Crystalline forms

Abstract

The present application provides crystalline forms of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; processes for preparing crystalline forms; intermediates useful in said processes; compositions comprising (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; and uses of said crystalline forms and compositions.

Description

[0001] Crystalline Forms

[0002] TECHNICAL FIELD

[0003] The present application provides crystalline forms of (5)-4-((l- benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4- yl)benzenesulfonamide; processes for preparing crystalline forms; intermediates useful in said processes; compositions comprising (5)-4-((l-benzylpyrrolidin-3- yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide; and uses of said crystalline forms and compositions.

[0004] BACKGROUND

[0005] Voltage gated sodium channels (NaUs) are critical determinants of cellular excitability in muscle and nerve. Four isoforms in particular, Najzl.l, NaH.2, NaH.3, and Najzl.6, account for the majority of sodium current in the neurons of the central nervous system. Nap4.3 is primarily expressed embryonically. Beyond the neonatal stage, NaH .1, NapT .2, and NaH .6 are the critical isoforms that regulate neuronal signaling in the brain.

[0006] Epilepsy is a condition characterized by excessive synchronous excitability in the brain that arises when the delicate balance of excitatory and inhibitory signals in the brain fall out of equilibrium. This can happen either due to an excess of excitation, or a deficiency of inhibition. Mutations in the genes encoding Nar channels have been linked to both types of disequilibrium.

[0007] Mutations in SCN8A have been reported to show a range of gain and loss of function effects on the NaH.6 channel. Though, for NaH .6, most mutations examined have been associated with gain of function phenotypes. Mutations in Najzl.6 have been linked with epilepsy and autism spectrum disorders. The best described SCN8A mutant patients have a syndrome known as early infantile epileptic encephalopathy, 13 (EIEE13). Over 100 EIEE13 patients have been identified. Patients typically present with intractable seizures between birth and 18 months of age. Patients have developmental and cognitive delays, and motor impairment often associated with chronic muscular hypotonia. The most severely impacted patients never gain sufficient motor control to walk. Many are not verbal. Less severe phenotypes learn to walk and talk but are motor-impaired and miss cognitive and social milestones. Most of the identified mutations are missense mutations, and it is assumed that the specific functional impact of the mutation contributes to the variability in the phenotype, though genetic background is also likely involved.

[0008] Voltage-gated sodium channel antagonism is the most common mechanism of widely prescribed antiepileptic drugs (AED’s). Carbamazepine, Esli carb azepine, Oxcarbazepine, Lacosamide, Lamotrigine, Phenytoin, Rufinamide and Zonisamide are all believed to act primarily by blocking that function of Nar channels. Despite the presumed mechanism of action, these drugs are relatively promiscuous. They block all Nar channel isoforms indiscriminately, thus blocking of Najzl.l would be expected to be proconvulsant. Blocking of Najzl .6, and perhaps Najzl .2, would be expected to be anticonvulsant. In addition to sodium channels, these compounds also block other targets, including voltage-gated calcium channels. Selective Nar antagonists that spare Najzl .1 and other off-target receptors are expected to have both improved efficacy and therapeutic index relative to the currently available Nar blocking drugs. There is, therefore, an unmet medical need to treat epilepsy and other Najzl .6 associated pathological states effectively and without adverse side effects due to the blocking of other sodium channels, such as Najzl. l and / or NaH.5. The present invention provides compounds, crystalline forms, and methods to meet these critical needs.

[0009] SUMMARY

[0010] The present application provides, inter alia, at least one crystalline form of (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4- yl)benzenesulfonamide.

[0011] The present application further provides pharmaceutical compositions comprising (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N- (thiazol-4-yl)benzenesulfonamide described herein, and a pharmaceutically acceptable excipient.

[0012] The present application further provides processes for preparing a crystalline form of (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N- (thiazol-4-yl)benzenesulfonamide.

[0013] The present application further provides methods of treating a disease or a condition associated with Najzl.6 activity in a subject, comprising administering to the subject a crystalline form or a pharmaceutical composition comprising (5)-4-((l- benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4- yljbenzenesulfonamide provided herein.

[0014] The present application further provides methods of decreasing ion flux through Najzl.6 in a cell, comprising contacting the cell with a crystalline form of (5)- 4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4- yljbenzenesulfonamide provided herein.

[0015] The present application further provides methods of selectively inhibiting a first voltage-gated sodium channel over a second voltage-gated sodium channel in a subject, comprising administering to the subject a crystalline form of (5)-4-((l - benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4- yljbenzenesulfonamide provided herein.

[0016] DESCRIPTION OF DRAWINGS

[0017] FIG. 1 shows a DSC thermogram / thermogravimetric analysis (TGA) representative of a crystalline form of (5)-4-((l-benzylpyrrolidin-3- yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide. FIG. 2 shows an absorption isotherm representative of a crystalline form of

[0018] (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4- yl)benzenesulfonamide.

[0019] FIG. 3 shows a XRPD pattern representative of a crystalline form of (S)-4-((l- benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4- yl)benzenesulfonamide.

[0020] FIG. 4 shows a representative image of primary particles of a crystalline form of (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4- yl)benzenesulfonamide, fused to form agglomerates ranging in size of 50-150 pm.

[0021] FIG. 5 shows a representative image of an individual agglomerate particle of a crystalline form of (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5- methyl-N-(thiazol-4-yl)benzenesulfonamide.

[0022] FIG. 6 shows a representative particle size distribution (PSD) of a crystalline form of (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N- (thiazol-4-yl)benzenesulfonamide.

[0023] DETAILED DESCRIPTION

[0024] (5)-4-((l-Benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol- 4-yl)benzenesulfonamide (structure shown below, compound of Formula I) is a selective Najzl.6 inhibitor and is useful, for example, in the treatment of diseases and conditions associated with Najzl.6 such as depression, bipolar disorders, schizophrenia, pain, epilepsy and / or epileptic seizure (see e.g., U.S. Patents Nos.: 10,246,453; 10,662,184; 10,815,229; and 11,299,490, the disclosures of each of which are incorporated herein by reference in their entireties).

[0025] (5)-4-((l-Benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4- yl)benzenesulfonamide (compound of Formula I)

[0026] The present application provides at least one crystalline form of (S)-4-((l- benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4- yl)benzenesulfonamide. In some embodiments, the at least one crystalline form is a crystalline form described herein.

[0027] Different forms of the same substance may have different bulk properties relating to, for example, hygroscopicity, solubility, stability, and the like. Forms with high melting points may have good thermodynamic stability which is advantageous in prolonging shelf-life of drug formulations containing the solid form. Forms with lower melting points may be less thermodynamically stable, but may be advantageous in that they have increased water solubility, which may translate to increased drug bioavailability. Forms that are weakly hygroscopic may be desirable for their stability to heat and humidity and may be resistant to degradation during long storage.

[0028] In some embodiments, the (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2- fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide provided herein is crystalline. As used herein, “crystalline” or “crystalline form” is meant to refer to a certain lattice configuration of a crystalline substance. Different crystalline forms of the same substance typically have different crystalline lattices (e.g., unit cells) which are attributed to different physical properties that are characteristic of each of the crystalline forms. In some instances, different lattice configurations have different water or solvent content.

[0029] The different crystalline forms can be identified by solid state characterization methods such as by X-ray powder diffraction (XRPD). Other characterization methods such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), and the like further help identify the form as well as help determine stability and solvent / water content.

[0030] An XRPD pattern of reflections (peaks) is typically considered a fingerprint of a particular crystalline form. It is well known that the relative intensities of the XRPD peaks can widely vary depending on, inter alia, the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. In some instances, new peaks may be observed or existing peaks may disappear, depending on the type of the instrument or the settings. As used herein, the term “peak” refers to a reflection having a relative height / intensity of at least about 4% of the maximum peak height / intensity. Moreover, instrument variation and other factors can affect the 2-theta values. Thus, peak assignments, such as those reported herein, can vary by plus or minus about 0.2° (2-theta), and the term “substantially” and “about” as used in the context of XRPD herein is meant to encompass the above-mentioned variations.

[0031] In the same way, temperature readings in connection with DSC, TGA, or other thermal experiments can vary about ±3 °C depending on the instrument, particular settings, sample preparation, etc. Accordingly, a crystalline form provided herein having a DSC thermogram “substantially” as shown in any of the Figures or the term “about” is understood to accommodate such variation.

[0032] In some embodiments, the crystalline form provided herein is substantially isolated. By “substantially isolated” is meant that the compound or crystalline form is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the salts described herein. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the crystalline forms described herein, or salt thereof.

[0033] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment (while the embodiments are intended to be combined as if written in multiply dependent form). Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable sub combination.

[0034] The salts, compounds, and crystalline forms described herein can be asymmetric (e.g., having one or more stereocenters). If no stereochemistry is indicated, then all stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated by the structure or name. Salts, compounds, and crystalline forms of the present application that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the salts and compounds described herein, and all such stable isomers are contemplated in the present application. Cis and trans geometric isomers of the salts, compounds, and crystalline forms of the present application are described and may be isolated as a mixture of isomers or as separated isomeric forms.

[0035] Resolution of racemic mixtures of salts, compounds, and crystalline forms can be carried out by any of the numerous methods known in the art. An example method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as P- camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one skilled in the art.

[0036] Salts, compounds, and crystalline forms of the invention can also include all isotopes of atoms occurring in the intermediates, final salts or compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0037] In some embodiments, the compounds or salts can be found together with other substances such as water and solvents (e.g. hydrates and solvates) or can be isolated.

[0038] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0039] As used herein and unless otherwise stated, the phrase “about” stands for ±20% of the stated value.

[0040] As used herein and unless otherwise stated, the phrase “strong base” means a base having a pKb of less than 1, such as, for example, sodium hydroxide.

[0041] As used herein and unless otherwise stated, the phrase “exact mass” means an experimentally determined mass of a singly charged molecular ion determined by mass spectrometry. For example, the exact mass may refer to a positively charged mass ion.

[0042] As used herein, the compound of Formula I:

[0043] I having a molecular formula of C22H25FN4O2S2 and a molecular weight of 460.59, may be referred to by the following names and identifiers:

[0044] (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4- yl)benzenesulfonamide; 2-Fluoro-5-methyl-4-[methyl[(3SJ-l-(phenylmethyl)-3-pyrrolidinyl]amino]-7V-4- thi azoly lb enzenesul fonami de;

[0045] Zandatrigine; and

[0046] CAS RN: 2154406-04-7.

