Salts of N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-fluorophenyl]-2,5-difluorobenzenesulfonamide and their crystalline forms

Abstract

A compound of formula (II) is provided: (II) A crystalline form of the compound of formula (II) is provided. The compound of formula (II) and its crystalline form can be used to treat several conditions associated with the inhibition of SGK-1, such as cardiovascular diseases selected from the group consisting of long QT syndrome, heart failure, arrhythmias such as atrial fibrillation, ischemic injury, ischemic infarction, cardiac fibrosis, vascular proliferation, restenosis, dilated cardiomyopathy, and stent failure, cancer, epilepsy, Parkinson's disease, and Lafora's disease. [Formula 1] JPEG2025525475000063.jpg47170

Description

[Technical Field]

[0001] The technical field relates to salts of the compound N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-fluorophenyl]-2,5-difluorobenzenesulfonamide and their crystalline forms, as well as pharmaceutical compositions, therapeutic uses thereof, and processes for manufacturing. [Background technology]

[0002] Long QT syndrome (LQTS) is an abnormality in the heart's electrical system that affects the heart's repolarization after a heartbeat. LQTS increases the risk of arrhythmias, which can result in fainting, drowning, or even sudden death. Several genetic causes of LQTS have been identified, with the majority of mutations found in genes encoding three major cardiac ion channels (KCNQ1, KCNH2, and SCN5a).

[0003] There are several existing treatment options for LQTS, including the use of beta-blockers, which slow the heart rate by reducing the effect of adrenaline on the heart, surgery on the nerves that regulate the heartbeat, and / or the use of implantable cardioverter-defibrillators. However, none of the existing treatment options address the underlying mechanistic problem.

[0004] Serine / threonine-protein kinase 1 (SGK-1), also known as serum / glucocorticoid-regulated kinase 1, is a protein kinase that plays a role in the cellular response to stress. SGK-1 activates specific potassium, sodium, and chloride channels. For example, SGK-1 is known to regulate the myo-inositol transporter during osmotic stress. Several challenges remain in the development of SGK-1 inhibitors for the treatment of cardiac disorders such as LQTS. Summary of the Invention

[0005] Compounds of formula (I) and formula (II) are provided.

[0006] [ka]

[0007] Crystalline forms of the compounds of formula (I) and formula (II) are also provided. The compounds of formula (I) and formula (II) and their crystalline forms can be used to treat several conditions associated with the inhibition of SGK-1, such as cardiovascular diseases selected from the group consisting of long QT syndrome, heart failure, arrhythmias such as atrial fibrillation, ischemic injury, ischemic infarction, cardiac fibrosis, vascular proliferation, restenosis, dilated cardiomyopathy, and stent failure, cancer, epilepsy, Parkinson's disease, and Lafora's disease. [Brief explanation of the drawings]

[0008] [Figure 1] 1 is an XRPD overlay of Compound 1 (a mixture of Substance A and Form B) and Compound 1 Form B. [Figure 2] 1 is an expanded XRPD of Compound 1 with accepted peak positions from an indexing solution of Form B (Compound 1). [Figure 3] 1H NMR spectrum of compound 1 in DMSO-d6. [Figure 4] 1H NMR spectrum of compound 2 in DMSO-d6. [Figure 5a] 1 is an XRPD overlay of Compound 2 (monoformate salt, anhydrous—Form A) and Compound 1. [Figure 5b] FIG. 1 is an XRPD pattern of Compound 2 (monoformate salt, anhydrous—Form A). [Figure 6] Indexing solution of Compound 2 (monoformate salt, anhydrous—Form A). [Figure 7] 1 is a TGA and DSC thermogram of Compound 2 (monoformate salt, anhydrous—Form A). [Figure 8] 1 is an XRPD pattern of Compound 3, monohydrochloride salt, unsolvated form A. [Figure 9]Indexing solution of Compound 3, monohydrochloride salt, unsolvated-form A. [Figure 10] 1 is a 1H NMR spectral overlay of Compound 1 and Compound 3 (monohydrochloride unsolvated, Form A) in DMSO-d6. [Figure 11] 1 is a TGA and DSC thermogram of Compound 3 (monohydrochloride salt unsolvated, Form A). [Figure 12] 1 is an XRPD overlay of Compound 4 (dimesylate salt, unsolvated—Form A), Compound 1, and Compound 1 Form C. [Figure 13] FIG. 1 is an XRPD pattern of Compound 4 (dimesylate salt, unsolvated—Form A). [Figure 14] Indexing solution of Compound 4 (dimesylate salt, unsolvated - Form A). [Figure 15] 1H NMR spectrum of compound 4 in DMSO-d6 (dimesylate salt, unsolvated—Form A). [Figure 16] 1 is a TGA and DSC thermogram for Compound 4 (dimesylate salt, unsolvated—Form A). [Figure 17] 1 is a DVS isotherm and results table for Compound 2 (formate salt, anhydrous—Form A). [Figure 18] FIG. 1 is an XRPD overlay of Compound 2 (formate salt, anhydrous—Form A) before and after DVS. [Figure 19] 1 is a DVS isotherm and results table for Compound 3 (hydrochloride salt, unsolvated—Form A). [Figure 20] FIG. 1 is an XRPD overlay of Compound 3 (hydrochloride salt, unsolvated—Form A) before and after DVS. [Figure 21] 1 is a DVS isotherm and results table for Compound 4 (dimesylate salt, unsolvated—Form A). [Figure 22] FIG. 1 is an XRPD overlay of Compound 4 (dimesylate salt, unsolvated—Form A) before and after DVS. [Figure 23] 1 is an XRPD pattern of Compound 1 (free form—Form D). [Figure 24]1 is a TGA and DSC thermogram for Compound 1 (free form - Form D). [Figure 25] 1 is an XRPD pattern of Compound 3 (Form B). [Figure 26] 1 is a TGA and DSC thermogram for Compound 3 (Form B). [Figure 27] 1 is an XRPD pattern of Compound 3 (Form C). [Figure 28] 1 is a TGA and DSC thermogram for Compound 3 (Form C). [Figure 29] 1 is an XRPD pattern of Compound 3 (Form D). [Figure 30] 1 is a TGA and DSC thermogram for Compound 3 (Form D). [Figure 31] FIG. 1 is an XRPD pattern of Compound 3 (Form E). [Figure 32] 1 is a TGA and DSC thermogram for Compound 3 (Form E). [Figure 33] Overlay of Compound 1 (second row from the top: Free Form E / Free Form D) and Compound 3 (third row from the bottom: Form E / Form D / Form C). [Figure 34] 1 is a DVS plot of Compound 3 (Form D). [Figure 35] 1 is a DVS mass plot of Compound 3 (Form D). [Figure 36] 1 is an XRPD overlay of Compound 3 (Form D) before (bottom) and after (top) DVS. [Figure 37] 1 is an XRPD pattern of Compound 4 (Form B). [Figure 38] 1 is a TGA and DSC thermogram for Compound 4 (Form B). [Figure 39] FIG. 1 is an XRPD pattern of Compound 4 (Form C). [Figure 40] 1 is a TGA and DSC thermogram for Compound 4 (Form C). [Figure 41] FIG. 1 is an XRPD pattern of Compound 4 (Form D). [Figure 42]1 is a TGA and DSC thermogram for Compound 4 (Form D). [Figure 43] FIG. 1 is an XRPD pattern of Compound 4 (Form E). [Figure 44] 1 is an XRPD pattern of Compound 4 (Form F). [Figure 45] 1 is a TGA and DSC thermogram for Compound 4 (Form F). [Figure 46] FIG. 1 is an XRPD pattern of Compound 4 (Form G). [Figure 47] 1 is a TGA and DSC thermogram for Compound 4 (Form G). [Figure 48] 1 is a DVS plot of Compound 4 (Form B). [Figure 49] 1 is an XRPD overlay of Compound 4 (Form B) before (bottom) and after (top) DVS. [Figure 50] 1 is a DVS plot of Compound 4 (Form D). [Figure 51] XRPD overlay of Compound 4 (Form D) before (bottom) and after (top) DVS. DETAILED DESCRIPTION OF THE INVENTION

[0009] definition The term "stable" as used herein includes chemical stability and / or solid-state stability. A compound is considered to be chemically stable when it can be stored under normal storage conditions without any significant degree of chemical degradation or decomposition, either in isolated solid form or in the form of a solid formulation, which may be provided in admixture with a pharmaceutically acceptable carrier, diluent, or adjuvant.

[0010] A compound is considered to have solid-state stability when it can be stored under normal storage conditions without any significant degree of solid-state transformation (e.g., crystallization, recrystallization, loss of crystallinity, solid-state phase transition, hydration, dehydration, deliquescence, solvation, or desolvation), either in isolated solid form or in the form of a solid formulation which it may be provided in admixture with a pharmaceutically acceptable carrier, diluent, or adjuvant.

[0011] The crystalline form of solid chemical compounds not only affects their dissolution behavior (i.e., bioavailability), but also their solid-state stability. One way to compare the solid-state stability of crystalline forms is to evaluate their relative "thermodynamic stability." To evaluate the thermodynamic stability of crystalline forms, typical techniques include, but are not limited to, slurrying, slow evaporation, slow cooling, slow antisolvent addition, or a combination of these methods. Calorimetric techniques (e.g., differential scanning calorimetry) can also be used to measure thermal events and phase transitions over a wide temperature range, and comparison between crystalline forms can provide an indication of their relative thermodynamic stability.

[0012] As used herein, the expression "pharmaceutically acceptable carrier or excipient" includes, without limitation, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier known to be acceptable for pharmaceutical use in humans or veterinary animals.

[0013] As used herein, the phrase "pharmaceutical composition" refers to a formulation of a compound and a pharmaceutically acceptable carrier or excipient.

[0014] As used herein, the term "about" generally means within an acceptable standard error of the mean as considered by one of ordinary skill in the art. For example, depending on the value or range being considered, the term "about" can mean within 10%, within 5%, or within 1% of the value or range.

[0015] As used herein, the term "hydrate" refers to a crystalline form of a molecule that further includes water molecules incorporated into the crystal lattice structure. The water molecules in a hydrate may be in an ordered and / or disordered arrangement. A hydrate may contain either a stoichiometric or non-stoichiometric amount of water molecules. For example, a hydrate having a non-stoichiometric amount of water molecules may result from the partial loss of water from a hydrate.

[0016] As used herein, the term "non-stoichiometric hydrate" refers to a hydrate that exists as a channel structure with water filled throughout the crystal lattice, thus forming both stoichiometric and non-stoichiometric phases.

[0017] As used herein, the terms "anhydrate" or "anhydrous" refer to the crystalline form of the molecule itself that does not further contain molecules of water incorporated into the crystal lattice structure.

[0018] As used herein, the term "solvate" refers to a crystalline form of a molecule that further comprises molecules of a solvent or solvents incorporated into the crystal lattice structure. The solvent molecules in a solvate may be in an ordered arrangement and / or an irregular arrangement. A solvate may contain either a stoichiometric or non-stoichiometric amount of solvent molecules. For example, a solvate having a non-stoichiometric amount of solvent molecules may result from partial loss of solvent from the solvate. The solvent may comprise various organic solvents. It should also be understood that a "solvate" may comprise a single solvent, a mixture of solvents, or a mixture of a solvent(s) and water.

[0019] As used herein to describe an X-ray diffraction pattern, the term "substantially the same" means including a pattern in which the peaks are within a standard deviation of ±0.2° 2θ, or an X-ray diffraction pattern containing at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 peaks in common with the reference pattern. Furthermore, one skilled in the art will understand that relative peak intensities will exhibit instrument-to-instrument variability, as well as variability due to crystallinity, preferred orientation, prepared sample surface, and other factors. As such, relative peak intensities should be interpreted as a qualitative measure.

[0020] The present specification provides salt screening experiments for N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-fluorophenyl]-2,5-difluorobenzenesulfonamide (Compound 1) and its crystalline forms. In particular, the present specification provides compounds of Formula I and Formula II below.

[0021] [ka]

[0022] Structures depicted for compounds of Formula I or Formula II are also meant to include all tautomeric forms of the compounds of Formula I or Formula II. Additionally, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of a hydrogen with a deuterium or tritium, or 13 C or 14 Compounds having the structure of the compounds of Formula I, except for the replacement of a carbon with a C-enriched carbon, are within the scope of this specification.

[0023] The term "substantially pure," when used in reference to a crystalline form of a compound of Formula I or Formula II, is intended to include crystalline forms having a purity of greater than about 90%. This means that the crystalline form may contain no more than about 10% of any other compounds, and particularly no more than about 10% of any other crystalline form of a compound of Formula I or Formula II. Preferably, the term "substantially pure" refers to a crystalline form having a purity of greater than about 95%. This means that the crystalline form may contain no more than about 5% of any other compounds, and particularly no more than about 5% of any other crystalline form of a compound of Formula I or Formula II. More preferably, the term "substantially pure" refers to a crystalline form having a purity of greater than about 99%. This means that the crystalline form may contain no more than about 1% of any other compounds, and particularly no more than about 1% of any other crystalline form of a compound of Formula I or Formula II.

