Salts of 5-chloro-2-fluoro-n-(2-fluoro-4-(3-methyl-4-[(1-methylpiperidin-4-YL)OXY]-1h-pyrazolo[3,4-d]pyrimidin-6-YL)phenyl)benzene sulfonamide and crystalline forms thereof

Abstract

A compound of Formula (I) is provided: (I) Salts and 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, ischemic injury, ischemic infarction, inflammatory and fibrotic diseases, cardiac fibrosis, vascular proliferation, restenosis, dilated cardiomyopathy, and stent failure; cancer; epilepsy; Parkinson's disease; and Lafora disease.

Description

SALTS OF 5-CHLORO-2-FLUORO-N-(2-FLUORO-4-(3-METHYL-4-[(1-METHYL PIPERIDIN-4-YL)OXY]-1 H-PYRAZOLO[3,4-D]PYRIMIDIN-6-YL)PHENYL)BENZENE SULFONAMIDE AND CRYSTALLINE FORMS THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of PCT / CN2024 / 114977 filed August 28, 2024 and U.S. provisional patent application serial number 63 / 702,320 filed on October 2, 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 5-chloro-2-fluoro-N-(2- fluoro-4-{3-methyl-4-[(1-methylpiperidin-4-yl)oxy]-1 H-pyrazolo[3,4-d]pyrimidin-6- yl}phenyl)benzene sulfonamide 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, for the treatment of fibrosis and / or for the treatment of cancer.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 sulfate 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 compound or pharmaceutical composition as defined herein, as an inhibitor of SGK-1.

[0008] In a further aspect, there is provided the use of compound or pharmaceutical composition as defined herein, for the treatment of cancer or tumor.

[0009] In a further aspect, there is provided the use of compound or pharmaceutical composition 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 compound or pharmaceutical composition as defined herein, for the manufacture of a medicament for the treatment of cancer or tumor.

[0011] 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.

[0012] In a further aspect, there is provided a method for the treatment of cancer or tumor, comprising administering to a subject a compound or pharmaceutical composition as defined herein.

[0013] In a further aspect, there is provided a compound or pharmaceutical composition as defined herein for inhibits SGK-1 in a subject, or in the manufacture of a medicament for inhibits SGK-1 in a subject.

[0014] In a further aspect, there is provided a compound or pharmaceutical composition as defined herein for use in the treatment of cancer or tumor or in the manufacture of a medicament for the treatment of cancer or tumor.

[0015] In a further aspect, there is provided a process for preparing a compound as defined herein, comprising: combining 5-chloro-2-fluoro-N-(2-fluoro-4-{3-methyl-4- [(1-methylpiperidin-4-yl)oxy]-1 H-pyrazolo[3,4-d]pyrimidin-6-yl}phenyl)benzene sulfonamide in a solvent with sulfuric acid 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.

[0016] 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 of the 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

[0017] 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:

[0018] Figure 1 is an XRPD of Compound 2, Form I (HCI salt), black line corresponds to the XPRD recorded on the wet cake and the grey line corresponds to the XPRD recorded on the dry solid.

[0019] Figure 2 are TGA and DSC thermograms of Compound 2, Form I (HCI salt).

[0020] Figure 3 is an XRPD of Compound 2, Form II (HCI salt).

[0021] Figure 4 are TGA and DSC thermograms of Compound 2, Form II (HCI salt).

[0022] Figure 5 is an XRPD of Compound 3, Form I (sulfate salt).

[0023] Figure 6 are TGA and DSC thermograms of Compound 3, Form I (sulfate salt).

[0024] Figure 7 is an XRPD of Compound 3, Form II (sulfate salt).

[0025] Figure 8 are TGA and DSC thermograms of Compound 3, Form II (sulfate salt).

[0026] Figure 9 is an XRPD of Compound 4, Form I (tosylate salt).

[0027] Figure 10 are TGA and DSC thermograms of Compound 4, Form I (tosylate salt).

[0028] Figure 11 is an XRPD of Compound 4, Form II (tosylate salt).

[0029] Figure 12 are TGA and DSC thermograms of Compound 4, Form II(tosylate salt).

[0030] Figure 13 is an XRPD of Compound 5, Form I (besylate salt).

[0031] Figure 14 are TGA and DSC thermograms of Compound 5, Form I (besylate salt).

[0032] Figure 15 is an XRPD of Compound 5, Form II (besylate salt).

[0033] Figure 16 are TGA and DSC thermograms of Compound 5, Form II(besylate salt).

[0034] Figure 17 is an XRPD of Compound 6, Form I (mesylate salt).

[0035] Figure 18 are TGA and DSC thermograms of Compound 6, Form I(mesylate salt).

[0036] Figure 19 is an XRPD of Compound 7, Form I (phosphate salt).

[0037] Figure 20 are TGA and DSC thermograms of Compound 7, Form I(phosphate salt).

[0038] Figure 21 is an XRPD of Compound 8, Form I (maleate salt).

[0039] Figure 22 are TGA and DSC thermograms of Compound 8, Form I (maleate salt).

[0040] Figure 23 is an XRPD of Compound 8, Form II (maleate salt).

[0041] Figure 24 are TGA and DSC thermograms of Compound 8, Form II(maleate salt).

[0042] Figure 25 is an XRPD of Compound 9, Form I (tartrate salt).

[0043] Figure 26 are TGA and DSC thermograms of Compound 9, Form I (tartrate salt).

[0044] Figure 27 is an XRPD of Compound 10, hemi-fumarate salt Form I.

[0045] Figure 28 are TGA and DSC thermograms of Compound 10, hemi- fumarate salt Form I.

[0046] Figure 29 is an XRPD of Compound 10, fumarate salt Form I.

[0047] Figure 30 are TGA and DSC thermograms of Compound 10, fumarate salt Form I.

[0048] Figure 31 is an XRPD of Compound 1 Form I.

[0049] Figure 32 are TGA and DSC thermograms of Compound 1 Form I.

[0050] Figure 33 is an XRPD overlay of Compound 1 Form II (bottom) andCompound 1 Form III (top).

[0051] Figure 34 are TGA and DSC thermograms of Compound 1 Form II.

[0052] Figure 35 are TGA and DSC thermograms of Compound 1 Form III.

[0053] Figure 36 is a DVS of sulfate salt (Compound 3) Form I.

[0054] Figure 37 is a DVS of sulfate salt (Compound 3) Form II.

[0055] Figure 38 is a DVS of sulfate salt (Compound 3) Form III.

[0056] Figure 39 is a DVS of fumarate salt (Compound 10) Form I.

[0057] Figure 40 is an XRPD overlay of Compound 3, sulfate salt Form III obtained via anti-solvent precipitation by normal addition (bottom) and sulfate salt Form III obtained via seeding technique (top).

[0058] Figure 41 are TGA and DSC thermograms of sulfate salt Compound 3 Form III.

[0059] 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

[0060] 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 technology may 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 thereof.Definitions

[0061] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art to which the present invention pertains. As used herein, and unless stated otherwise or required otherwise by context, each of the following terms shall have the definition set forth below.

[0062] 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 oradjuvants, under normal storage conditions, without any significant degree of chemical degradation or decomposition.

[0063] 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).

[0064] Crystalline forms of solid chemical compounds influence not only their dissolution behavior ( / .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.

[0065] 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.

[0066] The expression “pharmaceutical composition”, as used herein, refers to the formulation of a compound and a pharmaceutically acceptable carrier or excipient.

[0067] The term “about”, as used herein, generally means within an acceptable standard error of the mean, when considered by a person skilled in the art. For example, depending on the value or range considered, the term “about” can mean within 10%, within 5%, or within 1% of the value or range.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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-apparatus variability 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.

[0072] The present description provides salt screening experiments from 5- chloro-2-fluoro-N-(2-fluoro-4-{3-methyl-4-[(1-methylpiperidin-4-yl)oxy]-1 H- pyrazolo[3,4-d]pyrimidin-6yl}phenyl) benzenesulfonamide (Compound 1) and the crystalline forms thereof. In particular, the present description provides a sulfate salt of the compound of Formula I:

[0073] 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.

[0074] The term “substantially pure”, when used in reference to a crystalline form of the compound of Formula I or a crystalline form of a salt 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 or its salts. 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 or its salts. More preferably, the term “substantially pure” means a crystalline form which has a purity that is greater than about 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 or its salts.

[0075] 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.

[0076] XRPD data were obtained using a PANalytical X’Pert PRO MPD or a PANanalytical Empyrean X-ray powder diffractometers, using an incident beam of Curadiation 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).

[0077] 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.

[0078] 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 nontoxic salts of the compounds of the present description.

[0079] 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 from Compound 1Compound 1 (also referred to as compound of Formula I herein)

[0080] 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 (5-chloro-2-fluoro-N-(2-fluoro- 4-{3-methyl-4-[(1-methylpiperidin-4-yl)oxy]-1 H-pyrazolo[3,4-d]pyrimidin-6- yl}phenyl)benzenesulfonamide).Hydrochloride salt (Compound 2)

[0081] Two crystalline forms of Compound 2 were obtained, Form I and Form II.Form I (hydrate)

[0082] Form I showed irregular crystals with low crystallinity. XPRD patterns were recorded on the wet cake and after drying and is showed in Figure 1 .

[0083] According to DSC, Form I shows two endothermic peaks at 96°C (onset: 40°C) and 298 °C (onset: 293°C), likely due to desolvation, melting and decomposition. TGA analysis of Form I shows a ~3.0% weight loss from RT to 150 °C. (Figure 2)

[0084] Only about ~0.2% residual THF was observed by NMR. Theoretical water content of a monohydrate is 3%.Form II (hydrate)

[0085] Form II showed irregular crystals with moderate crystallinity. XPRD pattern was recorded and is showed in Figure 3.

[0086] According to DSC, Form II shows two endothermic peaks at 57 °C (onset: 32°C) and 299 °C (onset: 290°C), likely due to desolvation, melting and decomposition (Figure 4). TGA analysis of Form II shows a ~0.2% weight loss prior to 150 °C and 0.6% weight loss between 100 °C and 250 °C.

[0087] There was a ~0.2% residual MeOH by NMR. HCI salt Form II is a hydrate.Sulfate salt (Compound 3)

[0088] Three crystalline forms of Compound 3 were obtained, Form I, Form II and Form III.Form I (channel hydrate)

[0089] Form I showed irregular crystals with high crystallinity. Form I is a 1 / 1 base to acid (mono-sulfate) as determined by ion chromatography.

[0090] Compound 3 Form I exhibits an XRPD pattern (Figure 5) having characteristic peaks expressed in degrees 2© (±0.2° 2©) at 13.95, 17.84 and 5.87. The XRPD pattern of Compound 3 Form I can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 19.50, 16.20 and 24.97. The XRPD pattern of Compound 3 Form I can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 23.66, 11.83 and 22.65. The XRPD pattern of Compound 3 Form I can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 15.29, 20.45 and 25.67. The XRPD pattern of Compound 3 Form I can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 9.67, 25.25 and 18.54. The XRPD pattern of Compound 3 Form I can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 12.29, 30.74 and 28.40. The XRPD pattern of Compound 3 Form I can also exhibit further characteristic peaks expressed in degrees 2© (±0.2° 2©) at 24.50, 33.86 and 32.42.

[0091] According to DSC, Form I show two endothermic peaks at about 60 °C and about 267 °C, likely due to desolvation, melting and decomposition (Figure 6). More specifically, the first peak temperature is at 59.85 °C with an onset at 30.23 °C and the second peak temperature is at 266.51 °C with an onset at 253.91 °C. TGA analysis shows a ~0.7% weight loss prior to 150 °C.

[0092] Only about ~0.2% of residual IPA was observed by NMR. Sulfate Form I is a hydrate. Theoretical water content of a mono-hydrate of 2.7%.Form II (hydrate)

[0093] Form II showed irregular crystals with moderate crystallinity. XPRD pattern was recorded and is showed in Figure 7. Form II is a 1 / 0.75 base to acid as determined by ion chromatography.

[0094] According to DSC, Form II shows two endothermic peaks at 134 °C (onset: 104°C) and 209 °C (onset: 203°C), likely due to desolvation and melting (Figure 8). TGA analysis of Form II shows a ~2.8% weight loss prior to 150 °C.

[0095] There was a ~0.1% residual IPA by NMR. Sulfate salt Form II is a hydrate and has a higher dehydration temperature by DSC. Theoretical water content of a mono-hydrate is 2.8%.Form III (anhydrate)

[0096] Form III showed irregular crystals with high crystallinity. XRPD pattern was recorded and is showed in Figure 40. Form III is a 1 / 1 base to acid (mono-sulfate).

