Salts of n-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1h-pyrazolo[3,4-d]pyrimidin-6-YL)-2-chlorophenyl]-2,5-difluorobenzenesulfonamide and crystalline forms thereof

Abstract

A maleate salt of the compound of Formula (I) is provided: Crystalline forms of the compound of Formula (I) are also provided. The compound of Formula (I) and crystalline forms thereof can be used for the treatment of several conditions linked to the inhibition of SGK-1, such as a cardiovascular disease selected from the group consisting of Long QT syndrome, heart failure, arrhythmia, atrial fibrillation, ischemic injury, ischemic infarction, cardiac fibrosis, vascular proliferation, restenosis, dilated cardiomyopathy, and stent failure; inflammatory or fibrotic diseases, cancer, epilepsy, Parkinson's disease, and Lafora disease.

Description

SALTS OF N-[4-(4-[[2-(DIMETHYLAMINO)ETHYL]AMINO]-3-METHYL-1 H- PYRAZOLO[3,4-D]PYRIMIDIN-6-YL)-2-CHLOROPHENYL]-2,5- DIFLUOROBENZENESULFONAMIDE AND CRYSTALLINE FORMS THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of PCT patent application serial number PCT / CN2024 / 133445 filed on November 21 , 2024 and of U.S. provisional patent application serial number 63 / 736,222 filed on December 19, 2024. The contents of each of the above-referenced documents are incorporated herein by reference in their entirety.TECHNICAL FIELD

[0002] The technical field relates to salts of the compound N-[4-(4-[[2- (DIMETHYLAMINO)ETHYL]AMINO]-3-METHYL-1 H-PYRAZOLO[3,4-D]PYRIMIDIN- 6YL)-2-CHLOROPHENYL]-2,5-DIFLUOROBENZENESULFONAMIDE and their crystalline forms, as well as pharmaceutical compositions, therapeutic uses thereof and processes of manufacture.BACKGROUND

[0003] Serine / threonine-protein kinase (SGK-1) (also known as serum / glucocorticoid- regulated kinase 1) is a protein kinase that plays a role in a cell's response to stress. SGK-1 activates certain potassium, sodium, and chloride channels. For instance, SGK- 1 is known to regulate the myo-inositol transporter during osmotic stress. Several challenges remain in the development of an SGK-1 inhibitor for the treatment of heart conditions such as LOTS, atrial fibrillation, heart failure and / or for the treatment of inflammatory or fibrotic diseases.SUMMARY

[0004] This Summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key aspects or essential aspects of the claimed subject matter.

[0005] In one aspect, there is provided, a maleate salt of the compound of Formula I which is crystalline:

[0006] In a further aspect, there is provided a pharmaceutical composition, comprising a compound as defined herein and a pharmaceutically acceptable carrier or excipient.

[0007] In a further aspect, there is provided the use of a compound as defined herein, as an inhibitor of SGK-1 .

[0008] In a further aspect, there is provided the use of a compound or pharmaceutical composition as defined herein, for the treatment of atrial fibrillation, heart failure and inflammatory or fibrotic diseases.

[0009] In a further aspect, there is provided the use of a compound as defined herein, for the manufacture of a medicament that inhibits SGK-1 in a subject.

[0010] In a further aspect, there is provided the use of a compound as defined herein, for the manufacture of a medicament for the treatment of atrial fibrillation or heart failure.

[0011] In a further aspect, there is provided the use of a compound as defined herein, for the manufacture of a medicament for the treatment of inflammatory or fibrotic diseases.

[0012] In a further aspect, there is provided a method for inhibiting SGK-1 , comprising administering to a subject a compound or pharmaceutical composition as defined herein.

[0013] In a further aspect, there is provided a method for the treatment of atrial fibrillation or heart failure, comprising administering to a subject in need thereof a compound or pharmaceutical composition as defined herein.

[0014] In a further aspect, there is provided a method for the treatment of inflammatory or fibrotic diseases, comprising administering to a subject in need thereof a compound or pharmaceutical composition as defined herein.

[0015] In a further aspect, there is provided a compound as defined herein for use in the treatment of atrial fibrillation or heart failure, or in the manufacture of a medicament for the treatment of atrial fibrillation or heart failure.

[0016] In a further aspect, there is provided a compound as defined herein for use in the treatment of inflammatory or fibrotic diseases, or in the manufacture of a medicament for the treatment of inflammatory or fibrotic diseases.

[0017] In a further aspect, there is provided a pharmaceutical composition comprising a compound as defined herein, and a pharmaceutically acceptable excipient, for use in the treatment of atrial fibrillation or heart failure or in the manufacture of a medicament for the treatment of atrial fibrillation or heart failure.

[0018] In a further aspect, there is provided a pharmaceutical composition comprising a compound as defined herein, and a pharmaceutically acceptable excipient, for use in the treatment of inflammatory or fibrotic diseases, or in the manufacture of a medicament for the treatment of inflammatory or fibrotic diseases.

[0019] In a further aspect, there is provided a process for preparing a compound as defined herein, comprising: combining 1 molar equivalent of N-[4-(4-[[2- (dimethylamino)ethyl]amino]-3-methyl-1 H-pyrazolo[3,4D]pyrimidin-6yl)-2- chlorophenyl]-2,5-difluorobenzenesulfonamide with at least 1 molar equivalent of maleic acid in a solvent to obtain a mixture; stirring the mixture isolating the crystalline material; and wherein said process is conducted under conditions suitable to obtain said crystalline material.

[0020] All features of embodiments which are described in this disclosure and are not mutually exclusive can be combined with one another. Elements of one embodiment can be utilized in the other embodiments without further mention. Other aspects, features, advantages, and benefits of the compositions, formulations, and methods ofthe present disclosure will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments in conjunction with the accompanying Figures.BRIEF DESCRIPTION OF THE FIGURES

[0021] For a better understanding of the various embodiments described herein, and to show more clearly how these various embodiments may be carried into effect, reference will be made, by way of example, to the accompanying drawings which show at least one example embodiment, and which are now described. The drawings are not intended to limit the scope of the teachings described herein. In the drawings:

[0022] Figure 1 is an XRPD of Compound 2, Form I (HCI salt).

[0023] Figure 2 are TGA and DSC thermograms of Compound 2, Form I (HCI salt).

[0024] Figure 3 is an XRPD of Compound 2, Form II (HCI salt).

[0025] Figure 4 are TGA and DSC thermograms of Compound 2, Form II (HCI salt).

[0026] Figure 5 is an XRPD of Compound 2, Form III (HCI salt).

[0027] Figure 6 are TGA and DSC thermograms of Compound 2, Form III (HCI salt).

[0028] Figure 7 is an XRPD of Compound 3, Form I (sulfate salt).

[0029] Figure 8 are TGA and DSC thermograms of Compound 3, Form I (sulfate salt).

[0030] Figure 9 is an XRPD of Compound 3, Form II (sulfate salt).

[0031] Figure 10 are TGA and DSC thermograms of Compound 3, Form II (sulfate salt).

[0032] Figure 11 is an XRPD of Compound 3, Form III (sulfate salt).

[0033] Figure 12 are TGA and DSC thermograms of Compound 3, Form III (sulfate salt).

[0034] Figure 13 is an XRPD of Compound 4, Form I (tosylate salt).

[0035] Figure 14 are TGA and DSC thermograms of Compound 4, Form I (tosylate salt).

[0036] Figure 15 is an XRPD of Compound 5, Form I (mesylate salt).

[0037] Figure 16 are TGA and DSC thermograms of Compound 5, Form I (mesylate salt).

[0038] Figure 17 is an XRPD of Compound 5, Form II (mesylate salt).

[0039] Figure 18 are TGA and DSC thermograms of Compound 5, Form II (mesylate salt).

[0040] Figure 19 is an XRPD of Compound 5, Form III (mesylate salt).

[0041] Figure 20 are TGA and DSC thermograms of Compound 5, Form III (mesylate salt).

[0042] Figure 21 is an XRPD of Compound 6, Form I (besylate salt).

[0043] Figure 22 are TGA and DSC thermograms of Compound 6, Form I (besylate salt).

[0044] Figure 23 is an XRPD of Compound 6, Form II (besylate salt).

[0045] Figure 24 are TGA and DSC thermograms of Compound 6, Form II (besylate salt).

[0046] Figure 25 is an XRPD of Compound 7, Form I (maleate salt).

[0047] Figure 26 are TGA and DSC thermograms of Compound 7, Form I (maleate salt).

[0048] Figure 27 is an XRPD of Compound 7, Form II (maleate salt).

[0049] Figure 28 are TGA and DSC thermograms of Compound 7, Form II (maleate salt).

[0050] Figure 29 is an XRPD of Compound 8 Form I (phosphate salt).

[0051] Figure 30 are TGA and DSC thermograms of Compound 8 Form I (phosphate salt).

[0052] Figure 31 is an XRPD of Compound 9 Form I (tartrate salt).

[0053] Figure 32 are TGA and DSC thermograms of Compound 9 Form I (tartrate salt).

[0054] Figure 33 is an XRPD of Compound 10 Form I (fumarate salt).

[0055] Figure 34 are TGA and DSC thermograms of Compound 10 Form I (fumarate salt).

[0056] Figure 35 is an XRPD of Compound 11 Form I (citrate salt).

[0057] Figure 36 are TGA and DSC thermograms of Compound 11 Form I (citrate salt).

[0058] Figure 37 is an XRPD of Compound 1 Form I (free form).

[0059] Figure 38 are TGA and DSC thermograms of Compound 1 Form I (free form).