[0047] Process of Preparing (S)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5- methyl-N-(thiazol-4-yl) benzenesulfonamide

[0048] The present application further provides processes for preparing a crystalline form of (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N- (thiazol-4-yl)benzenesulfonamide (e.g., a process for preparing (5)-4-((l- benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4- yl)benzenesulfonamide). In some embodiments, the crystalline form is a crystalline form described herein.

[0049] In some embodiments, the process provided herein comprises reacting a compound of Formula II:

[0050] II or a salt thereof, under a deprotection condition to afford a compound of Formula I:

[0051] I or a salt thereof, wherein PG1is an amine protecting group.

[0052] Example amine protecting groups include, but are not limited, to the protecting groups for amines delineated in Wuts and Greene, Protective Groups in Organic Synthesis, 4thed., John Wiley & Sons: New Jersey, pages 696-887 (and, in particular, pages 872-887) (2007), which is incorporated herein by reference in its entirety. Example amine protecting groups include, but are not limited to, - methoxybenzyl (PMB), benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2-(4- trifluoromethylphenylsulfonyl)ethoxy carbonyl (Tsc), t-butoxy carbonyl (BOC), 1- adamantyloxy carbonyl (Adoc), 2-adamantylcarbonyl (2-Adoc), 2,4-dimethylpent-3- yloxy carbonyl (Doc), cyclohexyloxy carbonyl (Hoc), l,l-dimethyl-2,2,2- trichloroethoxycarbonyl (TcBOC), vinyl, 2-chloroethyl, 2-phenylsulfonylethyl, allyl, benzyl, 2-nitrobenzyl, 4 -nitrobenzyl, diphenyl-4-pyridylmethyl, N’,N’- dimethylhydrazinyl, methoxymethyl, t-butoxymethyl (Bum), benzyloxymethyl (BOM), or 2-tetrahydropyranyl (THP), tri(Ci-4 alkyl)silyl (e.g., tri(isopropyl)silyl), 1,1 -di ethoxymethyl, or N-pivaloyloxymethyl (POM). In some embodiments, PG1is p- m ethoxybenzyl.

[0053] In some embodiments, the deprotection condition comprises reacting the compound of Formula II, or a salt thereof, with an acid. In some embodiments, the acid is an organic acid. In some further embodiments, the organic acid is trifluoroacetic acid.

[0054] In some embodiments, the deprotection is performed in a solvent. In some embodiments, the deprotecting is performed in a solvent comprising dichloromethane.

[0055] In some embodiments, the deprotecting is performed at a temperature from about 35°C to about 45°C.

[0056] In some embodiments, the process of deprotecting the compound of Formula II to afford the compound of Formula I, or a salt thereof, further comprising reacting the compound of Formula I, or a salt thereof, with a strong base to form the free base form of the compound of Formula I. In some embodiments, the strong base is sodium hydroxide.

[0057] In some embodiments, the compound of Formula II is a compound of Formula Ila: or a salt thereof.

[0058] In some embodiments, the processes herein further comprise reacting the free base form of the compound of Formula I with / ?-toluenesulfonic acid to form a -toluenesulfonic acid salt of the compound of Formula I.

[0059] In some embodiments, the process of preparing the / ?-toluenesulfonic acid salt of the compound of Formula I further comprises reacting the -toluenesulfonic acid salt of the compound of Formula I with a base to form the free base form of the compound of Formula I. In some embodiments, the base is a bicarbonate base. In some embodiments, the base is sodium bicarbonate.

[0060] In some embodiments, the process provided herein further comprises crystallizing the free base form of the compound of Formula I to afford (5)-4-((l- benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4- yl)benzenesulfonamide in a crystalline form described herein.

[0061] In some embodiments, the (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2- fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide, in a crystalline form described herein, is crystallized from a solvent. In some embodiments, the (5)-4-((l- benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4- yl)benzenesulfonamide, in a crystalline form described herein, is crystallized from a solvent comprising ethanol.

[0062] In some embodiments, the compound of Formula II provided herein, or a salt thereof, is prepared by reacting a compound of Formula III: or a salt thereof, under a Suzuki coupling condition to form the compound of Formula II, or a salt thereof.

[0063] In some embodiments, the Suzuki coupling condition comprises heating a reaction mixture comprising the compound of Formula II, a Suzuki coupling catalyst, methylboronic acid, a base, and a solvent component.

[0064] In some embodiments, the Suzuki coupling catalyst comprises palladium (II) acetate. In some embodiments, the Suzuki coupling catalyst comprises palladium (II) acetate and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos). In some embodiments, the base is potassium phosphate. In some embodiments, the solvent comprises ethyl acetate.

[0065] In some embodiments, the compound of Formula III is a compound of Formula Illa:

[0066] Illa or a salt thereof.

[0067] In some embodiments, the process of preparing the compound of Formula II, or a salt thereof, further comprises reacting the compound of Formula II, or a salt thereof, with 2,3-dibenzoyl-D-tartaric acid to form a 2,3-dibenzoyl-D-tartaric acid salt of the compound of Formula II. In some embodiments, the process comprises reacting the compound of Formula II with 2,3-dibenzoyl-D-tartaric acid to form a 2,3- dibenzoyl-D-tartaric acid salt of the compound of Formula II.

[0068] In some embodiments, the compound of Formula III provided herein, or a salt thereof, is prepared by reacting a compound of Formula IV: or a salt thereof, with a compound of Formula V:

[0069] V or a salt thereof, under a S\Ar reaction condition to afford the compound of Formula III, or a salt thereof.

[0070] In some embodiments, the S\Ar reaction condition comprises reacting the compound of Formula IV and the compound of Formula V in the presence of a coupling agent and a solvent. In some embodiments, the coupling agent is 1,4- diazabicyclo-[2.2.2]-octane (DABCO). In some embodiments, the solvent comprises dimethyl sulfoxide. In some embodiments, the S\Ar reaction is performed at a temperature from about 65 °C to about 75 °C.

[0071] In some embodiments, the compound of Formula IV is a compound of Formula IVa: or a salt thereof.

[0072] In some embodiments, the compound of Formula IV provided herein is prepared by reacting a compound of Formula VI: rj

[0073] HN'AN^

[0074] PG1 or a salt thereof, with 5-chloro-2,4-difluorobenzenesulfonyl chloride under coupling conditions to afford to the compound of Formula IV, or a salt thereof.

[0075] In some embodiments, the coupling condition comprises reacting the compound of Formula VI and 5-chloro-2,4-difluorobenzenesulfonyl chloride in the presence of a coupling agent and a solvent. In some embodiments, the coupling agent is l,4-diazabicyclo-[2.2.2]-octane (DABCO). In some embodiments, the solvent comprises acetonitrile. In some embodiments, the coupling is performed at a temperature from about 0°C to about 30°C.

[0076] In some embodiments, the compound of Formula VI is a compound of Formula Via: or a salt thereof.

[0077] In some embodiments, the present application further provides a process comprising reacting a compound of Formula Via: with 5-chloro-2,4-difluorobenzenesulfonyl chloride under a coupling condition to afford a compound of Formula IVa: or a salt thereof; reacting the compound of Formula IVa with a compound of Formula V: or a salt thereof, under a S\Ar reaction condition to afford the compound of Formula

[0078] Illa: Illa or a salt thereof; reacting the compound of Formula Illa, or a salt thereof, under a Suzuki coupling condition to form a compound of Formula Ila: or a salt thereof; reacting the compound of Formula Ila, or a salt thereof, under a deprotection condition to afford the compound of Formula I:

[0079] I or a salt thereof; reacting the compound of Formula I, or a salt thereof, with sodium hydroxide to form the free base form of the compound of Formula I; reacting the free base form of the compound of Formula I with p- toluenesulfonic acid to form a -toluenesulfonic acid salt of the compound of Formula I; reacting the -toluenesulfonic acid salt of the compound of Formula I with sodium bicarbonate to form the free base form of the compound of Formula I; and crystallizing the free base form of the compound of Formula I to afford crystalline (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N- (thiazol-4-yl)benzenesulfonamide.

[0080] The present application further provides a compound of Formula Ila: or a salt thereof.

[0081] The present application further provides a compound of Formula Illa:

[0082] Illa or a salt thereof.

[0083] The present application further provides a compound of Formula IVa: or a salt thereof.

[0084] The present application further provides a salt of compound of Formula I:

[0085] I or a salt thereof.

[0086] In some embodiments, the salt is a p-toluenesulfonic acid salt. In some embodiments, the salt is a 2,3-dibenzoyl-D-tartaric acid salt. In some further embodiments, the salt of Ila, Illa, and I are intermediates for the preparation of a crystalline form of a compound of Formula I free base. In yet a further embodiment, the crystalline form of a compound of Formula I free base is a crystalline form described herein.

[0087] The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.,JH or13C), infrared spectroscopy, or spectrophotometry (e.g., UV-visible); or by chromatography such as high-performance liquid chromatography (HPLC) or thin layer chromatography (TLC) or other related techniques.

[0088] The present application provides a crystalline form which is prepared by any one of the processes described herein. In some further embodiments, the crystalline form is a crystalline form described herein.

[0089] The present application provides a crystalline form which is substantially isolated. In some further embodiments, the crystalline form is a crystalline form described herein. In some embodiments, the crystalline form contains at least one impurity selected from the group consisting of impurities A, B, and C, wherein impurities A and B are represented by formulae:

[0090] Impurity B and wherein impurity C has an exact mass of 904.

[0091] Without wishing to be bound by theory, impurity C may be a compound having the following structural formulae: Without wishing to be bound by theory, impurity C may be a compound having the following structural formulae:

[0092] In some embodiments, the crystalline form is characterized by a DSC thermogram having an endothermic peak at about 151°C. In some embodiments, the crystalline form is characterized by a DSC thermogram having an endothermic peak with onset at about 151°C. In some embodiments, the crystalline form is characterized by a DSC thermogram substantially as shown in FIG. 1.

[0093] In some embodiments, the crystalline form has no substantial weight loss from room temperature to about 125 °C. As used herein, the term “no substantial weight loss” means weight loss which is less than 0.25%. In some embodiments, the crystalline form has a weight loss of <0.3% up to about 170 °C. In some embodiments, the crystalline form has a TGA thermogram substantially as shown in FIG. 1.