[0024] The term "solid mixture" as used in reference to compounds herein refers to a mixture of crystalline forms. For example, a solid mixture can include at least two different crystalline forms.

[0025] XRPD data were obtained using a PANalytical X'Pert PRO MPD or a PANanalytical Empyrean X-ray powder diffractometer, using an incident beam of Cu radiation generated by an Optix long fine focus source. The radiation used was Cu Kα (λ=1.5405929 Å). It should be understood that the 2θ values listed herein depend on the form of radiation used, and one skilled in the art would understand that the XRPD of a given crystalline form will show different 2θ values when different radiation (e.g., molybdenum radiation) is used.

[0026] As used herein, the term "crystalline form" or "polymorph" refers to a crystalline structure of a compound that has the same chemical composition but a different spatial arrangement of the molecules, atoms, and / or ions that form the crystalline structure.

[0027] The compounds of the present invention can exist in solvated form, for example, hydrated form and non-solvated form. Typically, but not necessarily, the salts of the compounds of the present invention are pharmaceutically acceptable salts. The salts encompassed by the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of the present invention.

[0028] Examples of suitable pharmaceutically acceptable salts include inorganic acid addition salts such as chloride, bromide, sulfate, phosphate, and nitrate; organic acid addition salts such as acetate, galactarate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate; salts with acidic amino acids such as aspartic acid and glutamic acid; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salt; organic basic salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, and N,N'-dibenzylethylenediamine salt; and salts with basic amino acids such as lysine salt and arginine salt. The salt may optionally be a hydrate or ethanol solvate.

[0029] Salt formation experiments of compound 1 and crystalline forms

[0030] [ka] Salt formation experiments were carried out using various acids (i.e., formic acid, hydrochloric acid, phosphoric acid, L-tartaric acid, sulfuric acid, succinic acid, maleic acid, citric acid, L-lysine, and methanesulfonic acid) with compound 1 (N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-fluorophenyl]-2,5-difluorobenzenesulfonamide).

[0031] formate

[0032] [ka] The formate salt (compound 2) can be prepared by combining compound 1 with 2 molar equivalents of formic acid in MeOH at 55°C. After dissolution of the solids, the solution was cooled to room temperature and stirred for 3 days. Compound 2 was isolated from the previous slurry as a distinct crystalline material.

[0033] Compound 2 exhibits an XRPD pattern (FIGS. 5a and 5b) with characteristic peaks at 6.58 and 21.97 degrees 2θ (±0.2° 2θ). The XRPD pattern of Compound 2 may also exhibit additional characteristic peaks at 18.55 and 25.44 degrees 2θ (±0.2° 2θ). The XRPD pattern of Compound 2 may also exhibit additional characteristic peaks at 14.59 and 24.31 degrees 2θ (±0.2° 2θ). The XRPD pattern of Compound 2 may also exhibit additional characteristic peaks at 23.35 and 18.68 degrees 2θ (±0.2° 2θ). The XRPD pattern of Compound 2 may also exhibit additional characteristic peaks at 15.61 and 20.88 degrees 2θ (±0.2° 2θ).

[0034] Successful indexing of the pattern (Figure 6) indicates that the sample is composed primarily or exclusively of a single crystalline phase. The volume from the indexing solution was consistent with the anhydrous monoformate salt due to crystalline Form A of Compound 2.

[0035] By DSC, Form A exhibits a broad endotherm with an onset of 188° C. and a peak temperature of 211° C. Form A also exhibits an endotherm with an onset of 287° C. and a peak temperature at about 289° C. TGA analysis of Form A shows a weight loss of about 0.1% from 51° C. to 141° C. and a weight loss of about 8.2% from 140° C. to 228° C. (FIG. 7).

[0036] Hydrochloride

[0037] [ka]

[0038] Form A Crystalline form A is unsolvated mono-HCl.

[0039] The hydrochloride salt (Compound 3) can be prepared by combining Compound 1 with 2 molar equivalents of hydrochloric acid in MeOH at 55° C. Stirring for several days yielded a mixture of Compound 3 as a distinctive crystalline material (Form A) and few additional unidentified XRPD peaks. The solid mixture was slurried in acetone for 2 days at ambient temperature, yielding a mixture of Compound 3 as a distinctive crystalline material (Form A) and few additional unidentified XRPD peaks.

[0040] The hydrochloride salt (Compound 3) can also be prepared by combining Compound 1 with 2 molar equivalents of hydrochloric acid in MeOH at room temperature. The slurry was then stirred at 60°C, and water was added. Additional stirring at room temperature for 12 days resulted in a mixture of Compound 3 as a distinctive crystalline material (Form A) and minor additional unknown XRPD peaks. The solid mixture was then slurried in water (RT, stirring for 1 day), resulting in Form A as a single crystalline phase. Form A of Compound 3 was identified as the non-solvated monohydrochloride salt, as shown by the XRPD pattern in Figure 8.

[0041] Form A exhibits an XRPD pattern ( FIG. 8 ) with characteristic peaks at 6.81 and 14.53 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form A may also exhibit additional characteristic peaks at 25.76 and 24.59 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form A may also exhibit additional characteristic peaks at 22.45 and 19.13 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form A may also exhibit additional characteristic peaks at 23.56 and 27.34 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form A may also exhibit additional characteristic peaks at 15.12 and 20.83 degrees 2θ (±0.2° 2θ).

[0042] By DSC, Form A exhibits an endotherm with an onset of 308° C. and a peak temperature of 311° C. TGA analysis of Form A shows a weight loss of approximately 1.0% between 54° C. and 120° C. (FIG. 11).

[0043] Form B Crystalline form B is anhydrous.

[0044] Form B can be prepared by suspending Compound 1 in water (e.g., 6 volumes) to obtain a suspension, and adjusting the pH of the suspension to 20-30° C. with HCl (e.g., HCl 3N) to give 3-4; stirring the suspension at 20-30° C. for 2-4 hours, or 3-4 hours, or about 3 hours; filtering the suspension to obtain a filter cake; washing the filter cake with water (e.g., 1 volume); suspending the washed filter cake in 5% NaHCO solution (e.g., 6 volumes); stirring the suspension at 20-30° C. for 4-6 hours, or 4-5 hours, or about 4.5 hours; filtering to obtain a filter cake; washing the filter cake with water (e.g., 1 volume); suspending the washed filter cake in MeOH / water (¼, 5 volumes) at 20-30° C. for 7-8 hours, or about 7.5 hours; filtering the suspension to obtain a filter cake; washing the filter cake with water (1 volume);

[0045] Form B exhibits an XRPD pattern (Figure 25) with characteristic peaks at 6.7 and 14.6 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form B may also exhibit additional characteristic peaks at 24.0 and 19.0 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form B may also exhibit additional characteristic peaks at 28.8 and 25.7 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form B may also exhibit additional characteristic peaks at 20.8 and 20.3 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form B may also exhibit additional characteristic peaks at 15.9 and 22.3 degrees 2θ (±0.2 degrees 2θ).

[0046] By DSC, Form B exhibits two endothermic peaks observed at 49.65°C and 300.81°C, corresponding to the release of water and melting / decomposition, respectively. TGA analysis of Form B shows a weight loss of approximately 1.6% from 25°C to 118°C (Figure 26).

[0047] Form C Crystalline form C is an anhydrate.

[0048] Form C can be obtained by slurrying Compound 3, Form B, in MeOH at 50° C. for 4 days. Form C was collected by filtration and dried under vacuum at 50° C. for 3 hours. The recovery is 74.9%.

[0049] Form C exhibits an XRPD pattern (Figure 27) with characteristic peaks at 6.6 and 22.1 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form C may also exhibit additional characteristic peaks at 20.8 and 14.7 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form C may also exhibit additional characteristic peaks at 15.8 and 25.6 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form C may also exhibit additional characteristic peaks at 24.1 and 19.1 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form C may also exhibit additional characteristic peaks at 28.7 and 22.3 degrees 2θ (±0.2 degrees 2θ).

[0050] By DSC, Form C exhibits an endotherm with an onset of 308.86° C. and a peak temperature of 312.06° C. TGA analysis of Form C shows no weight loss before melting (FIG. 28).

[0051] Form D Crystalline form D is anhydrous.

[0052] Form D (compound of formula II) can be obtained from DMSO / water by reverse anti-solvent precipitation. 150 mg of compound 3 was dissolved in 2 mL of DMSO at 70° C., and the solution was then filtered at room temperature. The filtrate was added to 20 mL of water (anti-solvent), and the suspension was stirred at room temperature for 4 days. Compound 3, Form D, was collected by filtration and dried under vacuum at 50° C. for 3 hours. The recovery is 73.5%.

[0053] Form D exhibits an XRPD pattern (Figure 29) with characteristic peaks at 6.7 and 22.3 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form D may also exhibit additional characteristic peaks at 29.0 and 15.9 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form D may also exhibit additional characteristic peaks at 20.5 and 20.7 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form D may also exhibit additional characteristic peaks at 28.7 and 20.2 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form D may also exhibit additional characteristic peaks at 13.5 and 26.2 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form D may also exhibit additional characteristic peaks at 23.5 and 36.1 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form D may also exhibit additional characteristic peaks at 24.1 and 10.2 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form D may also exhibit additional characteristic peaks at 25.6 and 19.0 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form D may also exhibit additional characteristic peaks at 27.2 and 32.3 degrees 2θ (±0.2 degrees 2θ).

[0054] By DSC, Form D exhibits four endothermic peaks observed at 49.36°C (onset 26.09°C), 279.63°C (onset 274.85°C), 306.56°C (onset 302.61°C), and 315.75°C (onset 313.93°C). The first peak (49.36°C) is due to DMSO and water. The sharp peak at 306.56°C is due to melting, and the peak at 315.75°C is due to decomposition. TGA analysis of Form D shows a weight loss of approximately 1.1% from 25°C to 90°C (Figure 30).

[0055] Form E Crystalline form E is a mono-DMA solvate.

[0056] Form E can be obtained from NMP / MTBE, DMA / MTBE, DMA / EA, DMA / IPAC, or DMA / MIBK by anti-solvent precipitation, and from DMA / MTBE, DMA / EA, or DMA / MIBK by reverse anti-solvent precipitation.

[0057] 150 mg of Compound 3, Form B, was dissolved in 7 mL of DMA at 70° C., and then the solution was filtered at room temperature. 49 mL of MTBE (anti-solvent) was added to the filtrate over 10 hours. The suspension was stirred at room temperature for 4 days. Compound 3, Form E, was collected by filtration and dried under vacuum at 50° C. for 3 hours. The recovery is 96.4%.

[0058] Form E exhibits an XRPD pattern (Figure 31) with characteristic peaks at 6.6 and 18.0 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form E may also exhibit additional characteristic peaks at 11.8 and 12.2 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form E may also exhibit additional characteristic peaks at 16.5 and 18.7 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form E may also exhibit additional characteristic peaks at 12.7 and 21.4 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form E may also exhibit additional characteristic peaks at 10.8 and 16.0 degrees 2θ (±0.2 degrees 2θ).

[0059] By DSC, Form E exhibits two endothermic peaks observed at 73.09° C. (onset 26.59° C.) and 129.98° C. (onset 128.21° C.). TGA analysis of Form E shows a weight loss of approximately 3.6% and 12.5% from 25° C. to 110° C. and from 110° C. to 160° C. (FIG. 32).

[0060] From the XRPD diffractograms of Compound 3, Forms A, B, and C, it appears that Forms A, B, and C are made up in part of crystalline Form D and also contain other unidentified crystalline materials / forms. From the examples shown below, Form D appears to be the most stable anhydrous crystalline form of Compound 3 identified.

[0061] Mesylate

[0062] [ka] The mesylate salt (compound 4 or compound of formula I) can be prepared by combining compound 1 with 2 molar equivalents of methanesulfonic acid in MeOH at room temperature. Partial slow evaporation followed by stirring at room temperature for several days afforded compound 4 as a distinct crystalline material.

[0063] Form A Crystalline form A is anhydrous.

[0064] Form A can be prepared by following the procedure reported in Example 6. Form A has an XRPD pattern substantially identical to that shown in Figures 12 and 13, and indexing of the pattern (Figure 14) indicated the formation of a non-solvated dimesylate salt, identified as crystalline Form A of Compound 4.

[0065] Form A exhibits an XRPD pattern (Figures 12 and 13) with characteristic peaks at 17.76 and 23.38 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form A may also exhibit additional characteristic peaks at 22.80 and 12.29 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form A may also exhibit additional characteristic peaks at 8.26 and 13.75 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form A may also exhibit additional characteristic peaks at 23.16 and 21.63 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form A may also exhibit additional characteristic peaks at 17.07 and 18.44 degrees 2θ (±0.2 degrees 2θ).

[0066] Form A can be subjected to drying in a vacuum oven at 62-72°C for 1 day and retain its crystalline form (Figure 22: XPRD pattern before DVS), thus demonstrating its physical stability under such conditions.