[0097] According to DSC, Form III shows one endothermic peak at 280.04 °C with an onset temperature of 275.99 °C. TGA analysis of Form III shows a ~0.5% weight loss between 100 °C and 240 °C. (Figure 41)

[0098] SO42' content of this sample is 14.5% by ion chromatography (IC), suggesting it is a 1 / 1 salt (the theoretical SO42-content of the 1 / 1 salt is 14.8%). Based on thermal profile, Form III is an anhydrate, but it may contain some residual DMSO and MeOH (can not be determined by NMR, since the overlapped peaks).Tosylate salt (Compound 4)

[0099] Two crystalline forms of Compound 4 were obtained, Form I and Form II.Form I (hydrate / solvate)

[0100] Form I showed irregular crystals with low crystallinity. XPRD pattern was recorded and is showed in Figure 9.

[0101] According to DSC, Form I exhibited two endothermic peaks at 94 °C (onset: 48°C) and 243 °C (onset: 238°C), due to desolvation, melting anddecomposition. TGA analysis of form I shows a ~1.8% weight loss prior to 100 °C. (Figure 10)

[0102] Only about ~0.9% residual MeOH was observed by NMR.

[0103] Tosylate salt Form I is a hydrate / solvate. Theoretical water content of a mono-hydrate is 2.4%.Form II (hydrate / solvate)

[0104] Form II showed irregular crystals with low crystallinity. XPRD pattern was recorded and is showed in Figure 11 .

[0105] According to DSC, Form I exhibited two endothermic peaks at 76 °C (onset: 37°C) and 240 °C (onset: 232°C), attributed to desolvation, melting and decomposition. TGA analysis of Form I shows a ~2.0% weight loss between RT and 150 °C. (Figure 12)

[0106] Only ~1.1% residual EtOH was observed by NMR.

[0107] Tosylate Form II is a hydrate / solvate.Besylate salt (Compound 5)

[0108] Two crystalline forms of Compound 5 were obtained, Form I and Form II.Form I (hydrate / solvate)

[0109] Form I showed irregular crystals with low crystallinity. XPRD pattern was recorded and is showed in Figure 13.

[0110] According to DSC, Form I exhibited multiply thermal events, suggesting besylate had complex polymorphism. TGA analysis shows a ~2.1% weight loss prior to 120 °C. (Figure 14)

[0111] Only about ~0.5% residual acetone was observed by NMR.

[0112] Besylate salt Form I is a hydrate / solvate.Form II (hydrate)

[0113] Form II showed irregular crystals with moderate crystallinity. XPRD pattern was recorded and is showed in Figure 15.

[0114] According to DSC, Form II exhibited two endothermic peaks at 60 °C (onset: 31 °C) and 253 °C (onset: 246°C). TGA analysis of Form II shows a ~0.3% weight loss from RT to 150 °C.

[0115] No residual organic solvent was observed by NMR.

[0116] Besylate salt Form II is a hydrate with low dehydration temperature and moderate crystallinity. Theoretical water content of a mono-hydrate is 2.5%.Mesylate salt (Compound 6)

[0117] One crystalline form of Compound 6 was obtained: Form I. Form I showed irregular crystals with high crystallinity. XPRD pattern was recorded and is showed in Figure 17.

[0118] According to DSC, Form I exhibited two endothermic peaks at 62°C (onset: 33°C) and 263 °C (onset: 257°C), likely due to desolvation, melting and decomposition. TGA analysis of Form I shows a ~0.7% weight loss prior to 100 °C. (Figure 18)

[0119] Only about ~0.2% residual IPA was observed by NMR.

[0120] Thus, this sample should be a hydrate (theoretical water content of monohydrate is 2.5%). However, mesylate had complex polymorph and Form I was not easily repeated.Phosphate salt (Compound 7)

[0121] One crystalline form of Compound 7 was isolated from IPA / water (see Examples): Form I. Form I showed irregular crystals with high crystallinity. XPRD pattern was recorded and is showed in Figure 19.

[0122] According to DSC, Form I exhibited two endothermic peaks at 71 °C (onset: 51 °C) and 228 °C (onset: 217°C), likely due to desolvation, melting and decomposition. TGA analysis of Form I shows a ~1.8% weight loss prior to 150 °C. (Figure 20)

[0123] Only about ~0.4% residual IPA was observed by NMR.

[0124] Phosphate salt Form I is a hydrate. Theoretical water content of a monohydrate is 2.7%.Maleate salt (Compound 8)

[0125] Two crystalline forms of Compound 8 were obtained, Form I and Form II.Form I (hydrate)

[0126] Form I showed irregular crystals with moderate crystallinity. XPRD pattern was recorded and is showed in Figure 21.

[0127] According to DSC, Form I exhibited two endothermic peaks at 61 °C (onset: 44°C) and 188 °C (onset: 176°C), attributed to desolvation, melting and decomposition. TGA analysis shows a ~1 .5% weight loss prior to 120 °C. (Figure 22)

[0128] No residual solvent was observed by NMR.

[0129] Maleate salt Form I is a hydrate. Theoretical water content of a monohydrate is 2.6%. This salt showed relatively low crystallinity and low dehydration temperature.Form II (hydrate)

[0130] Form I showed irregular crystals with high crystallinity. XPRD pattern was recorded and is showed in Figure 23.

[0131] According to DSC, Form I exhibited one broad overlapped peak at 58 °C (onset: 55°C), followed by a melting / decomposition peak at 213 °C (onset: 205°C). TGA analysis shows a ~1 .0% weight loss prior to 120 °C. (Figure 24)

[0132] Based on NMR, the sample only contained about ~0.2% residual IPA.

[0133] Maleate salt Form II is a hydrate.Tartrate salt (Compound 9)

[0134] One crystalline form of Compound 9 was isolated from methanol (see Examples): Form I. Form I showed irregular crystals with low crystallinity. XPRD pattern was recorded and is showed in Figure 25.

[0135] According to DSC, Form I exhibited several thermal events and the last peak was likely attributed to the melting of the free form of Compound 1. TGA analysis of Form I shows a ~1.5% weight loss prior to 150 °C followed by a ~12.6% weight loss prior from 150 °C to 260 °C. (Figure 26)

[0136] No residual solvent was observed by NMR. The 1 / 1 ratio base / acid was confirmed by NMR.

[0137] Tartrate salt Form I is a hydrate.Fumarate salt (Compound 10)

[0138] One crystalline form of fumarate salt, Compound 10, was obtained: Form I.Hemi-fumarate Form I (hydrate)

[0139] Hemi-fumarate (stoichiometry was determined by NMR) Form I showed irregular crystals with high crystallinity. XPRD pattern was recorded and is showed in Figure 27.

[0140] According to DSC, Form I exhibited two endothermic peaks at 77 °C (onset: 54°C) and 274 °C (onset: 271 °C), attributed to desolvation, melting and decomposition, and one form transition peak at 211 °C (onset: 190°C). TGA analysis shows a ~0.9% weight loss prior to 120 °C. (Figure 28)

[0141] No residual solvent was observed by NMR.

[0142] Hemi-fumarate salt Form I is a hydrate. Theoretical water content of a mono-hydrate is 1.5%.Fumarate Form I (hydrate)

[0143] Fumarate Form I (mono-fumarate salt, as determined by NMR) showed irregular crystals with high crystallinity. XPRD pattern was recorded and is showed in Figure 29.

[0144] According to DSC, Form I exhibited one broad desolvated peak at 122 °C (onset: 67°C), one melting / decomposition peak at 266 °C (onset: 263°C) and one formtransition peak at 140 °C (onset: 138°C). TGA analysis shows a ~3.4% weight loss prior to 160 °C. (Figure 30)

[0145] Only ~0.3% residual IPA was observed by NMR.

[0146] Fumarate salt Form I is a hydrate. Theoretical water content of a monohydrate is 2.6%.Other salts

[0147] The salt screening experiments also include the attempted synthesis of the following salts of Compound 1 : citrate, malate and succinate.Formulations, Methods and Uses

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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. Forexample, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] 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 agents include 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.

[0165] 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.

[0166] 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.

[0167] Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

[0168] Formulations suitable for parenteral administration include aqueous and non-aqueous 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.

[0169] 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.

[0170] 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.

[0171] 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.

[0172] 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 ofapproximately 70 kg body weight will range from about 0.05 mg to about 100 mg, or between 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

[0173] 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, ischemic injury, ischemic infarction, inflammatory and fibrotic diseases, cardiac fibrosis, vascular proliferation, restenosis, genetic or acquired dilated cardiomyopathy, hypertrophic cardiomyopathy, and stent failure.

[0174] 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 as a result 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.

[0175] The present description also relates to compounds or pharmaceutically acceptable salts thereof, for the treatment of other conditions related to SGK-1 mediated mechanisms, such as cancer, Parkinson’s disease and Lafora disease.

[0176] In some embodiments, the present description provides compounds or pharmaceutically acceptable salts thereof for treating cancer, tumor, or another proliferative disorder. As used herein, the terms “inhibition of cancer”, “inhibition of cancer cell proliferation”, and “inhibition of cancer invasion and metastasis” refer to the inhibition, or decrease in the rate, of the growth, division, maturation, viability, or ability to invade and colonize other organs and tissues of cancer cells, and / or causing the death of cancer cells, individually or in aggregate with other cancer cells, by cytotoxicity, nutrient depletion, induction of differentiation or apoptosis, or recognition by the immune system in order to elicit an immune response to the cancer cells.

[0177] Examples of tissues containing cancerous cells whose proliferation can be inhibited by a compound, salt or composition thereof described herein and against which the methods described herein are useful include but are not limited to breast, prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney, colon, intestine, endometrium, ovary, lung, testicle, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gall bladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph nodes, sweat glands, sebaceous glands, muscle, heart, bone, and stomach.

[0178] In some embodiments, the cancer treated by a provided compound, salt or composition thereof is a cancer or tumor that is a melanoma, liposarcoma, lung cancer (e.g., non-small cell lung cancer), breast cancer (e.g., ER+, ER-, HER2+, HER2-, HER2-low, PR-, PR+, triple negative, luminal, basal), Luminal androgen receptor (LAR)) prostate cancer, neuroendocrine prostate cancer (NEPC), treatment-induced NEPC (t-NEPC), leukemia, kidney cancer, esophageal cancer, thyroid cancer (e.g., Anaplastic Thyroid Cancer (ATC), Poorly Differentiated Thyroid Cancer (PDTC)), ovarian cancer, endometrial cancer, Head and Neck Squamous Cell Carcinoma, brain cancer, lymphoma, rectal cancer, colon cancer, uterine cancer, cervical cancer, Hepatocellular carcinoma, Papillary thyroid carcinoma (PTC), or colorectal cancer

[0179] In some embodiments, the compounds of the present description can be used to treat cancer by inhibiting signaling of the AKT / PI3K / mTOR pathway in patients whose tumors have activation of this pathway through mutations in PIK3CA, AKT 1 , and / or PTEN for example.

[0180] In some embodiments, the compounds of the present description can be used in combination with compounds that inhibit AKT / PI3K / mTOR signaling to treat cancer in patients whose tumors have activation of this pathway through mutations in PIK3CA, AKT 1 , and / or PTEN for example. Non-limiting examples of AKT / PI3K / mTOR inhibitors include NVP-BEZ235 (BEZ235, Dactolisib), GDC-0084 (RG7666), GDC- 0980 (Apitolisib, RG7422), LY3023414, PF-05212384 (Gedatolisib, PKI-587), PQR309 (Bimiralisib), P7170, SF-1126, Copanlisib (BAY 80-6946), Buparlisib (BKM120 NVP- BKM120), IPI-145 (Duvelisib), RP6530 (Tenalisib), GDC-0032 (Taselisib), KA2237, BYL719 (Alpelisib), CAL-101 (GS-1101 , Idelalisib), GSK2636771 , INCB050465 (Parsaclisib), Serabelisib (INK-1117, MLN- 1117.TAK-117), ME401 (PWT-143), Umbralisib (RP5264, TGR-1202), CUDC-907 (Fimepinostat), Rigosertib (GN-01910), samotolisib, paxalisib, voxtalisib, CH5132799, pilaralisib, ZSTK474, sonolisib,pictilisib, B591 , TG-100-115, RIDR-PI-103, zandelisib, AMG319, linperlisib, leniolisib, eganelisib, AZD8186, AZD8835, MK-2206, ipatasertib, GSK690693, capivasertib, PF- 04691502, AT7867, MAY1125976, TAS117, Afuresertib, Uprosertib, AT13148, everolimus, temsirolimus, ridaforolimus, sirolimus, umirolimus, zotarolimus, ICSN3250, LY3023414, OSU-53, AZD8055, and rapamycin.