[0094] In some embodiments, the crystalline form is characterized by at least one XRPD peak, in terms of 2-theta, selected from 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by at least two XRPD peaks, in terms of 2-theta, selected from 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by at least three XRPD peaks, in terms of 2-theta, selected from 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by at least four XRPD peaks, in terms of 2-theta, selected 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by at least five XRPD peaks, in terms of 2-theta, selected from 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by at least six XRPD peaks, in terms of 2-theta, selected from 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by at least seven XRPD peaks, in terms of 2-theta, selected from 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by XRPD peaks, in terms of 2-theta, at 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°.

[0095] In some embodiments, the crystalline form is characterized by six XRPD peaks, in terms of 2-theta, at 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, and 21.7°± 0.2°. In some embodiments, the crystalline form is characterized by six XRPD peaks, in terms of 2-theta, at 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 21.7°± 0.2°, and 27.0°± 0.2°. In some embodiments, the crystalline form is characterized by six XRPD peaks, in terms of 2-theta, at 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 21.7°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by six XRPD peaks, in terms of 2- theta, at 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, and 27.0°± 0.2°. In some embodiments, the crystalline form is characterized by six XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by six XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°.

[0096] In some embodiments, the crystalline form is characterized by at least one XRPD peak, in terms of 2-theta, selected from 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°. In some embodiments, the crystalline form is characterized by at least two XRPD peaks, in terms of 2-theta, selected from 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°. In some embodiments, the crystalline form is characterized by at least three XRPD peaks, in terms of 2-theta, selected from 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°.

[0097] In some embodiments, the crystalline form is characterized by three XRPD peaks, in terms of 2-theta, at 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°. In some embodiments, the crystalline form is characterized by three XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°. In some embodiments, the crystalline form is characterized by three XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, and 21.7°± 0.2°. In some embodiments, the crystalline form is characterized by three XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, and 17.7 °± 0.2°. In some embodiments, the crystalline form is characterized by four XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°.

[0098] In some embodiments, the crystalline form comprises no more than 0.5% of impurity A as determined by HPLC by comparing the peak area of impurity A to the total peak area. In some embodiments, the crystalline form comprises at least about 0.1% of impurity A as determined by HPLC by comparing the peak area of impurity A to the total peak area. In some embodiments, the crystalline form comprises at least about 0.2% of impurity A as determined by HPLC by comparing the peak area of impurity A to the total peak area. In some embodiments, the crystalline form comprises at least about 0.3% of impurity A as determined by HPLC by comparing the peak area of impurity A to the total peak area. In some embodiments, the pharmaceutical composition comprises about 0.4% of impurity A as determined by HPLC by comparing the peak area of impurity A to the total peak area.

[0099] In some embodiments, the crystalline form comprises no more than 0.5% of impurity B as determined by HPLC by comparing the peak area of impurity B to the total peak area. In some embodiments, the pharmaceutical composition comprises an undetectable level of impurity B by HPLC analysis.

[0100] In some embodiments, the crystalline form comprises no more than 0.4% of impurity C as determined by HPLC by comparing the area of impurity C to the total peak area. In some embodiments, the crystalline form comprises at least about 0.05% of impurity C as determined by HPLC by comparing the peak area of impurity C to the total peak area. In some embodiments, the pharmaceutical composition comprises about 0.1% of impurity C as determined by HPLC by comparing the area of impurity C to the total peak area.

[0101] In some embodiments, the HPLC method comprises a C18 250 x 4.6 mm, 5.0 pm column. In some embodiments, the HPLC method comprises a photodiode array / ultraviolet detector at 260 nm. In some embodiments, the HPLC method comprises a C18 250 x 4.6 mm, 5.0 pm column; and a photodiode array / ultraviolet detector at 260 nm.

[0102] In some embodiments, the crystalline form has less than 30 ppm of di chi oromethane .

[0103] In some embodiments, the crystalline form has less than 72 ppm of tetrahydrofuran.

[0104] In some embodiments, the crystalline form has about 1% by weight of ethanol. In some embodiments, the crystalline form has about 1% by weight of solvent. In any one of the above embodiments, the crystalline form is prepared by any one of the processes described herein,

[0105] In any one of the above embodiments, the crystalline form is substantially isolated.

[0106] As used herein, the term “reacting” is used as known in the art and generally refers to the bringing together of chemical reagents in such a manner so as to allow their interaction at the molecular level to achieve a chemical or physical transformation. In some embodiments, the reacting involves two reagents, wherein one or more equivalents of second reagent are used with respect to the first reagent. The reacting steps of the processes described herein can be conducted for a time and under conditions suitable for preparing the identified product.

[0107] The reactions of the processes described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected.

[0108] Suitable solvents can include, by way of example and without limitation, halogenated solvents such as carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachloroethylene, trichloroethylene, 1,1,1 -tri chloroethane, 1,1,2-tri chloroethane, 1,1 -di chloroethane, 2- chloropropane, 1,2-di chloroethane, 1,2-dibromoethane, hexafluorobenzene, 1,2,4- tri chlorobenzene, 1,2-di chlorobenzene, chlorobenzene, fluorobenzene, mixtures thereof and the like.

[0109] Suitable ether solvents can include, by way of example and without limitation: dimethoxymethane, tetrahydrofuran, 1,3 -di oxane, 1,4-di oxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, mixtures thereof and the like.

[0110] Suitable protic solvents can include, by way of example and without limitation, water, methanol, ethanol, 2 -nitroethanol, 2-fluoroethanol, 2,2,2- trifluoroethanol, ethylene glycol, 1 -propanol, 2-propanol, 2-methoxy ethanol, 1- butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, di ethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol.

[0111] Suitable aprotic solvents can include, by way of example and without limitation, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N- dimethylacetamide (DMA), l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU), l,3-dimethyl-2-imidazolidinone (DMI), N methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexamethylphosphoramide.

[0112] Suitable hydrocarbon solvents can include, by way of example and without limitation, benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or naphthalene.

[0113] The reactions of the processes described herein can be carried out at appropriate temperatures which can be readily determined by the skilled artisan. Reaction temperatures will depend on, for example, the melting and boiling points of the reagents and solvents, if present; the thermodynamics of the reaction (e.g., vigorously exothermic reactions may need to be carried out at reduced temperatures); and the kinetics of the reaction (e.g., a high activation energy barrier may need elevated temperatures).

[0114] The expressions, “ambient temperature” and “room temperature” or “rt” as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 °C to about 30 °C.

[0115] The reactions of the processes described herein can be carried out in air or under an inert atmosphere. Typically, reactions containing reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques that are well known to the skilled artisan.

[0116] Methods of Use

[0117] The present application further provides methods of treating a disease or a condition associated with Najzl.6 activity in a subject (e.g., a mammal such as a human subject).

[0118] In some embodiments, the methods provided herein comprise administering to the subject in need thereof a therapeutically effective amount of a compound, a crystalline form, or a pharmaceutical composition provided herein.

[0119] The present application provides use of a crystalline form of (5)-4-((l- benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4- yl)benzenesulfonamide as described herein for the manufacture of a medicament for the treatment of a disease or a condition associated with Najzl.6 activity in a subject.

[0120] The present application provides a crystalline form of (S)-4-((l - benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4- yl)benzenesulfonamide or a pharmaceutical composition comprising (S)-4-(( 1 - benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4- yl)benzenesulfonamide as described herein for use in the treatment of a disease or a condition associated with Najzl.6 activity in a subject.

[0121] In some embodiments, the disease, disorder or condition associated with Najzl.6 activity is depression, bipolar disorders, schizophrenia, pain, epilepsy or epileptic seizure disorder. In some embodiments, the epilepsy or epileptic seizure disorder is selected from photosensitive epilepsy, self-induced syncope, intractable epilepsy, Angelman syndrome, benign rolandic epilepsy, CDKL5 disorder, childhood and juvenile absence epilepsy, Dravet syndrome, frontal lobe epilepsy, Glutl deficiency syndrome, hypothalamic hamartoma, infantile spasms / West' s syndrome, juvenile myoclonic epilepsy, Landau -KI effner syndrome, Lennox-Gastaut syndrome (LGS), epilepsy with myoclonic-absences, Ohtahara syndrome, Panayiotopoulos syndrome, PCDH19 epilepsy, progressive myoclonic epilepsies, Rasmussen's syndrome, ring chromosome 20 syndrome, reflex epilepsies, temporal lobe epilepsy, Lafora progressive myoclonus epilepsy, neurocutaneous syndromes, tuberous sclerosis complex, early infantile epileptic encephalopathy, early onset epileptic encephalopathy, SCN8A developmental and epileptic encephalopathy (SCN8A-DEE), focal onset seizure including adult focal onset seizure, generalized focal onset seizure, and unknown onset seizure, generalized epilepsy with febrile seizures, Rett syndrome, multiple sclerosis, Alzheimer’s disease, autism, ataxia, hypotonia and paroxysmal dyskinesia.

[0122] In some embodiments, the epilepsy or epileptic seizure disorder is focal onset seizures. In some further embodiments, the epilepsy or epileptic seizure disorder is adult focal onset seizures. In some other further embodiments, the epilepsy or epileptic seizure disorder is generalized onset seizures. In some other further embodiments, the epilepsy or epileptic seizure disorder is unknown onset seizures.

[0123] In some embodiments, the patient has a SCN8A mutation. In some embodiments, the disease or condition is SCN8A developmental and epileptic encephalopathy (SCN8A-DEE).

[0124] In some embodiments, the epilepsy or epileptic seizure disorder is selected from Dravet syndrome, infantile spasms / West' s syndrome, temporal lobe epilepsy, Lennox-Gastaut syndrome (LGS), generalized epilepsy with febrile seizures and early infantile epileptic encephalopathy.

[0125] In some embodiments, the disease, disorder, or condition associated with Najzl.6 activity is a bipolar disorder.

[0126] In some embodiments, the disease, disorder, or condition associated with Najzl.6 activity is depression. In some embodiments, the disease, disorder, or condition associated with Najzl.6 activity is schizophrenia.

[0127] In some embodiments, the disease, disorder, or condition associated with Najzl.6 activity is pain.

[0128] In some embodiments, the present application further provides methods of decreasing ion flux through Najzl.6 in a cell (e.g., a mammalian cell). In some embodiments, the method comprises contacting the cell with a compound or crystalline form provided herein.

