 96.7 77.2 93.4 8 87.2 95.7 94.1 75.6 93.4 0 94.6 98.8 99.4 92.4 99.6 2 92.7 98.2 97.6 92.5 94.2 93% RH4 90.1 98.0 97.4 90.2 94.18 87.8 98.0 97.6 89.8 96.6Example 11. Solubility Test

[0153] Test Method

[0154] The equilibrium solubilities of the fumarate salt, aspartate salt, and mucate salt were measured in two aqueous solutions, DW(H20) and pH 6.8 buffer, using the following method, and the results are shown in Table 5 below.

[0155] The solubility test method is as follows.

[0156] About 3 to 10 mL of each of the acid addition salts of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide prepared according to Examples 5 to 7 was added to an Eppendorf tube, and water or a pH 6.8 buffer was added thereto, followed by shaking at 150 rpm at 37°C. After 24 hours, the saturated solution was filtered using a 0.45-pm filter, and diluted two-fold using MeOH, and then the solubility was measured using HPLC (Azura, KNAUER, P6.1 IL, DAD 6. IL). The approximate final pH was measured using pH paper.

[0157] HPLC analysis conditions are as follows.

[0158] Column: Capcell pack MG Cl 8 (4.6 mm x 250 mm, 5 pm)

[0159] Mobile phase: A= 0.1 % TFA in water / B= acetonitrile

[0160] Isotropic, A: B=60:40

[0161] Flow rate: l. O ml / min.

[0162] Column temp.: 25 °C

[0163] Detector: UV 254 nm

[0164] Injection volume: 10 pL

[0165] Test Results

[0166] Referring to Table 5 below, it was confirmed that both the fumarate salt and the aspartate salt showed solubility between 0.1 and 1.0 mg / ml in water and pH 6.8 buffer, indicating that they were very slightly soluble, and that they would be disadvantageous in terms of bioavailability. It was confirmed that the mucate salt showed solubility of less than 0.1 mg / ml in water and pH 6.8 buffer, indicating that it was practically insoluble or insolubleAttorney Docket: NRA-005WO category, suggesting that it has very low bioavailability.Table 5Solvent Fumarate Aspartate Mucate H2O Solubility 0.6 0.17 0.046(mg / ml)Final pH About pH 4.3 6.8 4.7 pH 6.8 Solubility 0.22 0.1 0.065(mg / ml)Final pH About pH 6.5 6.8 6.8Example 12. Summary of Results for Examples 3 to 5

[0167] The bromide salt and the glucuronate salts were highly hygroscopic (moisture absorption of 22% or more at 93% RH), and thus had poor moisture stability, and showed a tendency for related substances to increase by 5% or more in the results of the stability tests under stress conditions.

[0168] In addition, the fumarate salt absorbed 4% moisture under 93% RH conditions, but as changes in the appearance thereof were observed, stability issues due to moisture exposure were raised, and thus the fumarate was excluded from the candidate group.

[0169] In addition, the aspartate salt was excluded due to its high hygroscopicity (moisture absorption of 22% or more at 93% RH) and low solubility of 0.1 to 1.0 mg / mL compared to the other salt candidates.

[0170] In addition, the mucate salt was observed to have a very low solubility of 0.1 mg / mL or less under pH 6.8 conditions, and showed no significant improvement in the bioavailability, hygroscopicity, and stability tests of the drug.

[0171] Based on these results, further evaluation was conducted on the mesylate salt according to the present disclosure, which is an additional salt candidate.Example 13. Solubility test for the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide according to the present disclosure

[0172] Test Method

[0173] The solubility of the mesylate salt according to the present disclosure was measured in a total of five aqueous solutions, including DW, FaSSIF (pH 6.5), FaSSIF-V2, FeSSIF (pH 5), and FeSSIF-V2 (pH 5.8), using the following method, and the results are shown in Table 7 below.