[0181] The inhibitor of AKT, PI3K, and / or mTOR may be selected from the group consisting of vistusertib (AZD2014), NU7441 (KU-57788), KU-0063794, TGX-221 , RLY-2608, CYH33, STX-478, LOXO-783, GSK2334470, CC-223, ABTL0812, DCBCI0901 , AZD-8055, sapanisertib, JR-AB2-011 , omipalisib, and torkinibm PI-103.

[0182] In some embodiments, the compounds of the present description can be used in combination with at least one inhibitor of PDK1 , RAS, RTK, RAF, MEK, ERK, HER2, EGFR, SOS1 , SOS2, SHP1 , SHP2, and / or MAPK.

[0183] The inhibitor of PDK1 , RAS, RTK, RAF, MEK, ERK, HER2, EGFR, SOS1 , SOS2, SHP1 , and / or MAPK may be selected from the group consisting of dabrafenib, trametinib (GSK1120212), encorafenib (LGX818), binimetinib, cobimetinib, naporafenib (LXH254), sorafenib (BAY 43-9006), vemurafenib (PLX4032), PLX-4720, regorafenib (BAY 73-4506), GDC_0879, RAF265 (CHIR-265), AZ 628, lifirafenib (BGB-283), NVP-BHG712, SB590885, ZM 336372, GW5074, TAK-632, agerafenib (RXDX-105), GNE-9815, TBAP-001 , L-779450, belvarafenib (HM95573), AZ304, PLX8394, RAF709, OCT 196969, BAW2881 (N P-BAW2881), LY3009120, avutometinib (RO5126766, CH5126766), doramapimod (BIRB 796), MCP110, PLX7904, tovorafenib (MLN2480), selumetinib (AZD6244), mirdametinib (PD0325901), U0126, PD98059, PD184352 (CI-1040), BIX 02189, pimasertib (AS- 70326), pelitinib (EKB-569), BIX 02188, TAK-733, AZD8330, binimetinib (MEK162), SL-327, refametinib (RDEA119), zapnometinib (PD0184264), GDC-0623, BI-847325, cobimetinib (GDC_0973), PD318088, SCH772984, ASN007, MRTX-1257, AZD0634 (ATG-017), MK-8353 (SCH900353), temuterkib (LY3214996), VX-11e, ulixertinib (BVD-523), ravoxertinib (GDC-0994), exarafenib, ERAS-601 , BDTX-4933, ADT007, HM99462, DCC-3084, PHI-501 , MRTX1133. Sotorasib (AMG510), lonafamib (SCH66336), ASP2453, BI-3406, BI-2852, BAY-293, KRpep-2d, ARS-853, adagrasib (MRTX849), JDQ443, LY3537982, D-1553, JAB-21822, GFH925, , ARS1620, RSC- 1255, Bl 1701963, VS-6766, MTX-531 , Bl 1823911 , JNJ-74699157, MK-1084, BPI- 421286, GH35, RMC-6291 , RMC-9805, HRS-4642, ASP3082, siG12D-LODER, mRNA-5671 / V941 , ELI-0022P, RMC-6236, divarasib (GDC-6036), GDC-1971 , IACS-13909, JAB-3068, RMC-4550, RMC-4630, SHP099, TNO155, GDC-1971 , HBI-2376, BBP-398 (IACS-15509), PF-07284892, selpercatinib (LOXO-292), pralsetinib (BLU- 667), LOXO-260, TAS-0953 / HM06, TPX-0046, EP0031 , APS03118, TP-0903, BGB324 (R428), bosutinib (SKI-606), and gilteritinib (ASP2215).

[0184] In some embodiments, the compounds of the present description can be combined with an inhibitor of the RAS / RAF / MAPK pathway in cells that have a mutation activating RAS, RAF, MEK, or ERK signaling. Non-limiting examples of RAF / RAS / MEK / ERK / SOS1 / SOS2 / SHP2 inhibitors include dabrafenib, trametinib (GSK1120212), encorafenib (LGX818), binimetinib, cobimetinib, naporafenib (LXH254), sorafenib (BAY 43-9006), vemurafenib (PLX4032), PLX-4720, regorafenib (BAY 73-4506), GDC_0879, RAF265 (CHIR-265), AZ 628, lifirafenib (BGB-283), NVP- BHG712, SB590885, ZM 336372, GW5074, TAK-632, agerafenib (RXDX-105), GNE- 9815, TBAP-001 , L-779450, belvarafenib (HM95573), AZ304, PLX8394, RAF709, CCT196969, BAW2881 (NVP-BAW2881), LY3009120, avutometinib (RO5126766, CH5126766), doramapimod (BIRB 796), MCP110, PLX7904, tovorafenib (MLN2480), selumetinib (AZD6244), mirdametinib (PD0325901), U0126, PD98059, PD184352 (CI- 1040), BIX 02189, pimasertib (AS-70326), pelitinib (EKB-569), BIX 02188, TAK-733, AZD8330, binimetinib (MEK162), SL-327, refametinib (RDEA119), zapnometinib (PD0184264), GDC-0623, BI-847325, cobimetinib (GDC_0973), PD318088, SCH772984, ASN007, MRTX-1257, AZD0634 (ATG-017), MK-8353 (SCH900353), temuterkib (LY3214996), VX-11e, ulixertinib (BVD-523), ravoxertinib (GDC-0994), exarafenib, ERAS-601 , BDTX-4933, ADT007, HM99462, DCC-3084, PHI-501 , MRTX1133. Sotorasib (AMG510), lonafamib (SCH66336), ASP2453, BI-3406, Bl- 2852, BAY-293, KRpep-2d, ARS-853, adagrasib (MRTX849), adagrasib (MRTX849), ARS1620, divarasib (GDC-6036), GDC-1971 , IACS-13909, JAB-3068, RMC-4550, RMC-4630, SHP099, TNO155, GDC-1971 , HBI-2376, BBP-398 (IACS-15509), and PF-07284892.

[0185] In some embodiments, the compounds of the present description can be combined with an inhibitor of the RTK, PI3K, AKT, RAS, RAF or MAPK pathway in cancer cells that, for example, have up-regulation of gene expression associated with ribosomal protein synthesis, ribosome biogenesis, protein translation, translation initiation, and / or translation elongation.

[0186] In some embodiments, the compounds of the present description can be combined with an inhibitor of the PI3K or AKT pathway in cancer cells that, for example,have upregulation of gene signatures associated with basal and / or mesenchymal breast cancer.

[0187] In some embodiments, the compounds of the present description can be combined with an inhibitor of the PI3K or AKT pathway in cancer cells that, for example, have a downregulation of gene signatures associated with luminal breast cancer.

[0188] Non-limiting examples of AKT / PI3K / mTOR inhibitors include PDK1 inhibitors, and other mTORC1 / 2 inhibitors such as vistusertib (AZD2014), NU7441 (KU-57788), KU-0063794, TGX-221 , RLY-2608, CYH33, STX-478, LOXO-783, GSK2334470, CC-223, ABTL0812, DCBCI0901 , AZD-8055, sapanisertib, JR-AB2- 011 , omipalisib, and torkinibm PI-103.

[0189] In some embodiments, the compounds of the present description can be used to treat cancer by inhibiting signaling of the RAF / MEK / ERK pathway in patients whose tumors have activation of this pathway through, for example, mutations in KRAS, HRAS, NRAS, NF1 , BRAF, ARAF1 , NF2, MAP2K1 , RRAS2, and / or CIO.

[0190] In some embodiments, the compounds of the present description can be used to treat cancer by inhibiting signaling of the RAF / MEK / ERK and / or PI3K, AKT, mTOR pathway in patients whose tumors have concomitant activation of these pathways through, for example, concomitant mutations in KRAS / PIK3CA, HRAS / PIK3CA, NRAS / PIK3CA, NF1 / BRAF / PIK3CA, BRAF / PIK3CA, ARAF1 / PIK3CA, NF2 / PIK3CA, MAP2K1 / PIK3CA, BRAF / AKT1 , and / or BRAF / PTEN.

[0191] In some embodiments, the compounds of the present description can be used to treat cancer in patients that had prior progression on prior a treatment (i.e., cancers that are resistant to one or more anticancer therapies) (e.g., BRAF inhibitors, MEK inhibitors, EGFR inhibitors, or combinations thereof).) (e.g., combination of inhibitors). For example, a combination of BRAF inhibitors, MEK inhibitor, PI3K, and / or EGFR.

[0192] In some embodiments, the compounds of the present description can be combined with an inhibitor of the RTK, PI3K, AKT, RAS, RAF or MAPK pathway in cancers or tumors that have an upregulation of a mitogen activated protein kinase (MAPK) gene expression signature, such as CCND1 , DUSP4, DUSP6, PHLDA1 , SPRY2, SPRY4, EPHA2, EPHA4, ETV4, and ETV, or DUSP6, ETV4, ETV5 and / or SPRY4.

[0193] In some embodiments, the compounds of the present description can be combined with an inhibitor of one or more inhibitors of the pathways described in Table V of W02024011307A1.

[0194] In some embodiments, the compounds of the present description can be combined with an inhibitor of one or more inhibitors described herein in the cancers or tumors have an upregulation in one or more genes described in Tables W-Z of W02024011307A1 .

[0195] In some embodiments, the compounds of the present description can be combined with an inhibitor of a receptor tyrosine kinase (RTK). Non-limiting examples of RTK inhibitors include epidermal growth factor receptor (EGFR) inhibitors erlotinib, osimertinib, neratinib, gefitinib, cetuximab, panitumumab, dacomitinib, lapatinib, necitumumab, mobercitinib, vandetanib, sapitinib, afatinib, canertinib, CP-724714, CUDC-101 , mubritinib (TAK 165), OSI-420, pelitinib, irbinitinib (ARRY-380, ONT-380), varlitinib, TAK-285, BIBX 1382, PD168393, raciletinib, poziotinib, CL-387785, icotinib, CTX-2006, WHI-P154, AZ5104, AZD3759, Erb-B2 receptor tyrosine kinase 2 (HER2) such as neratinib, trastuzumab and its derivatives such as trastuzumab deruxtecan, lapatinib, dacomitinib, tucatinib, pertuzumab, margetuximab, afatinib, AZD8931 , AST1306, AEE788, canertinib, CP724,714, CUDC101 , TAK285, dacomitinib, pelitinib, AC480, canertinib, sapitinib, mubritinib (TAK 165), BDTX-189, epertinib, TAS0728, poziotinib, multikinase inhibitors cabozantinib, imatinib, Lenvatinib, regorafenib, sorafenib, sunitinib, vandetinib, MET inhibitors crizotinib, cabozantinib, foretinib, PHA- 665752, SU11274, SGX-523, BMS-777607, tivantinib (ARQ 197), JNJ-38877605, PF- 04217903, MGCD-265, capmatinib (INCB28060), BMS-754807, BMS-794833, AMG- 208, MK-2461 , golvatinib (E7050), AMG-458, NVP-BVU972, XL092, UNC2025, elzovantinib (TPX-0022), AMG-1 , JNJ-38877618 (OMO-1), altiratinib, SAR125844, glumetinib (SCC244), savolitinib (AZD6094), RXDX-106 (CEP-40783), S49076, merestinib (LY2801653), AMG 337, tepotinib, neurotrophic receptor tyrosine kinase 1 (NTRK1) inhibitors larotrectinib, entrectinib, danusertib, BMS-754807, GW441756, UNC2025, taletrectinib, altiratinib, selitrectinib (LOXO-195), CH7057288, BMS- 935177, PF-06273340, sitravatinib (MGCD516), GNF-5837, vascular endothelial growth factor receptor inhibitors bevacizumab, ramucirumab, SU5408, linifanib (ABT- 869), axitinib (AG 013736), nintedanib (BIBF 1120), cediranib (AZD2171), motesanib (AMG-706), pazopanib (GW786034), vandetanib, sunitinib (SU11248), sorafenib (BAY 43-9006), brivanib (BMS-540215), vatalanib (PTK787), foretinib (GSK1363089), cabozantinib (BMS-907351), brivanib (BMS-582664), Lenvatinib (E7080), CYC116,regorafenib (BAY 73-4506), ENMD-2076, tivozanib, ponatinib (AP24534), apatinib (YN968D1), telatinib, PP121 , pazopanib, dovitinib, SAR131675, semaxanib (SU5416), golvatinib (E7050), fibroblast growth factor receptor inhibitors ponatinib (AP24534), infigratinib (BGJ398), nintedanib (BIBF 1120), PD173074, AZD4547, dovitinib, pemigatinib, futibatinib, infigratinib, and RLY-4008.