[0129] In some embodiments, the present application further provides methods of selectively inhibiting a first voltage-gated sodium channel over a second voltagegated sodium channel in a subject (e.g., a mammal such as a human subject). In some embodiments, the method comprises administering to the subject a modulating amount of a compound or crystalline form provided herein.

[0130] In some embodiments, the first voltage-gated sodium channel is Najzl.6.

[0131] In some embodiments, the first voltage-gated sodium channel is Najzl.6 and the second voltage-gated sodium channel is Najzl.5.

[0132] In some embodiments, the first voltage-gated sodium channel is Najzl.6 and the second voltage-gated sodium channel is Najzl. l.

[0133] Any of these consequences may ultimately be responsible for the overall therapeutic benefit provided by these compounds and crystalline forms.

[0134] Accordingly, the compounds and crystalline forms provided herein are voltage-gated sodium channel inhibitors, preferably NaH.6 inhibitors, and are therefore useful for treating diseases and conditions, preferably epilepsy and / or epileptic seizure disorder, in mammals, preferably humans, and other organisms, including all human diseases and conditions which are the result of aberrant voltagedependent sodium channel biological activity, preferably aberrant NaH.6 activity, or which may be ameliorated by modulation of voltage-dependent sodium channel biological activity. In particular, the compounds and crystalline forms provided herein are useful for treating diseases and conditions in a subject (e.g., a mammal, preferably a human subject), which are the result of aberrant voltage-dependent Nacl .6 biological activity or which may be ameliorated by the modulation, preferably the inhibition, of Najzl.6 biological activity. In some embodiments, the compounds and crystalline forms provided herein selectively inhibit NaH.6 over Najzl.5 and / or NaH.l.

[0135] As defined herein, a disease, disorder or condition associated with Najzl.6 activity includes, but is not limited to, bipolar disorders, depression, schizophrenia, pain, epilepsy and / or epileptic seizure disorder. Such epilepsy and / or epileptic seizure disorders include, but are not limited to, photosensitive epilepsy, self-induced syncope, intractable epilepsy, Angelman syndrome, benign rolandic epilepsy, CDKL5 disorder, childhood and juvenile absence epilepsy, Dravet syndrome, frontal lobe epilepsy, Glutl deficiency syndrome, hypothalamic hamartoma, infantile spasms / West's syndromejuvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome (LGS), epilepsy with myoclonic-absences, Ohtahara syndrome, Panayiotopoulos syndrome, PCDH19 epilepsy, progressive myoclonic epilepsies, Rasmussen's syndrome, ring chromosome 20 syndrome, reflex epilepsies, temporal lobe epilepsy, Lafora progressive myoclonus epilepsy, neurocutaneous syndromes, tuberous sclerosis complex, early infantile epileptic encephalopathy, early onset epileptic encephalopathy, SCN8A developmental and epileptic encephalopathy (SCN8A-DEE), focal onset seizure including adult focal onset seizure, generalized focal onset seizure, and unknown onset seizure, generalized epilepsy with febrile seizures, Rett syndrome, multiple sclerosis, Alzheimer’s disease, autism, ataxia, hypotonia and paroxysmal dyskinesia.

[0136] The present application therefore provides compounds and crystalline forms for the treatment of diseases or conditions associated with the activity of Najzl.6 in a subject (e.g., a mammal, such as a human subject), by administering to the subject in need of such treatment an effective amount of a compound or crystalline form provided herein or a pharmaceutical composition comprising a compound or crystalline form provided herein.

[0137] The general value of the compounds and crystalline forms provided herein in inhibiting the Najzl.6 ion flux can be determined, e.g., according to one or more of the assays described herein. Alternatively, the general value of the compounds and crystalline forms in treating conditions and diseases in humans may be established in industry standard animal models for demonstrating the efficacy of compounds and crystalline forms in treating epilepsy and / or epileptic seizure disorder. Animal models of human epileptic conditions have been developed that result in reproducible sensory deficits over a sustained period of time that can be evaluated by sensory testing.

[0138] For example, many rodent models have been developed to assess the propensity for seizures or epileptiform activity (Klein, B.R. et al., (2016), "Models Currently in Active Use. In: Epilepsy Therapy Screening Program", Vol. 2016, National Institute of Neurological Disorders and Stroke). These include acute chemical or electrical insults that induce seizures, as well as chronic chemical or genetic insults that create seizure prone animals. These models can be used to determine the relative ability of a compound to promote or prevent seizure activity. The maximal electroshock seizure (MES) assay and the 6 hertz psychomotor seizure test (6Hz) are two examples of acute insult seizure assays used to evaluate anti convulsive interventions (see e.g., Suzuki, F. et al., Neuroscience (1995), Vo. 64, pp. 665-674; and Barton, M.E. et cd., Epilepsy Research (2001), Vol. 47, pp. 217- 227). Both assays involve an electrical insult applied with electrodes placed on the corneas or ears in order to provoke an acute seizure. Acute seizures may also be induced chemically, for instance by administration of the proconvulsant ether compound flurothyl (see e.g., Makinson, C.D. et al., Exp. Neurol. (2016), Vol. 275, Pt 1, pp. 46-58).

[0139] Genetic epilepsies have been linked to many distinct genes, including multiple voltage gated sodium channel genes. Genetically modified mice can be created that harbor mutations identified in human patients. In some cases, these genetic modifications result in animals that behave much like the human patients in whom the genetic variations were initially identified. Mutant mice can be used to test anticonvulsant interventions. Such experiments can involve prevention of spontaneous seizures or may make use of similar seizure provoking stimuli as those employed in wild type mice. Animal models of early infantile epileptic encephalopathy 6 (EIEE6), also known as severe myoclonic epilepsy of infancy or Dravet syndrome, have been created by mutating the SCN1A gene that encodes the Najzl.l voltage gated sodium channel (see e.g., Yu, F.H. et al., Nat. Neurosci. (2006), Vol. 9, pp. 1142-1149). Models of EIEE13 have likewise been created by mutating the SCN8A gene that encodes the Najzl.6 voltage gated sodium channel (see e.g., Wagnon, J.L. et al., Human Molecular Genetics(2014)). Both of these mouse strains provide the opportunity to evaluate potential therapeutic interventions that might prove useful in clinical patient populations (see e.g., Martin, M.S. et cd., J. Biol. Chem. (2010), Vol. 285, pp. 9823-9834; and Martin, M.S. et al., Human Molecular Genetics (2007), Vol. 16, pp. 2892-2899).

[0140] The present application readily affords many different means for identification of Najzl.6 inhibitory agents that are useful as therapeutic agents. Identification of Najzl.6 inhibitors can be assessed using a variety of in vitro and in vivo assays, e.g., measuring current, measuring membrane potential, measuring ion flux, (e.g., sodium or guanidinium), measuring sodium concentration, measuring second messengers and transcription levels, and using e.g., voltage-sensitive dyes, radioactive tracers, and patch-clamp electrophysiology.

[0141] One such protocol involves the screening of chemical agents for the ability to modulate the activity of a sodium channel thereby identifying it as a modulating agent.

[0142] A typical assay described in Bean et al., J. General Physiology (1983), 83:613-642, and Leuwer, M., et al., Br. J. Pharmacol (2004), 141 (l):47-54, uses patch-clamp techniques to study the behavior of channels. Such techniques are known to those skilled in the art, and may be developed, using current technologies, into low or medium throughput assays for evaluating compounds for their ability to modulate sodium channel behavior.

[0143] Modulating agents so identified are then tested in a variety of in vivo models to determine if they are useful in treating the disease or condition associated with the activity of the sodium channel of interest, preferably Najzl.6, with minimal adverse events. The assays described below in the Biological Assays Section are useful in assessing the biological activity of the instant compounds.

[0144] The efficacy of a compound or crystalline form provided herein can be expressed, for example, by its IC50 value ("Inhibitory Concentration - 50%"), which is the measure of the amount of compound required to achieve 50% inhibition of the activity of the target sodium channel over a specific time period.

[0145] In some embodiments, the compounds and crystalline forms provided herein can be used in in vitro or in vivo studies as exemplary agents for comparative purposes to find other compounds also useful in treatment of, or protection from, the various diseases disclosed herein.

[0146] In some embodiments, the present application provides methods of inhibiting Najzl.6 activity in a biological sample or a subject (e.g., a mammal, such as a human subject). In some embodiments, the method comprises administering to the subject or contacting said biological sample with a compound and crystalline form provided herein, or a pharmaceutical composition comprising the compound or crystalline form. As used herein, the term “biological sample”, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0147] Inhibition of Najzl.6 activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, the study of sodium ion channels in biological and pathological phenomena; and the comparative evaluation of new sodium ion channel inhibitors.

[0148] The compounds and crystalline forms provided herein and pharmaceutical compositions comprising the compounds and crystalline forms can be used in the preparation of a medicament for the treatment of diseases or conditions associated with voltage-gated sodium channel activity, preferably Najzl.6 activity, in a subject (e.g., a mammal, such as a human subject).

[0149] Compositions

[0150] The present application further provides pharmaceutical compositions comprising the compound or its crystalline forms provided herein. In some embodiments, the present application provides a composition (e.g., a pharmaceutical composition) comprising a compound or crystalline form provided herein, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0151] The present application further provides a composition, wherein the composition comprises (S)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5- methyl-N-(thiazol-4-yl)benzenesulfonamide (compound of Formula I), and at least one impurity selected from the group consisting of impurities A, B, and C, wherein impurities A and B are represented by formulae: and wherein impurity C has an exact mass of 904. Without wishing to be bound by theory, impurity C may be a compound having the following structural formulae:

[0152] Without wishing to be bound by theory, impurity C may be a compound having the following structural formulae:

[0153] In some embodiments, (S)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2- fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide is in an amorphous form.

[0154] In some embodiments, (S)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2- fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide is in a crystalline form. In some embodiments, the crystalline form of (S)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)- 2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide is a crystalline form described herein.

[0155] In some embodiments, the crystalline form is characterized by a DSC thermogram having an endothermic peak at about 151°C. In some embodiments, the crystalline form is characterized by a DSC thermogram having an endothermic peak with onset at about 151°C. In some embodiments, the crystalline form is characterized by a DSC thermogram substantially as shown in FIG. 1.

[0156] In some embodiments, the crystalline form has no substantial weight loss from room temperature to about 125 °C. As used herein, the term “no substantial weight loss” means weight loss which is less than about 0.25%. In some embodiments, the crystalline form has a weight loss of <0.3% up to about 170 °C. In some embodiments, the crystalline form has a TGA thermogram substantially as shown in FIG. 1.