[0067] By DSC, Form A exhibits a broad endotherm with an onset of 164° C. and a peak temperature of 80° C. Form A also exhibits two endotherms with peak temperatures at approximately 175° C. and 189° C. TGA analysis of Form A shows a weight loss of approximately 0.8% between 53° C. and 129° C. (FIG. 16).

[0068] Form B Crystalline form B is a non-stoichiometric hydrate of the dimesylate salt (3.5 equivalents, 90% RH).

[0069] Form B can be obtained from a variety of conditions, including slurrying, slow cooling, and anti-solvent precipitation, and is summarized in Example 7.

[0070] Form B exhibits an XRPD pattern (Figure 37) with characteristic peaks at 22.8 and 6.8 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form B may also exhibit additional characteristic peaks at 26.1 and 23.7 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form B may also exhibit additional characteristic peaks at 15.9 and 18.5 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form B may also exhibit additional characteristic peaks at 17.4 and 22.4 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form B may also exhibit additional characteristic peaks at 31.7 and 27.8 degrees 2θ (±0.2 degrees 2θ).

[0071] DSC shows that Form B exhibits one broad endothermic peak due to dehydration at 73.78°C (onset 26.12°C) and one melting peak at 220.35°C (onset 218.10°C). TGA analysis of Form B shows a weight loss of approximately 5.39% from 25°C to 120°C (Figure 38).

[0072] Form C Crystalline form C is a metastable form of the dimesylate salt, THF solvate (0.5 equivalents).

[0073] Form C can be obtained from slurrying Compound 4, Form B, in THF at room temperature and 50° C. for 3 days.

[0074] Form C exhibits an XRPD pattern (Figure 39) with characteristic peaks at 15.2 and 16.0 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form C may also exhibit additional characteristic peaks at 17.6 and 23.0 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form C may also exhibit additional characteristic peaks at 20.5 and 23.3 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form C may also exhibit additional characteristic peaks at 23.9 and 19.3 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form C may also exhibit additional characteristic peaks at 22.1 and 6.9 degrees 2θ (±0.2 degrees 2θ).

[0075] By DSC, Form C exhibits three endothermic peaks at 61.29°C (onset 30.46°C), 151.56°C (onset 140.02°C), and 218.34°C (onset 215.73°C). These three peaks may correspond to the elimination of free water, desolvation, and melting. TGA analysis of Form C shows a weight loss of approximately 0.8% and 3.5% between 30°C and 95°C and between 95°C and 165°C (Figure 40).

[0076] Form D Crystalline form D is the dimesylate monohydrate.

[0077] Form D can be obtained by a variety of methods, including slurrying, anti-solvent precipitation, and reverse anti-solvent precipitation, summarized in Example 7.

[0078] Form D exhibits an XRPD pattern (Figure 41) with characteristic peaks at 17.6 and 23.2 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form D may also exhibit additional characteristic peaks at 22.0 and 8.2 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form D may also exhibit additional characteristic peaks at 9.8 and 25.9 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form D may also exhibit additional characteristic peaks at 17.1 and 24.1 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form D may also exhibit additional characteristic peaks at 25.2 and 15.0 degrees 2θ (±0.2 degrees 2θ).

[0079] By DSC, Form D exhibits three endothermic peaks at 139.82°C (onset 120.26°C), 174.07°C (onset 165.28°C), and 218.80°C (onset 214.73°C), and one exothermic peak at 196.82°C (onset 179.91°C). The first endothermic peak at 140°C corresponded to dehydration. The second endothermic peak at 174°C corresponded to melting. The subsequent exothermic peak was attributed to the transformation from Form D to Form F. When the sample was heated to high temperatures, Form F melted at 219°C. TGA analysis of Form D shows a weight loss of approximately 2.4% from 90°C to 157°C (Figure 42).

[0080] Form E Crystalline form E is the dimesylate unstable form.

[0081] Form E was obtained by cooling crystallization in NMP.

[0082] Form E exhibits an XRPD pattern (Figure 43) with characteristic peaks at 14.9 and 7.3 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form E may also exhibit additional characteristic peaks at 19.3 and 13.1 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form E may also exhibit additional characteristic peaks at 10.2 and 8.7 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form E may also exhibit additional characteristic peaks at 22.1 and 18.0 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form E may also exhibit additional characteristic peaks at 23.0 and 23.8 degrees 2θ (±0.2 degrees 2θ).

[0083] Form F Crystalline form F is a non-stoichiometric hydrate of the dimesylate salt (1.5 equivalents at 30-50% RH).

[0084] Form F was obtained by heating Form D to 210°C.

[0085] Form F exhibits an XRPD pattern (Figure 44) with characteristic peaks at 23.4 and 12.1 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form F may also exhibit additional characteristic peaks at 24.6 and 20.0 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form F may also exhibit additional characteristic peaks at 7.9 and 24.9 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form F may also exhibit additional characteristic peaks at 19.0 and 16.6 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form F may also exhibit additional characteristic peaks at 20.6 and 22.1 degrees 2θ (±0.2 degrees 2θ).

[0086] By DSC, Form F exhibits two endothermic peaks at 61.33°C (onset 27.81°C) and 217.22°C (onset 212.63°C). The first endothermic peak at 61.33°C corresponds to dehydration. The second endothermic peak at 217°C corresponds to melting. TGA analysis of Form F shows a weight loss of approximately 3.6% from 25°C to 110°C (Figure 45).

[0087] Form G Crystalline form G is the monomesylate dihydrate.

[0088] Form G was obtained by slurrying Form B in water at 50°C.

[0089] Form G exhibits an XRPD pattern (Figure 46) with characteristic peaks at 14.0 and 18.5 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form G may also exhibit additional characteristic peaks at 5.7 and 19.2 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form G may also exhibit additional characteristic peaks at 23.3 and 23.9 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form G may also exhibit additional characteristic peaks at 19.8 and 11.5 degrees 2θ (±0.2 degrees 2θ). The XRPD pattern of Form G may also exhibit additional characteristic peaks at 21.7 and 15.7 degrees 2θ (±0.2 degrees 2θ).

[0090] By DSC, Form G exhibits four endothermic peaks at 96.51°C (onset 66.74°C), 163.76°C (onset 151.93°C), 238.96°C (onset 233.03°C), and 265.96°C (onset 263.15°C), and two exothermic peaks at 181.23°C (onset 172.55°C) and 241.97°C (onset 240.18°C). TGA analysis of Form G shows a weight loss of approximately 6.4% from 25°C to 100°C (Figure 47).

[0091] Other salts Salt screening experiments also included attempts to synthesize the following salts of Compound 1: phosphate, L-tartrate, sulfonate, succinate, maleate, citrate, and L-lysine.

[0092] Formulations, Methods, and Uses As used herein, the term "effective amount" or "effective dose" refers to an amount of a drug or agent that elicits the biological or medical response of a tissue, system, animal, or human that is being sought, for example, by a researcher or clinician. Furthermore, the term "effective amount" or "effective dose" refers to any amount that results in improved treatment, cure, prevention, or amelioration of a disease, disorder, or side effects, or a reduction in the rate of progression of a disease or disorder, compared to a corresponding subject who does not receive such amount. The term also includes within its scope an amount effective to enhance normal physiological function.

[0093] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder as described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account the history of symptoms and / or taking into account genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0094] As used herein, the term "patient" or "subject" refers to a mammal. Thus, a subject refers to, for example, a dog, cat, horse, cow, pig, guinea pig, etc. Preferably, the subject is a human. When the subject is a human, the subject can be either a patient or a healthy human.

[0095] The compounds herein can be formulated with conventional carriers and excipients, which are selected according to ordinary practice. Tablets contain excipients, glidants, fillers, binders, etc. Aqueous formulations are prepared in sterile form and, if intended for delivery by routes other than oral administration, are generally isotonic. All formulations may contain excipients such as those described in the Handbook of Pharmaceutical Excipients (1986), incorporated herein by reference in their entirety. Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, etc. The pH of the formulations ranges from about 3 to about 11, but is typically about 7 to 10.

[0096] While it is possible for the active ingredients to be administered alone, it may be preferable to present them as pharmaceutical formulations. The formulations of the present invention, for both veterinary and human use, comprise at least one active ingredient together with one or more acceptable carriers and optionally other therapeutic ingredients.

[0097] The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.

[0098] Formulations include those suitable for the aforementioned routes of administration. Formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.), which is incorporated herein by reference in its entirety. Such methods include the step of bringing into association the active ingredient with the carrier, which constitutes one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0099] Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, pastilles, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary, or paste.

[0100] A tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active agent, or dispersing agent.

[0101] Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient.

[0102] Pharmaceutical formulations according to the present invention comprise one or more compounds together with one or more pharmaceutically acceptable carriers or excipients, and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral administration, for example, tablets, pastilles, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs may be prepared. Compositions intended for oral administration may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation.

[0103] Tablets containing the active ingredient mixed with non-toxic pharmaceutically acceptable excipients suitable for tablet manufacture are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin, or acacia; and lubricating agents such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated by known techniques, such as microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, sustained-release materials such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with a wax.

[0104] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0105] The aqueous suspensions of the present invention contain the active substance in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic, as well as dispersing or wetting agents such as natural phosphatides (e.g., lecithin), condensates of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensates of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), and condensates of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.

[0106] Oily suspensions may be formulated by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, or in mineral oils such as liquid paraffin. Oral suspensions may contain thickening agents such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavoring agents, such as those described herein, may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant, such as ascorbic acid.

[0107] Dispersible powders and granules of the present invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, such as sweeteners, flavorings, and coloring agents, may also be present.

[0108] The pharmaceutical composition may be in the form of an oil-in-water emulsion.The oily phase may be vegetable oil such as olive oil or peanut oil, mineral oil such as liquid paraffin, or a mixture thereof.Suitable emulsifiers include natural gums such as gum acacia and gum tragacanth, natural phosphatides such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.Emulsions may also contain sweeteners and flavoring agents.Syrups and elixirs may be formulated with sweeteners such as glycerol, sorbitol, or sucrose.Such formulations may also contain demulcents, preservatives, flavorings, or coloring agents.

[0109] The pharmaceutical compositions of the present invention may be in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as mentioned herein. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol, or may be prepared as a lyophilized powder. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil may be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid may also be used in the preparation of injectables.

[0110] The amount of active ingredient that may be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a sustained-release formulation intended for oral administration to humans may contain about 1 to 1000 mg of active ingredient, compounded with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain about 3 to 500 μg of active ingredient per milliliter of solution, such that infusion of a suitable volume at a rate of about 30 mL / hour can occur.

[0111] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0112] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0113] The formulations may be presented in single-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind described above. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.

[0114] It should be understood that in addition to the ingredients particularly mentioned above, the formulations of the present invention may include other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0115] The compounds herein can also be formulated to provide controlled release of the active ingredient, allowing for less frequent administration or to improve the pharmacokinetic or toxicity profile of the active ingredient. Thus, compositions comprising one or more compounds herein formulated for sustained or controlled release are also provided.

[0116] The effective dose of the active ingredient will depend, at least, on the nature of the condition being treated, its toxicity, whether the compound is being used prophylactically (at low doses) or for an active disease or condition, the delivery method, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose-escalation studies. Effective doses can be expected to be about 0.0001 to about 10 mg / kg body weight / day, typically about 0.001 to about 1 mg / kg body weight / day, more typically about 0.01 to about 1 mg / kg body weight / day, and even more typically about 0.05 to about 0.5 mg / kg body weight / day. For example, a daily candidate dose for an adult weighing about 70 kg will range from about 0.05 mg to about 100 mg, or about 0.1 mg to about 25 mg, or about 0.4 mg to about 4 mg, and may take the form of single or multiple doses.

[0117] The present specification relates to a compound or a pharmaceutically acceptable salt thereof for treating various conditions treatable by inhibiting SGK-1. For example, the condition may be long QT syndrome (LQTS), such as hereditary LQTS or acquired LQTS, or other cardiovascular diseases treatable by inhibiting SGK-1 (e.g., hereditary or acquired dilated cardiomyopathy). Without being bound by theory, it is believed that in vivo SGK-1 inhibition has a protective effect and can alleviate symptoms associated with LQTS, and can reduce and alleviate symptoms associated with heart failure, arrhythmias such as atrial fibrillation, ischemic injury, ischemic infarction, cardiac fibrosis, vascular proliferation, restenosis, hereditary or acquired dilated cardiomyopathy, hypertrophic cardiomyopathy, and stent failure.

[0118] Long QT syndrome (LQTS) can be genetic (e.g., due to mutations in the KCNQ1, KCNH2, or SCN5a genes). Alternatively, long QT syndrome is not associated with a genetic mutation but is acquired as a result of exposure to external stimuli. For example, acquired long QT syndrome can be a side effect of medications such as erythromycin or haloperidol. Acquired long QT syndrome is also associated with other cardiac conditions, such as myocardial ischemia.

[0119] The present specification also relates to compounds, or pharmaceutically acceptable salts thereof, for treating other conditions associated with SGK-1 mediated mechanisms, such as cancer, Parkinson's disease, and Lafora's disease.