[0196] In some embodiments, the compounds of the present description can be combined with immunotherapies. Non-limiting examples of immunotherapies include pembrolizumab, panitumumab, peginterferon alfa-2b, pertuzumab, atezolizumab, avelumab, cemiplimab-rwlc, dostarlimab-gxly, durvulamab, ipilimumab, nivolumab, nivolumab and relatlimab-rmbw, retifanlimab-dlwr, toripalimab-tpzi, and tremelimumab-actl.

[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, including radiation-induced fibrosis, and auto-immune diseases.

[0198] 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. In vivo, SGK-1 activates certain potassium, sodium, and chloride channels. For instance, the protein is known to regulate the myo-inositol transporter during osmotic stress. The term “inhibitor of SGK-1”, as used herein, refers to any compound that can block, arrest, interfere with, or reduce the biological activity of SGK- 1.

[0199] In some embodiments, the compounds of the present description can be used for increasing fetal hemoglobin (HbF) in erythrocytes. In some embodiments, the compounds of the present description can be used for the treatment of a |3- hemoglobinopathy. In some embodiments, the compounds of the present description can be used for the treatment of sickle cell disease.

[0200] In some embodiments, the compounds of the present description can be used for the treatment of prostate cancer. In other embodiments, the compounds of the present description can be used for the treatment of epilepsy.

[0201] in some embodiments, there is described a method for the treatment of cancer or tumor in a subject, comprising: determining that cells from said cancer or tumor (e.g., cancer or tumor sample or biopsy): i. have an upregulation in expression of genes associated with ribosomal protein synthesis, ribosome biogenesis, protein translation, translation initiation, and / or translation elongation; ii. have an upregulation of gene signatures associated with basal and / or mesenchymal breast cancer;Hi. have a downregulation of gene signatures associated with luminal breast cancer iv. the cancer or tumor comprises cells having an activation of a RAF, MEK, ERK, PI3K, AKT, and / or mTOR pathway; v. have an activation of a RAF, MEK, ERK, PI3K, AKT, and / or mTOR pathway that is mediated by at least one mutation in KRAS, HRAS, NRAS, NF1 , BRAF, ARAF1 , NF2, MAP2K1 , RRAS2, and / or CIC; vi. have an activation of a RAF, MEK, ERK, PI3K, AKT, and / or mTOR pathway that is mediated by one or more concomitant mutations in KRAS / PIK3CA, HRAS / PIK3CA, NRAS / PIK3CA, NF1 / BRAF / PIK3CA, BRAF / PIK3CA, ARAF1 / PIK3CA, NF2 / PIK3CA, MAP2K1 / PIK3CA, BRAF / AKT1 , and / or BRAF / PTEN; vii. have an upregulation of a mitogen activated protein kinase (MAPK) gene expression (e.g., CCND1 , DUSP4, DUSP6, PHLDA1 , SPRY2, SPRY4, EPHA2, EPHA4, ETV4, and ETV, or DUSP6, ETV4, ETV5 and SPRY4); and / or viii. are resistant to one or more anticancer therapies (e.g., BRAF inhibitors, MEK inhibitors, EGFR inhibitors, or combinations thereof); and

[0202] administering to the subject one or more compounds or pharmaceutically acceptable salts thereof as defined herein, the pharmaceutical compositions defined herein, or the combinations defined herein.

[0203] In some embodiments, there is described a use of one or more compounds or pharmaceutically acceptable salts thereof as defined herein, the pharmaceutical compositions defined herein, or the combinations defined herein, for the treatment of cancer or tumor or for the manufacture of a medicament for the treatment of cancer or tumor, wherein the cancer or tumor (e.g., cancer or tumor sample or biopsy) has been predetermined as: a. having an upregulation in expression of genes associated with ribosomal protein synthesis, ribosome biogenesis, protein translation, translation initiation, and / or translation elongation; b. having an upregulation of gene signatures associated with basal and / or mesenchymal breast cancer; c. having a downregulation of gene signatures associated with luminal breast cancer d. the cancer or tumor comprises cells having an activation of a RAF, MEK, ERK, PI3K, AKT, and / or mTOR pathway; e. having an activation of a RAF, MEK, ERK, PI3K, AKT, and / or mTOR pathway that is mediated by at least one mutation in KRAS, HRAS, NRAS, NF1 , BRAF, ARAF1 , NF2, MAP2K1 , RRAS2, and / or CIC; f. having an activation of a RAF, MEK, ERK, PI3K, AKT, and / or mTOR pathway that is mediated by one or more concomitant mutations in KRAS / PIK3CA, HRAS / PIK3CA, NRAS / PIK3CA, NF1 / BRAF / PIK3CA, BRAF / PIK3CA, ARAF1 / PIK3CA, NF2 / PIK3CA, MAP2K1 / PIK3CA, BRAF / AKT1 , and / or BRAF / PTEN; g. having an upregulation of a mitogen activated protein kinase (MAPK) gene expression (e.g., CCND1 , DUSP4, DUSP6, PHLDA1 , SPRY2, SPRY4, EPHA2, EPHA4, ETV4, and ETV, or DUSP6, ETV4, ETV5 and SPRY4); and / or h. being resistant to one or more anticancer therapies (e.g., BRAF inhibitors, MEK inhibitors, EGFR inhibitors, or combinations thereof).

[0204] In some embodiments, there is described a use of one or more compounds or pharmaceutically acceptable salts thereof as defined herein, the pharmaceutical compositions defined herein, or the combinations defined herein, for the treatment of one or more side effects or toxicities caused by an anticancer therapy in a subject undergoing said anticancer therapy. The one or more side effects or toxicities caused by the anticancer therapy may be selected from the group consisting of: hyperglycemia and hyperinsulinemia, increased ALT / AST, pyrexia, rash, diarrhea, nausea, fatigue, thrombocytopenia, anemia, dermatitis acneiform, QT elongation, and dyspnea.

[0205] In some embodiments, there is described a method for treating one or more side effects or toxicities caused by an anticancer therapy, comprising administering to a subject undergoing said anticancer therapy one or more compounds or pharmaceutically acceptable salts thereof as defined herein, the pharmaceutical compositions defined herein, or the combinations defined herein. The one or more side effects or toxicities caused by the anticancer therapy may be selected from the group consisting of: hyperglycemia and hyperinsulinemia, increased ALT / AST, pyrexia, rash, diarrhea, nausea, fatigue, thrombocytopenia, anemia, dermatitis acneiform, QT elongation, and dyspnea.

[0206] In some embodiments, there is described a method for monitoring the progression of an anticancer therapy in a subject that was previously administered with one or more compounds or pharmaceutically acceptable salts thereof as defined herein, the pharmaceutical compositions defined herein, or the combinations defined herein, wherein the method comprises determining in a sample from said subject: a. a loss of phosphorylation of NDRG1 ; b. an increase in phosphorylation of MAPK14 (i.e., p38); c. an increase in phosphorylation of MAPK14 (i.e., p38); d. an increase in phosphorylation of heat shock protein family B1 (i.e., HSPB1 or HSP27); e. an increase in phosphorylation of tumor suppressor p53 (TP53); f. an increase in phosphorylation of ribosomal protein S6 kinase A1 (RSK1);g. an increase in phosphorylation of mitogen-activated protein kinase 1 (i.e., MAPK1 or ERK2); h. an increase in phosphorylation of mitogen-activated protein kinase 1 (i.e., MAPK1 or ERK2); i. an increase in phosphorylation of mitogen-activated protein kinase 3 (i.e., MAPK3 or ERKI); j. an increase in phosphorylation of mitogen-activated protein kinase 3 (i.e., MAPK3 or ERK1); and / or k. an increase in phosphorylation of AKT1 substrate 1 (PRAS40).

[0207] In some embodiments, said loss of phosphorylation of NDRG1 is at threonine 346 of the NDRG1 ; said increase in phosphorylation of MAPK14 (i.e., p38) is at threonine 180 of the MAPK14; said increase in phosphorylation of MAPK14 (i.e., p38) is at tyrosine 182 of the MAPK14; said increase in phosphorylation of heat shock protein family B1 (i.e., HSPB1 or HSP27) at serine 82 of the HSPB1 ; said increase in phosphorylation of tumor suppressor p53 (TP53) is at serine 15 of the TP53; said increase in phosphorylation of ribosomal protein S6 kinase A1 (RSK1) is at serine 380 of the RSK1 ; said increase in phosphorylation of mitogen-activated protein kinase 1 (i.e., MAPK1 or ERK2) is at tyrosine 185 of the MAPK1 ; said increase in phosphorylation of mitogen-activated protein kinase 1 (i.e., MAPK1 or ERK2) is at tyrosine 187 of the MAPK1 ; said increase in phosphorylation of mitogen-activated protein kinase 3 (i.e., MAPK3 or ERK1) is at threonine 202 of the MAPK3; said increase in phosphorylation of mitogen-activated protein kinase 3 (i.e., MAPK3 or ERK1) is at tyrosine 204 of the MAPK3; and / or said increase in phosphorylation of AKT 1 substrate 1 (PRAS40) is at threonine 246 of the AKT 1 substrate 1 .

[0208] In some embodiments, said loss or increase in phosphorylation is in comparison to a sample from a healthy subject or a subject that is not undergoing said anticancer therapy. In some embodiments, said monitoring the progression of said anticancer therapy includes determining if the anticancer therapy is effective or if the cancer is becoming resistant to the anticancer therapy.

[0209] 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 geneticLQTS or acquired LQTS, 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 LQTS; can reduce and alleviate symptoms associated with heart failure, arrhythmia, ischemic injury, ischemic infarction, inflammatory and fibrotic diseases, cardiac fibrosis, vascular proliferation, restenosis, genetic or acquired dilated cardiomyopathy, hypertrophic cardiomyopathy, and stent failure.

[0210] 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 as a result 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.

[0211] The present description also relates to compounds or pharmaceutically acceptable salts thereof, for the treatment of other conditions related to SGK-1 mediated mechanisms, such as cancer, Parkinson’s disease and Lafora disease.

[0212] In some embodiments, the present description provides compounds or pharmaceutically acceptable salts thereof for treating cancer, tumor, or another proliferative disorder. As used herein, the terms “inhibition of cancer”, “inhibition of cancer cell proliferation”, and “inhibition of cancer invasion and metastasis” refer to the inhibition, or decrease in the rate, of the growth, division, maturation, viability, or ability to invade and colonize other organs and tissues of cancer cells, and / or causing the death of cancer cells, individually or in aggregate with other cancer cells, by cytotoxicity, nutrient depletion, induction of differentiation or apoptosis, or recognition by the immune system in order to elicit an immune response to the cancer cells.

[0213] Examples of tissues containing cancerous cells whose proliferation can be inhibited by a compound, salt or composition thereof described herein and against which the methods described herein are useful include but are not limited to breast, prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney, colon, intestine, endometrium, ovary, lung, testicle, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gall bladder, rectum, salivary gland,adrenal gland, throat, esophagus, lymph nodes, sweat glands, sebaceous glands, muscle, heart, bone, and stomach.

[0214] In some embodiments, the cancer treated by a provided compound, salt or composition thereof is a cancer or tumor that is a melanoma, liposarcoma, lung cancer (e.g., non-small cell lung cancer), breast cancer (e.g., ER+, ER-, HER2+, HER2-, PR- , PR+, triple negative, luminal, basal), Luminal androgen receptor (LAR)) prostate cancer, leukemia, kidney cancer, esophageal cancer, thyroid cancer (e.g., Anaplastic Thyroid Cancer (ATC), Poorly Differentiated Thyroid Cancer (PDTC)), ovarian cancer, endometrial cancer, Head and Neck Squamous Cell Carcinoma, brain cancer, lymphoma, rectal cancer, colon cancer, uterine cancer, cervical cancer, Hepatocellular carcinoma, Papillary thyroid carcinoma (PTC), or colorectal cancer

[0215] In some embodiments, the compounds of the present description can be used to treat cancer by inhibiting signaling of the AKT / PI3K / mTOR pathway in patients whose tumors have activation of this pathway through mutations in PIK3CA, AKT 1 , and / or PTEN for example.