[0157] In some embodiments, the crystalline form is characterized by at least one XRPD peak, in terms of 2-theta, selected from 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by at least two XRPD peaks, in terms of 2-theta, selected from 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by at least three XRPD peaks, in terms of 2-theta, selected from 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by at least four XRPD peaks, in terms of 2-theta, selected 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by at least five XRPD peaks, in terms of 2-theta, selected from 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by at least six XRPD peaks, in terms of 2-theta, selected from 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by at least seven XRPD peaks, in terms of 2-theta, selected from 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by XRPD peaks, in terms of 2-theta, at 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°.

[0158] In some embodiments, the crystalline form is characterized by six XRPD peaks, in terms of 2-theta, at 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, and 21.7°± 0.2°. In some embodiments, the crystalline form is characterized by six XRPD peaks, in terms of 2-theta, at 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 21.7°± 0.2°, and 27.0°± 0.2°. In some embodiments, the crystalline form is characterized by six XRPD peaks, in terms of 2-theta, at 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 21.7°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by six XRPD peaks, in terms of 2- theta, at 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, and 27.0°± 0.2°. In some embodiments, the crystalline form is characterized by six XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by six XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°.

[0159] In some embodiments, the crystalline form is characterized by at least one XRPD peak, in terms of 2-theta, selected from 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°. In some embodiments, the crystalline form is characterized by at least two XRPD peaks, in terms of 2-theta, selected from 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°. In some embodiments, the crystalline form is characterized by at least three XRPD peaks, in terms of 2-theta, selected from 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°.

[0160] In some embodiments, the crystalline form is characterized by three XRPD peaks, in terms of 2-theta, at 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°. In some embodiments, the crystalline form is characterized by three XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°. In some embodiments, the crystalline form is characterized by three XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, and 21.7°± 0.2°. In some embodiments, the crystalline form is characterized by three XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, and 17.7 °± 0.2°. In some embodiments, the crystalline form is characterized by four XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°.

[0161] In some embodiments, the composition comprises no more than 0.5% of impurity A as determined by HPLC by comparing the peak area of impurity A to the total peak area. In some embodiments, the crystalline form comprises at least about 0.1% of impurity A as determined by HPLC by comparing the peak area of impurity A to the total peak area. In some embodiments, the crystalline form comprises at least about 0.2% of impurity A as determined by HPLC by comparing the peak area of impurity A to the total peak area. In some embodiments, the crystalline form comprises at least about 0.3% of impurity A as determined by HPLC by comparing the peak area of impurity A to the total peak area. In some embodiments, the composition comprises about 0.4% of impurity A as determined by HPLC by comparing the peak area of impurity A to the total peak area.

[0162] In some embodiments, the composition comprises no more than about 0.5% of impurity B as determined by HPLC by comparing the peak area of impurity B to the total peak area. In some embodiments, the composition comprises an undetectable level of impurity B by HPLC analysis.

[0163] In some embodiments, the composition comprises no more than about 0.4% of impurity C as determined by HPLC by comparing the area of impurity C to the total peak area. In some embodiments, the crystalline form comprises at least about 0.05% of impurity C as determined by HPLC by comparing the peak area of impurity C to the total peak area. In some embodiments, the composition comprises about 0.1% of impurity C as determined by HPLC by comparing the peak area of impurity C to the total peak area.

[0164] In some embodiments, the HPLC method comprises a C18 250 x 4.6 mm, 5.0 pm column. In some embodiments, the HPLC method comprises a photodiode array / ultraviolet detector at 260 nm. In some embodiments, the HPLC method comprises a C18 250 x 4.6 mm, 5.0 pm column; and a photodiode array / ultraviolet detector at 260 nm. The present application further provides a pharmaceutical composition, wherein the pharmaceutical composition comprises one of the compositions described herein and at least one pharmaceutically acceptable excipient.

[0165] In some embodiments, the pharmaceutical composition comprises (S)-4-((l- benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4- yl)benzenesulfonamide (compound of Formula I), and at least one impurity selected from the group consisting of impurities A, B, and C, wherein impurities A and B are represented by formulae:

[0166] Impurity B and wherein impurity C has an exact mass of 904.

[0167] Without wishing to be bound by theory, impurity C may be a compound having the following structural formulae:

[0168] Without wishing to be bound by theory, impurity C may be a compound having the following structural formulae:

[0169] In some embodiments, (S)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2- fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide is in an amorphous form.

[0170] In some embodiments, (S)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2- fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide is in a crystalline form. In some embodiments, the crystalline form of (S)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)- 2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide is a crystalline form described herein.

[0171] In some embodiments, the crystalline form is characterized by a DSC thermogram having an endothermic peak at about 151°C. In some embodiments, the crystalline form is characterized by a DSC thermogram having an endothermic peak with onset at about 151°C. In some embodiments, the crystalline form is characterized by a DSC thermogram substantially as shown in FIG. 1.

[0172] In some embodiments, the crystalline form has no substantial weight loss from room temperature to about 125 °C. As used herein, the term “no substantial weight loss” means weight loss which is less than about 0.25%. In some embodiments, the crystalline form has a weight loss of <0.3% up to about 170 °C. In some embodiments, the crystalline form has a TGA thermogram substantially as shown in FIG. 1.

[0173] In some embodiments, the crystalline form is characterized by at least one XRPD peak, in terms of 2-theta, selected from 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by at least two XRPD peaks, in terms of 2-theta, selected from 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by at least three XRPD peaks, in terms of 2-theta, selected from 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by at least four XRPD peaks, in terms of 2-theta, selected 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by at least five XRPD peaks, in terms of 2-theta, selected from 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by at least six XRPD peaks, in terms of 2-theta, selected from 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by at least seven XRPD peaks, in terms of 2-theta, selected from 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by XRPD peaks, in terms of 2-theta, at 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°.

[0174] In some embodiments, the crystalline form is characterized by six XRPD peaks, in terms of 2-theta, at 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, and 21.7°± 0.2°. In some embodiments, the crystalline form is characterized by six XRPD peaks, in terms of 2-theta, at 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 21.7°± 0.2°, and 27.0°± 0.2°. In some embodiments, the crystalline form is characterized by six XRPD peaks, in terms of 2-theta, at 10.8°± 0.2°, 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 21.7°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by six XRPD peaks, in terms of 2- theta, at 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, and 27.0°± 0.2°. In some embodiments, the crystalline form is characterized by six XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 18.1°± 0.2°, 21.7°± 0.2°, and 28.6°± 0.2°. In some embodiments, the crystalline form is characterized by six XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, 21.7°± 0.2°, 27.0°± 0.2°, and 28.6°± 0.2°.

[0175] In some embodiments, the crystalline form is characterized by at least one XRPD peak, in terms of 2-theta, selected from 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°. In some embodiments, the crystalline form is characterized by at least two XRPD peaks, in terms of 2-theta, selected from 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°. In some embodiments, the crystalline form is characterized by at least three XRPD peaks, in terms of 2-theta, selected from 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°.

[0176] In some embodiments, the crystalline form is characterized by three XRPD peaks, in terms of 2-theta, at 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°. In some embodiments, the crystalline form is characterized by three XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°. In some embodiments, the crystalline form is characterized by three XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, and 21.7°± 0.2°. In some embodiments, the crystalline form is characterized by three XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, and 17.7 °± 0.2°. In some embodiments, the crystalline form is characterized by four XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°.

[0177] In some embodiments, the composition comprises no more than 0.5% of impurity A as determined by HPLC by comparing the peak area of impurity A to the total peak area. In some embodiments, the crystalline form comprises at least about 0.1% of impurity A as determined by HPLC by comparing the peak area of impurity A to the total peak area. In some embodiments, the crystalline form comprises at least about 0.2% of impurity A as determined by HPLC by comparing the peak area of impurity A to the total peak area. In some embodiments, the crystalline form comprises at least about 0.3% of impurity A as determined by HPLC by comparing the peak area of impurity A to the total peak area. In some embodiments, the composition comprises about 0.4% of impurity A as determined by HPLC by comparing the peak area of impurity A to the total peak area.

[0178] In some embodiments, the composition comprises no more than about 0.5% of impurity B as determined by HPLC by comparing the peak area of impurity B to the total peak area. In some embodiments, the composition comprises an undetectable level of impurity B by HPLC analysis.

[0179] In some embodiments, the composition comprises no more than about 0.4% of impurity C as determined by HPLC by comparing the area of impurity C to the total peak area. In some embodiments, the crystalline form comprises at least about 0.05% of impurity C as determined by HPLC by comparing the peak area of impurity C to the total peak area. In some embodiments, the composition comprises about 0.1% of impurity C as determined by HPLC by comparing the peak area of impurity C to the total peak area.

[0180] In some embodiments, the HPLC method comprises a C18 250 x 4.6 mm, 5.0 pm column. In some embodiments, the HPLC method comprises a photodiode array / ultraviolet detector at 260 nm. In some embodiments, the HPLC method comprises a C18 250 x 4.6 mm, 5.0 pm column; and a photodiode array / ultraviolet detector at 260 nm.

[0181] As used herein, the term “total peak area” means the combined peak area of an HPLC chromatogram of a sample of compound of Formula I. The sample of compound of Formula I may be amorphous or may be crystalline. Peaks may be detected at a certain wavelength, e.g., 260 nm. In addition to a main peak from compound of Formula I, there may be other peaks, e.g., peaks from impurities A, B, and C.

[0182] Administration of the compounds and crystalline forms provided herein in pure form or in an appropriate pharmaceutical composition, can be performed via any of the accepted modes of administration of agents for serving similar utilities. The pharmaceutical compositions provided herein can be prepared, for example, by combining a compound or crystalline form provided herein with an appropriate pharmaceutically acceptable carrier, diluent, or excipient, and may be formulated into preparations in solid, semi-solid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical routes of administering such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, vaginal, and intranasal. As used herein, the term “parenteral” includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Pharmaceutical compositions provided herein can be formulated, for example, so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound of the invention in aerosol form may hold a plurality of dosage units. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease or condition of interest as described herein.