[0060] Figure 39 is a XRPD overlay of Compound 1 Form I, Compound 1 Form II and the sample with low crystallinity after heating to 185 °C.

[0061] Figure 40 is a DVS of Compound 1 Form I (free form).

[0062] Figure 41 is a XRPD overlay of Compound 1 Form I (free form) before (down) and after (up) DVS analysis.

[0063] Figure 42 is a DVS of Compound 4 Form I (tosylate salt).

[0064] Figure 43 is a XRPD overlay of Compound 4 Form I (tosylate salt) before (up) and after (down) DVS analysis.

[0065] Figure 44 is a DVS of Compound 7 Form II (maleate salt).

[0066] Figure 45 is a XRPD overlay of Compound 7 Form II (maleate salt) before (down) and after (up) DVS analysis.

[0067] Figure 46 is an XRPD of Compound 7, Form II (maleate salt) obtained via scale- up protocol (5g scale).

[0068] Figure 47 are TGA and DSC thermograms of Compound 7, Form II (maleate salt) obtained via scale-up protocol (5g scale).

[0069] Figure 48 is a XRPD overlay (from top to bottom) of Compound 7 Form II (maleate salt), Compound 7 Form III (wet sample) and a mixture of Form II and Form III (dry sample).

[0070] Figure 49 is an XRPD of Compound 7, Form IV (maleate salt).

[0071] Figure 50 are TGA and DSC thermograms of Compound 7, Form IV (maleate salt).

[0072] Figure 51 is an XRPD of Compound 7, Form V (maleate salt).

[0073] Figure 52 are TGA and DSC thermograms of Compound 7, Form V (maleate salt).

[0074] Figure 53 is an XRPD of Compound 7, Form VI (maleate salt).

[0075] Figure 54 are TGA and DSC thermograms of Compound 7, Form VI (maleate salt).

[0076] Figure 55 is an XRPD of Compound 7, Form VII (maleate salt).

[0077] Figure 56 are TGA and DSC thermograms of Compound 7, Form VII (maleate salt).

[0078] Figure 57 is an XRPD of Compound 7, Form VIII (maleate salt).

[0079] Figure 58 are TGA and DSC thermograms of Compound 7, Form VIII (maleate salt).

[0080] In the drawings, exemplary embodiments are illustrated by way of example. It is to be expressly understood that the description and drawings are only for the purpose of illustrating certain embodiments and are an aid for understanding. They are not intended to be a definition of the limits of the invention.DETAILED DESCRIPTION

[0081] The present technology is explained in greater detail below. This description is not intended to be a detailed catalog of all the different ways in which the technologymay be implemented, or all the features that may be added to the instant technology. For example, features illustrated with respect to one embodiment may be incorporated into other embodiments, and features illustrated with respect to a particular embodiment may be deleted from that embodiment. In addition, numerous variations and additions to the various embodiments suggested herein will be apparent to those skilled in the art considering the instant disclosure which variations and additions do not depart from the present technology. Hence, the following description is intended to illustrate some embodiments of the technology, and not to exhaustively specify all permutations, combinations, and variations thereofDefinitions

[0082] The term “stable”, as used herein, includes chemical stability and / or solid-state stability. A compound is considered chemically stable when the compound can be stored in an isolated solid form, or in the form of a solid formulation in which it may be provided in admixture with pharmaceutically acceptable carriers, diluents or adjuvants, under normal storage conditions, without any significant degree of chemical degradation or decomposition.

[0083] A compound is considered to have solid-state stability when the compound can be stored in an isolated solid form, or in the form of a solid formulation in which it may be provided in admixture with pharmaceutically acceptable carriers, diluents or adjuvants, under normal storage conditions, without any significant degree of solid state transformation (e.g. crystallisation, recrystallisation, loss of crystallinity, solid state phase transition, hydration, dehydration, deliquescence, solvation or desolvation).

[0084] Crystalline forms of solid chemical compounds influence not only their dissolution behavior (i.e., bioavailability) but also their solid-state stability. One way of comparing the solid-state stability of crystalline forms is to evaluate the relative “thermodynamic stability” of the crystalline forms. 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. Calorimetry techniques (e.g., Differential Scanning Calorimetry) can also be used to measure thermal events and phase transitions across a wide temperature range, and a comparison between the crystalline forms can give an indication as to their relative thermodynamic stability.

[0085] The expression “pharmaceutically acceptable carrier or excipient”, as used herein, includes without limitation any adjuvant, carrier, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier which is known as being acceptable for pharmaceutical use in humans or domestic animals.

[0086] The expression “pharmaceutical composition”, as used herein, refers to the formulation of a compound and a pharmaceutically acceptable carrier or excipient.

[0087] As used herein, the term "hydrate" refers to a crystalline form of a molecule that further comprises molecules of water incorporated into the crystalline lattice structure. The water molecules in the hydrate may be present in a regular arrangement and / or a non-ordered arrangement. The hydrate may comprise either a stoichiometric or nonstoichiometric amount of the water molecules. For example, a hydrate with a nonstoichiometric amount of water molecules may result from partial loss of water from the hydrate.

[0088] As used herein, the terms “anhydrate” or "anhydrous" refer to a crystalline form of a molecule per se that does not further comprise molecules of water incorporated into the crystalline lattice structure.

[0089] 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 crystalline lattice structure. The solvent molecules in the solvate may be present in a regular arrangement and / or a non-ordered arrangement. The solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. For example, a solvate with a nonstoichiometric amount of solvent molecules may result from partial loss of solvent from the solvate. The solvent can include various organic solvents. It should also be understood that a “solvate” can include a single solvent, a mixture of solvents or a mixture of a solvent (or solvents) and water.

[0090] The term “substantially the same”, used herein to describe X-ray diffraction patterns, is meant to include patterns in which peaks are within a standard deviation of ±0.2° 2© or an X-ray diffraction pattern comprising least 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 or 16 peaks in common with the referenced pattern. Further, a person skilled in the art will appreciate that relative peak intensities will show inter-apparatusvariability as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors. As such, the relative peak intensities should be taken as a qualitative measure.

[0091] The present description provides salt screening experiments N-[4-(4-[[2- (DIMETHYLAMINO)ETHYL]AMINO]-3-METHYL-1 H-PYRAZOLO[3,4-D]PYRIMIDIN- 6-YL)-2-CHLOROPHENYL]-2,5-DIFLUOROBENZENESULFONAMIDE (Compound 1 , also referred to as Compound of Formula (I)) and the crystalline forms thereof. In particular, the present description provides the following compound of Formula I:

[0092] The structure depicted for the compound of Formula I is also meant to include all tautomeric forms of the compound of Formula I. 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, compounds having the structure of the compound of Formula I except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the present description.

[0093] The term “substantially pure”, when used in reference to a crystalline form of the compound of Formula I, is meant to include a crystalline form which has a purity that is greater than about 90%. This means that the crystalline form may not contain more than about 10% of any other compound, and in particular, does not contain more than about 10% of any other crystalline form of the compound of Formula I. Preferably, the term “substantially pure” means a crystalline form which has a purity that is greater than about 95%. This means that the crystalline form may not contain more than about 5% of any other compound, and in particular, does not contain more than about 5% of any other crystalline form of the compound of Formula I. More preferably, the term “substantially pure” means a crystalline form which has a purity that is greater thanabout 99%. This means that the crystalline form may not contain more than about 1% of any other compound, and in particular, does not contain more than about 1 % of any other crystalline form of the compound of Formula I.

[0094] The term “solid mixture” when used in reference to the compounds of the present description, refers to a mixture of crystalline forms. For example, a solid mixture can include at least two different crystalline forms.

[0095] XRPD data were obtained using a PANalytical X’Pert PRO MPD or a PANanalytical Empyrean X-ray powder diffractometers, using an incident beam of Cu radiation produced by an Optix long, fine-focus source. The radiation used was Cu Ka (A = 1.5405929 A). It should be understood that the 2© values listed herein are dependent on the Form of radiation used, and that a person skilled in the art would understand that the XRPD of a given crystalline form will exhibit different 2© values if a different radiation is used (e.g., a molybdenum radiation).

[0096] As used herein the terms “crystalline Form” or "polymorph" refers to crystal structure of a compound, having the same chemical composition but different spatial arrangements of the molecules, atoms, and / or ions forming the crystal structure.

[0097] The compounds of the present description may exist in solvated, for example hydrated, as well as unsolvated forms. Typically, but not absolutely, the salts of the compounds of the present description are pharmaceutically acceptable salts. Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of the present description.

[0098] 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 acid such as aspartate and glutamate; 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 acid such as lysine salt and arginine salt. The salts may be in some cases hydrates or ethanol solvates.Salts formation experiments of compound 1Compound 1(also referred to as Compound of Formula (I))

[0099] Salt formation experiments were conducted using a variety of acids (i.e. hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, phosphoric acid, maleic acid, L-tartaric acid, fumaric acid, citric acid, L-malic acid and succinic acid) with Compound 1 (N-[4-(4-[[2- (DIMETHYLAMINO)ETHYL]AMINO]-3-METHYL-1 H-PYRAZOLO[3,4-D]PYRIMIDIN- 6-YL)-2-CHLOROPHENYL]-2,5-DIFLUOROBENZENESULFONAMIDE).Hydrochloride salt - Compound 2

[0100] Three crystalline forms of Compound 2 were obtained, Form I, Form II and Form III.Form I (hydrate)

[0101] Form I showed high crystallinity. XRPD patterns was recorded and is showed in Figure 1.