[0174] The solubility test method is as follows.Attorney Docket: NRA-005WO

[0175] 15 mg of the mesylate salt was weighed into a glass vial, and 3 mL of each of FaSSIF, FeSSIF, FaSSIF-V2, FeSSIF-V2, and DW was added thereto to reach a final concentration of 5 mg / mL. After stirring at 300 rpm at 37°C for 24 hours, 1 mL of each solution was collected, placed in a 1.5-mL centrifuge tube, and centrifuged at 12,000 rpm for 5 minutes. The pH of the filtrate was measured, and the supernatant was analyzed by HPLC.

[0176] HPLC analysis conditions are as follows.Table 6Content InformationColumn X-bridge Shield RP18(4.6mm*150, 3.5 pm)B: 0.1% TFA in H2OMobile phaseC: ACNTime (min) B (%) C (%)0 95 5 Gradient 10 5 9510.1 95 515 95 5 Column temp. 30 °CFlow rate 1 ml / minInjection volume 5 pLWavelength 254 nmDilution MeOH / H2O (v:v. 1:1)

[0177] Test Results

[0178] Referring to Table 7 below, the mesylate salt according to the present disclosure showed solubilities of 17.79 mg / ml and 0.61 mg / ml in water (pH 7) and FaSSIF (pH 6.5), respectively, showing the best solubility compared to those at the other pHs (marked in shading in Table 7). The mesylate salt showed solubilities of 0.30 mg / ml, 0.14 mg / ml, and 0.36 mg / ml in FeSSIF (pH 5), FaSSIF-V2 (pH 6.5), and FeSSIF-V2 (pH 5.8), respectively.Table 7pH 24 h solubility (mg / mL)7 Water 17.96.5 FaSSiF 0.615 FeSSiF 0.306.5 FaSSiF- V2 0.145.8 FeSSiF- V2 0.36Example 14. Long-term and accelerated stability tests for the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide according to the present disclosure (content stability under longterm and accelerated conditions)Attorney Docket: NRA-005WO

[0179] Test Method

[0180] Long-term and accelerated stability tests for the mesylate salt according to the present disclosure were conducted in the following manner, and the results are shown in Table 8 below.

[0181] At this time, the instrument operating conditions are as follows, and the long-term stability test was conducted in an environment with 60% humidity at 25°C for 6 weeks, and the accelerated stability test was conducted in an environment with 75% humidity at 40 °C.

[0182] Test Results

[0183] Referring to Table 8 below, it could be confirmed that the mesylate salt according to the present disclosure did not show a significant increase in the content of related substances in the long-term and accelerated tests up to 6 weeks.Table 8Mesylate salt initial 2 weeks 4 weeks 6 weeks long-term(25 °C / 60%), vial 0.24 0.25 0.37 0.34 closedphenomenon white powder white powder white powder white powder accelerated(40 °C / 75%), 0.24 0.24 0.30 0.27 vial closedphenomenon white powder white powder white powder white powderExample 15. Hygroscopicity test for the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide according to the present disclosure

[0184] Test Method

[0185] The hygroscopicity test for the mesylate salt according to the present disclosure was conducted using a dynamic vapor sorption (DVS) analyzer according to the European Pharmacopoeia Technical Guidelines.

[0186] The evaluation criteria in the guidelines are as follows: “Slightly absorbs moisture” means that the mass of the material increases by 0.2 to 2.0%, and “significantly absorbs moisture” means that the mass of the material increases by 2 to 15%.

[0187] The hygroscopicity test method is as follows in Table 9. Using a moisture absorption analyzer (Surface Measurement System, DVS intrinsic), 10 mg of the mesylate salt according to the present disclosure was evaluated according to the following parameters under a cycle of changing from 0% RH to 95% RH and back to 0% RH at 25 °C.Attorney Docket: NRA-005WO Table 9Setting ParametersTemperature 25 °CEquilibrium dm / dt: 0.01% / min RH (%) measurement step scope 0%~95%~0% RHRH (%) measurement step 5% RHSamples 10 mg