[0183] The pharmaceutical compositions provided herein also contain a pharmaceutically acceptable carrier, including any suitable diluent or excipient, which includes any pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity. Pharmaceutically acceptable carriers include, but are not limited to, liquids, such as water, saline, glycerol and ethanol, and the like. A thorough discussion of pharmaceutically acceptable carriers, diluents, and other excipients is presented in Remington's Pharmaceutical Sciences (Mack Pub. Co., N.J. current edition).

[0184] A pharmaceutical composition provided herein may be in the form of a solid or liquid. In some embodiments, the carrier(s) are particulate, so that the compositions are, for example, in tablet or powder form. The carrier(s) may be liquid, with the compositions being, for example, an oral syrup, injectable liquid or an aerosol, which is useful in, for example, inhalatory administration.

[0185] When intended for oral administration, the pharmaceutical composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.

[0186] As a solid composition for oral administration, a pharmaceutical composition provided herein may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer, or the like form. Such a solid composition will typically contain one or more inert diluents or edible carriers. In addition, one or more of the following may be present: binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, com starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent.

[0187] When the pharmaceutical composition is in the form of a capsule, for example, a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.

[0188] The pharmaceutical compositions provided herein may be in the form of a liquid, for example, an elixir, syrup, solution, emulsion, or suspension. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, exemplary compositions may contain, in addition to a compound or crystalline form provided herein, one or more of a sweetening agent, preservatives, dye / colorant and flavor enhancer. In a composition intended to be administered by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer, and isotonic agent may be included.

[0189] A liquid pharmaceutical composition provided herein, whether it be a solution, suspension, or other like form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. A parenteral preparation can be enclosed, for example, in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. An injectable pharmaceutical composition is preferably sterile.

[0190] A liquid pharmaceutical composition provided herein, intended for either parenteral or oral administration, may contain, for example, an amount of a compound or crystalline form provided herein such that a suitable dosage will be obtained.

[0191] A pharmaceutical composition provided herein may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device.

[0192] A pharmaceutical composition provided herein may be intended for rectal administration, in the form, for example, of a suppository, which will melt in the rectum and release the drug. The composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient. Such bases include, without limitation, lanolin, cocoa butter, and polyethylene glycol.

[0193] A pharmaceutical composition provided herein may include various materials, which modify the physical form of a solid or liquid dosage unit. For example, the composition may include materials that form a coating shell around the active ingredient(s). The materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredients may be encased in a gelatin capsule.

[0194] A pharmaceutical composition provided herein in solid or liquid form may include, for example, an agent that binds to the compound or crystalline form provided herein and thereby assists in the delivery of the compound or crystalline form. Suitable agents that may act in this capacity include, for example, a monoclonal or polyclonal antibody, a protein, or a liposome.

[0195] A pharmaceutical composition provided herein may consist of dosage units that can be administered, for example, as an aerosol. As used herein, the term “aerosol” is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredient(s). Aerosols of compounds or crystalline forms provided herein may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit. One skilled in the art, without undue experimentation may determine preferred aerosols. A pharmaceutical composition provided herein may be prepared, for example, by methodology well known in the pharmaceutical art. For example, a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound or crystalline form provided herein with sterile, distilled water so as to form a solution. A surfactant may be added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that non-covalently interact with the compound of the invention so as to facilitate dissolution or homogeneous suspension of the compound or crystalline form in the aqueous delivery system.

[0196] The compounds and crystalline forms provided herein are administered in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject undergoing therapy. Preferred dosages will be tailored to the individual subject, as is understood and determinable by one skilled in the relevant arts (see e.g., Berkow et al., eds., The Merck Manual, 19thedition, Merck and Co., Rahway, N.J., 2011; Brunton et al. eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12thedition, McGraw-Hill 2011; Avery's Drug Treatment: Principles and Practice of Clinical Pharmacology and Therapeutics, 3rd edition, ADIS Press, LTD., Williams and Wilkins, Baltimore, MD. (1987), Ebadi, Pharmacology, Little, Brown and Co., Boston, (1985); Osolci al., eds., Remington's Pharmaceutical Sciences, current edition, Mack Publishing Co., Easton, PA; Katzung, Basic and Clinical Pharmacology, Appleton and Lange, Norwalk, CT (1992)).

[0197] The total dose required for each treatment can be administered by multiple doses or in a single dose over the course of the day, if desired. The recipients of administration of compounds, crystalline forms, and / or compositions provided herein can be any vertebrate animal, such as mammals. Example mammals include, but are not limited to, mammals of the Orders Primate (including humans, apes, and monkeys), Arteriodactyla (including horses, goats, cows, sheep, pigs), Rodenta (including mice, rats and hamsters), Lagamorpha (including rabbits) and Carnivora (including cats and dogs). Among birds, the preferred recipients are turkeys, chickens, and other members of the same order. In some embodiments, the recipient is a human (e.g., a human subject or patient).

[0198] For topical applications, the compositions provided herein can be administered to a target area, e.g., skin surfaces, mucous membranes, and the like, which are adjacent to peripheral neurons which are to be treated. The pharmaceutical composition can be formulated as transdermal compositions or transdermal delivery devices (“patches”). Such compositions include, for example, a backing, active compound reservoir, a control membrane, liner and contact adhesive. Such transdermal patches may be used to provide continuous pulsatile, or on demand delivery of the compounds or crystalline forms provided herein.

[0199] The compositions provided herein can be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. Controlled release drug delivery systems include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos. 3,845,770 and 4,326,525 and in P. J. Kuzma et al., Regional Anesthesia 22 (6): 543-551 (1997), all of which are incorporated herein by reference.

[0200] The compositions provided herein can also be delivered through intra-nasal drug delivery systems for local, systemic, and nose-to-brain medical therapies. Controlled Particle Dispersion (CPD)™ technology, traditional nasal spray bottles, inhalers, or nebulizers are known by those skilled in the art to provide effective local and systemic delivery of drugs by targeting the olfactory region and paranasal sinuses.

[0201] The present application further provides an intravaginal shell or core drug delivery device suitable for administration to the human or animal female. The device may be comprised of the active pharmaceutical ingredient in a polymer matrix, surrounded by a sheath, and capable of releasing the compound or crystalline form in a substantially zero order pattern on a daily basis similar to devises used to apply testosterone as described in PCT Published Patent Application No. WO 98 / 50016.

[0202] Current methods for ocular delivery include topical administration (eye drops), subconjunctival injections, periocular injections, intravitreal injections, surgical implants and iontophoresis (uses a small electrical current to transport ionized drugs into and through body tissues). Those skilled in the art would combine the best suited excipients with the compound or crystalline form provided herein for safe and effective intra-ocular administration.

[0203] The most suitable route will depend on the nature and severity of the condition being treated. Those skilled in the art are also familiar with determining administration methods (e.g., oral, intravenous, inhalation, sub-cutaneous, rectal, etc.), dosage forms, suitable pharmaceutical excipients, and other matters relevant to the delivery of the compounds or crystalline form provided herein to a subject in need thereof.

[0204] Kits

[0205] The present invention also provides kits that contain a pharmaceutical composition which includes one or more compounds or crystalline forms provided herein. The kit also includes instructions for the use of the pharmaceutical composition for inhibiting the activity of voltage-gated sodium channels, preferably Najzl.6, for the treatment of epilepsy, as well as other utilities as disclosed herein. Preferably, a commercial package will contain one or more unit doses of the pharmaceutical composition. For example, such a unit dose may be an amount sufficient for the preparation of an intravenous injection. It will be evident to those of ordinary skill in the art that compounds which are light and / or air sensitive may require special packaging and / or formulation. For example, packaging may be used which is opaque to light, and / or sealed from contact with ambient air, and / or formulated with suitable coatings or excipients.

[0206] EXAMPLES

[0207] The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes and are not intended to limit the invention in any manner. The example compounds, or salts thereof, containing one or more chiral centers were obtained in racemate form or as isomeric mixtures, unless otherwise specified.

[0208] General Methods and Materials

[0209] The following general methods and materials were used during the process described in Example 1.

[0210] X-Ray Powder Diffraction (XRPD):

[0211] The XRPD analysis described in Example 1 was performed on a Rigaku Powder X-Ray Diffractometer Miniflex 600 Serial Number BD70000351-01. For analysis, approximately 0.5-1 mg of sample was added to a XRPD zero-background sample holder. The powder was pressed down gently with a piece of weigh paper, and the sample holder was placed in the sample changer. Run Parameters: Miniflex Counter Detector, Kb Filter (x2), Scan Axis Theta / 2-Theta, Mode Continuous, Start (deg) 2.0, Stop (deg) 45.0, Step (deg) 0.020, Speed (deg / min) 10.0, Spin-yes, Voltage (kV) 40, Current (mA) 15.

[0212] It is understood that peak intensities can vary from one diffractogram to another for the same crystalline form based on any number of factors that are known to those skilled in the art, such as, preferred orientation effects, preparation technique, the sample mounting procedure, the instrument employed, etc. In some instances, peak intensities can be rather dramatical. Accordingly, the diffraction peak intensities shown herein are illustrative and identical diffraction peak intensities are not necessarily required. One skilled in the art would readily be capable of comparing the diffractogram provided herein with a diffractogram generated for an unknown crystal form and confirm whether the diffractogram is characterizing the same crystal form as provided herein or a different form. Thermal Analysis

[0213] The DSC and TGA analyses described in Example 1 were performed on TA Instruments Discovery 2500 calorimeter with serial number: 2500-00547 (DSC) and Discovery 5500 with serial number: 5500-0126 (TGA).

[0214] For TGA analysis, a standard aluminum sample pan was placed into the platinum TGA pan and the blank was tared with the instrument. Approximately 1-5 mg of sample was added to the standard aluminum pan and analyzed at 10 °C / min up to 400 °C.

[0215] For the DSC analysis, obtained and recorded the weight of a Tzero pan and a Tzero lid. ~l-3 mg of sample was weighed into the Tzero Pan and the Tzero lid was pressed on. The pan was transferred to the DSC autosampler for analysis. The method for analysis was a ramp at 10 °C / min to 225 °C. The reference pan was prepared with the same procedures, absent of the sample.

[0216] For DSC and TGA, it is known that the temperatures observed for thermal events will depend upon sample purity and may also depend on the rate of temperature change, as well as sample preparation technique, and the instrument employed. Thus, the values reported herein relating to DSC thermograms can vary by plus or minus 3 °C. For example, “about 151 °C” means 151 °C ± 3 °C. The values reported herein relating to DSC thermograms can also vary by plus or minus 10 joules per gram (z.e., ± 10 joules per gram).