[0102] According to DSC, Form I shows two endothermic peaks at 86.5°C (onset: 60°C) and 178.5°C (onset: 169°C), likely due to dehydration. TGA analysis of Form I shows a one-step weight loss of 9.0% from room temperature to 140°C. (Figure 2)

[0103] HCI salt form I is postulated to be a hydrate (calculated: 8.8% for 3eq. H2O).Form II (hydrate)

[0104] Form II showed high crystallinity. XRPD pattern was recorded and is showed in Figure 3.

[0105] According to DSC, Form II shows two endothermic peaks at 135.5°C (onset: 106.5°C) and 227°C (onset: 209.5°C) (Figure 4). TGA analysis of Form II shows a two- step weight loss of 2.9% from room temperature to 169°C and 3.4% from 197°C to 250°C.

[0106] There was a ~0.5% wt (0.05 eq.) residual Acetone detected by1H NMR. HCI salt Form II is postulated to be a hydrate (calculated: 2.9% for 1eq. H2O).Form III (hydrate)

[0107] Form II showed moderate crystallinity. XRPD pattern was recorded and is showed in Figure 5.

[0108] According to DSC, Form III shows four endothermic peaks at 83°C (onset: 52°C), 184°C (onset: 176°C), 232°C (onset: 212.5°C) and 258.5°C (onset: 251 °C) (Figure 6). TGA analysis of Form III shows a one-step weight loss of 6.0% from room temperature to 116°C.

[0109] HCI salt Form III is postulated to be a hydrate (calculated: 5.7% for 2eq. H2O).Sulfate salt - Compound 3

[0110] Three crystalline forms of Compound 3 were obtained, Form I, Form II and Form III.Form I (heterosolvate)

[0111] Form I showed moderate crystallinity. XRPD pattern was recorded and is showed in Figure 7.

[0112] According to DSC, Form I show three broad endothermic peaks at about 68.5°C (onset 35°C), about 163°C (onset 155°C) and about 202°C (onset 190°C), possiblydue to desolvation (Figure 8). TGA analysis shows a 5.7% weight loss from room temperature to 171 °C.

[0113] About 2.8% of residual EtOH was detected by1H NMR (0.39 eq.). Sulfate Form I is postulated to be a heterosolvate of EtOH and water.Form II (heterosolvate)

[0114] Form II showed moderate crystallinity. XRPD pattern was recorded and is showed in Figure 9.

[0115] According to DSC, Form II shows three endothermic peaks at about 63°C (onset: 33.5°C), about 169°C (onset: 163.5°C) and about 233°C (onset: 217°C) and one exothermic peak at about 134°C (onset: 106°C), possibly due to desolvation (Figure 10). TGA analysis of Form II shows a 3.6% weight loss from room temperature to 155°C.

[0116] About 1.8% of residual THF was detected by1H NMR (0.16 eq.). Sulfate salt Form II is postulated to be a heterosolvate of THF and water.Form III (hydrate)

[0117] Form III showed high crystallinity. XRPD pattern was recorded and is showed in Figure 11.

[0118] According to DSC, Form III shows three endothermic peaks at about 68.5°C (onset: 33.5°C), about 190°C (onset: 178.5°C) and about 261.5°C (onset: 252°C) and one exothermic peak at about 196.5°C (onset: 193.5°C), possibly due to dehydration. TGA analysis of Form III shows a 6.3% weight loss between room temperature and 145°C. (Figure 12)

[0119] Negligeable acetone residue was detected by1H NMR. Sulfate salt form III is postulated to be a hydrate.Tosylate salt - Compound 4

[0120] One crystalline form of Compound 4 was obtained, Form I (anhydrate).

[0121] Form I showed fine crystals with high crystallinity. XRPD pattern was recorded and is showed in Figure 13.

[0122] Compound 4 Form I exhibits an XRPD pattern (Figure 27) having characteristic peaks expressed in degrees 2© (±0.2° 2©) at 14.29, 24.60 and 25.08. The XRPD pattern of Compound 4 Form I can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 20.30, 15.97 and 10.03. The XRPD pattern of Compound 4 Form I can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 21.85, 13.81 and 16.39. The XRPD pattern of Compound 4 Form I can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 12.87, 25.52 and 22.21. The XRPD pattern of Compound 4 Form I can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 9.74, 10.73 and 18.16. The XRPD pattern of Compound 4 Form I can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 23.12, 26.26 and 31.57. The XRPD pattern of Compound 4 Form I can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 28.92, 26.82 and 20.81. The XRPD pattern of Compound 4 Form I can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 17.52, 28.33 and 37.03. The XRPD pattern of Compound 4 Form I can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 34.72, 21.25 and 23.51 . The XRPD pattern of Compound 4 Form I can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 34.16, 27.26 and 18.50. The XRPD pattern of Compound 4 Form I can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 9.04, 15.03 and 7.2. The XRPD pattern of Compound 4 Form I can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 6.10, 11.36 and 29.96.

[0123] According to DSC, Form I exhibited two endothermic peaks at about 184.5°C (onset: 180°C) and about 254°C (onset: 249°C) and one exothermic peak at about 219°C (onset: 199.5°C). TGA analysis of form I showed a 0.4% weight loss prior to 85°C. (Figure 14)

[0124] No THF residue was detected by1H NMR and the ratio of base to acid was determined to be 1 : 1. Tosylate salt Form I is postulated to be an anhydrate.Mesylate salt - Compound 5

[0125] Two crystalline forms of Compound 5 were obtained: Form I and Form II.Form I (hydrate)

[0126] Form I showed high crystallinity. XRPD pattern was recorded and is showed in Figure 15.

[0127] According to DSC, Form I exhibited five endothermic peaks at about 79°C (onset: 48°C), about 134°C (onset: 125°C), about 194°C (onset: 184°C), about 224°C (onset: 213°C) and about 243°C (onset: 238°C), corresponding to dehydration. TGA analysis of Form I shows a 7.3% weight loss prior to 178°C. (Figure 16)

[0128] About 1.2% wt. (0.16 eq.) of EtOH was detected by1H NMR and the ratio of base to acid was determined to be 1 : 1.3. Mesylate salt form I is postulated to be a hydrate (calculated: 5.5%, 2 eq. H2O).Form II (hydrate)

[0129] Form II showed high crystallinity. XRPD pattern was recorded and is showed in Figure 17.

[0130] According to DSC, Form II exhibited three endothermic peaks at about 80°C (onset: 35°C), about 134°C (onset: 130°C), and about 218°C (onset: 215°C), corresponding to dehydration. TGA analysis of Form II showed a two-step weight loss of 6.6% from room temperature to 112°C. (Figure 18)

[0131] Negligeable EtOH residue was detected by1H NMR and the ratio of base to acid is determined to be approximately 1 : 2. Mesylate salt form II is postulated to be a hydrate (calculated: 7.0%, 3 eq. H2O).Form III (hydrate)

[0132] Form III showed high crystallinity. XRPD pattern was recorded and is showed in Figure 19.

[0133] According to DSC, Form III exhibited three endothermic peaks at about 132°C (onset: 108°C), about 166°C (onset: 157°C), and about 219°C (onset: 216°C), corresponding to dehydration. TGA analysis of Form III showed a weight loss of 2.9% from room temperature to 176°C. (Figure 20)

[0134] About 0.52% wt. (0.06 eq.) of acetone was detected by1H NMR and the ratio of base to acid is determined to be 1 : 2. Mesylate salt form III is postulated to be a hydrate (calculated: 2.5%, 1 eq. H2O).Besylate salt - Compound 6

[0135] Two crystalline forms of Compound 6 were obtained: Form I and Form II.Form I (solvate)

[0136] Form I showed moderate crystallinity. XRPD pattern was recorded and is showed in Figure 21.

[0137] According to DSC, Form I exhibited two endothermic peaks at about 61 °C (onset: 31 °C), and about 124°C (onset: 115°C). TGA analysis shows a 1.7% weight loss at 103°C and a 7.8% weight loss from 108°C to 165°C. (Figure 22)

[0138] About 10% wt. of THF (1.05 eq.) was detected by1H NMR and the ratio of base to acid was determined to be 1 : 1 . Besylate salt Form I is postulated to be a THF solvate.Form II (hydrate)

[0139] Form II showed high crystallinity. XRPD pattern was recorded and is showed in Figure 23.

[0140] According to DSC, Form II exhibited two endothermic peaks at about 109°C (onset: 66°C) and about 160°C (onset: 150°C). TGA analysis shows a 2.2% weight loss from room temperature to 146°C. (Figure 24)

[0141] About 0.34% wt. (0.04 eq.) of acetone was detected by1H NMR and the ratio of base to acid was determined to be 1 : 1 .5. Besylate salt Form II is postulated to be a hydrate (calculated: 2.6%, 1.0 eq. H2O).Maleate salt - Compound 7

[0142] Two crystalline forms of Compound 7 were obtained, Form I and Form II.Form I (hydrate)

[0143] Form I showed moderate crystallinity. XRPD pattern was recorded and is showed in Figure 25.

[0144] According to DSC, Form I exhibited two endothermic peaks at about 73°C (onset: 43°C) and about 132°C (onset: 125°C). TGA analysis shows a 5.8% weight loss prior to 115°C. (Figure 26)

[0145] No residual EtOH was observed by1H NMR and the ratio of base to acid was determined to be 1 : 1 .

[0146] Maleate salt Form I is postulated to be a hydrate (calculated: 5.3%, 2.0 eq. H2O).Form II (an hydrate)

[0147] Form II showed fine crystals with high crystallinity. XRPD pattern was recorded and is showed in Figure 27.