[0120] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof for treating cancer or another proliferative disorder. As used herein, the terms "inhibiting cancer," "inhibiting cancer cell growth," and "inhibiting cancer invasion and metastasis" refer to inhibiting or reducing the rate of cancer cell growth, division, maturation, viability, or ability to invade and colonize other organs and tissues, and / or causing the death of cancer cells, either individually or aggregated with other cancer cells, by cytotoxicity, nutrient deprivation, induction of differentiation or apoptosis, or recognition by the immune system to elicit an immune response against the cancer cells.

[0121] Examples of tissues containing cancerous cells whose growth can be inhibited by the compounds, salts, or compositions thereof described herein, and for which the methods described herein are useful, include, but are not limited to, breast, prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney, colon, intestine, endometrium, ovaries, lung, testes, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gallbladder, rectum, salivary glands, adrenal glands, throat, esophagus, lymph nodes, sweat glands, sebaceous glands, muscle, heart, bone, and stomach.

[0122] In some embodiments, the cancer treated by provided compounds, salts, or compositions thereof is melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, colon cancer, or colorectal cancer. In some embodiments, the cancer treated by provided compounds, salts, or compositions thereof is prostate cancer, colorectal cancer, or breast cancer (e.g., resistant breast cancer).

[0123] In some embodiments, the compounds herein can be used to treat cancer by inhibiting signaling of the AKT / PI3K / mTOR pathway in patients whose tumors have activation of this pathway, for example, through mutations in PIK3CA, AKT1, and / or PTEN.

[0124] In some embodiments, the compounds herein can be used in combination with compounds that inhibit signaling in the AKT / PI3K / mTOR pathway to treat cancer in patients whose tumors have activated AKT / PI3K / mTOR pathways, for example, through mutations in PIK3CA, AKT1, and / or PTEN. Non-limiting examples of AKT / PI3K / mTOR inhibitors include NVP-BEZ235 (BEZ235, dactolisib), GDC-0084 (RG7666), GDC-0980 (apitolithib, RG7422), LY3023414, PF-05212384 (gedatolisib, PKI-587), PQR309 (bimiralisib), P7170, SF-1126, copanlisib (BAY), and others. 80-6946), buparlisib (BKM120, NVP-BKM120), IPI-145 (duvelisib), RP6530 (tenalisib), GDC-0032 (taselisib), KA2237, BYL719 (alpelisib), CAL-101 (GS-1101, idelalisib), GSK2636771, INCB050465( Parsaclisib), ceravelisib (INK-1117, MLN-1117, TAK-117), ME401 (PWT-143), ambralisib (RP5264, TGR-1202), CUDC-907 (fimepinostat), rigosertib (ON-01910), samotricisib, paxalisib, voxtalisib, CH51327 99, pilaralisib, ZSTK474, sonolisib, pictilisib, B591, TG-100-115, RIDR-PI-103, zandelisib, AMG319, rimpellisib, leniolisib, eganelisib, AZD8186, AZD8835, MK-2206, ipatasertib, GSK690693, capivasertib, PF-0 4691502, AT7867, MAY1125976, TAS117, afuresertib, uprosertib, AT13148, everolimus, temsirolimus, ridaforolimus, sirolimus, umirolimus, zotarolimus, ICSN3250, LY3023414, OSU-53, AZD8055, and rapamycin.

[0125] In some embodiments, the compounds herein can be used to treat inflammatory and fibrotic diseases, which may include fatty liver disease, endometriosis, type 1 or type 2 diabetes, inflammatory bowel disease, asthma, rheumatoid arthritis, obesity, systemic sclerosis, scleroderma graft-versus-host disease, nephrogenic systemic fibrosis, and organ-specific fibrosis, including radiation-induced fibrosis, and autoimmune diseases.

[0126] Serine / threonine-protein kinase (SGK-1), also known as serum / glucocorticoid-regulated kinase 1, is a protein kinase that plays a role in cellular responses to stress. In vivo, SGK-1 activates specific potassium, sodium, and chloride channels. For example, this protein is known to regulate the myo-inositol transporter during osmotic stress. As used herein, the term "inhibitor of SGK-1" refers to any compound that can block, stop, interfere with, or reduce the biological activity of SGK-1.

[0127] In some embodiments, the compounds herein can be used to increase fetal hemoglobin (HbF) in red blood cells. In some embodiments, the compounds herein can be used to treat β-hemoglobinopathies. In some embodiments, the compounds herein can be used to treat sickle cell disease.

[0128] In some embodiments, the compounds herein can be used for the treatment of prostate cancer, hi other embodiments, the compounds herein can be used for the treatment of epilepsy.

[0129] The compounds and pharmaceutically acceptable salts thereof described herein are pharmacologically active compounds that modulate protein kinase activity, specifically the activity of serum and glucocorticoid-regulated kinase isoform 1 (SGK-1). The compounds described herein, or pharmaceutically acceptable salts thereof, may be suitable for treating conditions in which SGK-1 activity is inappropriate. Non-limiting examples of such conditions include long QT syndrome, heart failure, arrhythmias such as atrial fibrillation, ischemic injury, ischemic infarction, cardiac fibrosis, vascular proliferation, restenosis, dilated cardiomyopathy, stent failure, prostate cancer, and epilepsy. Other non-limiting examples of such conditions include β-hemoglobinopathies, such as sickle cell disease.

[0130] Experiments and Examples Materials and equipment Selected XRPD patterns were collected on a PANalytical X'Pert PRO MPD or PANalytical Empyrean diffractometer using an incident beam of Cu radiation generated by an Optix long fine-focus source. An ellipsoidal multilayer mirror was used to focus Cu Kα. X-rays passed through the sample to the detector. Prior to analysis, a silicon specimen (NIST SRM 640f) was analyzed to verify the Si 111 peak position. Samples were sandwiched between 3 μm-thick films and analyzed in transmission geometry. A beam stop and short anti-scatter extensions were used to minimize background generated by air. Soller slits for the incident and diffracted beams were used to minimize spread from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) positioned 240 mm from the sample and Data Collector software v.5.5.

[0131] [Table 1]

[0132] XRPD patterns were also collected on a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu Kα radiation generated using a long fine-focus source and a nickel filter. The diffractometer was configured using a symmetric Bragg-Brentano geometry. Prior to analysis, a silicon specimen (NIST SRM 640f) was analyzed to verify that the observed position of the Si 111 peak matched the NIST-certified position. The specimen was prepared as a thin, annular layer centered on a silicon zero-background substrate. An antiscatter slit (SS) was used to minimize background generated by air. Soller slits for the incident and diffracted beams were used to minimize spread from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) positioned 240 mm from the specimen and Data Collector software v.2.2b. Data acquisition parameters for each pattern are displayed above the images in the data section of this report, including the divergence slit (DS) and incident beam SS.

[0133] [Table 2]

[0134] XRPD patterns were indexed using X'Pert High-Score Plus 2.2a (2.2.1), TOPAS, or dedicated software.

[0135] Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were performed on a Mettler-Toledo TGA / DSC3+ analyzer. Temperature and enthalpy adjustments were made using indium, tin, and zinc, then verified with indium. The balance was verified with calcium oxalate. Samples were placed in open aluminum pans. The pans were sealed, the lids pierced, and then inserted into the TG furnace. A weighed aluminum pan, configured as a sample pan, was placed on the reference platform. The furnace was heated under nitrogen. Data were collected from 25 °C to 350 °C at 10 °C / min.

[0136] Other XRPD diffractograms were collected on an X-ray diffractometer. Samples were prepared on a zero-background silicon wafer by gently pressing it onto a flat surface. The parameters for XRPD diffraction were:

[0137] [Table 3]

[0138] Other TGA analyses were performed using a TA instrument. Data were analyzed using TRIOS. Approximately 1-5 mg of sample was loaded onto a pre-weighed aluminum pan and heated using the following parameters:

[0139] [Table 4]

[0140] Other DSC analyses were performed using a TA instrument. Data were analyzed using TRIOS. Approximately 1-3 mg of sample was loaded onto an aluminum pan with a pinhole and heated using the following parameters:

[0141] [Table 5]

[0142] Moisture sorption / desorption data were collected on a DVS Intrinsic. Samples of 7-20 mg were placed in a pre-weighed sample chamber and automatically weighed. The anhydrous samples were analyzed with the following set parameters:

[0143] [Table 6]

[0144] Some solution nuclear magnetic resonance spectra were obtained on an Avance 600 MHz NMR spectrometer. 1 H-NMR spectra were collected on a Bruker 400 MHz instrument. Samples were prepared by dissolving approximately 4–7 mg of sample in dimethyl sulfoxide-d6. Data were analyzed using MestReNova.

[0145] Solvent abbreviations are as follows: MeOH: methanol, THF, tetrahydrofuran: tetrahydrofuran, EtOH, Ethanol: ethanol, IPAC, Isopropyl acetate: isopropyl acetate, EtOAc or EA, Ethyl acetate: ethyl acetate, DMF, Dimethylformamide: dimethylformamide, IPA, Isopropanol: isopropanol, DCM, dichloromethane: dichloromethane, DMSO, Dimethylsulfoxide: dimethyl sulfoxide, ACN, Acetonitrile: acetonitrile, MTBE, Methyl tert-butyl ether: methyl tert-butyl ether, EA, Ethyl amine: ethylamine, NMP, N-methyl-2-pyrrolidone: N-methyl-2-pyrrolidone, DMA, Dimethylformamide: dimethylformamide, MEK, Methylethylketone: methyl ethyl ketone, MTBE, Methyl tert-butyl ether: methyl tert-butyl ether, MIBK, Methylisobutylketone: methyl isobutyl ketone, IPE, Isopropyl ether: isopropyl ether.

[0146] HPLC analysis was performed on an Agilent HPLC 1260 series instrument. The HPLC method for stability testing is as follows:

[0147] [Table 7]

[0148] Summary of Experimental Results Salt formation experiments were carried out with compound 1 (N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-fluorophenyl]-2,5-difluorobenzenesulfonamide).

[0149] The obtained pharmaceutically acceptable salts, isolated as crystalline compounds, were characterized by various techniques (XRPD, DSC, TGA, NMR) and their stability was investigated (DVS, slurry experiments).

[0150] Example 1: Synthesis of Compound 1 N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-fluorophenyl]-2,5-difluorobenzenesulfonamide

[0151] [ka]

[0152] (i) 6-chloro-N-[2-(dimethylamino)ethyl]-3-methyl-1-(oxan-2-yl)pyrazolo[3,4-d]pyrimidin-4-amine An 8 mL vial was charged with 4,6-dichloro-3-methyl-1-(oxan-2-yl)-2H,3H-pyrazolo[3,4-d]pyrimidine (74.3 mg, 0.259 mmol, 1 equiv.), (2-aminoethyl)dimethylamine (22.8 mg, 0.259 mmol, 1 equiv.), dichloromethane (3.0 mL), and triethylamine (57.7 mg, 0.571 mmol, 2.2 equiv.). The resulting solution was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane / methanol (95 / 5) to give the desired product 6-chloro-N-[2-(dimethylamino)ethyl]-3-methyl-1-(oxan-2-yl)pyrazolo[3,4-d]pyrimidin-4-amine (55.0 mg, 62% yield) as a colorless solid.

[0153] (ii) N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-fluorophenyl]-2,5-difluorobenzenesulfonamide An 8 mL vial was charged with 2,5-difluoro-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-fluorophenyl]benzenesulfonamide (1 equivalent), 6-chloro-N-[2-(dimethylamino)ethyl]-3-methyl-1-(oxan-2-yl)pyrazolo[3,4-d]pyrimidin-4-amine (1 equivalent), 1,4-dioxane / water (10:1), cesium carbonate (2 equivalents), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 equivalent). The resulting solution was stirred at 100 °C overnight. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase column chromatography using the following conditions: Column: Agela C18 column, 120 g, Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 40 mL / min; Gradient: 0% B to 55% B in 45 min; Detector: 220 nm to give the desired product N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1-(oxan-2-yl)pyrazolo[3,4-d]pyrimidin-6-yl)-2-fluorophenyl]-2,5-fluorobenzenesulfonamide (51% yield) as a brown solid.

[0154] A 25 mL, two-necked round-bottom flask was charged with N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1-(oxan-2-yl)pyrazolo[3,4-d]pyrimidin-6-yl)-2-fluorophenyl]-2,5-difluorobenzenesulfonamide (1 equivalent) in 1,4-dioxane, isopropanol, and 2 M hydrochloric acid (gas). The resulting solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: Column: Xselect CSH OBD column 30 x 150 mm, 5 μm. Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 18% B to 38% B in 7 min; Detector: 220 nm to give the desired product as a white solid (7.84% yield). LCMS (ES m / z): 522 [M-TFA + H]+. 1H-NMR(CD3OD,300MHz)δ(ppm):8.19-8.16(m,1H),8.10-8.06(dd,J=1.8&12Hz,1H),7.81-7.78(m,1H),7.68-7.63(m,2H),7.57( t,J=8.2Hz,1H),7.35-7.29(t,J=9.3Hz,1H),4.16-4.13(t,J=5.7Hz,2H),3.56-3.53(t,J=5.7Hz,2H),2.98(s,6H),2.65(s,3H).