[0216] In some embodiments, the compounds of the present description can be used in combination with compounds that inhibit AKT / PI3K / mTOR signaling to treat cancer in patients whose tumors have activation of this pathway through mutations in PIK3CA, AKT 1 , and / or PTEN for example. Non-limiting examples of AKT / PI3K / mTOR inhibitors include NVP-BEZ235 (BEZ235, Dactolisib), GDC-0084 (RG7666), GDC- 0980 (Apitolisib, RG7422), LY3023414, PF-05212384 (Gedatolisib, PKI-587), PQR309 (Bimiralisib), P7170, SF-1126, Copanlisib (BAY 80-6946), Buparlisib (BKM120 NVP- BKM120), IPI-145 (Duvelisib), RP6530 (Tenalisib), GDC-0032 (Taselisib), KA2237, BYL719 (Alpelisib), CAL-101 (GS-1101 , Idelalisib), GSK2636771 , INCB050465 (Parsaclisib), Serabelisib (INK-1117, MLN- 1117.TAK-117), ME401 (PWT-143), Umbralisib (RP5264, TGR-1202), CUDC-907 (Fimepinostat), Rigosertib (GN-01910), samotolisib, paxalisib, voxtalisib, CH5132799, pilaralisib, ZSTK474, sonolisib, pictilisib, B591 , TG-100-115, RIDR-PI-103, zandelisib, AMG319, linperlisib, leniolisib, eganelisib, AZD8186, AZD8835, MK-2206, ipatasertib, GSK690693, capivasertib, PF- 04691502, AT7867, MAY1125976, TAS117, Afuresertib, Uprosertib, AT13148, everolimus, temsirolimus, ridaforolimus, sirolimus, umirolimus, zotarolimus, ICSN3250, LY3023414, OSU-53, AZD8055, and rapamycin.

[0217] The inhibitor of AKT, PI3K, and / or mTOR may be selected from the group consisting of vistusertib (AZD2014), NU7441 (KU-57788), KU-0063794, TGX-221 , RLY-2608, CYH33, STX-478, LOXO-783, GSK2334470, CC-223, ABTL0812, DCBCI0901 , AZD-8055, sapanisertib, JR-AB2-011 , omipalisib, and torkinibm PI-103.

[0218] In some embodiments, the compounds of the present description can be used in combination with at least one inhibitor of PDK1 , RAS, RTK, RAF, MEK, ERK, HER2, EGFR, SOS1 , SOS2, SHP1 , and / or MAPK.

[0219] The inhibitor of PDK1 , RAS, RTK, RAF, MEK, ERK, HER2, EGFR, SOS1 , SOS2, SHP1 , and / or MAPK may be selected from the group consisting of dabrafenib, trametinib (GSK1120212), encorafenib (LGX818), binimetinib, cobimetinib, naporafenib (LXH254), sorafenib (BAY 43-9006), vemurafenib (PLX4032), PLX-4720, regorafenib (BAY 73-4506), GDC_0879, RAF265 (CHIR-265), AZ 628, lifirafenib (BGB-283), NVP-BHG712, SB590885, ZM 336372, GW5074, TAK-632, agerafenib (RXDX-105), GNE-9815, TBAP-001 , L-779450, belvarafenib (HM95573), AZ304, PLX8394, RAF709, OCT 196969, BAW2881 (N P-BAW2881), LY3009120, avutometinib (RO5126766, CH5126766), doramapimod (BIRB 796), MCP110, PLX7904, tovorafenib (MLN2480), selumetinib (AZD6244), mirdametinib (PD0325901), U0126, PD98059, PD184352 (CI-1040), BIX 02189, pimasertib (AS- 70326), pelitinib (EKB-569), BIX 02188, TAK-733, AZD8330, binimetinib (MEK162), SL-327, refametinib (RDEA119), zapnometinib (PD0184264), GDC-0623, BI-847325, cobimetinib (GDC_0973), PD318088, SCH772984, ASN007, MRTX-1257, AZD0634 (ATG-017), MK-8353 (SCH900353), temuterkib (LY3214996), VX-11e, ulixertinib (BVD-523), ravoxertinib (GDC-0994), exarafenib, ERAS-601 , BDTX-4933, ADT007, HM99462, DCC-3084, PHI-501 , MRTX1133. Sotorasib (AMG510), lonafamib (SCH66336), ASP2453, BI-3406, BI-2852, BAY-293, KRpep-2d, ARS-853, adagrasib (MRTX849), adagrasib (MRTX849), ARS1620, divarasib (GDC-6036), GDC-1971 , IACS-13909, JAB-3068, RMC-4550, RMC-4630, SHP099, TNO155, GDC-1971 , HBI- 2376, BBP-398 (IACS-15509), PF-07284892, selpercatinib (LOXO-292), pralsetinib (BLU-667), LOXO-260, TAS-0953 / HM06, TPX-0046, EP0031 , APS03118, TP-0903, BGB324 (R428), bosutinib (SKI-606), and gilteritinib (ASP2215).

[0220] In some embodiments, the compounds of the present description can be combined with an inhibitor of the RAS / RAF / MAPK pathway in cells that have a mutation activating RAS, RAF, MEK, or ERK signaling. Non-limiting examples of RAF / RAS / MEK / ERK / SOS1 / SOS2 / SHP2 inhibitors include dabrafenib, trametinib(GSK1120212), encorafenib (LGX818), binimetinib, cobimetinib, naporafenib (LXH254), sorafenib (BAY 43-9006), vemurafenib (PLX4032), PLX-4720, regorafenib (BAY 73-4506), GDC_0879, RAF265 (CHIR-265), AZ 628, lifirafenib (BGB-283), NVP- BHG712, SB590885, ZM 336372, GW5074, TAK-632, agerafenib (RXDX-105), GNE- 9815, TBAP-001 , L-779450, belvarafenib (HM95573), AZ304, PLX8394, RAF709, CCT196969, BAW2881 (NVP-BAW2881), LY3009120, avutometinib (RO5126766, CH5126766), doramapimod (BIRB 796), MCP110, PLX7904, tovorafenib (MLN2480), selumetinib (AZD6244), mirdametinib (PD0325901), U0126, PD98059, PD184352 (CI- 1040), BIX 02189, pimasertib (AS-70326), pelitinib (EKB-569), BIX 02188, TAK-733, AZD8330, binimetinib (MEK162), SL-327, refametinib (RDEA119), zapnometinib (PD0184264), GDC-0623, BI-847325, cobimetinib (GDC_0973), PD318088, SCH772984, ASN007, MRTX-1257, AZD0634 (ATG-017), MK-8353 (SCH900353), temuterkib (LY3214996), VX-11e, ulixertinib (BVD-523), ravoxertinib (GDC-0994), exarafenib, ERAS-601 , BDTX-4933, ADT007, HM99462, DCC-3084, PHI-501 , MRTX1133. Sotorasib (AMG510), lonafamib (SCH66336), ASP2453, BI-3406, Bl- 2852, BAY-293, KRpep-2d, ARS-853, adagrasib (MRTX849), adagrasib (MRTX849), ARS1620, divarasib (GDC-6036), GDC-1971 , IACS-13909, JAB-3068, RMC-4550, RMC-4630, SHP099, TNO155, GDC-1971 , HBI-2376, BBP-398 (IACS-15509), and PF-07284892.

[0221] In some embodiments, the compounds of the present description can be combined with an inhibitor of the RTK, PI3K, AKT, RAS, RAF or MAPK pathway in cancer cells that, for example, have up-regulation of gene expression associated with ribosomal protein synthesis, ribosome biogenesis, protein translation, translation initiation, and / or translation elongation.

[0222] In some embodiments, the compounds of the present description can be combined with an inhibitor of the PI3K or AKT pathway in cancer cells that, for example, have upregulation of gene signatures associated with basal and / or mesenchymal breast cancer.

[0223] In some embodiments, the compounds of the present description can be combined with an inhibitor of the PI3K or AKT pathway in cancer cells that, for example, have a downregulation of gene signatures associated with luminal breast cancer.

[0224] Non-limiting examples of AKT / PI3K / mTOR inhibitors include PDK1 inhibitors, and other mTORC1 / 2 inhibitors such as vistusertib (AZD2014), NU7441(KU-57788), KU-0063794, TGX-221 , RLY-2608, CYH33, STX-478, LOXO-783, GSK2334470, CC-223, ABTL0812, DCBCI0901 , AZD-8055, sapanisertib, JR-AB2- 011 , omipalisib, and torkinibm PI-103.

[0225] In some embodiments, the compounds of the present description can be used to treat cancer by inhibiting signaling of the RAF / MEK / ERK pathway in patients whose tumors have activation of this pathway through, for example, mutations in KRAS, HRAS, NRAS, NF1 , BRAF, ARAF1 , NF2, MAP2K1 , RRAS2, and / or CIO.

[0226] In some embodiments, the compounds of the present description can be used to treat cancer by inhibiting signaling of the RAF / MEK / ERK and / or PI3K, AKT, mTOR pathway in patients whose tumors have concomitant activation of these pathways through, for example, concomitant mutations in KRAS / PIK3CA, HRAS / PIK3CA, NRAS / PIK3CA, NF1 / BRAF / PIK3CA, BRAF / PIK3CA, ARAF1 / PIK3CA, NF2 / PIK3CA, MAP2K1 / PIK3CA, BRAF / AKT1 , and / or BRAF / PTEN.

[0227] In some embodiments, the compounds of the present description can be used to treat cancer in patients that had prior progression on prior a treatment (i.e., cancers that are resistant to one or more anticancer therapies) (e.g., BRAF inhibitors, MEK inhibitors, EGFR inhibitors, or combinations thereof).) (e.g., combination of inhibitors). For example, a combination of BRAF inhibitors, MEK inhibitor, and / or EGFR.

[0228] In some embodiments, the compounds of the present description can be combined with an inhibitor of the RTK, PI3K, AKT, RAS, RAF or MAPK pathway in cancers or tumors that have an upregulation of a mitogen activated protein kinase (MAPK) gene expression signature, such as CCND1 , DUSP4, DUSP6, PHLDA1 , SPRY2, SPRY4, EPHA2, EPHA4, ETV4, and ETV, or DUSP6, ETV4, ETV5 and / or SPRY4.

[0229] In some embodiments, the compounds of the present description can be combined with an inhibitor of one or more inhibitors of the pathways described in Table V of W02024011307A1.

[0230] In some embodiments, the compounds of the present description can be combined with an inhibitor of one or more inhibitors described herein in the cancers or tumors have an upregulation in one or more genes described in Tables W-Z of W02024011307A1 .

[0231] In some embodiments, the compounds of the present description can be combined with an inhibitor of a receptor tyrosine kinase (RTK). Non-limiting examples of RTK inhibitors include epidermal growth factor receptor (EGFR) inhibitors erlotinib, osimertinib, neratinib, gefitinib, cetuximab, panitumumab, dacomitinib, lapatinib, necitumumab, mobercitinib, vandetanib, sapitinib, afatinib, canertinib, CP-724714, CUDC-101 , mubritinib (TAK 165), OSI-420, pelitinib, irbinitinib (ARRY-380, ONT-380), varlitinib, TAK-285, BIBX 1382, PD168393, raciletinib, poziotinib, CL-387785, icotinib, CTX-2006, WHI-P154, AZ5104, AZD3759, Erb-B2 receptor tyrosine kinase 2 (HER2) such as neratinib, trastuzumab and its derivatives such as trastuzumab deruxtecan, lapatinib, dacomitinib, tucatinib, pertuzumab, margetuximab, afatinib, AZD8931 , AST1306, AEE788, canertinib, CP724,714, CUDC101 , TAK285, dacomitinib, pelitinib, AC480, canertinib, sapitinib, mubritinib (TAK 165), BDTX-189, epertinib, TAS0728, poziotinib, multikinase inhibitors cabozantinib, imatinib, Lenvatinib, regorafenib, sorafenib, sunitinib, vandetinib, MET inhibitors crizotinib, cabozantinib, foretinib, PHA- 665752, SU11274, SGX-523, BMS-777607, tivantinib (ARQ 197), JNJ-38877605, PF- 04217903, MGCD-265, capmatinib (INCB28060), BMS-754807, BMS-794833, AMG- 208, MK-2461 , golvatinib (E7050), AMG-458, NVP-BVU972, XL092, UNC2025, elzovantinib (TPX-0022), AMG-1 , JNJ-38877618 (OMO-1), altiratinib, SAR125844, glumetinib (SCC244), savolitinib (AZD6094), RXDX-106 (CEP-40783), S49076, merestinib (LY2801653), AMG 337, tepotinib, neurotrophic receptor tyrosine kinase 1 (NTRK1) inhibitors larotrectinib, entrectinib, danusertib, BMS-754807, GW441756, UNC2025, taletrectinib, altiratinib, selitrectinib (LOXO-195), CH7057288, BMS- 935177, PF-06273340, sitravatinib (MGCD516), GNF-5837, vascular endothelial growth factor receptor inhibitors bevacizumab, ramucirumab, SU5408, linifanib (ABT- 869), axitinib (AG 013736), nintedanib (BIBF 1120), cediranib (AZD2171), motesanib (AMG-706), pazopanib (GW786034), vandetanib, sunitinib (SU11248), sorafenib (BAY 43-9006), brivanib (BMS-540215), vatalanib (PTK787), foretinib (GSK1363089), cabozantinib (BMS-907351), brivanib (BMS-582664), Lenvatinib (E7080), CYC116, regorafenib (BAY 73-4506), ENMD-2076, tivozanib, ponatinib (AP24534), apatinib (YN968D1), telatinib, PP121 , pazopanib, dovitinib, SAR131675, semaxanib (SU5416), golvatinib (E7050), fibroblast growth factor receptor inhibitors ponatinib (AP24534), infigratinib (BGJ398), nintedanib (BIBF 1120), PD173074, AZD4547, dovitinib, pemigatinib, futibatinib, infigratinib, and RLY-4008.