[0148] Compound 7 Form II exhibits an XRPD pattern (Figure 27) having characteristic peaks expressed in degrees 2© (±0.2° 2©) at 6.61 and 29.68. The XRPD pattern of Compound 7 Form II can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 20.41 , 24.50 and 13.25. The XRPD pattern of Compound 7 Form II can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 26.41 , 10.01 and 12.12. The XRPD pattern of Compound 7 Form II can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 14.79 and 19.84. The XRPD pattern of Compound 7 Form II can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 22.24, 23.64 and 28.43. The XRPD pattern of Compound 7 Form II can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 14.01 , and 11.60. The XRPD pattern of Compound 7 Form II can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 26.82, 17.52 and 30.08. The XRPD pattern of Compound 7 Form II can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 20.14, 25.02, 25.81 and 10.96. The XRPD pattern of Compound 7 Form II can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 21.29, 16.57, 11.41 and 29.36. The XRPD pattern of Compound 7 Form II can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 15.12, 8.58, 28.81 and 36.79. The XRPD pattern of Compound 7 Form II can also exhibit further characteristic peaks expressedin degrees 26 (±0.2° 26) at 17.77, 25.34, 26.15 and 27.96. The XRPD pattern of Compound 7 Form II can also exhibit further characteristic peaks expressed in degrees 26 (±0.2° 26) at 35.72, 18.41 , 22.94 and 32.43. The XRPD pattern of Compound 7 Form II can also exhibit further characteristic peaks expressed in degrees 26 (±0.2° 26) at 20.71 , 23.95, 31.34 and 18.79. The XRPD pattern of Compound 7 Form II can also exhibit further characteristic peaks expressed in degrees 26 (±0.2° 26) at 30.54, 31.58, 19.37 and 38.26. The XRPD pattern of Compound 7 Form II can also exhibit further characteristic peaks expressed in degrees 26 (±0.2° 26) at 37.91 , 30.74, 33.38, 33.01 and 39.05. The XRPD pattern of Compound 7 Form II can also exhibit further characteristic peaks expressed in degrees 26 (±0.2° 26) at 39.58, 18.01 , 30.94, 9.63 and 16.90.

[0149] According to DSC, Form II exhibited a single sharp endothermic peak at about 217°C (onset: 215°C). TGA analysis showed almost no weight loss prior to 200°C. (Figure 28)

[0150] Negligeable acetone residue was detected by1H NMR and the ratio of base to acid was determined to be 1 :1. Maleate salt Form II is postulated to be an an hydrate.Phosphate salt - Compound 8

[0151] One crystalline form of Compound 8 was isolated: Form I.

[0152] Form I showed moderate crystallinity. XRPD pattern was recorded and is showed in Figure 29.

[0153] According to DSC, Form I exhibited two endothermic peaks at about 129°C (onset: 122°C) and about 223°C (onset: 216°C). TGA analysis of Form I shows a 7.0% weight loss from room temperature to 189°C. (Figure 30)

[0154] About 6.9% wt. (0.63 eq.) of THF was detected by1H NMR.

[0155] Phosphate salt Form I is postulated to be a heterosolvate of THF and water.Tartrate salt - Compound 9

[0156] One crystalline form of Compound 9 was isolated: Form I.

[0157] Form I showed moderate crystallinity. XRPD pattern was recorded and is showed in Figure 31.

[0158] According to DSC, Form I exhibited five endothermic peaks at about 65°C (onset: 40°C), about 110°C (onset: 95°C), about 141 °C (onset: 137°C), about 226°C (onset: 213°C) and about 253°C (onset: 252°C). TGA analysis of Form I shows a one- step weight loss of 5.1% from room temperature to 149°C. (Figure 32)

[0159] Negligible EtOH residue was detected by1H NMR and the ratio of base to acid was determined to be 1 : 0.5. Tartrate salt Form I is postulated to be a hydrate (calculated: 5.7%, 2.0eq. H2O).Fumarate salt - Compound 10

[0160] One crystalline form of fumarate salt, Compound 10, was obtained: Form I.

[0161] Fumarate Form I showed moderate crystallinity. XRPD pattern was recorded and is showed in Figure 33.

[0162] According to DSC, Form I exhibited three endothermic peaks at about 63°C (onset: 41 °C), about 180°C (onset: 170°C) and at about 228°C (onset: 225°C) and one exothermic peak at about 186°C (onset: 183°C). TGA analysis shows a 2.3% weight loss from room temperature to 115°C. (Figure 34)

[0163] Negligible EtOH residue was detected by1H NMR and the ratio of base to acid was determined to be 1 : 0.5. Fumarate salt Form I is postulated to be a hydrate (calculated: 3.0%, 1.0 eq. H2O).Citrate salt - Compound 11

[0164] One crystalline form of citrate salt, Compound 11 , was obtained: Form I.

[0165] Citrate Form I showed moderate crystallinity. XRPD pattern was recorded and is showed in Figure 35.

[0166] According to DSC, Form I exhibited two endothermic peaks at about 61 °C (onset: 40°C) and at about 184°C (onset: 179°C). TGA analysis shows a 2.2% weight loss from room temperature to 92°C. (Figure 36)

[0167] Negligible EtOH residue was detected by1H NMR and the ratio of base to acid was determined to be 1 : 1 . Citrate salt Form I is postulated to be a hydrate (calculated: 2.5%, 1.0 eq. H2O).Other salts

[0168] The salt screening experiments also include the attempted synthesis of the following salts of Compound 1 : malate and succinate.Formulations, Methods and Uses

[0169] As used herein, the terms "effective amount" or “effective dose” mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the terms "effective amount" or “effective dose” mean any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

[0170] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0171] The term "patient” or “subject" as used herein refers to a mammal. A subject therefore refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, and the like. Preferably the subject is a human. When the subject is a human, the subject may be either a patient or a healthy human.

[0172] The compounds of the present description can be formulated with conventional carriers and excipients, which will be selected in accordance with ordinary practice.Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the Handbook of Pharmaceutical Excipients (1986), herein incorporated by reference in its entirety. Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH of the formulations ranges from about 3 to about 11 but is ordinarily about 7 to 10.

[0173] 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 invention, both for veterinary and for human use, comprise at least one active ingredient, together with one or more acceptable carriers and optionally other therapeutic ingredients.

[0174] The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.

[0175] The formulations include those suitable for the foregoing administration routes. The 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 generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.), herein incorporated 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, the 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.

[0176] 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 a suspension in an aqueous or non-aqueous liquid; or as an oil-in- water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste.

[0177] 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 ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.

[0178] 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.

[0179] Pharmaceutical formulations according to the present description include 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 use for example, tablets, pastilles, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.

[0180] Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets 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 maize starch, or alginic acid; binding agents, 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 may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0181] Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0182] Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

[0183] Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth herein, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0184] Dispersible powders and granules of the 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, for example sweetening, flavoring and coloring agents, may also be present.

[0185] The pharmaceutical compositions may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agentsinclude naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring 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. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.

[0186] The pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been 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 prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

[0187] The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weightweight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 pg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL / hr can occur.

[0188] Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

[0189] Formulations suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, 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.

[0190] The formulations are presented in unit-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 the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. 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 the active ingredient.

[0191] It should be understood that in addition to the ingredients particularly mentioned above the formulations of this 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.

[0192] The compounds of the present description can also be formulated to provide controlled release of the active ingredient to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of the active ingredient. Accordingly, there is also provided compositions comprising one or more compounds of the present description formulated for sustained or controlled release.

[0193] The effective dose of an active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or against an active disease or condition, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. The effective dose can be expected to be from about 0.0001 to about 10 mg / kg body weight per day, typically from about 0.001 to about 1 mg / kg body weight per day, more typically from about 0.01 to about 1 mg / kg body weight per day, even more typically from about 0.05 to about 0.5 mg / kg body weight per day. For example, the daily candidate dose for an adult human of approximately 70 kg body weight will range from about 0.05 mg to about 100 mg, orbetween about 0.1 mg and about 25 mg, or between about 0.4 mg and about 4 mg, and may take the form of single or multiple doses.SGK-1 and associated conditions

[0194] The present description relates to compounds or pharmaceutically acceptable salts thereof, for the treatment various conditions treatable by inhibiting SGK-1. For example, the condition can be Long QT syndrome (LOTS), such as genetic LOTS or acquired LOTS, or other cardiovascular diseases (e.g., dilated cardiomyopathy - genetic or acquired) that are treatable by inhibiting SGK-1. Without being bound by theory, it is believed that SGK-1 inhibition in vivo has a protective effect and can alleviate symptoms associated with LOTS; can reduce and alleviate symptoms associated with heart failure, arrhythmia, atrial fibrillation, ischemic injury, ischemic infarction, cardiac fibrosis, inflammatory or fibrotic diseases, vascular proliferation, restenosis, genetic or acquired dilated cardiomyopathy, hypertrophic cardiomyopathy, stent failure, cancer, prostate cancer, epilepsy, Parkinson’s disease and Lafora disease. Other non-limiting examples of such conditions include |3- hemoglobinopathies, such as sickle cell disease.

[0195] Long QT syndrome (LQTS) can be genetic (e.g. caused by a mutation in the KCNQ1 gene, the KCNH2 gene, or the SCN5a gene). Alternatively, Long QT syndrome is not associated with a genetic mutation and is acquired because of exposure to an external stimulus. For instance, acquired Long QT syndrome can be a side effect of drugs such as erythromycin or haloperidol. Acquired Long QT syndrome is also associated with other heart conditions such as myocardial ischemia.Inhibitors of SGK-1

[0196] The compounds of the present description, their pharmaceutically acceptable salts thereof and crystalline forms thereof are pharmacologically active compounds that modulate protein kinase activity, specifically the activity of serum and glucocorticoid regulated kinase isoform 1 (SGK-1). The compounds of the present description or their pharmaceutically acceptable salts, and crystalline forms thereof can be suitable for the treatment of conditions in which SGK-1 activity is inappropriate. Non-limiting examples of such conditions can include Long QT syndrome, heart failure, arrhythmia, atrial fibrillation, ischemic injury, ischemic infarction, cardiac fibrosis, inflammatory or fibrotic diseases, vascular proliferation, restenosis, dilatedcardiomyopathy, hypertrophic cardiomyopathy, stent failure, cancer, prostate cancer, epilepsy, Parkinson’s disease and Lafora disease. Other non-limiting examples of such conditions include |3-hemoglobinopathies, such as sickle cell disease.