[0155] Compound 1 was further characterized to have pKa values of 2.7, 5.81, 8.85, and 11.84.

[0156] [Table 8]

[0157] Example 2: Solubility Screening of Compound 1 Solubility estimation was performed using the aliquot addition method in various solvents at ambient temperature. Low solubility was observed in most solvents at ambient temperature. Immediate solubility was observed in DMF and DMSO.

[0158] [Table 9]

[0159] Samples containing solvents with low solubility were heated at 50° C. Dissolution was observed in methanol and THF.

[0160] Example 3: Crystalline Form of Compound 1 (Free Base) Compound 1 was characterized as a crystalline material consisting of Form A and Form B, as shown in Figure 1 (XRPD pattern) and Figure 2 (enlarged XRPD pattern). The compound was also characterized by proton NMR (Figure 3).

[0161] Free form Form C was identified as a MeOH solvate of Compound 1. The XRPD pattern is shown in FIG.

[0162] Free Form D can be obtained by anti-solvent precipitation from NMP / water and DMA / water, and by reverse anti-solvent precipitation in DMSO / water. The starting material used to obtain Free Form D is HCl salt (Compound 3) Form B.

[0163] 150 mg of Compound 3 (Form B) was dissolved in 7 mL of DMA at 70° C., and then the solution was filtered at room temperature. 84 mL of water (antisolvent) was added to the filtrate over 10 hours. The suspension was stirred at room temperature for 4 days. Free Form D was recovered by filtration and dried under vacuum at 50° C. for 3 hours. The recovery rate is 13.8%. Characterization data for Free Form D are shown in Figures 23-24. The sample was in the form of long, rod-shaped crystals. 1 No residual solvent was detected by H-NMR. 1 Chemical shifts in the H-NMR spectrum were observed relative to the HCl salt, indicating that the HCl salt was dissociated into the free form. TG analysis of free form D showed a weight loss of 3.2% (1 equivalent of water) from 25 to 140 °C due to dehydration. The first and second endothermic peaks, 58.37 °C (onset 35.72 °C) and 143.11 °C (onset 121.39 °C), are due to the elimination of absorbed water and dehydration, respectively. Free form D is converted to form E after dehydration, and therefore the sharp endothermic peak at 287.19 °C (onset 285.28 °C) corresponds to the melting of form E. Free form D is a monohydrate with moderate crystallinity. Free form E is an anhydrate with high crystallinity.

[0164] Example 4: Preparation of formate salt The formate salt was obtained via the following synthetic steps.

[0165] [ka] 1) Compound 1 (92 mg) was stirred in methanol (1 mL) at 55° C. to obtain a slurry. 2) Add 2 molar equivalents of formic acid (14 μL). Most of the solid dissolves, resulting in a thin slurry. 3) The solution is cooled to room temperature at a rate of 6° C. per hour and stirred at room temperature for 3 days. 4) Use a Swinnex filter assembly to isolate the solid for XRPD analysis.

[0166] Compound 2 was obtained as shown by proton NMR (Figure 4).

[0167] XRPD pattern analysis (FIGS. 5a and 5b) and pattern indexing (FIG. 6) indicated the formation of a crystalline anhydrous monoformate salt of Compound 1 (Form A).

[0168] Thermal analysis (TGA) performed on the salt showed a weight loss of 0.1% from 51 to 141 °C and a weight loss of 8.2% from 140 to 228 °C (approximately 1 mol formic acid). DSC analysis also revealed a broad endothermic peak (maximum) at 211 °C with an onset of 188 °C and an endothermic peak (maximum) at 289 °C with an onset of 287 °C, as shown in Figure 7.

[0169] Solubility in water: <1mg / mL.

[0170] Example 5: Preparation of the hydrochloride salt and its crystalline forms The hydrochloride salt was obtained via the following experimental procedure.

[0171] [ka]

[0172] Form A Testing Procedure A: 1) Compound 1 (94 mg) was stirred in methanol (0.5 mL) at 55° C. to obtain a slurry. 2) Add 2 molar equivalents of hydrochloric acid (30 μL of 37%) to obtain an immobile slurry. 3) 2.5 mL of methanol was added to give a mobile slurry. The solution was stirred at 55° C. for 3 days. 4) Use a Swinnex filter assembly to isolate the solid for XRPD analysis.

[0173] XRPD pattern analysis showed the formation of a mixture of Compound 3 as a distinctive crystalline material (Form A) and minor unknown XRPD peaks. 5) The previously isolated solid is taken up in acetone to form a slurry. 6) Stir at RT for 2 days. 7) Use a Swinnex filter assembly to isolate the solid for XRPD analysis.

[0174] XRPD pattern analysis showed the formation of a mixture of Compound 3 as a distinctive crystalline material (Form A) and minor unidentified XRPD peaks. or

[0175] Testing Procedure B: 1) Compound 1 (98 mg) was stirred in methanol (1 mL) at RT to give a slurry. 2) Add 2 molar equivalents of hydrochloric acid (32 μL of 37%) to obtain an immobile slurry. 3) Stir at 60°C to obtain an immobile slurry. 4) Add water (0.2 mL) to obtain a mobile slurry. 5) Mix on a rotating wheel at room temperature for 12 days. 6) Use a Swinnex filter assembly to isolate the solid for XRPD analysis.

[0176] XRPD pattern analysis showed the formation of a mixture of Compound 3 as a distinctive crystalline material (Form A) and minor additional unknown XRPD peaks.

[0177] Aqueous Slurry: The solid mixture was then slurried in water at RT (with stirring for 1 day) and the resulting solid was isolated using a Swinnex filter assembly. The aqueous slurry yielded a single crystalline phase, and Form A of Compound 3 was identified as the non-solvated monohydrochloride salt, as shown by the XRPD pattern in Figure 8 (pattern indexing in Figure 9).

[0178] The proton NMR of compound 3 is shown in FIG. Solubility in water: <1mg / mL.

[0179] Thermal analysis (TGA) performed on the salt showed a weight loss of 1.0% (0.3 mol water) between 54 and 120 °C. DSC analysis also revealed an endothermic peak (maximum) at 311 °C with an onset of 308 °C, as shown in Figure 11.

[0180] Ion chromatography for the hydrochloride salt - Form A showed 5.78% chlorine (theoretical: 6.65% - slight deviations may be due to the presence of residual solvent or impurities).

[0181] Form B Compound 3, Form B, can be obtained from the following procedure: Compound 1 is charged in HO (6 volumes). Adjust the pH to 3-4 with HCl (3N) at 20-30°C. Stir for 3.17 hours at 20-30°C. Adjust the pH to 7-8 with 5% NaHCO3 solution at 20-30°C. Stir for 3.52 hours at 20-30°C. Filter and wash the cake with HO (1 volume). The cake is charged in 5% NaHCO3 solution (6 volumes) and stirred at 20-30°C for 4.4 hours. Filter and wash the cake with HO (1 volume). The cake is charged in a co-solvent of MeOH / HO (1 / 4, 5 volumes) for 7.3 hours at 20-30°C. Filter and wash the cake with HO (1 volume). The cake is dried at 55-65°C to obtain Compound 3, Form B.

[0182] Characterization of Compound 3, Form B is shown in Figures 25-26. Compound 3, Form B exhibited fine particle size with moderate crystallinity. 6.4% Cl was detected by IC, indicating that the stoichiometry of Form B was 1 / 1. 1 No residual solvent was detected by H-NMR, but a weight loss of 1.6% was observed by TGA between 25 and 118 °C due to the loss of absorbed water. DSC showed two endothermic peaks at 50 and 301 °C, corresponding to the release of water and melting / decomposition, respectively.

[0183] The solubility of Compound 3 Form B was estimated in 30 solvents at room temperature and in 9 organic solvents at 70° C. using the solvent addition method via visual assessment. The results are summarized in Table 2. Compound 3 Form B showed low solubility in most solvents at room temperature and moderate solubility in DMSO, NMP, DMA, and DMF at 70° C. Protocol: Approximately 3 mg of Compound 3 Form B was weighed into a sample vial and solvent was slowly added by vortexing until the drug solution was clear by observation or until a total of 2 mL of solvent had been added. The estimated solubility (mg / mL) was then calculated.

[0184] [Table 10]

[0185] Form C Compound 3, Form C, can be obtained by slurrying Compound 3, Form B, in MeOH at 50° C. for 4 days. Form C was collected by filtration and dried under vacuum at 50° C. for 3 hours. The recovery is 74.9%.

[0186] The characterization of Compound 3, Form C, is shown in Figures 27-28. Fine particle size with moderate crystallinity was obtained. 1 H-NMR detected 0.2% residual MeOH. TG analysis of Compound 3, Form C, showed no weight loss before melting. The DSC trace showed two endothermic peaks at 312 °C and 321 °C, which are attributed to melting and decomposition, respectively. Therefore, Compound 3, Form C, is an anhydrous form.

[0187] Form D Compound 3, Form D, can be obtained from DMSO / water by reverse anti-solvent precipitation. 150 mg of Compound 3, Form B, was dissolved in 2 mL of DMSO at 70° C., and the solution was then filtered at room temperature. The filtrate was added to 20 mL of water (anti-solvent), and the suspension was stirred at room temperature for 4 days. Compound 3, Form D, was collected by filtration and dried under vacuum at 50° C. for 3 hours. The recovery is 73.5%.

[0188] The characterization analysis for Compound 3, Form D is shown in Figures 29-30. Compound 3, Form D exhibited fine particle size with high crystallinity. 1 H-NMR revealed 0.3% residual DMSO. The TGA curve showed a weight loss of 1.1% between 25 and 90°C, due to the release of residual DMSO and water. The DSC thermogram showed four endothermic peaks. A small endothermic peak at 49°C corresponded to the release of residual DMSO and water. A second endothermic peak at 280°C was still unclear. A sharp endothermic peak at 306°C was due to melting. Decomposition occurred at 316°C.

[0189] Form E Compound 3, Form E, can be obtained from NMP / MTBE, DMA / MTBE, DMA / EA, DMA / IPAC, or DMA / MIBK by anti-solvent precipitation, and from DMA / MTBE, DMA / EA, or DMA / MIBK by reverse anti-solvent precipitation.

[0190] The sample obtained by anti-solvent precipitation from DMA / MTBE was further characterized. 150 mg of Compound 3, Form B, was dissolved in 7 mL of DMA at 70° C., and then the solution was filtered at room temperature. 49 mL of MTBE (anti-solvent) was added to the filtrate over 10 hours. The suspension was stirred at room temperature for 4 days. Compound 3, Form E, was collected by filtration and dried under vacuum at 50° C. for 3 hours. The recovery is 96.4%.

[0191] The characterization of Compound 3, Form E is shown in Figures 31-36. Compound 3, Form E was characterized as irregularly shaped crystals. 1 Approximately 17.6% residual DMA and 0.4% residual MTBE were detected by H-NMR. The TGA thermogram of Compound 3, Form E, showed a weight loss of 3.6% and 12.5% between 25 and 110°C and between 110 and 160°C, respectively, due to the release of residual solvent and desolvation. DSC showed two adjacent endothermic peaks at 73°C and 130°C. Compound 3, Form E is a DMA (1 equivalent) solvate.

[0192] comparison The XRPD overlay shows patterns for Compound 1, free forms D and E, and for Compound 3, forms C, D, and E.

[0193] Comparative studies between Forms B, C, D, and E revealed that Form D is the most stable form of Compound 3 in non-aqueous and aqueous systems. Form D is slightly hygroscopic. It exhibits physical and chemical stability at 60°C (capped) and 40°C and 75% relative humidity (open).

[0194] Example 6: Preparation of Mesylate Salt The mesylate salt was obtained via the following synthetic steps.

[0195] [ka] 1) Compound 1 (99 mg) and 2 molar equivalents of methanesulfonic acid (26 μL) are combined in methanol (1 mL) at room temperature. 2) The visually clear solution is slowly evaporated (partially) and stirred at RT for 5 days. 3) Use a Swinnex filter assembly to isolate the solid for XRPD analysis.

[0196] Compound 4 was obtained as a crystalline material. XRPD pattern analysis (FIGS. 12 and 13) and pattern indexing (FIG. 14) indicated the formation of the non-solvated dimesylate salt of Compound 1.

[0197] Example 7: Crystalline form of the mesylate salt Form A After drying in a vacuum oven at 62-72°C for 1 day, Form A was characterized by XRPD (Figure 22: before DVS) and proton NMR (Figure 15). The results showed that Form A of the dimesylate salt (unsolvated) was preserved.

[0198] Thermal analysis performed on Form A showed a weight loss of 0.8% (0.3 mol water) from 53 to 129° C. and a weight loss of 1.6% from 129 to 197° C. DSC analysis also revealed a broad endothermic peak at 80° C. with an onset of 164° C., and two endothermic peak temperatures at 175° C. and 189° C. (peak maxima), as shown in FIG.

[0199] The aqueous solubility of Form A was determined by adding 0.1 mL of water to 2.5 mg of mesylate Form A. The initially clear solution was stirred at room temperature for 1 day, and precipitated solids were observed. The solubility in water is >25 mg / mL.