[0232] In some embodiments, the cancer treated by a provided compound, salt or composition thereof is a melanoma, liposarcoma, lung cancer, breast cancer, prostatecancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, colon cancer or colorectal cancer. In some embodiments, the cancer treated by a provided compound, salt or composition thereof is prostate cancer, colorectal cancer or breast cancer (e.g., resistant breast cancer).

[0233] 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, including radiation-induced fibrosis, and auto-immune diseases.

[0234] 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. In vivo, SGK-1 activates certain potassium, sodium, and chloride channels. For instance, the protein is known to regulate the myo-inositol transporter during osmotic stress. The term “inhibitor of SGK-1”, as used herein, refers to any compound that can block, arrest, interfere with, or reduce the biological activity of SGK- 1.

[0235] In some embodiments, the compounds of the present description can be used for increasing fetal hemoglobin (HbF) in erythrocytes. In some embodiments, the compounds of the present description can be used for the treatment of a |3- hemoglobinopathy. In some embodiments, the compounds of the present description can be used for the treatment of sickle cell disease.

[0236] In some embodiments, the compounds of the present description can be used for the treatment of prostate cancer. In other embodiments, the compounds of the present description can be used for the treatment of epilepsy.

[0237] In some embodiments, there is described a method for the treatment of cancer or tumor in a subject, comprising: determining that cells from said cancer or tumor (e.g., cancer or tumor sample or biopsy): i. have an upregulation in expression of genes associated with ribosomal protein synthesis, ribosome biogenesis, protein translation, translation initiation, and / or translation elongation;ii. have an upregulation of gene signatures associated with basal and / or mesenchymal breast cancer;Hi. have a downregulation of gene signatures associated with luminal breast cancer iv. the cancer or tumor comprises cells having an activation of a RAF, MEK, ERK, PI3K, AKT, and / or mTOR pathway; v. have an activation of a RAF, MEK, ERK, PI3K, AKT, and / or mTOR pathway that is mediated by at least one mutation in KRAS, HRAS, NRAS, NF1 , BRAF, ARAF1 , NF2, MAP2K1 , RRAS2, and / or CIC; vi. have an activation of a RAF, MEK, ERK, PI3K, AKT, and / or mTOR pathway that is mediated by one or more concomitant mutations in KRAS / PIK3CA, HRAS / PIK3CA, NRAS / PIK3CA, NF1 / BRAF / PIK3CA, BRAF / PIK3CA, ARAF1 / PIK3CA, NF2 / PIK3CA, MAP2K1 / PIK3CA, BRAF / AKT1 , and / or BRAF / PTEN; vii. have an upregulation of a mitogen activated protein kinase (MAPK) gene expression (e.g., CCND1 , DUSP4, DUSP6, PHLDA1 , SPRY2, SPRY4, EPHA2, EPHA4, ETV4, and ETV, or DUSP6, ETV4, ETV5 and SPRY4); and / or viii. are resistant to one or more anticancer therapies (e.g., BRAF inhibitors, MEK inhibitors, EGFR inhibitors, or combinations thereof); and

[0238] administering to the subject one or more compounds or pharmaceutically acceptable salts thereof as defined herein, the pharmaceutical compositions defined herein, or the combinations defined herein.

[0239] In some embodiments, there is described a use of one or more compounds or pharmaceutically acceptable salts thereof as defined herein, the pharmaceutical compositions defined herein, or the combinations defined herein, for the treatment of cancer or tumor or for the manufacture of a medicament for the treatment of cancer or tumor, wherein the cancer or tumor (e.g., cancer or tumor sample or biopsy) has been predetermined as:a. having an upregulation in expression of genes associated with ribosomal protein synthesis, ribosome biogenesis, protein translation, translation initiation, and / or translation elongation; b. having an upregulation of gene signatures associated with basal and / or mesenchymal breast cancer; c. having a downregulation of gene signatures associated with luminal breast cancer d. the cancer or tumor comprises cells having an activation of a RAF, MEK, ERK, PI3K, AKT, and / or mTOR pathway; e. having an activation of a RAF, MEK, ERK, PI3K, AKT, and / or mTOR pathway that is mediated by at least one mutation in KRAS, HRAS, NRAS, NF1 , BRAF, ARAF1 , NF2, MAP2K1 , RRAS2, and / or CIC; f. having an activation of a RAF, MEK, ERK, PI3K, AKT, and / or mTOR pathway that is mediated by one or more concomitant mutations in KRAS / PIK3CA, HRAS / PIK3CA, NRAS / PIK3CA, NF1 / BRAF / PIK3CA, BRAF / PIK3CA, ARAF1 / PIK3CA, NF2 / PIK3CA, MAP2K1 / PIK3CA, BRAF / AKT1 , and / or BRAF / PTEN; g. having an upregulation of a mitogen activated protein kinase (MAPK) gene expression (e.g., CCND1 , DUSP4, DUSP6, PHLDA1 , SPRY2, SPRY4, EPHA2, EPHA4, ETV4, and ETV, or DUSP6, ETV4, ETV5 and SPRY4); and / or h. being resistant to one or more anticancer therapies (e.g., BRAF inhibitors, MEK inhibitors, EGFR inhibitors, or combinations thereof).

[0240] In some embodiments, there is described a use of one or more compounds or pharmaceutically acceptable salts thereof as defined herein, the pharmaceutical compositions defined herein, or the combinations defined herein, for the treatment of one or more side effects or toxicities caused by an anticancer therapy in a subject undergoing said anticancer therapy. The one or more side effects or toxicities caused by the anticancer therapy may be selected from the group consisting of: hyperglycemia and hyperinsulinemia, increased ALT / AST, pyrexia, rash, diarrhea, nausea, fatigue, thrombocytopenia, anemia, dermatitis acneiform, QT elongation, and dyspnea.

[0241] In some embodiments, there is described a method for treating one or more side effects or toxicities caused by an anticancer therapy, comprising administering to a subject undergoing said anticancer therapy one or more compounds or pharmaceutically acceptable salts thereof as defined herein, the pharmaceutical compositions defined herein, or the combinations defined herein. The one or more side effects or toxicities caused by the anticancer therapy may be selected from the group consisting of: hyperglycemia and hyperinsulinemia, increased ALT / AST, pyrexia, rash, diarrhea, nausea, fatigue, thrombocytopenia, anemia, dermatitis acneiform, QT elongation, and dyspnea.

[0242] In some embodiments, there is described a method for monitoring the progression of an anticancer therapy in a subject that was previously administered with one or more compounds or pharmaceutically acceptable salts thereof as defined herein, the pharmaceutical compositions defined herein, or the combinations defined herein, wherein the method comprises determining in a sample from said subject: a. a loss of phosphorylation of NDRG1 ; b. an increase in phosphorylation of MAPK14 (i.e., p38); c. an increase in phosphorylation of MAPK14 (i.e., p38); d. an increase in phosphorylation of heat shock protein family B1 (i.e., HSPB1 or HSP27); e. an increase in phosphorylation of tumor suppressor p53 (TP53); f. an increase in phosphorylation of ribosomal protein S6 kinase A1 (RSK1); g. an increase in phosphorylation of mitogen-activated protein kinase 1 (i.e., MAPK1 or ERK2); h. an increase in phosphorylation of mitogen-activated protein kinase 1 (i.e., MAPK1 or ERK2); i. an increase in phosphorylation of mitogen-activated protein kinase 3 (i.e., MAPK3 or ERKI);j. an increase in phosphorylation of mitogen-activated protein kinase 3 (i.e., MAPK3 or ERK1); and / or k. an increase in phosphorylation of AKT1 substrate 1 (PRAS40).

[0243] In some embodiments, said loss of phosphorylation of NDRG1 is at threonine 346 of the NDRG1 ; said increase in phosphorylation of MAPK14 (i.e., p38) is at threonine 180 of the MAPK14; said increase in phosphorylation of MAPK14 (i.e., p38) is at tyrosine 182 of the MAPK14; said increase in phosphorylation of heat shock protein family B1 (i.e., HSPB1 or HSP27) at serine 82 of the HSPB1 ; said increase in phosphorylation of tumor suppressor p53 (TP53) is at serine 15 of the TP53; said increase in phosphorylation of ribosomal protein S6 kinase A1 (RSK1) is at serine 380 of the RSK1 ; said increase in phosphorylation of mitogen-activated protein kinase 1 (i.e., MAPK1 or ERK2) is at tyrosine 185 of the MAPK1 ; said increase in phosphorylation of mitogen-activated protein kinase 1 (i.e., MAPK1 or ERK2) is at tyrosine 187 of the MAPK1 ; said increase in phosphorylation of mitogen-activated protein kinase 3 (i.e., MAPK3 or ERK1) is at threonine 202 of the MAPK3; said increase in phosphorylation of mitogen-activated protein kinase 3 (i.e., MAPK3 or ERK1) is at tyrosine 204 of the MAPK3; and / or said increase in phosphorylation of AKT 1 substrate 1 (PRAS40) is at threonine 246 of the AKT 1 substrate 1 .

[0244] In some embodiments, said loss or increase in phosphorylation is in comparison to a sample from a healthy subject or a subject that is not undergoing said anticancer therapy. In some embodiments, said monitoring the progression of said anticancer therapy includes determining if the anticancer therapy is effective or if the cancer is becoming resistant to the anticancer therapy.Inhibitors of SGK-1

[0245] The compounds of the present description and their pharmaceutically acceptable salts 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 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, ischemic injury, ischemic infarction, inflammatory and fibrotic diseases, cardiac fibrosis, vascular proliferation, restenosis, dilated cardiomyopathy, stent failure, cancer, prostate cancer and epilepsy.Other non-limiting examples of such conditions include p-hemoglobinopathies, such as sickle cell disease.EXPERIMENTS AND EXAMPLES

[0246] 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.Materials and instruments

[0247] XRPD diffractograms were collected with an X-ray diffractometer (Bruker, D8 Advance). 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.Radiation Cu Ka (A= 1 .5418 A)Detector LynxEye XE-TScan angle 3-40° (29)Scan step 0.02° (29)Scan speed 0.1 s / stepTube voltage / current 40 KV / 40 mADivergence slit 0.6 mmRotation 30 rpmSample holder Zero-background sample pan

[0248] HPLC analysis was performed with an Agilent HPLC 1260 series instrument. The following method was used:Column XBridge® C18, 3.5 pm, 4.6 x 150 mmColumn temperature 40 °CMobile phase A: 0.1% TFA in H2O, B: 0.1% TFA in ACNFlow rate 1.0 mL / minInjection volume 5 pLDetector and Wavelength DAD; 210 nmPost time 3.0 minDiluent 0.1% TFA in ACN, 0.1% TFA in water (v:v 1 :1)Time (min) %A %B0.0 75 25Gradient 5 60 4011 0 10012 0 100Concentration 0.2 mg / mL (Free form)

[0249] Differential Scanning Calorimetry (DSC) analysis was performed with TA Instruments (TA, Discovery DSC 250 or Q200). 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 usingTRIOS or TA Universal Analysis.

[0250] TGA analysis was performed using TA Instruments (TA, Discovery TGA 55 or Q500). About 1-5 mg of a sample was loaded onto a pre-tared aluminum pan and heated under nitrogen. The data were collected from room temperature to 300 °C at 10 °C / min. Flow rate for TGA 55: Balance chamber: 40 mL / min I Sample chamber:25 mL / min. Flow rate for Q500: Balance chamber: 40 mL / min I Sample chamber: 60 mL / min. The data were analyzed using TRIOS or TA Universal Analysis.