[0197] In some embodiments, the compounds of the present description can be used to treat inflammatory and fibrotic diseases that can include fatty liver diseases, endometriosis, types 1 or 2 diabetes mellitus, inflammatory bowel disease, asthma, rheumatoid arthritis, obesity, systemic sclerosis, sclerodermatous graft vs. host disease, nephrogenic systemic fibrosis, as well as organ-specific fibrosis such as, but not limited to, Idiopathic Pulmonary Fibrosis (IPF), including radiation-induced fibrosis, and auto-immune diseases.

[0198] The following examples describe some example modes of making and practicing certain compositions that are described herein. These examples are for illustrative purposes only and are not meant to limit the scope of the compositions and methods described herein.EXAMPLESMaterials and instruments

[0199] Light microscopy analysis was performed using an ECLIPSE LV100POL (Nikon, JPN) microscope. Each sample was placed on a glass slide with a drop of immersion oil and covered with a glass slip. The sample was observed using a 4 - 20x objective with polarized light.

[0200] XRPD diffractograms were collected with an X-ray diffractometer. The sample was prepared on a zero-background silicon wafer by gently pressing onto the flat surface. The parameters of XRPD diffraction are given in the table bellow.Bruker BrukerPANalytical,D8 Advance D2 phaser EmpyreanCu Koc ( = 1.5418 Cu Koc ( = 1.5418 Cu Koc ( = 1 .5418 RadiationA) A) A)Detector LynxEye PSD LynxEye PIXcel1 DScan angle 3 - 40° (20) 3 - 40° (20) 3 - 40° (20)Scan step 0.013° (20) 0.02° (20) 0.013° (20)Scan speed 0.1 s / step 0.2 s / step 20.4 s / stepTube voltageCurrent 40 kV / 40 mA 30 kV / 10 mA 45 kV / 40 mADivergence slit 0.6 mm 1.0 mm 1 / 8°Rotation On On OnZero-background Zero-background Zero-backgroundSample holder sample pan sample pan sample pan

[0201] HPLC analysis was performed with an Agilent HPLC 1260 series instrument.The following methods were used:Column Poroshell HPH-C18, 2.7 pm, 4.6 x 100 mmColumn temperature 40 °CA: 5 mM CH3COONH4in water, pH= 9.0 (±0.05)Mobile phaseB: ACNFlow rate 1.0 mL / minInjection volume 5 pLDetector and Wavelength DAD; 220 nmPost time 3.0 minDiluent 0.05% TFA in (MeOH : water = 8:2)Gradient Time (min) %A %BMethod 1 0.0 90 107.00 0 1008.00 0 1008.01 90 10Method 2 0.0 90 1015.00 50 5020.00 5 9525.00 5 9525.10 90 10Column HALO ES-CN, 2.7 m, 4.6 x 100 mmColumn temperature 40 °CMobile phase A: 5 mM NH4FA in water / B: ACNFlow rate 1.5 ml_ / minInjection volume 5 pLDetector and Wavelength DAD; 220 nmPost time 3.0 minDiluent ACN / H2O (1 / 1 , v / v)Gradient Time (min) %A %B0.0 90 108.00 5 9510.00 5 9510.1 90 10

[0202] Differential Scanning Calorimetry (DSC) analysis was performed with TA Instruments (TA, Discovery DSC 250 / 2500). About 1-3 mg of a sample was placed into an aluminum pan with pinhole and heated under nitrogen. The data were collected from 25°C to 300°C at 10°C / min (flow rate 50 mL / min). The data were analyzed using TRIOS.

[0203] TGA analysis was performed using a TA Instrument (TA, Discovery TGA 55 / 5500). About 1-5 mg of a sample was loaded onto a pre-tared aluminum pan (aluminium pin-holed) and heated under nitrogen. The data were collected from room temperature to 300°C at 10°C / min. Flow rate, Balance chamber: 40 mL / min I Sample chamber: 60 mL / min and / or Balance chamber: 10 mL / min I Sample chamber: 40 mL / min. The data were analyzed using TRIOS.

[0204] The solution nuclear magnetic resonance spectra were acquired with a Bruker 400 MHz NMR Spectrometer. The samples were prepared in dimethylsulfoxide-d6 unless specified otherwise. The data were analyzed using MestReNova.

[0205] DVS experiments were conducted on a DVS Intrinsic (SMS). 10 - 30 mg of a sample was placed into a fared sample chamber and automatically weighed. The anhydrate was analyzed using the setting parameters in the table bellow:Dm / dt 0.002% / minSample size 10 - 30 mgMeasurement temperature 25°CCycle Full cycleMinimum dm / dt stability30 min durationMaximum dm / dt equilibrium120 min timeSave data rate 5 sGas and total flow rate N2, 200 seemPost experiment total flow 200 seemRH step size 10% RHMethod 0% RH, 40°C for 180 minAdsorption: 0, 10, 20, 30, 40, 50, 60, 70, 80, 90% RHDesorption: 80, 70, 60, 50, 40, 30, 20, 10, 0%RH

[0206] The solvent abbreviations are as follows:Abbreviation Solvent Abbreviation SolventMeOH Methanol THF TetrahydrofuranEtOH Ethanol AON AcetonitrileMTBE Methyl tert-butyl ether TFA Trifluoroacetic acidNMP N-methyl pyrolidone TFE TrifluoroethanolIPAc Isopropyl acetate DMSO DimethylsulfoxideDCM Dichloromethane DMAC DimethylacetamideBuOH Butanol IPA Isopropyl alcoholEA Ethyl acetate MEK Methyl ethyl ketone2-MeTHF 2-methyl tetrahydrofuran MeCYH MethylcyclohexaneSummary of the Experimental Results

[0207] Salt formation experiments were conducted with Compound 1 N-[4-(4-[[2- (DIMETHYLAMINO)ETHYL]AMINO]-3-METHYL-1 H-PYRAZOLO[3,4-D]PYRIMIDIN- 6YL)-2-CHLOROPHENYL]-2,5-DIFLUOROBENZENESULFONAMIDE.

[0208] The resulting pharmaceutically acceptable salts, isolated as crystalline compounds, were characterized by various techniques (XRPD, DSC, TGA, NMR) and the stability of selected salts investigated (DVS, in solution stability and solid-state stability).Example 1 : Characterization of Compound 1 and crystalline forms thereof

[0209] N-[4-(4-[[2-(DIMETHYLAMINO)ETHYL]AMINO]-3-METHYL-1 H-PYRAZOLO[3,4D] PYRIMIDIN-6YL)-2-CHLOROPHENYL]-2,5-DIFLUOROBENZENESULFONAMIDECompound 1

[0210] Compound 1 has two basic sites and two acidic sites with measured pKa of 8.88, 2.67, 5.56 and 11.8. Particularly, Compound 1 has a strong basic site and a relatively weak acidic site with pKa values of 8.88 and 5.56.

[0211] The samples of Compound 1 used herein have a purity of about 98.4%. Compound 1 can be obtained according to the procedure described in W02024011307A1 .Form I

[0212] Compound 1 Form I (Scheme 1) can be obtained according to the following procedure (73% yield and 98.5% purity):Schemel

[0213] Charged Pyridine (10 V), INT-1 (Free base, 6.88 kg, 1.0 eq.) into reactor, concentrated to 5 v at no more than 80°C, then charged Pyridine (5 V) into the residual.

[0214] Cooled to 0-10°C.

[0215] Charged 2,5-difluorobenzenesulfonyl chloride (2.5eq.) dropwise at 5±5°C

[0216] Stirred for 8 hours at 0-10°C.

[0217] Charged K2CO3solution (10 eq., dissolved in 10 of H2O) into reaction mixture at 0-30°C and stirred for 6 hours at 80±5°C.

[0218] Cooled the reaction mixture to 35±5°C.

[0219] Separated and collected organic layer.

[0220] Charged K2CO3solution (10 eq., dissolved in 10 V of H2O) into reaction mixture and stirred for 6 hours at 80±5°C.

[0221] Cooled the reaction mixture to 35±5°C.

[0222] Separated collected organic layer.

[0223] Charged K2CO3solution (10 eq., dissolved in 10 V of H2O) which contained 0.5 w / w of cysteine into reaction mixture and stirred for 6 hours at 80±5°C.

[0224] Cooled the reaction mixture to 35±5°C.

[0225] Separated and collected organic layer.

[0226] Charged K2CO3solution (10 eq., dissolved in 10 V of H2O) which contained 0.5 w / w of cysteine into reaction mixture and stirred for 6 hours at 80±5°C.

[0227] Cooled the reaction mixture to 35±5°C.

[0228] Separated and collected organic layer.

[0229] The organic layer was concentrated at no more than 80°C under vacuum to 5- 6 V.

[0230] Charged IPA (7 V) into the residual mixture then concentrated at NMT 50°C under vacuum to 5-6 V.

[0231] Charged MTBE (10 V) into reactor at 25±5°C.

[0232] Stirred for 2 hours at 25±5°C.