[0188] Test Results

[0189] Referring to Table 10 below and FIGS. 2A and 2B, the test results show that the mesylate salt according to the present disclosure had a moisture absorption of 2.174% from 0% RH to 80% RH. Referring to the contents of the European Pharmacopoeia Technical Guidelines, it was confirmed that the mesylate salt according to the present disclosure had a slight hygroscopicity, but there was no significant change in its appearance, suggesting that the mesylate salt does not have a substantial effect on the stability and quality of the product.Table 10Target Change in Mass (%) - refRH(%) Sorption Desorption Hysteresis 0.0 0.000 -0.0815.0 0.047 -0.023 -0.070 10.0 0.124 0.035 -0.089 15.0 0.195 0.113 -0.082 20.0 0.257 0.211 -0.046 25.0 0.324 0.322 -0.002 30.0 0.421 0.452 0.030 35.0 0.522 0.599 0.077 40.0 0.632 0.756 0.124 45.0 0.747 0.921 0.174 50.0 0.917 1.088 0.171 55.0 1.065 1.260 0.194 60.0 1.195 1.452 0.257 65.0 1.321 1.658 0.337 70.0 1.508 1.894 0.385 75.0 1.782 2.182 0.399 80.0 2.174 2.539 0.365 85.0 2.793 3.062 0.268 90.0 3.755 3.972 0.21795.0 5.598 5.598

[0190] As a result of comparing a total of the six acid addition salts of 5-chloro-2-fluoro-4-Attorney Docket: NRA-005WO ((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide acid evaluated, it was confirmed that the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide according to the present disclosure had relatively excellent nonhygroscopicity and improved stability and solubility. Based on these results, it can be considered that the mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide is an optimal candidate.EQUIVALENTS

[0191] Although the invention has been described in detail with reference to the specific features, it will be apparent to those skilled in the art that this description is only of a preferred embodiment thereof, and does not limit the scope of the present invention. Thus, the substantial scope of the present invention will be defined by the appended claims and equivalents thereto.

Claims

Attorney Docket: NRA-005WO CLAIMS:

1. A mesylate salt of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide represented by Chemical Formula 2 below:O OH3C OH[Chemical Formula 2]2. The mesylate salt of claim 1, wherein the mesylate salt exhibits a solubility of about 10 mg / mL or higher, about 11 mg / mL or higher, about 12 mg / mL or higher, about 13 mg / mL or higher, about 14 mg / mL or higher, about 15 mg / mL or higher, about 16 mg / mL or higher, about 17 mg / mL or higher, about 18 mg / mL or higher, about 19 mg / mL or higher, or about 20 mg / mL or higher in water at a pH value of about 7.0.

3. The mesylate salt of claim 1, wherein the mesylate salt exhibits a solubility of about 17.9±5.0 mg / mL, about 17.9±4.0 mg / mL, about 17.9±3.0 mg / mL, about 17.9±2.0 mg / mL, about 17.9±1.5 mg / mL, about 17.9±1.0 mg / mL, about 17.9±0.5 mg / mL, about 17.9±0.4 mg / mL, about 17.9±0.3 mg / mL, about 17.9±0.2 mg / mL, or about 17.9±0.1 mg / mL (e.g., about 17.9 mg / mL), in water at a pH value of about 7.0.

4. The mesylate salt of claim 1, wherein the mesylate salt exhibits an increase of impurity concentration of about 0.5% or less, about 0.4% or less, about 0.3% or less, about 0.2% or less, about 0.1% or less, about 0.05% or less, about 0.04% or less, about 0.03% or less, about 0.02% or less, or about 0.01 % or less upon storage at about 25 °C and about 60% humidity for 6 weeks.

5. The mesylate salt of claim 1, wherein the mesylate salt exhibits an increase of impurity concentration of about 0.5% or less, about 0.4% or less, about 0.3% or less, about 0.2% or less, about 0.1% or less, about 0.05% or less, about 0.04% or less, about 0.03% or less, about 0.02% or less, or about 0.01 % or less upon storage at about 40 °C and about 75% humidity for 6 weeks.Attorney Docket: NRA-005WO6. The mesylate salt of claim 1, wherein the mesylate salt exhibits a moisture absorption of about 3.0% w / w or less, about 2.5% w / w or less, about 2.0% w / w or less, about 1.5% w / w or less, about 1.4% w / w or less, about 1.3% w / w or less, about 1.2% w / w or less, about 1.1% w / w or less, or about 1.0% w / w or less, at 60% RH.