[0217] Microscopy

[0218] Scanning Electron Microscopy (SEM) was used to assess the morphology and particle size. Images were taken using a Phenom ProX scanning electron microscope with serial number MVE052018-0480-S. The samples were added to a section of an SEM mount using carbon conductive double coated tape. The mount was tapped to remove excess particles, then gold sputter coated with a Cressington 108. Imaging was performed at 5kV with an SED detector.

[0219] Particle Size Analysis (PSD)

[0220] The particle size distribution was determined using a Malvern Mastersizer 3000 equipped with a Hydro MV wet dispersion unit. A concentrated stock suspension was prepared at approximately 10 mg / mL using a dispersant of 0.1% (v / v) Tween 80 in water. The stock suspension was added along with the rinsate to the Hydro MV while stirring at 3000 RPM. The d(0.1), d(0.5), and d(0.9) results, as well as the span, were reported.

[0221] The following general methods and materials were used during the process described in Example 2.

[0222] HPLC

[0223] HPLC analyses described in Example 2 were performed using Waters 2695

[0224] Separations module with 2998 Photodiode Array detector, using the parameters provided in Table 1.

[0225] Table 1. NMR & Titrations

[0226] 'H-NMR analyses of Example 2 were performed on Bruker 300 MHz and 500 MHz spectrometers. Karl -Fisher titrations of Example 2 were analyzed on a Metrohm 756 KF coulometer using Hydranal AG reagent. Example 1. Synthesis of Crystalline (5)-4-((l-Benzylpyrrolidin-3-yl)(methyl)amino)-

[0227] 2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide Step 1. 5-Chloro-2,4-dijluoro-N-(4-methoxybenzyl)-N-(thiazol-4- yl) benzenesulfonamide

[0228] N-(4-Methoxybenzyl)thiazol-4-amine (limiting reagent), 1,4-diazabicyclo- [2.2.2]-octane (DABCO) and acetonitrile (MeCN) were charged to a reactor, stirred to dissolve, and the batch was cooled to < 10 °C. 5-Chl oro-2, 4-difluorobenzenesulfonyl chloride was added as a solid or as a solution in MeCN at a rate to keep the internal temperature < 20 °C. The batch was warmed to 20 °C ± 5 °C and stirred. The reaction was checked for completion by HPLC. Upon completion, the batch was quenched with water maintaining an internal batch temperature of 20 °C ± 5 °C and upon complete addition, the product crystallized. The product was isolated by filtration and the solid sequentially washed with 1 : 1 MeCN / water, water, and methanol. The batch was dried to constant weight. A typical yield of 5-chloro-2,4-difluoro-N-(4- methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide was 90%. Step 2. (S)-4-((l-Benzylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(4- methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide

[0229] 5-Chl oro-2, 4-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4- yl)benzenesulfonamide (limiting reagent), DABCO, (5)- 1 -Benzyl -N- methylpyrrolidin-3 -amine (1.1 equiv.), CaCh (needed only if the reaction was performed in a glass lined reactor) and dimethyl sulfoxide (DMSO) were charged to a reactor and the solution degassed with nitrogen. The solution was agitated and heated to 70 °C. The reaction was checked for completion by HPLC. Upon completion, ethyl acetate was added to the reaction, the mixture was cooled and filtered through celite. Water was added to the filtrate. The mixture was stirred, and the aqueous and organic layers were separated. The organic layer was sequentially washed with water followed by 25% aqueous sodium chloride. The organic layer was distilled under vacuum followed by addition of ethyl acetate. The organic layer was again distilled under vacuum followed by the addition of ethyl acetate. The water content of the organic layer was analyzed to be less than 1 wt% before proceeding. The organic layer was heated to approx. 45 °C and dibenzoyl -D-tartaric acid (D-DBTA) plus (S)-4-((l- benzylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(4-methoxybenzyl)-N- (thiazol-4-yl)benzenesulfonamide seed (1 wt%) were added. The mixture was heated to 55 °C ± 5 °C and then cooled to 20 °C ± 5 °C. After mixing at 20 °C ± 5 °C, the product was isolated by filtration and the solid washed with ethyl acetate. The batch was dried to constant weight. A typical yield of (5)-4-((l-benzylpyrrolidin-3- yl)(methyl)amino)-5-chloro-2-fluoro-N-(4-methoxybenzyl)-N-(thiazol-4- yl)benzenesulfonamide was 88%. Step 3. (S)-4-((l-Benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(4-methoxybenzyl)- 5-methyl-N -( thiazol-4-yl) benzenesulfonamide

[0230] The D-DBTA salt of (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-5- chloro-2-fluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide was charged to a reactor followed by ethyl acetate and 1 molar aqueous potassium phosphate tribasic (K3PO4). The mixture was stirred and settled before the aqueous layer was separated from the organic layer. The organic layer was concentrated by vacuum distillation and ethyl acetate is added. The water content of the organic layer was analyzed to be less than 0.5 wt% before proceeding. To the reactor with the solution of (5)-4-((l -benzylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(4- methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide in ethyl acetate was added methyl boronic acid, palladium acetate (0.04 equiv.), 2-dicyclohexylphosphino-2',6'- diisopropoxybiphenyl (RuPhos, 0.08 equiv.), K3PO4, and water. The oxygen in the mixture was removed by at least three vacuum / nitrogen purging cycles and the reactor was placed under a nitrogen atmosphere. The reaction was heated to > 70 °C, and the mixture was stirred. The reaction was checked for completion by HPLC. Once complete, the reaction was cooled to 20 °C ± 5 °C and quenched with water, followed by addition of celite. The solids in the reactor were removed by filtration, and the filtrate was returned to a clean reactor. The aqueous and organic layers were separated, and the organic layer washed with 25% aqueous sodium chloride solution before the aqueous layer was again separated after settling. The organic layer was distilled under vacuum, followed by addition of ethyl acetate. Silicycle thiourea (30 wt%) was added and the mixture was agitated to scavenge palladium. The mixture was filtered, and the filtrate returned to a clean reactor. The organic layer was distilled under vacuum followed by addition of ethyl acetate. The water content of the organic layer was analyzed to be less than 0.5 wt% before proceeding. The organic layer was heated and dib enzoyl-D -tartaric acid (D-DBTA) plus (5)-4-((l-benzylpyrrolidin-3- yl)(methyl)amino)-2-fluoro-N-(4-methoxybenzyl)-5-methyl-N-(thiazol-4- yl)benzenesulfonamide seed (1 wt%) were added. The mixture was agitated at 45 °C ± 5 °C and then cooled to 20 °C ± 5 °C. After mixing at 20 °C ± 5 °C, the product was isolated by filtration and the solid washed with ethyl acetate. The batch was dried to constant weight. A typical yield of (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2- fluoro-N-(4-methoxybenzyl)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide was 80%.

[0231] Step 4. Crystalline (S)-4-((l-Benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl- N-( thiazol-4-yl) benzenesulfonamide

[0232] The D-DBTA salt of (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro- N-(4-methoxybenzyl)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide (limiting reagent) was charged to a reactor followed by dichloromethane and trifluoroacetic acid. The batch temperature was raised to 40 °C ± 5 °C and stirred. Reaction completion was confirmed by HPLC. The batch temperature was lowered to approximately 5 °C and 2-methyltetrahydrofuran (2-MeTHF) was added, maintaining the internal batch temperature < 30 °C. The solution was quenched with aqueous sodium hydroxide to achieve a pH of > 3, the mixture was stirred, and the aqueous and organic layers were settled and separated. The organic layer was sequentially washed with 6 wt% aqueous sodium bicarbonate twice, followed by water. The organic layer was distilled under vacuum, after which tetrahydrofuran (THF) was added. Distillation by adding more THF was repeated until the amount of 2-MeTHF was < 5% v / v by GC analysis. (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2- fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide pTsOH seed crystals (1 wt%) were added to the batch followed by -toluenesulfonic acid monohydrate and the mixture was stirred. The product was isolated by filtration and the solid washed with THF. The batch was then dried to constant weight.

[0233] After the mass of this salt was determined, the solids were returned to a clean reactor followed by 2-MeTHF and 6 wt% aqueous sodium bicarbonate. This mixture was stirred until full dissolution. The aqueous and organic layers were settled and separated before the organic layer was washed with water at least two times to achieve an aqueous pH of 6-8. The organic layer was distilled under vacuum, after which 2-MeTHF was added. The water content was confirmed by Karl Fisher targeting < 0.5 wt% and the 2-MeTHF solution containing the product was filtered through a polish filter into a clean reactor. The organic layer was distilled under vacuum to approx, half of the original volume and ethanol (EtOH) was added to the reactor through a polish filter. The solvent was removed by vacuum distillation to approx, half the original volume and EtOH was added to the reactor through a polish filter. This vacuum distillation and EtOH addition process was continued until the amount of 2-MeTHF present in the EtOH solvent mixture is < 5% v / v by GC. The mixture was granulated before the product was isolated by filtration and the solid washed with EtOH. The batch was dried to constant weight. A typical yield range of crystalline (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N- (thiazol-4-yl)benzenesulfonamide was 60-80%.

[0234] The thermogram provided in FIG. 1 exhibited little-to-no weight loss (-0%) from room temperature out to -125 °C, suggesting the material was anhydrous. A second weight loss was observed (-0.285%) and appears to be associated with the melt which may be due to unbound / trapped solvent. The material exhibited an onset melt of 151.67 °C and enthalpy of fusion of 111.46 J / g. A representative sorpotion isotherm is shown in FIG. 2.

[0235] A representative power X-Ray Power Diffraction (XRPD) pattern is shown in FIG. 3 and Table 2 shows the corresponding peaks and intensities. The XRPD diffractogram in FIG. 3 suggested the sample was crystalline and exhibited a pattern consistent with that of the crystalline form of (k)-4-(( l -benzylpyrrolidin-3- yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide.

[0236] Table 2.

[0237] The primary particles were observed as tabular particles that appeared to be fused to form agglomerates ranging in size of 50-150 pm, as shown in FIG. 4. The primary particles appeared to have sizes ranging from 10-40 pm. A representative image of an individual agglomerate particle is shown in FIG. 5. The average particle size results are provided in Table 3. A representative particle size distribution (PSD) is shown in FIG. 6 and illustrates that the agglomerate size distribution was monomodal and symmetrical.