[0233] Filtered and washed the cake with MTBE (2V).

[0234] Collected the cake and dried at 60±5°C for 8 hours.

[0235] Charged Compound 1 potassium salt (17.2 kg) into THF (30 v).

[0236] Adjusted pH to 2-3 with 60% H2SO4(3.0 eq.) at 20-30°C and stirred for 2 hours.

[0237] Filtrated and washed cake with THF (4 v).

[0238] Charged wet cake into water (7 v). Charged 5% NaHCO3(20 v) into the slurry dropwise at 20-30°C. Stirred for 2 hours at 25±5°C.

[0239] Filtrated and washed cake with water (4 v).

[0240] Collected the cake and dried at 60±5°C for 10 hours.

[0241] Charged wet cake into MeOH (10 v), then charged 6N HCI (3.0 eq.) into the slurry at 25±5°C. Stirred for 2 hours at 25±5°C.

[0242] Charged co-solvents (MeOH:35 v, water: 15 v) into the mixture to obtain a clear solution.

[0243] Filtered through active carbon filter and washed with co-solvents (MeOH:6 v, water:3 v).

[0244] Concentrated the filtrate at no more than to 5-6 V left. Charged water (5 v) into the residual.

[0245] Filtered and washed the cake with water (2 V).

[0246] Slurry the wet cake with 5% NaHCO3solution (15 V) for 2 hours at 25±5°C.

[0247] Filtered and washed the cake with H2O (2V).

[0248] Dried the cake at 60±5°C for 18 hours.

[0249] Compound 1 Form I (monohydrate) was characterized by small rod-like crystals (~10 pm) with high crystallinity and analyzed by XRPD (Figure 37).

[0250] TGA analysis performed on Form I showed a 1 .0% weight loss from RT to 70°C, followed by 2.8% weight loss from 140°C to 180°C. DSC exhibited multiple thermal events suggesting complex transition behaviors (Figure 38).

[0251] The first broad endothermic peak at 27°C (onset) was attributed to loss of residual solvent, the second endothermic peak at 147°C (onset) was attributed to dehydration and the final peak at 254°C (onset) was attributed to melting of Form II. Two exothermic peaks at 168 and 199°C (onset) were both attributed to phase transition.

[0252] Negligible organic solvent residues were detected by gas chromatography (470 ppm of MeOH, 535 ppm of pyridine, 405 ppm of acetic acid and 4.6% water). Form I is postulated to be a monohydrate (theoretical water content of monohydrate is 3.3%).

[0253] Thermal treatment of Form I was conducted (sample was heated by DSC to target temperature and cooled to ambient condition for XRPD analysis), and the results are shown in Figure 39. The starting material converted into sample with low crystallinity after heating to 185°C. After further heating to 210°C, a new crystal form with high crystallinity was obtained, assigned as Form II.

[0254] DVS result showed that Form I adsorbed 2.3 / 2.7% moisture at 80 / 90% RH (Figure 40). Sorption and desorption were reversible and slight hysteresis was observed. The crystal form remained unchanged after DVS testing (Figure 41).Example 2: Solubility screening of Compound 1

[0255] Solubility estimates were conducted using via visual assessment of samples. About 5 mg of Compound 1 (Form I) was added into a 4 mL glass vial and the solventwas added stepwise until the solid was dissolved completely, or a total volume of solvent reached 5 mL.Table 1. Solubility assays for Compound 1 Form I in various solvents (mg / mL) at room temperature

[0256] Three solvent systems of THF, EtOH and acetone / water (49: 1 , v / v) were selected for salt screening.Example 3: Preparation of the salts of Compound 1

[0257] Salt screening was conducted with 12 acids in three solvent systems (Table 2). Salts were prepared on a 20 mg scale using Compound 1 Form I as the starting material, according to the general procedure below:

[0258] 20 mg of Compound 1 Form I was suspended into 1.0 mL of selected solvent and 1.1 eq. or 2.1 eq. of selected acid was added to the suspension. The solution / suspension was kept stirring at room temperature for about 24 hours and 0.5 - 1 mL of MTBE was added as anti-solvent if no precipitation occurred. The suspensions were filtered, and the solids were vacuum dried at 40 - 50°C for about 4 hours before characterization.

[0259] Selected acids include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, phosphoric acid, L-tartaric acid, fumaric acid, citric acid, L-malic acid and succinic acid.

[0260] Selected solvents include THF (solvent A), EtOH (solvent B) and Acetone / Water (49:1) (solvent C).

[0261] Results of the salt screen are presented in Table 2:Table 2 - Summary of salt screen*: anti-solvent was added into solution and trace solid was obtained.Example 4: Preparation of the tosylate salt Form I and the maleate salt Form II on a larger scale

[0262] Scale-up experiments were conducted to prepare samples of tosylate salt (Compound 4) Form I and maleate salt (Compound 7) Form II. The preparation details are summarized in Table 3.Table 3. Preparation of tosylate salt (Compound 4) Form I and maleate salt (Compound 7) Form II

[0263] Tosylate salt Form I and Maleate salt Form II, were selected for stability testing compared with Compound 1 Form I (Examples 5, 6 and 7).Example 5: Dynamic Vapor Sorption / Desorption (DVS) experiments

[0265] DVS experiments and XRPD post-DVS experiments (Figures 42, 43, 44 and 45) were conducted to study the deliquescence behaviour of the crystalline salts upon exposure to humidity. Table 4: Summary of the DVS experiments and corresponding XRPDs conducted for the tosylate salt (Compound 4: Form I) and the maleate salt (Compound 7, Form II).Example 6: Solubility test in bio-relevant media and water

[0266] The solubility of Compound 7 Form II (maleate salt) and Compound 4 Form I (tosylate salt) was evaluated in water and bio-relevant media (SGF, FaSSIF and FeSSIF) and water at 37°C.

[0267] About 20 mg of tosylate salt Form I and maleate salt Form II were weighed into sample vials and 3 mL of bio-relevant media and water were added to obtain suspensions. All samples were kept shaking at 37°C with 800 rpm for up to 24 hours. At 0.5, 2 and 24 hours, about 1 mL of each suspension was filtered, the filtrate was analyzed by HPLC, pH of the filtrate was measured and the filter cake checked by XRPD, all the results were summarized in Table 5.Table 5. Evaluation of the solubility of tosylate Form I and maleate Form II in water, SGF, FaSSIF and FeSSIF at 37°C.

[0268] Simulated Gastric Fluid (SGF), Fed State Simulated Intestinal Fluid (FeSSIF) and Fasted State Simulated Intestinal Fluid (FaSSIF) I NP1 = New pattern 1 I LOQ = Limit of quantification

[0269] The two salts both mostly dissociated into Compound 1 Form I (free form) in FaSSIF, partly dissociated into Compound 1 Form I (free form) in water and dissociated into NP1 in SGF and FeSSIF.

[0270] Compound 1 Form I (free form) showed acceptable solubility in SGF and was insoluble in water, FaSSIF and FeSSIF, while Tosylate Form I and Maleate Form II showed improved solubility in bio-relevant media and water.

[0271] One new pattern (NP1) was observed in solubility study, and DSC analysis was conducted. Broad endothermic peak before 100°C was detected by DSC, likely corresponding to dehydration. Therefore, NP1 might be a hydrate of Compound 1 Form I (free form).Example 7: Solid-state stability

[0272] Solid stability of tosylate salt (Compound 4) Form I and maleate salt (Compound 7) Form II was evaluated at 60°C (capped) and 40°C I 75% RH (open) for 7 days.

[0273] Samples were dissolved in 0.05% TFA in a mixture MeOH: Water (8:2) at 0.3 mg / mL, the samples were analyzed to check the purity by HPLC and the crystal form by XRPD and the results were summarized in Table 6.Table 6. Solid-state stability results (characterization by XRPD and HPLC)

[0274] Maleate Form II was both chemically and physically stable under 60°C (capped) and 40°C / 75%RH (open) for 1 week. Tosylate Form I was chemically stable under 60°C (capped) and 40°C / 75%RH (open). However, the XRPD pattern of Tosylate Form I slightly changed after keeping at 40°C / 75%RH (open) for 7 days.

[0275] Overall, maleate salt Form II showed more acceptable solid-state properties and solubility in bio-relevant media and water than Compound 1 Form I (free form).Example 8: Polymorph screen

[0276] A polymorph screen was conducted to try to identify new crystalline forms of the maleate salt (Compound 7) using various techniques in different solvents. The methods used include slurry conversion, evaporation, anti-solvent precipitation, cooling crystallization, cyclic heating-cooling and reactive crystallisation.

[0277] A total of eight crystal forms of the maleate salt (Compound 7) were identified, including two anhydrates (Form II and VIII) and three hydrates (Forms I, IV and V). Characterization data of maleate polymorphs are summarized in Table 7.Form I: can be obtained via Slurry conversion or Anti-solvent precipitation or Quench cooling

[0278] Form I with moderate crystallinity was obtained by salt reaction with 1.1 eq. of maleic acid in EtOH (Figure 25).

[0279] No EtOH residue was detected by1H-NMR, and the ratio of base to acid was determined to be 1 : 1. Thermal analysis showed 5.8% weight loss before 115 °C inTGA curve, and two endothermic peaks at 43 and 125°C (onset) in DSC curve. (Figure26) Form I is postulated to be a hydrate (calculated: 5.3%, 2.0 eq. H2O).Form II: can be obtained via Slurry conversion or Anti-solvent precipitation or Slow evaporation or Quench cooling or Cyclic heating-cooling or Reactive crystallization

[0280] As detailed below, many crystalline forms obtained eventually converted to Form II confirming the higher stability of Form II.