7. The mesylate salt of claim 1, wherein the mesylate salt exhibits a moisture absorption of about 5.0% w / w or less, about 4.5% w / w or less, about 4.0% w / w or less, about 3.5% w / w or less, about 3.0% w / w or less, about 2.5% w / w or less, or about 2.0% w / w or less, at 80% RH.

8. The mesylate salt of claim 1, wherein the mesylate salt exhibits a moisture absorption of about 10% w / w or less, about 9% w / w or less, about 8% w / w or less, about 7% w / w or less, about 6% w / w or less, or about 5% w / w or less, at 95% RH (e.g., as determined by DVS).

9. A method for preparing the mesylate salt of claim 1, comprising step (a) of reacting 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide with methanesulfonic acid in an organic solvent.

10. The method of claim 9, further comprising:step (b) of further stirring a solution from step (a), followed by concentration under reduced pressure to obtain a solid; andstep (c) of washing and drying the obtained solid.

11. The method of claim 9, wherein the organic solvent in step (a) is ethyl acetate or a mixed solution of ethyl acetate and water.

12. The method of claim 9, wherein the organic solvent in step (a) is added in an amount ranging from 10 times to 30 times (volume / weight) to the amount of 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide.

13. The method of claim 9, wherein the methanesulfonic acid in step (a) is added at a molar ratio ranging from 0.8 equivalents to 1.5 equivalents relative to 1.0 equivalent of a free base ofAttorney Docket: NRA-005WO 5-chloro-2-fluoro-4-((4-fluoro-2-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide.

14. The method of claim 10, wherein step (b) is a step of further stirring the solution from the step (a) under a temperature ranging from 20 °C to 25 °C for a time ranging from 20 hours to 30 hours, followed by concentration under reduced pressure to obtain a solid.

15. The method of claim 10, wherein step (c) comprises washing the obtained solid with a solvent selected from the group consisting of methanol, ethanol, acetone, isopropanol, ethyl acetate, and mixed solvents thereof.

16. The method of claim 10, wherein the drying in step (c) is performed under vacuum conditions for a time ranging from 15 hours to 35 hours.

17. A pharmaceutical composition comprising the mesylate salt of claim 1.

18. A method of inhibiting Nav1.7 in a subject, comprising administering the mesylate salt of claim 1 to the subject.

19. The mesylate salt of claim 1 for use in inhibiting Nav1.7 in a subject.

20. Use of the mesylate salt of claim 1 in the manufacture of a medicament for use in inhibiting Nav1.7 in a subject.

21. A method of preventing or treating a disease in a subject in need thereof, comprising administering a therapeutically effective amount of the mesylate salt of claim 1 to the subject.

22. The mesylate salt of claim 1 for use in preventing or treating a disease in a subject in need thereof.

23. Use of the mesylate salt of claim 1 in the manufacture of a medicament for use in preventing or treating a disease in a subject in need thereof.

24. The method, mesylate salt for use, or use of any one of claims 18-23, wherein theAttorney Docket: NRA-005WO subject is human.

25. The method, mesylate salt for use, or use of any one of claims 21-23, wherein the disease is a sodium channel blocker-related disease.

26. The method, mesylate salt for use, or use of any one of claims 21-23, wherein the disease is a pain, such as acute pain, chronic pain, neuropathic pain, post-surgical pain, migraine, arthralgia, neuropathy, nerve damage, diabetic neuropathy, neuropathic disease, epilepsy, arrhythmia, myotonia, ataxia, multiple sclerosis, irritable bowel syndrome, urinary incontinence, visceral pain, depression, erythromelalgia, or paroxysmal extreme pain disorder (PEPD).

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