[0251] The solution nuclear magnetic resonance spectra were acquired with a Bruker 400 MHz NMR Spectrometer. The samples were prepared in dimethylsulfoxide- d6. The data were analyzed using MestReNova.

[0252] 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 after drying at 40 °C for several hours, while the hydrate was tested without drying and measured with the sorption at the beginning of ambient RH using a 2-cycle method. The two-cycle method was used for the DVS testing, and the sample was tested without drying using the setting parameters in the table bellow:Dm / dt 0.002% / minSample size 10 - 30 mgMeasurement temperature 40 °C / 25 °CCycle Full cycleMinimum dm / dt stability 30 min durationMaximum dm / dt equilibrium 120 min timeSave data rate 5 sGas and total flow rate N2, 200 seemPost experiment total flow 200 seemRH step size 10% RHMethod for hydrate Adsorption 1 : ambient RH to 90% RHDesorption 1 : 80, 70, 60, 50, 40, 30, 20, 10, 0Adsorption 2: 0, 10, 20, 30, 40, 50, 60, 70, 80, 90Desorption 2: 80, 70, 60, 50, 40, 30, 20, 10, 0Method for anhydrate Adsorption: 0, 10, 20, 30, 40, 50, 60, 70, 80, 90Desorption: 80, 70, 60, 50, 40, 30, 20, 10, 0

[0253] The solvent abbreviations are as follows:Abbreviation Solvent Abbreviation SolventMeOH Methanol THF TetrahydrofuranEtOH Ethanol IPAC Isopropyl acetateEA Ethyl acetate DMF DimethylformamideIPA Isopropyl alcohol DCM DichloromethaneDMSO Dimethylsulfoxide ACN AcetonitrileSummary of the Experimental Results

[0254] Salt formation experiments were conducted with Compound 1 (N-[4-(4-[[2-(dimethylamino)ethyl]amino]-3-methyl-1 H-pyrazolo[3,4-d]pyrimidin-6-yl)-2- fluorophenyl]-2,5-difluorobenzenesulfonamide).

[0255] 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 stability).Example 1 : Characterization of Compound 1 and crystalline forms thereof

[0256] 5-chloro-2-fluoro-N-(2-fluoro-4-{3-methyl-4-[(1-methylpiperidin-4-yl)oxy]- 1 H-pyrazolo[3,4-d]pyrimidin-6-yl}phenyl)benzenesulfonamide (free form).Compound 1

[0257] Compound 1 has one basic site and one acidic site with calculated pKa values of 8.45 and 7.46.

[0258] The samples of Compound 1 used herein have a purity of about 98.91- 99.04 %.

[0259] Compound 1 can be obtained according to the procedure described in W02024011307A1 .Form I

[0260] Compound 1 Form I can be obtained according to the following procedure:

[0261] The crude Compound 1 was dissolved in NMP (100 ml_, 8v) and TFA (2 ml_). The resulting solution of the crude product was purified by reversed-phase flash chromatography eluted MeOH and water (0.1% of TFA aq.). Desired fractions were collected and concentrated to afford the desired product as a TFA salt. The TFA salt was added a solution of NaHCO3(5% aq.). After stirring, the solid was collected by filtration and dried under vacuum at <70 °C to give 7.7 g the desired product (Compound 1 Form I).

[0262] Compound 1 Form I (solvate / hydrate) was characterized by irregular shaped crystals with agglomeration and analyzed by XRPD (Figure 31).

[0263] TGA analysis performed on Form I showed a ~0.8% weight loss from RT to 115 °C, followed by ~1 .4% weight loss from 115 °C to 200 °C. DSC exhibited several thermal events including desolvation, melting and form transition. (Figure 32) Someextra peaks were detected by NMR, suggesting the sample may contain some residual solvents or impurities.Form II and Form III

[0264] Form II and Form III of compound 1 were also identified. Their characterization was conducted and summarized in Table 1. XRPD patterns are represented in Figure 33 and DSC / TGA thermograms are given in Figures 34 and 35.Table 1. Characterization of Compound 1 Form II and Form IIIExample 2: Solubility screening of Compound 1 Form I

[0265] Solubility estimates were conducted via visual assessment of samples.About 2-3 mg of Compound 1 (Form I) was added into a sample vial and the solvent was added with vortex gradually until the drug solution was clear by visual observation, or the volume of solvent was up to 1000 V. Then, the estimated solubility was calculated.Table 2. Solubility assays for Compound 1 Form I in various solvents (mg / mL) at room temperatureExample 3: Preparation of the salts of Compound 1

[0266] Salts were prepared on 20 - 30 mg scale successively using Compound 1Form I as the starting material, according to the general procedure below.

[0267] An appropriate amount of Compound 1 Form I was added into a solvent at RT or 50 °C, and then an acid (1 or 2 eq.) was added to form the salt. If no precipitation occurred, various crystallization methods were attempted to prepare crystalline salts, including cooling crystallization, evaporation, and anti-solvent precipitation. Solids were collected by filtration, vacuum dried and analyzed.Hydrochloride salt

[0268] HCI salt (Compound 2) was prepared in different solvents according to the general procedure as summarized in Table 3. Compared with Compound 1 , all samples showed chemical shifts by NMR, suggesting HCI salt was formed.Table 3. Experimental conditions tested for the preparation of Compound 2, Hydrochloride saltSulfate salt

[0269] Sulfate salt (Compound 3) was prepared with 1.1 eq. of sulfuric acid first according to the general procedure and parameters in Table 4, the resulting solids were checked by XRPD and NMR. Two XRPD patterns were obtained with relatively high crystallinity (Form I and Form II), and chemical shifts of them were different, suggesting sulfate salt was formed with the different ratios of the base to acid. Confirmed by IC analysis, sulfate Form I had a 1 / 1 ratio of base to acid, and the ratio of base to acid was 1 / 0.75 for Form II.Table 4. Experimental conditions tested for the preparation of Compound 3, Sulfate salt

[0270] Estimated solubility of sulfate salt Form I in DMSO is ~67 mg / mL.

[0271] A third crystalline form of Compound 3 (Form III) can be obtained via antisolvent precipitation by normal addition according to the following procedure.

[0272] About 30 mg of sulfate salt (Compound 3) Form I was weighed into a sample vial and DMSO was added (3.3 V) to make a clear solution at 50 °C. Then, an anti-solvent (MeOH, 33 V) was added dropwise into the filtrate. The solution was still clear after the anti-solvent was added. Precipitation occurred after stirring at 50 °C for 30 min. The mixture was then cooled to RT and filtered. The resulting solution wasstirred at RT overnight and the crystalline materials collected by filtration. Form III was identified as a 1 / 1 acid to base salt.

[0273] Compound 3 Form III can also be obtained via anti-solvent precipitation by reverse addition according to the following procedure.

[0274] About 30 mg of sulfate salt (Compound 3) Form I was weighed into a sample vial and 100 pL of DMSO (33 V) was added to make a clear solution. Then, the filtrate was added dropwise into an anti-solvent (MeOH, 33 V). The solution was still clear after the filtrate was added. Precipitation occurred after stirring at 50 °C for 1 hour. The mixture was stirred at RT overnight and the crystalline materials collected by filtration.Tosylate salt

[0275] Tosylate salt (Compound 4) was prepared in different solvent systems with 1.1 eq. of p-toluenesulfonic acid at RT or 50 °C following the general procedure and parameters summarized in Table 5. Table 5. Experimental conditions tested for the preparation of Compound 4, Tosylate salt

[0276] The samples generated from IPA, THF and acetone showed the same XRPD patterns, which had several extra peaks compared to the XPRD obtained for the sample prepared using EtOH, suggesting they may be mixed forms. Thus, the samples prepared from MeOH and EtOH were analyzed. Both of them were formed with a 1 / 1 ratio of base to acid, and assigned as Form I and II respectively.Besylate salt

[0277] Besylate salt (Compound 5) was prepared with 1.1 eq. benzenesulfonic acid using MeOH, acetone, IPA and IPA / water (5 / 1) as the solvents at RT or 50 °C following the general procedure and parameters summarized in Table 6. Table 6. Experimental conditions tested for the preparation of Compound 5, besylate salt

[0278] NMR spectra of the samples generated from MeOH and IPA / water were different from the samples from acetone and IPA, the ratio of base to acid was 1 / 0.7 for the first two samples and 1 / 1 for the last two samples. The two samples of 1 / 1 salt were characterized and assigned as besylate Form I and Form II respectively. Mesylate salt

[0279] Mesylate salt (Compound 6) was prepared with 1.1 eq. of methane sulfonic acid using MeOH, acetone, IPA and IPA / water (5 / 1) as the solvents at RT or 50 °C following the general procedure and the parameters summarized in Table 7.Table 7. Experimental conditions tested for the preparation of Compound 6, mesylate salt

[0280] NMR showed all resulting solids were formed with a 1 / 1 ratio of base / acid, except the 1 / 2 sample ratio for the sample obtained from acetone. XRPD patterns of the samples were similar, the sample obtained from IPA / Water was characterized due to higher crystallinity.Phosphate salt

[0281] Phosphate salt (Compound 7) was prepared with 1.1 eq. of phosphoric acid in different solvents at RT or 50 °C following the general procedure and the parameters summarized in Table 8. Table 8. Experimental conditions tested for the preparation of Compound 7, phosphate saltMaleate salt

[0282] Maleate salt (Compound 8) was prepared with 1.1 eq. of maleic acid in different solvents following the general procedure and the parameters summarized in Table 9.Table 9. Experimental conditions tested for the preparation of Compound 8, maleate salt

[0283] Maleate with a 1 / 1 ratio of base to acid was obtained from all solvent systems except IPA / water. Two XRPD patterns of mono-maleate were obtained and assigned as Form I (Figure 21) and II (Figure 23) respectively. Tartrate salt

[0284] Tartrate salt (Compound 9) was prepared with 1.1 eq. of tartaric acid in different solvents at RT or 50 °C following the general procedure and the parameters summarized in Table 10.Table 10. Experimental conditions tested for the preparation of Compound 9, tartrate salt0285] The free form, Compound 1 Form II was generated from IPA and IPA / water, the sample prepared from MeOH showed relatively high crystallinity and was further characterized (Figure 25).Fumarate salt

[0286] Fumarate salt (Compound 10) was prepared with 1.1 eq. of fumaric acid in different solvents at RT or 50 °C following the general procedure and the parameters summarized in Table 11 .Table 11. Experimental conditions tested for the preparation of Compound 10, fumarate salt

[0287] XRPD showed the free form Form II was obtained from IPA, and three new XRPD patterns were generated from other solvent systems. The sample generated from MeOH was a hemi-fumarate, the sample generated from IPA / water was a monofumarate, while the sample resulting from acetone had a ratio of base to acid of 1 / 0.9. Thus, the samples generated from MeOH and IPA / water were further characterized and assigned as hemi-fumarate Form I (Figure 27) and fumarate Form I (Figure 29), respectively.Other salts

[0288] Several trials were also performed to prepare malate, citrate and succinate salts with 1.1 eq. of acid (respectively L-malic acid, citric acid and succinic acid) in different solvents following the general procedure and the parameters summarized in Table 12.Table 12. Experimental conditions tested for the preparation of maleate, citrate and succinate salts

[0289] Compound 1 (free form) Form II was obtained from IPA and IPA / water at 50 °C with the 3 acids, Compound 1 (free form) Form III was obtained from acetone. The samples generated from MeOH had similar XRPD patterns but the crystallinity was very low. Thus, no crystalline salts were obtained with acceptable properties.

[0290] Sulfate salt (Compound 3) Form I, sulfate salt (Compound 3) Form III and fumarate salt (Compound 10) Form I, were evaluated for solubility and stability testing in comparison with Compound 1 Form I.Example 4: Dynamic Vapor Sorption / Desorption (DVS) experiments

[0291] DVS experiments (Figures 36, 37, 38 and 39) and XRPD post-DVS experiments were conducted in order to study the deliquescence behaviour of the crystalline salts upon expose to humidity.Table 13: Summary of the DVS experiments and corresponding XRPDs conducted for the sulfate salt (Compound 3: Forms I, II and III) and the fumarate salt (Compound 10, Form I).Example 5: Preparation of the sulfate salts and the fumarate salt on larger scale

[0292] Scale-up experiments were conducted to prepare samples of sulfate salt (Compound 3) Form I and fumarate salt (Compound 10) Form I. The preparation details are summarized in Table 14.Table 14. Preparation of sulfate salt (Compound 3) Form I and fumarate salt (Compound 10) Form ISulfate Form I (Compound 3) can also be prepared according to the following procedure:

[0293] about 2.7 g of Compound 1 Form I was weighed into a vial and 90 mL(33V) of IPA / water (5 / 1) was added to make a suspension at 50 °C. Then, 2.0 eq. of 3 M H2SO4aqueous solution was added and the mixture became nearly clear. Then, the seed of sulfate salt Form I was added. The mixture was stirred at 50 °C for 3 h and RT for 5 h, the resulting solids were collected by filtration and analyzed after drying at 50 °C under vacuum for 18 h. Sulfate Form I (mono-sulfate salt) was obtained with a 86 % yield.Sulfate Form III (Compound 3) can be prepared according to the following procedure:

[0294] about ~240 mg of sulfate salt (Compound 3) Form I was weighed into a vial and 0.8 mL of DMSO was added to make a clear solution at 50 °C. Then, 8 mL of MeOH was added dropwise into the filtrate and then Form III was added as the seeds.The mixture was stirred at 50 °C for 3 hours and RT for 5 hours. The solids werecollected by filtration and analyzed after drying at 50 °C under vacuum for 18 hours. Sulfate salt Form III was obtained with a 68% yield.