[0281] Form II with high crystallinity was obtained by salt reaction with 1.1 eq. of maleic acid in acetone / water (49:1 , v / v). After solid collection by filtration, solid was dried under vacuum at 40°C for ~4 hours. (Figure 27)

[0282] The stoichiometric ratio of base to acid was determined to be 1 :1 by1H-NMR. The sample contained negligible organic solvent residue and showed almost no weight loss before 150 °C in TGA curve. Single endothermic peak at 213 °C (onset) was detected by DSC, due to melting. (Figure 28)

[0283] DVS result showed absorbed moisture was 0.99 / 1.18% at 80%RH / 90%RH, indicating that Form II sample was slightly hygroscopic. The crystal form remained unchanged after DVS testing.

[0284] As detailed below, many crystalline forms obtained eventually converted entirely of partially into Form II confirming the higher stability of Form II.Form III: can be obtained via Reactive crystallization

[0285] Form III with high crystallinity was obtained by reactive crystallization in acetone / water (49 / 1 , v / v). It was unstable and converted into Form II after vacuum drying.

[0286] About 300 mg of Compound 1 Form I (free form) and 73.39 mg (1 .1eq.) of maleic acid were suspended in 6 mL (20V) of acetone / water (49 / 1 , v / v). The suspension was stirred at RT for 1 day. Solid was collected by filtration and characterized by XRPD. One unstable form (Form III) was obtained in this experiment, and it partly converted into Form II after vacuum drying at 40 °C for ~4 hours (FigureForm IV: can be obtained via Slow evaporation

[0287] Form IV was obtained in MeOH / DCM (1 / 1) by evaporation.

[0288] Form IV (Figure 49) showed moderate crystallinity. Negligible solvent residue was detected by1H-NMR. TGA showed 1.1% weight loss from 30 - 115 °C (calculated: 1.4%, 0.5 eq. H2O). DSC showed multiple thermal events, indicating phase transition upon heating. (Figure 50) Therefore, Form IV might be a hydrate. Thermal treatment of Form IV was conducted. After heating to 105 °C, a mixed form of Forms IV and II was obtained. After heating to 180 °C, it was still a mixed form of Forms IV and II.Form V: can be obtained via Slow evaporation

[0289] Form V (Figure 51) was obtained in acetone / water (19 / 1 , v / v) by slow evaporation.

[0290] The Form V sample was moderately crystalline. About 0.31% (0.04 eq.) acetone residue was detected by1H-NMR and the ratio of base to acid was determined to be ~ 1 : 1. TGA showed 2.3% weight loss from 45 - 135 °C. DSC showed multiple thermal events. (Figure 52) Therefore, Form V might be a hydrate (calculated: 2.7%, 1 eq. H2O). Thermal treatment of Form V was conducted. After heating to 110 °C, a mixed form of Forms V and II was obtained.Form VI: can be obtained via Slow evaporation or Anti-solvent precipitation

[0291] Form VI was obtained in TFE by evaporation.

[0292] The Form VI sample (Figure 53) was moderately crystalline. About 10.02% (0.7 eq.) TFE was detected by1H-NMR and the ratio of base to acid was determined to be ~ 1 : 1. TGA showed 6.9% weight loss from 115 - 200 °C. DSC showed two endothermic peak at 139 °C, and 202 °C (onset), due to desolvation and melting accompanied by decomposition, respectively. (Figure 54) Therefore, Form VI is postulated to be a solvate of TFE. Thermal treatment of Form VI was conducted. After heating to 180 °C, Form II was obtained.Form VII: can be obtained via Anti-solvent precipitation

[0293] Form VII was obtained by anti-solvent addition in NMP / MTBE mixture.

[0294] The Form VII sample (Figure 55) with high crystallinity was obtained by antisolvent addition in NMP / MTBE (1 / 10, v / v). Thermal analysis (Figure 56) showed the sample had no weight loss before 140 °C in TGA. DSC showed one overlapped endothermic peak at 140 °C (onset), due to desolvation. Negligible 13.91% (1.0 eq.) NMP and 0.32% (0.02eq.) MTBE were detected by1H-NMR and the ratio of base to acid was determined to be ~ 1 : 1. Form VII is postulated to be a solvate of NMP.Form VIII: can be obtained via Reactive crystallization

[0295] Form VIII was obtained by reactive crystallization in ACN / water (19 / 1 , v / v).

[0296] The Form VIII sample (Figure 57) was highly crystalline. Thermal analysis showed the sample had no weight loss before 200 °C in TGA. Single sharp endothermic peak at 216 °C (onset) was detected by DSC. (Figure 58)1H-NMR showed negligible organic solvent residue and the ratio of base to acid was determined to be ~ 1 : 1 . Form VIII is an anhydrate. Thermal treatment of Form VIII was conducted by DSC, and Form II was obtained after heating to 205 °C (before melting).Table 7. Maleate (Compound 7) polymorphs characterization (XRPD and DSC / TGA)

[0297] Competitive slurry results showed that Form II is a stable anhydrate at RT - 50 °C. Water activity study suggested that Form II is more stable than Form VIII and the hydrates at aw< 0.58. Solid-state properties of Form II are presented in Examples 5 and 7. Form II was slightly hygroscopic, physically and chemically stable at 60 °C (capped) and 40 °C / 75%RH (open) for one week.Example 9: Slurry competition study

[0298] Slurry competition study was conducted for anhydrates to determine the thermodynamic stability relationship. Appropriate amount of Compound 7 Form II and Form VIII (maleate salt) were suspended in different solvents at desired temperature. The mixture was stirred at RT and 50 °C for 2 days. Solids obtained were characterized by XRPD. The results are presented in Table 8.Table 8. Results from slurry competition study

[0299] Form II is the more stable anhydrate between RT - 50 °C.Example 10: Water activity study

[0300] Appropriate amount of maleate salt Form II was suspended in ACN / Water mixtures for 30 minutes to obtain a saturated solution. Then 10 mg equal amount of maleate salt Form I, Form II, Form IV, Form V and Form VIII were added into the filtrate. The suspension was stirred at RT for 1 day. The remaining solid was sampled for XRPD testing, the results are presented in Table 9.Table 9. Results of water activity study in ACN / Water mixtures#: awwas calculated by software Dynochem for reference

[0301] Water activity study showed that Form II is the more stable with aw< 0.58 conditions and Form VIII is the more stable at aw>0.78 conditions.Example 11 : Evaluation of maleate salt Form IIMechanical stability study

[0302] Appropriate amount of maleate salt Form II was manually ground by pestle and mortar for about 2 minutes, and the ground samples were analyzed by XRPD. The crystal form of Form II remained unchanged, indicating acceptable mechanical stability.Solid-state stability study

[0303] Form II was both chemically and physically stable under 60°C (capped) and 40°C / 75%RH (open) for 1 week (see Example 7).Solubility tests

[0304] The solubility of the maleate salt Form II was estimated at RT by visual observation in common solvent systems. Approximately 5 mg of solid was weighed into 8-mL glass vial, and then solvent was added stepwise until solid was dissolved completely or a total of solvent volume reached to 5 ml_. The results are summarized in Table 10. The starting material showed high solubility (> 50 mg / mL) in DMSO, NMP, and DMAC; and low solubility (< 5 mg / mL) in most tested single solvent. The solubility was estimated and for reference only.Table 10. Estimated Solubility of Maleate salt Form II at RT

[0305] Values are reported as “<” if dissolution was not observed, and as “>” if dissolution occurred after addition of first aliquot.Example 12: Pharmacokinetics

[0306] The pharmacokinetics of Compound 1 free form and Compound 7 (maleate salt) Form II have been evaluated as shown in Table 11 .Table 11. Concentration in plasma in function of time and Pharmacokinetics in dogs for Compound 1 Free Form and Compound 7 (maleate salt) Form II

[0307] As can be seen from Table 11 , Compound 7 (maleate salt), Form II has improved bioavailability compared to Compound 1 Free Form in dogs.XRPD peak lists

[0308] Observed peaks for the tosylate salt (Compound 4), Form I:

[0309] Observed peaks for the maleate salt (Compound 7), Form II:

[0310] Other examples of implementations will become apparent to the reader in view of the teachings of the present description and as such, will not be further described here.

[0311] All references cited throughout the specification are hereby incorporated by reference in their entirety for all purposes.

[0312] Note that titles or subtitles may be used throughout the present disclosure for convenience of a reader, but in no way these should limit the scope of the invention. Moreover, certain theories may be proposed and disclosed herein; however, in no way they, whether they are right or wrong, should limit the scope of the invention so long as the invention is practiced according to the present disclosure without regard for any particular theory or scheme of action.

[0313] As used herein, the wording “independently selected” in reference to a group of specified items refers to the fact that when more than one item is selected from the group of items, the decision of selecting a specific item is not influenced by the decision of selecting any of the previous or following item(s).

[0314] Reference throughout the specification to “some embodiments”, and so forth, means that a particular element (e.g., feature, structure, and / or characteristic) described in connection with the invention is included in at least one embodiment described herein, and may or may not be present in other embodiments. In addition, it is to be understood that the described inventive features may be combined in any suitable manner in the various embodiments.

[0315] It will be understood by those of skill in the art that throughout the present specification, the term “a” used before a term encompasses embodiments containing one or more to what the term refers. It will also be understood by those of skill in the art that throughout the present specification, the term “comprising”, which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open- ended and does not exclude additional, un-recited elements or method steps.

[0316] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to whichthis invention pertains. In the case of conflict, the present document, including definitions will control.