[0200] The solubility in MTBE is <2 mg / mL at RT.

[0201] Form B Compound 4 Form B can be obtained from a variety of conditions: slurrying, slow cooling, and anti-solvent precipitation, as summarized in Table 3.

[0202] [Table 11]

[0203] A sample of Compound 4 Form B was then obtained by filtration and dried under vacuum for 3 hours.

[0204] Compound 4 Form B exhibited a needle-like shape with moderate crystallinity. TGA showed a weight loss of 5.4% from 25 to 120°C (Figure 38). 1 No residual solvent was detected by H-NMR, and the base / acid ratio was detected as 1 / 2. The DSC trace showed one broad endothermic peak at 74 °C and one melting peak at 220 °C due to dehydration. Therefore, dimesylate Form 1 was likely a nonstoichiometric hydrate. The DVS isotherm of Compound 4 Form B was tested at 25 °C and 80% RH, and the water uptake was 9.16%. The water uptake process can be reversed by subsequently reducing the RH from 90% to 0%. The crystalline morphology of Form 1 remained unchanged after the DVS test.

[0205] The solubility of Compound 4, Form B, was estimated in 18 solvents at room temperature using the solvent addition method via visual assessment. The results are summarized in Table 4. Approximately 3 mg of Compound 4, Form B was weighed into a sample vial, and solvent was slowly added by vortexing until the solution was clear by observation or until a total of 2 mL of solvent had been added. The estimated solubility (mg / mL) was then calculated.

[0206] [Table 12]

[0207] Compound 4, Form B, exhibited low solubility in most solvents, moderate solubility in DMA, MeOH / water (9 / 1, v / v), ACN / water (9 / 1, v / v), MeOH, EtOH, and water, and high solubility in DMSO and NMP.

[0208] Form C Compound 4, Form C, is a metastable form obtained by slurrying Compound 4, Form B in THF at RT and 50° C. for 3 days. In a slurry experiment to re-prepare Compound 4, Form C starting from Compound 4, Form B, Form C formed in 30 minutes and was completely converted to dimesylate Form D in 60 minutes. Therefore, only a mixture of Form C and trace Form B was obtained for characterization.

[0209] Compound 4 Form C was irregularly shaped microcrystalline with low crystallinity. 1 Approximately 5.0% (0.5 equivalents) of residual THF was detected by H-NMR, and the base / acid ratio was determined as 1 / 2. The TGA thermogram of Compound 4 Form C showed a weight loss of 0.8% and 3.5% from 30 to 95°C and from 95 to 165°C, which may be attributed to the release of water and desolvation, respectively (Figure 40). The DSC trace showed three endothermic peaks at 61, 152, and 218°C, which may correspond to the elimination of free water, desolvation, and melting, respectively. Compound 4 Form C was solvated with THF (0.5 equivalents).

[0210] Form D Compound 4 Form D can be obtained from a variety of conditions: slurrying, anti-solvent precipitation, and reverse anti-solvent precipitation, as summarized in Table 5.

[0211] [Table 13]

[0212] Form D was prepared on a 150 mg scale. The resulting solid was collected by filtration and dried under vacuum at 50° C. for 3 hours. The recovery was approximately 81%. Form D exhibited an irregular shape with moderate crystallinity. 1 The H-NMR spectrum detected 0.2% MTBE residue, with a base / acid ratio of 1 / 2. TGA results indicated that Form D underwent a dehydration procedure between 90 and 157 °C, corresponding to a weight loss of 2.4% (Figure 42). The DSC curve of Form D had three endothermic peaks and one exothermic peak (Figure 42). The first endothermic peak at 140 °C corresponded to dehydration. The second endothermic peak at 174 °C corresponded to the melting of Form D. The subsequent exothermic peak was attributed to the transformation from Form D to Form F. When the sample was heated to a high temperature, Form F melted at 219 °C (peak temperature). Form D was likely a monohydrate. DVS testing of Form D showed a water uptake of 0.99% at 80% RH (Figure 48). The water uptake process could then be reversed with hysteresis when the RH was subsequently reduced from 90% to 0%. Furthermore, the XRPD of Form D remained unchanged after the DVS study (Figure 49).

[0213] Form E Form E was obtained by slow cooling crystallization in NMP (Figure 43). The unstable form was not further characterized. A clear solution of Compound 4, Form B, was dissolved in NMP at 50°C (30 mg) and cooled to 50°C to 2°C. Unstable Form E was obtained, which converted to Form D after drying.

[0214] Form F Form F was obtained by heating Form D to 210°C at a rate of 10°C / min and cooling to 25°C at a rate of 5°C / min.

[0215] Form F exhibited an irregular shape with moderate crystallinity. Humps were observed in the XRPD pattern (Figure 44), indicating that Form F contained an amorphous phase. 1 No solvent residue was detected by H-NMR spectrum, and the base / acid ratio was 1 / 2. TGA results showed a weight loss of 3.6% between 25 and 110 °C. The DSC curve showed one broad endothermic peak at 61 °C and one melting peak at 217 °C due to dehydration (Figure 45). Dimesylate Form F was likely a non-stoichiometric hydrate with 1.5 equivalents of water.

[0216] Form G Form G was obtained by slurrying Form B in water at 50° C. The preparation conditions are summarized in Table 6.

[0217] [Table 14] Additionally, the sample was dried under vacuum at 50° C. for 3 hours to obtain Form G.

[0218] The monomesylate salt form G sample was irregularly shaped aggregates with high crystallinity. 1 No organic solvent residues were detected by H-NMR spectroscopy, and the base / acid ratio was 1 / 1. Monomesylate Form G exhibited complex thermal behavior. TGA analysis showed a weight loss of 6.4% between 25 and 100 °C. The DSC curve showed four endothermic peaks at 96, 164, 239, and 266 °C and two exothermic peaks at 181 and 242 °C. According to the TGA and DSC thermograms, monomesylate Form G was likely a hydrate (2.5 equivalents).

[0219] comparison Comparative studies of Forms B to G (interconversion and water activity) revealed that Compound 4 Form D was the most stable form. Form D was stable at high water activity (0.16≦a w <0.90). Solid state stability studies have shown that Form D is physically and chemically stable at (near) 60°C and 40°C, 75% RH for 7 days. Form D is slightly hygroscopic. Form D also appears to be more stable than Form A, which is hygroscopic. Form B also exhibited good stability properties despite its hygroscopic nature.

[0220] Example 8: Dynamic Vapor Sorption / Desorption (DVS) Experiments DVS experiments (Figures 17, 19, 21, 34, 35, 48, and 50) and post-XRPD DVS experiments (Figures 18, 20, 22, 36, 49, and 51) were performed to examine the deliquescence behavior of the crystalline salts upon exposure to humidity.

[0221] [Table 15]

[0222] Example 9: Water activity test Competition studies for compound 3 form B and form D at different water activities Water activity tests were performed using Compound 3 Form B (anhydrous) as the input material in EtOH / water solutions with different water contents at room temperature. Approximately 5 mg of Compound 3, Form B was used to prepare a saturated solution, and the solution was filtered via syringe at room temperature. 5 mg of Compound 3, Form D was added to 1 mL of the filtrate, and the suspension was slurried at room temperature for 3 and 7 days. The solid collected after filtration was analyzed by XRPD. The data are summarized in Table 8.

[0223] [Table 16]

[0224] Compound 3, Form D, was found to be stable at water activities below 0.6. Extra peaks at 7° were observed at water activities of 0.8 and 0.9, indicating that Compound 3, Form D can be converted to the free base at higher water activities.

[0225] Testing of Compound 4 Form B and Form D The water activity test between Compound 4 Forms B and D was carried out in MeOH / water, ACN / water, and IPAC / water at room temperature. The experimental results are shown in Table 9. Compound 4 Form D has a high water activity, 0.16≦a w ≦0.90, making it the most stable form, while Compound 4 Form B has a low water activity, a w It was concluded that the most stable form was ≦0.08. Protocol: A saturated solution was prepared using an excess amount of Compound 4 Form B. 6-8 mg each of Compound 4 Form B and Form D was added to the solution. The suspension was slurried at room temperature for the corresponding time. The residual solid was collected by filtration through a syringe filter and characterized by XRPD.

[0226] [Table 17] a w was calculated using Dynochem with the NRTL model.

[0227] Example 10: Solid State Stability Experiments Testing for Compound 3 Form D The solid state stability study of Compound 3, Form D, was evaluated at 60°C (capped) and 40°C / 75% RH (open) conditions for 7 days. The polymorphic form and purity were analyzed by XRPD and HPLC, respectively. The experimental results are shown in Table 10. Compound 3, Form D, was found to be chemically and physically stable at 60°C (capped) and 40°C / 75% RH (open) for 7 days.

[0228] [Table 18]

[0229] Testing of Compound 4 Form B and Form D The solid-state stability studies of Compound 4 Forms B and D were evaluated at 60°C (closed vial) and 40°C / 75% RH (open vial) for 7 days. The polymorphic form and purity were confirmed by XRPD and HPLC, respectively. The experimental results are shown in Table 11. Form D was chemically and physically stable at 60°C (closed) and 40°C / 75% RH (open) for 7 days, while Form B was chemically and physically stable at 60°C (closed) but partially converted to Form D at 40°C / 75% RH (open) for 7 days.

[0230] [Table 19]

[0231] Example 11: Slurry Experiments Slurry Test for Compound 3 Form B Approximately 20 mg of Compound 3, Form B, was weighed into a sample vial, and then 1 mL of solvent was added to form a suspension. The suspension was stirred at room temperature or 50° C. for 3 and 11 days. The wet solid was then collected by filtration and analyzed by XRPD.

[0232] [Table 20]

[0233] Competitive Slurry Experiments on Compound 4 Form B and Form D A competitive slurry experiment of Compound 4 Forms B and D was conducted to verify their relative stability relationship. The experimental results are shown in Table 13. Form D was considered to be a stable form at high water activity, while Form B was considered to be stable at low water activity. All solvents used were analytical grade and should contain trace amounts of water. IPAC showed high water activity in the presence of small amounts of water. Therefore, Form B was converted to Form D in IPAC at both room temperature and 50°C. MeOH showed the lowest water activity with trace amounts of water, and therefore Form B was isolated as the product. The water activity at high temperatures was lower than that at low temperatures. Therefore, Form B was obtained in ACN at 50°C, while Form D was the stable form at room temperature.

[0234] [Table 21]

[0235] Slurry test for compound 4 20-30 mg of Compound 4 Form B was added to 1 mL of the selected solvent at room temperature or 50°C. The suspension was slurried for 3 and 11 days at room temperature or 50°C. The wet solid collected from the filtration was examined by XRPD. All results for the slurry experiments are summarized in Table 14. Four crystalline forms were obtained by slurrying, including dimesylate Forms B, C, and D, and monomesylate Form G.

[0236] [Table 22] N / A: Not applicable 1 The boiling points of DCM and MTBE are 40° C. and 55° C., respectively. The solvent was evaporated to dryness at 50° C.

[0237] Example 12: Cooling / Anti-solvent Precipitation / Reverse Anti-solvent Precipitation Experiments ·cooling Cooling experiments on Compound 3 Form B A clear solution was prepared by dissolving 20 mg of compound 3 in the corresponding solvent at 70° C. The solution was cooled from 70° C. to 2° C. The procedure and results are shown in Table 15. No precipitate was obtained from the cooling experiment.

[0238] [Table 23]

[0239] Cooling experiments on Compound 4 Form B A clear solution was prepared by dissolving 30 mg of Compound 4 Form B in the corresponding solvent at 50° C. The solution was cooled to 50° C. to 2° C. The procedure and results are shown in Table 16.

[0240] [Table 24]

[0241] Antisolvent precipitation Antisolvent precipitation experiments on Compound 3 Form B Compound 3 Form B was dissolved in 1 mL of DMSO, NMP, or DMA at 70° C. to a concentration of 30 mg / mL or 15 mg / mL. The filtrate was placed in an 8 mL or 20 mL vial at room temperature. Anti-solvent (S<1.5 mg / mL) was added until precipitation occurred or until a solvent to anti-solvent volume ratio of 1 to 15 was reached. The solid was isolated by filtration and analyzed by XRPD. All results are shown in Table 17. Compound 3 Form D was obtained from most solvents. Compound 3 Form E was obtained from NMP / MTBE, DMA / MTBE, DMA / EA, DMA / IPAC, and DMA / MIBK. Compound 1 free base Form D was obtained from NMP / water, and a mixture of free base Forms D and E was obtained from DMA / water.

[0242] [Table 25]

[0243] Antisolvent precipitation experiments on Compound 4 Form B 30 mg of Compound 4 Form B was dissolved in 1 mL of DMSO or DMA at room temperature (concentration of 30 mg / mL). The filtrate was placed in an 8 mL vial at room temperature. Anti-solvent (S<1.5 mg / mL) was added until precipitation occurred or until a solvent to anti-solvent volume ratio of 1 to 7 was reached. The solid was isolated by filtration and analyzed by XRPD. All results are shown in Table 18. Compound 4 Form B was obtained from DMA / ACN. Compound 4 Form D was obtained from DMA / DCM and DMSO / DCM. A mixture of Compound 4 Forms B and D was obtained from DMSO / ACN and DMA / acetone, and a mixture of Compound 4 Form D and trace Forms B or C was obtained from several solvent systems.