[0295] Sulfate salt Form I, sulfate salt Form III and fumarate salt Form I, which have high crystallinity and relatively high dehydration temperature, were selected as the lead salts for stability testing compared with Compound 1 Form I (Examples 6 and 7).Example 6: Stability in solution

[0296] The stability in solution of Compound 1 Form I, fumarate salt (Compound 10) Form I and sulfate salt (Compound 3) Form I was evaluated in water and bio- relevant media at 37 °C and the results were summarized in Table 15.

[0297] The samples were added into water, SGF, FaSSIF and FeSSIF at ~5 mg / mL, respectively. Duplicate samples were prepared for each medium. All samples were kept shaking at 37 °C with 200 rpm for up to 24 hours. At 24 hours, pH of the filtrate was measured, and the filter cake checked by XRPD. Table 15. Stability in solution evaluated by XRPD

[0298] The pH value of water, Simulated Gastric Fluid (SGF), Fed State Simulated Intestinal Fluid (FeSSIF) and Fasted State Simulated Intestinal Fluid (FaSSIF) is 5.93, 1.24, 4.97 and 6.47 respectively.

[0299] A polymorph screen was conducted in order to try to identify new crystalline forms of the sulfate salt (Compound 3) using various techniques in different solvents. The methods used include slurry, anti-solvent precipitation, cooling crystallization. Experimental conditions include stirring for several hours up to 1 day at RT or up to 50 °C. Solvent used include EtOH, CAN, MEK, water, MTBE, heptane, IBA, toluene, THF, IPA, IPAC, EA, acetone, MeOH, MeOH / water (1 / 9) and IPA / water (1 / 5). While Form III of the sulfate salt has been identified via anti-solvent precipitation in DMSO / MeOH, the crystalline materials isolated were essentially Form I of the sulfate salt. Thus, demonstrating the high stability of the Form I in water and organic solvents.Example 7: Solid stability

[0300] Solid stability of Compound 1 Form I, fumarate salt (Compound 10) Form I and sulfate salt (Compound 3) Form I and Form III was evaluated at 60 °C, 40 °C I 75% RH and RT I 92.5% RH conditions for 7 days and the results were summarized in Table 16.

[0301] Appropriate amounts of Compound 1 Form I, fumarate salt (Compound 10)Form I and sulfate salt (Compound 3) Form I and Form III were open placed at 60 °C, RT I 92.5% RH and 40 °C I 75% RH conditions for 7 days, respectively. At 0, 3 and 7 days, the samples were analyzed to check the purity by HPLC and the crystal form by XRPD.Table 16. Solid stability characterization by XRPD and HPLC

[0302] Sulfate salt (Compound 3) Form I has some purification effect, the purity increased by ~0.5% compared with the free form (Compound 1 Form I). During the stability testing, no degradation occurred, the purity and crystal forms all remained unchanged. The results indicated that all these salts and Compound 1 Form I are all physically and chemically stable under these conditions for 7 days.

[0303] Mechanical treatment was also conducted on sulfate salt Form I through dry grinding and solvent-drop grinding resulting in no changes being observed in XRPD. Thus, attesting the stability of sulfate salt Form I.

[0304] Thermal treatment was also conducted on sulfate salt Form I. Form I was heated to 150 °C and 220 °C at 10 °C / min by DSC, hold for 5 min and then cooled to RT. The resulting solids were checked by XRPD. The resulting solids were identified as sulfate salt Form I with minor peak shifts.

[0305] Overall, sulfate salt Form I showed more acceptable solid-state properties and best purification effect.Example 8: Interconversion study

[0306] Inter-conversion and water activity study for sulfate salt (Compound 3) Form I and Form III was carried out in selected solvents, the results are shown in Table 17.

[0307] About ~5 mg of sulfate salt Form I and 5 mg of sulfate salt Form III were suspended in 0.5 mL of a solvent at RT or 50 °C. The solids were collected by filtration and analyzed by XRPD after stirring for a certain time.Table 17. Interconversion experiments with sulfate salt (Compound 3) Form I andForm III

[0308] The mixture converted to Form I in MeOH with water and in ACN at 50 °C for2 days, and still contained traces of Form III after stirring at RT for 4-7 days in MeOH and ACN without water. Thus, Form III is sensitive to water and it has a tendency to convert to Form I in organic solvents. Thus, sulfate salt Form I is more stable than sulfate salt Form III.XRPD peak lists

[0309] Observed peaks for the sulfate salt (Compound 3), Form I:

[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 which this 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, and C,” “one or more of A, B, and C,” and “A, B, C, or any combination thereof’ maybe 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 sulfate salt of the compound of Formula I which is crystalline:(I).

2. The compound of claim 1 , which exhibits an X-ray powder diffraction (XRPD) pattern having characteristic peaks expressed in degrees 2© (±0.2° 2©) at 13.95, 17.84 and 5.87.

3. The compound of claim 2, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2© (±0.2° 2©) at 19.50, 16.20 and 24.97.

4. The compound of claim 2 or 3, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2© (±0.2° 2©) at 23.66, 11 .83 and 22.65.

5. The compound of any one of claims 2 to 4, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2© (±0.2° 2©) at 15.29, 20.45 and 25.67.

6. The compound of any one of claims 2 to 5, wherein the XRPD pattern further has characteristic peaks expressed in degrees 2© (±0.2° 2©) at 9.67, 25.25 and 18.54.

7. The compound of any one of claims 1 to 6, which has a Differential Scanning Calorimetry (DSC) thermogram that exhibits an endotherm having a first peak temperature of about 59.85 °C with an onset of about 30.23 °C and a second peak temperature of about 266.51 °C with an onset of about 253.91 °C.

8. The compound of claim 1 , which has an X-ray powder diffraction pattern substantially the same as shown in Figure 5.

9. A pharmaceutical composition, comprising the compound of any one of claims 1 to 8 and a pharmaceutically acceptable carrier or excipient.

10. Use of the compound of any one of claims 1 to 8, as an inhibitor of SGK-1.11 . Use of the compound of any one of claims 1 to 8 or the pharmaceutical composition of claim 9, for the treatment of cancer or tumor.

12. The use of claim 11 , wherein the cancer or tumor comprises cells having an upregulation in expression of genes associated with ribosomal protein synthesis, ribosome biogenesis, protein translation, translation initiation, and / or translation elongation.

13. The use of any one of claims 10 to 12, wherein the cancer or tumor is thyroid cancer (e.g., Anaplastic Thyroid Cancer (ATC)), prostate cancer, colorectal cancer or breast cancer.

14. Use of the compound of any one of claims 1 to 8, 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 8, for the manufacture of a medicament for the treatment of cancer or tumor.

16. The use of claim 14 or 15, wherein the cancer or tumor is thyroid cancer (e.g., Anaplastic Thyroid Cancer (ATC)), prostate cancer, colorectal cancer or breast cancer.

17. A method for inhibiting SGK-1 , comprising administering to a subject the compound as defined in any one of claims 1 to 8, or the pharmaceutical composition as defined in claim 9.

18. A method for the treatment of cancer or tumor, comprising administering to a subject in need thereof the compound as defined in any one of claims 1 to 8, or the pharmaceutical composition as defined in claim 9.

19. The method of claim 17 or 18, wherein the cancer or tumor is thyroid cancer (e.g., Anaplastic Thyroid Cancer (ATC)), prostate cancer, colorectal cancer or breast cancer.

20. A process for preparing the compound of any one of claims 1 to 8, comprising:a. combining 5-chloro-2-fluoro-N-(2-fluoro-4-{3-methyl-4-[(1 -methylpiperidin-4- yl)oxy]-1 H-pyrazolo[3,4-d]pyrimidin-6-yl}phenyl)benzene sulfonamide in a solvent with sulfuric acid to obtain a mixture; b. stirring the mixture; c. isolating the crystalline material; and wherein said process is conducted under conditions suitable to obtain said crystalline material.

21. The process of claim 20, wherein the sulfuric acid is used between 1 and 2 molar equivalents.

22. The process of claims 20 or 21 , wherein combining the 5-chloro-2-fluoro-N- (2-fluoro-4-{3-methyl-4-[(1-methylpiperidin-4-yl)oxy]-1 H-pyrazolo[3,4-d]pyrimidin6yl} phenyl) benzenesulfonamide and the sulfuric acid is performed at a temperature between about 20°C and about 60°C.

23. The process of claims 20 or 21 , wherein combining the 5-chloro-2-fluoro-N- (2-fluoro-4-{3-methyl-4-[(1-methylpiperidin-4-yl)oxy]-1 H-pyrazolo[3,4-d]pyrimidin- 6yl}phenyl) benzenesulfonamide and the sulfuric acid is performed at room temperature or at a temperature of about 50°C.

24. The process of any one of claims 20 to 23, wherein the solvent is a mixture of isopropyl alcohol and water.

25. The process of claim 24, wherein the solvent is a mixture of isopropyl alcohol and water at a 5 / 1 ratio.

26. The process of claim 24, wherein the solvent is a mixture of isopropyl alcohol and water at a 9 / 1 ratio.

27. The process of any one of claims 20 to 26, wherein the concentration of 5- chloro-2-fluoro-N-(2-fluoro-4-{3-methyl-4-[(1-methylpiperidin-4-yl)oxy]-1 H- pyrazolo[3,4d] pyrimidin-6yl}phenyl) benzenesulfonamide in the solvent is between about 10 mmol / L and about 100 mmol / L.

28. The process of any one of claims 20 to 26, wherein the concentration of 5- chloro-2-fluoro-N-(2-fluoro-4-{3-methyl-4-[(1-methylpiperidin-4-yl)oxy]-1 H-pyrazolo[3,4d] pyrimidin-6yl}phenyl) benzenesulfonamide in the solvent is between about 30 mmol / L and about 60 mmol / L.

29. The process of any one of claims 20 to 28, wherein the process further comprises adding seeds of the crystalline sulfate salt of the compound of Formula (I) as defined in any one of claims 1 to 8.

30. The process of any one of claims 20 to 29, wherein stirring the mixture is performed at a temperature between 20°C and 60°C.

31. The process of any one of claims 20 to 30, wherein stirring the mixture is performed during about 2 to 10 hours.

32. The process of any one of claims 20 to 31 , wherein stirring the mixture is performed first at a temperature of about 50°C for about 3 hours, followed by stirring at room temperature for about 4 to 5 hours.

33. The process of any one of claims 20 to 31 , wherein stirring the mixture is performed first at room temperature for about 30 minutes and a mixture of isopropyl alcohol and water at a 9 / 1 ratio is further added to reach a total concentration of the 5- chloro-2-fluoro-N-(2-fluoro-4-{3-methyl-4-[(1-methylpiperidin-4-yl)oxy]-1 H- pyrazolo[3,4d]pyrimidin6yl} phenyl) benzenesulfonamide of about 30 mmol / L and stirring the resulting mixture at room temperature for about 3 hours.

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

35. The process of any one of claims 20 to 34, wherein the crystalline material is dried in a vacuum oven.

36. The compound of any one of claims 1 to 8 for use in the treatment of cancer or tumor, or in the manufacture of a medicament for the treatment of cancer or tumor.

37. The compound for use of claim 36, wherein the cancer or tumor is thyroid cancer (e.g., Anaplastic Thyroid Cancer (ATC)), prostate cancer, colorectal cancer or breast cancer.

38. A pharmaceutical composition comprising the compound as defined in any one of claims 1 to 8, and a pharmaceutically acceptable excipient, for use in thetreatment of cancer or tumor or in the manufacture of a medicament for the treatment of cancer or tumor.

Images