[0317] As used in the present disclosure, when the terms “around”, “about” or “approximately” are before a quantitative value, the present disclosure also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the terms “around”, “about” or “approximately” refer to a ±10% variation from the nominal value unless otherwise indicated or inferred.

[0318] Unless otherwise noted, the expression “at least” or “at least one of’ as used herein includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. The expression “and / or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context.

[0319] The use of the term “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.

[0320] Unless otherwise noted, the order of steps or order for performing certain actions is immaterial so long as the present invention remain operable. Moreover, two or more steps or actions may be conducted simultaneously.

[0321] Unless otherwise noted, the use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present invention and does not pose a limitation on the scope of the invention. No language in the specification should be construed as indicating any nonclaimed element as essential to the practice of the present invention.

[0322] The word “exemplary” is used herein to mean “serving as an example, instance, or illustration.” Any aspect described herein as “exemplary” is not necessarily to be construed as preferred or advantageous over other aspects. Unless specifically stated otherwise, the term “some” refers to one or more.

[0323] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and including the endpoints. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.

[0324] All structural and functional equivalents to the elements of the various aspects described throughout this disclosure that are known or later come to be known to those of ordinary skill in the art are expressly incorporated herein by reference and are intended to be encompassed by the claims.

[0325] Various modifications to the embodiments described herein will be readily apparent to those skilled in the art, and the general principles described herein can be applied to other embodiments without departing from the spirit or scope of the claims. Thus, it is understood that the scope of the claims fully encompasses other embodiments that may become obvious to those skilled in the art and that the scope of the claims are accordingly not limited.

[0326] Combinations, described herein, such as “at least one of A, B, or C,” “one or more of A, B, or C,” “at least one of A, B, and C,” “one or more of A, B, and C,” and “A,B, C, or any combination thereof’ include any combination of A, B, and / or C, and may include multiples of A, multiples of B, or multiples of C. Specifically, combinations such as “at least one of A, B, or C,” “one or more of A, B, or C,” “at least one of A, B, andC,” “one or more of A, B, and C,” and “A, B, C, or any combination thereof’ may be A only, B only, C only, A and B, A and C, B and C, or A and B and C, and any such combination may contain one or more members of its constituents A, B, and / or C. For example, a combination of A and B may comprise one A and multiple B’s, multiple A’s and one B, or multiple A’s and multiple B’s.

[0327] Although various embodiments of the disclosure have been described and illustrated, it will be apparent to those skilled in the art considering the present description that numerous modifications and variations can be made. The scope of the invention is defined more particularly in the appended claims.

Claims

CLAIMS1 . A maleate salt of the compound of Formula I which is crystalline:(Formula I).

2. The compound of claim 1 , which is an anhydrate.

3. The compound of claim 1 or 2, which exhibits an X-ray powder diffraction (XRPD) pattern having characteristic peaks expressed in degrees 2© (±0.2° 2©) at 6.61 , and 29.68.

4. The compound of claim 3, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2© (±0.2° 2©) at 20.41 , 24.50, 13.25, 26.41 , or a combination thereof.

5. The compound of claim 3 or 4, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2© (±0.2° 2©) at 10.01 , 12.12, 8.58, or a combination thereof.

6. The compound of any one of claims 3 to 5, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2© (±0.2° 2©) at 14.79, 19.84 or a combination thereof.

7. The compound of any one of claims 3 to 6, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2© (±0.2° 2©) at 22.24, 23.64, 28.43, or a combination thereof.

8. The compound of any one of claims 3 to 7, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2© (±0.2° 2©) at 14.01 , 11.60, or a combination thereof.

9. The compound of claim 1 , which is crystalline and has a Differential Scanning Calorimetry (DSC) thermogram that exhibits an endotherm having a peak temperature of about 217.11 °C with an onset of about 214.57°C.

10. The compound of claim 1 , which has an X-ray powder diffraction pattern substantially the same as shown in Figure 27 or in Figure 46.

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

12. Use of the compound of any one of claims 1 to 10, as an inhibitor of SGK-1.

13. Use of the compound of any one of claims 1 to 10 or the pharmaceutical composition of claim 11 , for the treatment of atrial fibrillation, heart failure and inflammatory or fibrotic diseases.

14. Use of the compound of any one of claims 1 to 10, for the manufacture of a medicament that inhibits SGK-1 in a subject.

15. Use of the compound of any one of claims 1 to 10, for the manufacture of a medicament for the treatment of atrial fibrillation or heart failure.

16. Use of the compound of any one of claims 1 to 10, for the manufacture of a medicament for the treatment of inflammatory or fibrotic diseases.

17. A method for inhibiting SGK-1 , comprising administering to a subject the compound as defined in any one of claims 1 to 10, or the pharmaceutical composition as defined in claim 11 .

18. A method for the treatment of atrial fibrillation or heart failure, comprising administering to a subject in need thereof the compound as defined in any one of claims 1 to 10, or the pharmaceutical composition as defined in claim 11.

19. A method for the treatment of inflammatory or fibrotic diseases, comprising administering to a subject in need thereof the compound as defined in any one of claims 1 to 10, or the pharmaceutical composition as defined in claim 11.

20. A process for preparing the compound of any one of claims 1 to 10, comprising:a) combining 1 molar equivalent of N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3- methyl-1 H-pyrazolo[3,4-D]pyrimidin-6-yl)-2-chlorophenyl]-2,5- difluorobenzenesulfonamide with at least 1 molar equivalent of maleic acid in a solvent to obtain a mixture; b) stirring the mixture c) isolating the crystalline material; and d) wherein said process is conducted under conditions suitable to obtain said crystalline material.

21. The process of claim 20, wherein the maleic acid is used between 1.0 and 2.1 molar equivalents, preferably 1.05 or 1.1 equivalents.

22. The process of claims 20 or 21 , wherein combining the N-[4-(4-[[2- (dimethylamino)ethyl]amino]-3-methyl-1 H-pyrazolo[3,4-D]pyrimidin-6-yl)-2- chlorophenyl]-2,5-difluorobenzenesulfonamide and the maleic acid is performed at a temperature between about 18°C and about 25°C.

23. The process of any one of claims 20 to 22, wherein the solvent is a mixture of acetone / water or a mixture of acetonitrile / water.

24. The process of any one of claims 20 to 23, wherein the mixture of acetone / water or the mixture of acetonitrile / water have a volume ratio (v / v) between about 50 / 1 and about 10 / 1.

25. The process of any one of claims 20 to 24, wherein the concentration of N-[4-(4- [[2-(dimethylamino)ethyl]amino]-3-methyl-1 H-pyrazolo[3,4-D]pyrimidin-6-yl)-2- chlorophenyl]-2,5-difluorobenzenesulfonamide in the solvent is between about 30 mmol / L and about 200 mmol / L.

26. The process of any one of claims 20 to 25, wherein stirring the mixture is performed at a temperature between 18°C and 25°C.

27. The process of any one of claims 20 to 26, wherein stirring the mixture is performed during about 24 hours to about 48 hours.

28. The process of any one of claims 20 to 25, wherein stirring the mixture is performed at a temperature between 75°C and 85°C.

29. The process of claim 28, wherein stirring the mixture is performed during about 5 hours.

30. The process of claim 28 or 29, wherein the mixture is concentrated by 3 to 4 times in volume, at a temperature of no more than 60°C.31 . The process of any one of claims 28 to 30, wherein the mixture is further stirred at least 4 hours at a temperature between 55°C and 65°C.

32. The process of any one of claims 28 to 31 , wherein the mixture is cooled to a temperature between 10°C and 25°C and further stirred for at least 2 hours.

33. The process of any one of claims 20 to 32, wherein the crystalline material is isolated by filtration or centrifugation.

34. The process of any one of claims 20 to 33, wherein the crystalline material isolated by filtration or centrifugation is washed with acetonitrile, water or a mixture thereof.

35. The process of claim 34, wherein the crystalline material isolated by filtration is washed with a mixture of acetonitrile / water at about a 49 / 1 ratio (v / v).

36. The process of claim 34, wherein the crystalline material isolated by filtration is washed with acetonitrile.

37. The process of any one of claims 20 to 36, wherein the crystalline material is dried in a vacuum oven.

38. The process of claim 37, wherein drying in the vacuum oven is performed at about 40°C for about 4 hours.

39. The process of claim 37, wherein drying in the vacuum oven is performed at a temperature between 60°C and 70°C for at least 14 hours.

40. The process of any one of claims 20 to 33, wherein the crystalline material is slurred in a solvent at room temperature for about 24 hours.41 . The process of claim 40, wherein the solvent is acetonitrile.

42. The process of claim 40 or 41 , wherein the crystalline material is isolated by filtration.

43. The process of claim 42, wherein the crystalline material is dried in a vacuum oven at about 40°C for about 4 hours.

44. The compound of any one of claims 1 to 10 for use in the treatment of atrial fibrillation or heart failure, or in the manufacture of a medicament for the treatment of atrial fibrillation or heart failure.

45. The compound of any one of claims 1 to 10 for use in the treatment of inflammatory or fibrotic diseases, or in the manufacture of a medicament for the treatment of inflammatory or fibrotic diseases.

46. A pharmaceutical composition comprising the compound as defined in any one of claims 1 to 10, and a pharmaceutically acceptable excipient, for use in the treatment of atrial fibrillation or heart failure or in the manufacture of a medicament for the treatment of atrial fibrillation or heart failure.

47. A pharmaceutical composition comprising the compound as defined in any one of claims 1 to 10, and a pharmaceutically acceptable excipient, for use in the treatment of inflammatory or fibrotic diseases, or in the manufacture of a medicament for the treatment of inflammatory or fibrotic diseases.

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