[0244] [Table 26]

[0245] Reverse antisolvent precipitation Reverse antisolvent precipitation experiments on Compound 3 Form B Compound 3 Form B was dissolved in a selected solvent at 50°C with a concentration of 30 mg / mL or 15 mg / mL. 1 mL of the solution was then filtered at room temperature and added to an anti-solvent (solvent / anti-solvent, v / v, 1 / 10). The precipitate was collected and analyzed by XRPD. All results are shown in Table 19. Compound 1 free base Form D was obtained from DMSO / water, and Compound 3 Form E was obtained from DMA / MTBE, DMA / EA, and DMA / MIBK. In addition, mixed forms of Compound 1 free base were obtained from DMA / water and NMP / water.

[0246] [Table 27]

[0247] Reverse antisolvent precipitation experiments on Compound 4 Form B Compound 4 Form B was dissolved in selected solvents at room temperature with a concentration of 30 mg / mL. Then, 1 mL of the solution was filtered at room temperature and added to an anti-solvent (solvent / anti-solvent, v / v, 1 / 10). The precipitate was collected and analyzed by XRPD. All results are shown in Table 20. A mixture of Compound 4 Form B and Form D was obtained from most solvents, and Compound 4 Form D was obtained from DMSO / 2-Me THF, DMSO / EA, DMSO / DCM, DMA / 2-Me THF, and DMA / EA.

[0248] [Table 28]

[0249] Example 13: Heat Treatment Thermal Studies on Compound 3 Form E Compound 3, Form E, was subjected to a heating-cooling cycle by DSC. The resulting solid was characterized by XRPD. Compound 3, Form E, was converted to Compound 3, Form D after desolvation.

[0250] [Table 29]

[0251] Thermal Studies on Compound 4 Form B Compound 4 Form B was subjected to a heating-cooling cycle by DSC. The resulting solid was confirmed by XRPD. All results are shown in Table 22. The XRPD pattern remained unchanged after dehydration, suggesting a non-stoichiometric hydrate. Water was eliminated at high temperature and then re-entered the crystal lattice at room temperature.

[0252] [Table 30]

[0253] Thermal studies on compound 4 form C and trace amounts of form B Compound 4 Form C and minor Form B were subjected to heating-cooling cycles by DSC. The resulting solids were confirmed by XRPD. All results are shown in Table 23. The sample was converted to low crystalline (LC) Form B after heating to 175°C.

[0254] [Table 31]

[0255] Thermal studies on compound 4 form D Compound 4 Form D was subjected to a heating-cooling cycle by DSC. The resulting solid was confirmed by XRPD. All results are shown in Table 24. The sample remained unchanged after heating to 140°C, but transformed into a new, less crystalline form after heating to 210°C, which was assigned as Form F.

[0256] [Table 32]

[0257] XRPD Peak List Observed peaks for Compound 1, Form D:

[0258] [Table 33]

[0259] Observed peaks for Compound 1, Form E:

[0260] [Table 34]

[0261] Observed peaks for Compound 2, Form A:

[0262] [Table 35]

[0263] Observed peaks for Compound 3, Form A:

[0264] [Table 36]

[0265] Observed peaks for Compound 3, Form B:

[0266] [Table 37]

[0267] Observed peaks for Compound 3, Form C:

[0268] [Table 38]

[0269] Observed peaks for Compound 3, Form D (compound of formula II):

[0270] [Table 39]

[0271] Observed peaks for Compound 3, Form E:

[0272] [Table 40]

[0273] Observed peaks for Compound 4, Form A (compound of formula I):

[0274] [Table 41]

[0275] Observed Peaks for Compound 4, Form B

[0276] [Table 42]

[0277] Observed Peaks for Compound 4, Form C

[0278] [Table 43]

[0279] Observed Peaks for Compound 4, Form D

[0280] [Table 44]

[0281] Observed Peaks for Compound 4, Form E

[0282] [Table 45-1]

[0283] [Table 45-2]

[0284] Observed Peaks for Compound 4, Form F

[0285] [Table 46]

[0286] Observed Peaks for Compound 4, Form G

[0287] [Table 47]

[0288] Some of the embodiments herein are described in the following sections. 1. A compound of formula II:

[0289] [ka] 2. The compound of item 1, which is crystalline and exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 6.7, 22.3, and 29.0. 3. The compound of item 2, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 15.9, 20.5, and 20.7. 4. The compound of item 2 or 3, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 28.7, 20.2, and 13.5. 5. The compound of any one of items 2 to 4, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 26.2, 23.5, and 36.1. 6. The compound of any one of items 2 to 5, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 24.1, 10.2, and 25.6. 7. The compound of any one of items 2 to 6, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 19.0, 27.2, and 32.3. 8. The compound of any one of items 1 to 7, which is crystalline and has a differential scanning calorimetry (DSC) thermogram showing an endotherm with an onset of about 302°C. 9. The compound of item 1 having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 10. The compound of item 1, which is crystalline and exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 6.8, 14.5, and 25.8. 11. The compound of item 10, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 24.6, 22.45, and 19.1. 12. The compound of item 10 or 11, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 23.6 and 27.3. 13. The compound of any one of items 10 to 12, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2θ at 15.1 and 20.8 (±0.2° 2θ). 14. The compound of any one of items 1 and 10-13, which is crystalline and has a differential scanning calorimetry (DSC) thermogram showing an endotherm with an onset of about 308°C. 15. The compound of item 1 having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 8. 16. The compound of item 1, which is crystalline and exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 6.7, 14.6, and 24.0. 17. The compound of item 16, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 19.0, 28.8, and 25.7. 18. The compound of item 16 or 17, wherein the XRPD pattern further has characteristic peaks at 20.8 and 20.3 degrees 2θ (±0.2 degrees 2θ). 19. The compound of any one of items 16 to 18, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2θ at 15.9 and 22.3 (±0.2° 2θ). 20. The compound of any one of items 1 and 16-19, which is crystalline and has a differential scanning calorimetry (DSC) thermogram showing a first endotherm with an onset temperature of about 50°C and a second endotherm with an onset temperature of about 301°C. 21. The compound of item 1 having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 22. The compound of item 1, which is crystalline and exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 6.6, 22.1, and 20.8. 23. The compound of item 22, whose XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 14.7, 15.8, and 25.6. 24. The compound of item 22 or 23, wherein the XRPD pattern further has characteristic peaks at 24.1 and 19.1 degrees 2θ (±0.2 degrees 2θ). 25. The compound of any one of items 22 to 24, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 28.7 and 22.3. 26. The compound of any one of items 1 and 22-25, which is crystalline and has a differential scanning calorimetry (DSC) thermogram showing an endotherm with an onset of about 309°C. 27. The compound of item 1 having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 28. Formula I:

[0290] [ka] Compound. 29. The compound of item 28, which is crystalline and exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2θ (±0.2°2θ) at 17.76, 23.38, and 22.80. 30. The compound of item 29, whose XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 12.29, 8.26, and 13.75. 31. The compound of item 29 or 30, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 23.16, 21.63, and 17.07. 32. The compound of any one of items 29 to 31, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 18.44, 15.77, and 10.08. 33. The compound of any one of items 29 to 32, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 24.14, 19.65, and 24.73. 34. The compound of any one of paragraphs 28 to 33, which is crystalline and has a differential scanning calorimetry (DSC) thermogram showing an endotherm with an onset of about 164°C. 35. The compound of item 28, having an X-ray powder diffraction pattern substantially the same as that shown in Figure 12 or Figure 13. 36. The compound of item 28, having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 22. 37. The compound of item 28, which is crystalline and exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 22.8, 6.8, and 26.1. 38. The compound of item 37, whose XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 23.7, 15.9, and 18.5. 39. The compound of item 37 or 38, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 17.4 and 22.4. 40. The compound of any one of items 37 to 39, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2θ at 31.7 and 27.8 (±0.2° 2θ). 41. The compound of any one of items 28 and 37-40, which is crystalline and has a differential scanning calorimetry (DSC) thermogram showing a first endotherm with an onset of about 74°C and a second endotherm with an onset of about 218°C. 42. The compound of item 28, having an X-ray powder diffraction pattern substantially the same as that shown in Figure 37. 43. The compound of item 28, which is crystalline and exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 15.2, 16.0, and 17.6. 44. The compound of item 43, whose XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 23.0, 20.5, and 23.3. 45. The compound of item 43 or 44, wherein the XRPD pattern further has characteristic peaks at 23.9 and 19.3 degrees 2θ (±0.2 degrees 2θ). 46. The compound of any one of items 43 to 45, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 21.1 and 6.9. 47. The compound of any one of paragraphs 28 and 43-46, which is crystalline and has a differential scanning calorimetry (DSC) thermogram showing a first endotherm with an onset of about 61°C, a second endotherm with an onset of about 140°C, and a third endotherm with an onset of about 218°C. 48. The compound of item 28, having an X-ray powder diffraction pattern substantially the same as that shown in Figure 39. 49. The compound of item 28, which is crystalline and exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2θ (±0.2°2θ) at 17.6, 23.2, and 22.0. 50. The compound of item 49, whose XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 8.2, 9.8, and 25.9. 51. The compound of item 49 or 50, whose XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 17.1 and 24.1. 52. The compound of any one of items 49 to 51, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 25.2 and 15.0. 53. The compound of any one of items 28 and 49-52, which is crystalline and has a differential scanning calorimetry (DSC) thermogram showing a first endotherm with an onset of about 120°C, a second endotherm with an onset of about 165°C, and a third endotherm with an onset of about 215°C. 54. The compound of item 53, whose DSC thermogram shows an exotherm with an onset of about 180°C. 55. The compound of item 28, having an X-ray powder diffraction pattern substantially the same as that shown in Figure 41. 56. The compound of item 28, which is crystalline and exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2θ (±0.2°2θ) at 23.4, 12.1, and 24.6. 57. The compound of item 56, whose XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 20.0, 7.9, and 24.9. 58. The compound of item 56 or 57, wherein the XRPD pattern further has characteristic peaks at 19.0 and 16.6 degrees 2θ (±0.2 degrees 2θ). 59. The compound of any one of items 56 to 58, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 20.6 and 22.1. 60. The compound of any one of items 28 and 56-59, which is crystalline and has a differential scanning calorimetry (DSC) thermogram showing a first endotherm with an onset of about 28°C and a second endotherm with an onset of about 213°C. 61. The compound of item 28, having an X-ray powder diffraction pattern substantially the same as that shown in Figure 44. 62. A pharmaceutical composition comprising a compound according to any one of items 1 to 61 and a pharmaceutically acceptable carrier or excipient. 63. Use of a compound according to any one of items 1 to 61 as an inhibitor of SGK-1. 64. Use of a compound according to any one of items 1 to 61 or a pharmaceutical composition according to item 19 for the treatment of a cardiovascular disease selected from the group consisting of long QT syndrome, heart failure, arrhythmias such as atrial fibrillation, ischemic injury, ischemic infarction, cardiac fibrosis, vascular proliferation, restenosis, dilated cardiomyopathy, and stent failure. 65. Use of a compound according to any one of items 1 to 61 or a pharmaceutical composition according to item 62 for the treatment of long QT syndrome. 66. Use of item 65, where the long QT syndrome is hereditary long QT syndrome. 67. Use of item 65, where the long QT syndrome is acquired long QT syndrome. 68. Use of a compound according to any one of items 1 to 61 or a pharmaceutical composition according to item 62 for the treatment of epilepsy. 69. Use of a compound according to any one of items 1 to 61 or a pharmaceutical composition according to item 62 for the treatment of Parkinson's disease or Lafora's disease. 70. Use of a compound according to any one of items 1 to 61 or a pharmaceutical composition according to item 62 for the treatment of cancer. 71. The use of item 70, wherein the cancer affects tissue containing cancerous cells in at least one of the following: breast, prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney, colon, intestine, endometrium, ovaries, lung, testicles, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gallbladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph node, sweat gland, sebaceous gland, muscle, heart, bone, and stomach. 72. Use of item 70, wherein the cancer is melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, colon cancer, or colorectal cancer. 73. Use of item 70, wherein the cancer is prostate cancer, colorectal cancer, or breast cancer. 74. Use of a compound according to any one of paragraphs 1 to 61 for the manufacture of a medicament for inhibiting SGK-1 in a subject. 75. Use of a compound according to any one of items 1 to 61 for the manufacture of a medicament for the treatment of a cardiovascular disease selected from the group consisting of long QT syndrome, heart failure, arrhythmias such as atrial fibrillation, ischemic injury, ischemic infarction, cardiac fibrosis, vascular proliferation, restenosis, dilated cardiomyopathy, and stent failure. 76. Use of a compound according to any one of items 1 to 61 for the manufacture of a medicament for the treatment of long QT syndrome. 77. Use of item 76, where the long QT syndrome is hereditary long QT syndrome. 78. Use of item 76, where the long QT syndrome is acquired long QT syndrome. 79. Use of a compound according to any one of items 1 to 61 for the manufacture of a medicament for the treatment of epilepsy. 80. Use of a compound according to any one of items 1 to 61 for the manufacture of a medicament for the treatment of Parkinson's disease or Lafora's disease. 81. Use of a compound according to any one of items 1 to 61 for the manufacture of a medicament for the treatment of cancer. 82. Use of item 81, wherein the cancer affects tissue containing cancerous cells in at least one of the following: breast, prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney, colon, intestine, endometrium, ovaries, lung, testicles, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gallbladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph node, sweat gland, sebaceous gland, muscle, heart, bone, and stomach. 83. Use of item 81, wherein the cancer is melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, colon cancer, or colorectal cancer. 84. Use of item 81, wherein the cancer is prostate cancer, colorectal cancer, or breast cancer. 85. A method for inhibiting SGK-1, comprising administering to a subject a compound defined in any one of items 1 to 61 or a pharmaceutical composition defined in item 62. 86. A method for treating a cardiovascular disease selected from the group consisting of long QT syndrome, heart failure, arrhythmias such as atrial fibrillation, ischemic injury, ischemic infarction, cardiac fibrosis, vascular proliferation, restenosis, dilated cardiomyopathy, and stent failure, comprising administering to a subject a therapeutically effective amount of a compound defined in any one of items 1 to 61, or a pharmaceutical composition defined in item 62. 87. A method for treating long QT syndrome, comprising administering to a subject a therapeutically effective amount of a compound defined in any one of items 1 to 61, or a pharmaceutical composition defined in item 62. 88. The method of item 87, wherein the long QT syndrome is hereditary long QT syndrome. 89. The method of item 87, wherein the long QT syndrome is acquired long QT syndrome. 90. A method for treating epilepsy, comprising administering to a subject a therapeutically effective amount of a compound defined in any one of items 1 to 61, or a pharmaceutical composition defined in item 62. 91. A method for treating Parkinson's disease or Lafora's disease, comprising administering to a subject a therapeutically effective amount of a compound defined in any one of items 1 to 61, or a pharmaceutical composition defined in item 62. 92. A method for treating cancer, comprising administering to a subject a therapeutically effective amount of a compound defined in any one of items 1 to 61, or a pharmaceutical composition defined in item 62. 93. The method of item 92, wherein the cancer affects tissue containing cancerous cells in at least one of the following: breast, prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney, colon, ovary, lung, testicle, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gallbladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph node, sweat gland, sebaceous gland, muscle, heart, and stomach. 94. The method of item 93, wherein the cancer is melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, colon cancer, or colorectal cancer. 95. The method of item 94, wherein the cancer is prostate cancer, colorectal cancer, or breast cancer. 96. A process for preparing a compound according to any one of items 1 to 9, comprising: dissolving N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-fluorophenyl]-2,5-difluorobenzenesulfonamide hydrochloride in a solvent to obtain a solution; filtering the solution; adding an anti-solvent to the filtrate; stirring the mixture until a crystalline material is obtained; and isolating the crystalline material. 97. The process of item 96, wherein the solvent is DMSO. 98. The process of item 97, wherein the concentration of N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-fluorophenyl]-2,5-difluorobenzenesulfonamide hydrochloride in the solvent is 50 mg / mL to 100 mg / mL. 99. The process of item 97, wherein the dissolution is carried out at a temperature of 70°C. 100. The process of any one of items 96 to 99, wherein the filtration is carried out at room temperature. 101. The process of any one of items 96 to 99, wherein the antisolvent is water. 102. The process of item 101, wherein the ratio of solvent:antisolvent is 2:10 to 0.5:10. 103. The process of item 101, wherein the ratio of solvent:antisolvent is 1:10. 104. The process of any one of items 96 to 103, wherein the stirring of the mixture is carried out at a temperature of 18°C to 25°C. 105. The process of item 104, wherein stirring the mixture is performed at room temperature. 106. The process of any one of items 96 to 105, wherein the mixture is stirred for about 2 to 6 days. 107. The process of item 106, wherein the mixture is stirred for about 4 days. 108. The process of any one of items 96 to 107, wherein the crystalline material is dried in a vacuum oven at a drying temperature of 40°C to 60°C for about 2 to 4 hours. 109. The process of any one of items 96 to 108, wherein the crystalline material is isolated by filtration. 110. A process for preparing the compound of any one of items 28 to 36, comprising: combining 1 molar equivalent of N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-fluorophenyl]-2,5-difluorobenzenesulfonamide with at least 2 molar equivalents of methanesulfonic acid in a solvent; evaporating at least a portion of the solvent; stirring the mixture until a crystalline material is obtained; and isolating the crystalline material. 111. The process of item 110, wherein the solvent is methanol. 112. The process of item 110, wherein the concentration of N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-fluorophenyl]-2,5-difluorobenzenesulfonamide in the solvent is 0.1 mol / L to 0.3 mol / L. 113. The process of item 112, wherein the concentration is about 0.2 mol / L. 114. The process of item 111, wherein the stirring of the mixture is carried out at a temperature of 20°C to 25°C. 115. The process of item 114, wherein the temperature is 20°C to 22°C. 116. The process of any one of items 110 to 115, wherein stirring the mixture is carried out for about 4 to 6 days. 117. The process of any one of items 110 to 115, wherein the mixture is stirred for about 5 days. 118. The process of any one of items 110 to 115, wherein the crystalline material is dried in a vacuum oven at a drying temperature of 62°C to 72°C for about 1 day. 119. The process of any one of items 110 to 118, wherein the crystalline material is isolated by filtration.

[0291] While the present invention has been illustrated and described with respect to one or more implementations, equivalent alterations and modifications will occur to those skilled in the art upon reading and understanding this specification. In addition, while a particular feature of the invention may be disclosed with respect to only one of several implementations, such feature may be combined with one or more other features of other implementations, as may be desirable or advantageous for any given or particular application.

[0292] It is therefore understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be suggested to those skilled in the art and are intended to be included within the spirit and scope of this application and the appended claims. Any publications, documents, patents, patent applications, or publications referenced herein should be construed as being each incorporated by reference in their entirety for all purposes.

Claims

1. The compound of formula II is crystalline. 【Chemical 1】

2. 10. The compound of claim 1, which is crystalline and exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 6.7, 22.3, and 29.

0.

3. 3. The compound of claim 2, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 15.9, 20.5, and 20.

7.

4. 4. The compound of claim 2 or 3, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 28.7, 20.2, and 13.

5.

5. 5. The compound of any one of claims 2 to 4, wherein the XRPD pattern further has characteristic peaks expressed in degrees two-theta (±0.2 degrees two-theta) at 26.2, 23.5, and 36.

1.

6. 6. The compound of any one of claims 2 to 5, wherein the XRPD pattern further has characteristic peaks expressed in degrees two-theta (±0.2 degrees two-theta) at 24.1, 10.2, and 25.

6.

7. 7. The compound of any one of claims 2 to 6, wherein the XRPD pattern further has characteristic peaks expressed in degrees two-theta (±0.2 degrees two-theta) at 19.0, 27.2, and 32.

3.

8. 10. The compound of claim 1, which is crystalline and has a differential scanning calorimetry (DSC) thermogram that exhibits an endotherm with an onset of about 302°C.

9. 29. The compound of claim 1, having an X-ray powder diffraction pattern substantially the same as that shown in FIG.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier or excipient.

11. Use of a compound according to any one of claims 1 to 9 as an inhibitor of SGK-1.

12. Use of the compound of any one of claims 1 to 9 or the pharmaceutical composition of claim 10 for the treatment of a cardiovascular disease selected from the group consisting of long QT syndrome, heart failure, arrhythmias such as atrial fibrillation, ischemic injury, ischemic infarction, cardiac fibrosis, vascular proliferation, restenosis, dilated cardiomyopathy, and stent failure.

13. Use of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 for the treatment of long QT syndrome.

14. The use according to claim 13, wherein the long QT syndrome is hereditary long QT syndrome.

15. The use according to claim 13, wherein the long QT syndrome is acquired long QT syndrome.

16. Use of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 19 for the treatment of epilepsy.

17. Use of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 19 for the treatment of Parkinson's disease or Lafora's disease.

18. Use of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 for the treatment of cancer.

19. 19. The use of claim 18, wherein the cancer affects tissue containing cancerous cells in at least one of the following: breast, prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney, colon, intestine, endometrium, ovary, lung, testicle, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gallbladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph node, sweat gland, sebaceous gland, muscle, heart, bone, and stomach.

20. 19. The use of claim 18, wherein the cancer is melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, colon cancer, or colorectal cancer.

21. 19. The use of claim 18, wherein the cancer is prostate cancer, colorectal cancer, or breast cancer.

22. Use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for inhibiting SGK-1 in a subject.

23. 10. Use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment of a cardiovascular disease selected from the group consisting of long QT syndrome, heart failure, arrhythmias such as atrial fibrillation, ischemic injury, ischemic infarction, cardiac fibrosis, vascular proliferation, restenosis, dilated cardiomyopathy, and stent failure.

24. Use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment of long QT syndrome.

25. 25. The use according to claim 24, wherein the long QT syndrome is hereditary long QT syndrome.

26. 25. The use according to claim 24, wherein the long QT syndrome is acquired long QT syndrome.

27. Use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment of epilepsy.

28. Use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment of Parkinson's disease or Lafora's disease.

29. Use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment of cancer.

30. 30. The use of claim 29, wherein the cancer affects tissue comprising cancerous cells in at least one of the following: breast, prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney, colon, intestine, endometrium, ovary, lung, testicle, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gallbladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph node, sweat gland, sebaceous gland, muscle, heart, bone, and stomach.

31. 30. The use of claim 29, wherein the cancer is melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, colon cancer, or colorectal cancer.

32. 30. The use of claim 29, wherein the cancer is prostate cancer, colorectal cancer, or breast cancer.

33. A method for inhibiting SGK-1, comprising administering to a subject a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10.

34. A method for treating a cardiovascular disease selected from the group consisting of long QT syndrome, heart failure, arrhythmias such as atrial fibrillation, ischemic injury, ischemic infarction, cardiac fibrosis, vascular proliferation, restenosis, dilated cardiomyopathy, and stent failure, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 to a subject.

35. A method for treating long QT syndrome, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 to a subject.

36. 36. The method of claim 35, wherein the long QT syndrome is hereditary long QT syndrome.

37. 36. The method of claim 35, wherein the long QT syndrome is acquired long QT syndrome.

38. A method for treating epilepsy, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 to a subject.

39. A method for treating Parkinson's disease or Lafora's disease, comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10.

40. A method for treating cancer, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 to a subject.

41. 41. The method of claim 40, wherein the cancer affects tissue comprising cancerous cells in at least one of the following: breast, prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney, colon, ovary, lung, testicle, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gallbladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph node, sweat gland, sebaceous gland, muscle, heart, and stomach.

42. 42. The method of claim 41, wherein the cancer is melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, colon cancer, or colorectal cancer.

43. 43. The method of claim 42, wherein the cancer is prostate cancer, colorectal cancer, or breast cancer.

44. A process for preparing a compound according to any one of claims 1 to 9, comprising: dissolving N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-fluorophenyl]-2,5-difluorobenzenesulfonamide hydrochloride in a solvent to obtain a solution; filtering the solution; adding an anti-solvent to the filtrate; stirring the mixture until a crystalline material is obtained; and isolating said crystalline material.

45. 45. The process of claim 44, wherein the solvent is DMSO.

46. 46. The process of claim 45, wherein the concentration of N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-fluorophenyl]-2,5-difluorobenzenesulfonamide hydrochloride in the solvent is 50 mg / mL to 100 mg / mL.

47. 46. The process of claim 45, wherein the dissolving is carried out at a temperature of 70°C.

48. 48. The process of any one of claims 44 to 47, wherein the filtration is carried out at room temperature.

49. The process of any one of claims 44 to 47, wherein the anti-solvent is water.

50. 50. The process of claim 49, wherein the ratio of solvent to anti-solvent is from 2:10 to 0.5:

10.

51. 50. The process of claim 49, wherein the ratio of solvent to anti-solvent is 1:

10.

52. 52. The process of any one of claims 44 to 51, wherein the stirring of the mixture is carried out at a temperature of from 18°C to 25°C.

53. 53. The process of claim 52, wherein the stirring of the mixture is performed at room temperature.

54. 54. The process of any one of claims 44 to 53, wherein stirring the mixture is carried out for about 2 to 6 days.

55. 55. The process of claim 54, wherein the stirring of the mixture is carried out for about 4 days.

56. 56. The process of any one of claims 44 to 55, wherein the crystalline material is dried in a vacuum oven at a drying temperature of 40°C to 60°C for about 2 to 4 hours.

57. 57. The process of any one of claims 44 to 56, wherein the crystalline material is isolated by filtration.

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