[0238] Table 3.

[0239] 1. d(O l ) . d(0.5) d(0.9) Span | 42.9 ZZZZZZ 2ZZUZZZ ZZZZZZJ

[0240] Example 2. Alternative Synthesis of crystalline (5)-4-((l-Benzylpyrrolidin-3- yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide

[0241] A 100-L, glass, jacketed reactor equipped with temperature probe and data logger was inerted by N2 flow-through (15 L min'1, 1 h). N-(4- Methoxybenzyl)thiazol-4-amine (3.321 kg, 15.08 mol) was charged to the kettle under N2, followed by DABCO (4.203 kg, 27.61 mol, 1.83 equiv.). The solids were suspended in THF (29.5 kg, p = 0.889 g mL'1, 33.2 L, 10.0 vol); the batch was then warmed to room temperature and stirred at 20 ± 5 °C for 30 min.

[0242] A 40-L, glass carboy was inspected and inerted by N2 flow-through (10 L min' 1 h). 5-Chl oro-2, 4-difluorobenzenesulfonyl chloride (6.481 kg, 26.23 mol, 1.74 equiv.) was charged to the carboy under N2, followed by THF (14.765 kg, p = 0.889 g mL’1, 16.61 L, 5.00 vol). The resulting mixture was stirred for 30 min using a Teflon air-stirrer, rapidly forming a solution. After this period, the contents of the carboy were transferred to the 100-L, jacketed reactor using a calibrated Teflondiaphragm pump. The addition was performed over 1 h 40 min, using jacket cooling to maintain the batch temperature at <25 °C. The batch, a light tan slurry / suspension, was sampled 50 min after the end of addition of 5-chloro-2,4-difluorobenzenesulfonyl chloride and no 5-chloro-2,4-difluorobenzenesulfonyl chloride was detected by HPLC. The contents of the 100-L reactor were aged an additional 12 h 15 min at 20 °C. At this point, the batch was filtered over a 24” Hastelloy Nutsche filter outfitted with polypropylene filter cloth. The cake was conditioned to dryness before applying a series of THF slurry washes (2 x 8.88 kg, p = 0.889 g mL'1, 2 x 9.99 L, 2 x 3.00 vol) to the filter. The cake was conditioned after each wash until the surface was dry and no more liquors eluted from the base of the filter. The filtrand was offloaded from the filter at the end of filtration and weighed (13.173 kg). The 100-L reactor was rinsed with MeOH until visually clean and inerted by N2 flow-through (20 L inin'1, 1 h) before returning the batch to the kettle.

[0243] With the 100-L kettle configured for vacuum distillation, the batch (initial volume = 69 L, 21 vol) was concentrated to 16.5 L (5.0 vol) (100 mg BHT was added to carboy containing pooled distillates, where necessary). The batch became a brown suspension by the end of distillation with a ring of solids just above the solution level of the batch; a small amount of THF (1.0 L, 0.30 vol) was used to rinse the walls of the reactor before measuring the end volume; however, this did not dislodge the shell. MeOH (26.380 kg, p = 0.792 g mL'1, 33.3 L, 10.0 vol) was then dosed into the batch using a calibrated Teflon-diaphragm pump, performing the addition over 2 ’A h at 20 °C. The batch thickened throughout the course of addition, eventually forming a coffee-colored slurry / suspension. The kettle was reconfigured for distillation and the batch (initial volume = 51 L) concentrated to 32 L (9.6 vol); a sample of the supernatant pulled at the end of distillation showed 6.0 mol % THF (vs. MeOH) by 'H-NMR. Additional MeOH (13.160 kg, = 0.792 g mL'1, 16.6 L, 4.99 vol) was added to the batch; the resulting slurry / suspension was stirred 7 h overnight before resuming distillation. The batch was again concentrated, this time to 32.5 L (9.79 vol); at the end of distillation a Teflon stick was used to dislodge the discolored shell on the reactor walls and the walls were rinsed with fresh MeOH (1.205 kg, p = 0.792 g mL’1, 1.52 L, 2.18 vol). IPC of the supernatant showed 3.4 mol % THF, and the solvent-swap was deemed complete (target <4.0 mol % THF). The resulting slurry / suspension was stirred at 20 °C for 10 h 40 min before collecting over a 24” Hastelloy Nutsche filter. MeOH (2 x 5.26 kg, p = 0.792 g mL'1, 2 x 6.64 L, 2 x 2.00 vol) was used to rinse the 100-L reactor and then transferred to the filter as a series of displacement washes. A ring of discolored solids remained deposited on the kettle walls near the 20 L graduation. The wet cake was conditioned under vacuum on the filter for 14 h 45 min before transferring the solids to a set of drying trays. Inspection of the wet cake revealed a bulk white powder mixed with small plates of off-colored solids. (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol- 4-yl)benzenesulfonamide was homogenized and obtained as a white powder after drying in vacuo for 48 h (5.538 kg, 85.3% yield, >99.9 wt %) 'H NMR vs. 2, 3,5,6- tetrachloronitrobenzene, 99.74% AUC, KF = 0.14% H2O.

[0244] Example 3. Representative Analysis Profile of Crystalline (5)-4-((l-benzylpyrrolidin- 3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide

[0245] A representative sample of crystalline (5)-4-((l-benzylpyrrolidin-3- yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide prepared according to the process of Example 1, was analyzed and the profile of Table 4 was observed. NMT = not more than. NLT = “not less then”. RRT = relative retention time. LT = less then.

[0246] Table 4.

[0247] Example 4. In vitro Electrophysiological Assay

[0248] Patch voltage clamp electrophysiology allows for the direct measurement and quantification of block of voltage-gated sodium channels (Na s) and allows the determination of the time- and voltage-dependence of block which has been interpreted as differential binding to the resting, open, and inactivated states of the sodium channel (Hille, B., Journal of General Physiology (1977), 69: 497-515).

[0249] The following patch voltage clamp electrophysiology studies were performed on representative compounds of the invention using human embryonic kidney cells (HEK), permanently transfected with an expression vector containing the full-length cDNA coding for the desired human sodium channel a-subunit, grown in culture media containing 10% FBS, 1% PSG, and 0.5 mg / mL G418 at 37 °C with 5% CO2. HEK cells used for the electrophysiology (EP) recordings had a passage number of less than 40 for all studies and were used within three days from the time of plating. NaH.l, Nad.5 and Nad.6 cDNAs (NM_001165964 (SCN1A), NM_000335 (SCN5A) and NM_014191 (SCN8A), respectively) were stably expressed in HEK- 293 cells.

[0250] Sodium currents were measured using the patch clamp technique in the wholecell configuration using either a Patch Xpress automated voltage clamp or manually using an Axopatch 200B (Axon Instruments) or Model 2400 (A-M systems) amplifier. The manual voltage clamp protocol was as follows: Borosilicate glass micropipettes were fire-polished to a tip diameter yielding a resistance of 2-4 Mohms in the working solutions. The pipette was filled with a solution comprised of 5 mM NaCl, 10 mM CsCl, 120 mM CsF, 0.1 mM CaCh, 2 mM MgCh, 10 mM HEPES, 10 mM EGTA; and adjusted to pH 7.2 with CsOH. The external solution had the following composition: 140 mM NaCl, 5 mM KC1, 2 mM CaCh, 1 mM MgCh, 10 mM HEPES; and adjusted to pH 7.4 with NaOH. In some studies, the external sodium was reduced by equimolar replacement with choline. Osmolarity in the CsF internal and NaCl external solutions was adjusted to 300 mOsm / kg and 310 mOsm / kg with glucose, respectively. All recordings were performed at ambient temperature in a bath chamber with a volume of 150 pL. Control sodium currents were measured in 0.5% DMSO. Controls and representative compounds of the invention were applied to the recording chamber through a 4-pinch or 8-pinch valve bath perfusion system manufactured by ALA Scientific Instruments.

[0251] Currents were recorded at 40 kHz sampling frequency, filtered at 5 Hz, and stored using a Digidata-1322A analogue / digital interface with the pClamp software (Axon Instruments). Series resistance compensation was applied (60-80%). Cells were rejected if currents showed inadequate voltage control (as judged by the IV relationship during stepwise activation). All statistics in this study are given as mean ± SD.

[0252] The membrane potential was maintained at a voltage where inactivation of the channel is complete. The voltage is then stepped back to a very negative (Vhold = - 150mV) voltage for 20 ms and then a test pulse is applied to quantify the compound block. The 20 ms brief repolarization was long enough for compound-free channels to completely recover from fast inactivation, but the compound-bound channels recovered more slowly such that negligible recovery could occur during this interval. The percent decrease in sodium current following wash-on of compound was taken as the percent block of sodium channels. Example 5. In Vitro Sodium Influx Assay

[0253] This sodium influx assay employs the use of the cell permeable, sodium sensitive dye ANG2 to quantify sodium ion influx through sodium channels which are maintained in an open state by use of sodium channel modulators. This high throughput sodium influx assay allows for rapid profiling and characterization of sodium channel blockers.

[0254] In general, Trex HEK293 cells were stably transfected with an inducible expression vector containing the full-length cDNA coding for the desired human sodium channel a-subunit and with an expression vector containing full length cDNA coding for the pi -subunit. Sodium channel expressing cell lines were induced with tetracycline (Ipg / mL) and plated on 384-well PDL-coated plates at a density of 25K- 30K cells / well in culture media (DMEM, containing 10% FBS and 1% L-glutamine). After overnight incubation (37 °C, 5% CO2), culture media was removed and cells were loaded with 5pM ANG2 dye for 1 -1.5h in Buffer 1 (155 mM NMDG, 5 mM KC1, 2 mM CaCh, 1 mM MgCh, 10 mM HEPES, 10 mM glucose, adjusted with Tris to pH 7.4). Access dye was removed, and cells were incubated with test compounds for Ihr in buffer 1 containing sodium channel modulator(s) at room temperature. Hamamatsu FDSS pCell was used to perform a 1 : 1 addition of Na / K challenge buffer (140 mM NaCl, 20 mM HEPES, 1 mM CaCh, 15 mM KC1, 1 mM MgCh, 10 mM glucose, adjusted with Tris to pH 7.4) and simultaneously read plates at excitation wavelength of 530 nm and emission wavelength set at 558 nm. Percent inhibition of sodium ion influx was calculated for each test compound at each test concentration to determine the IC50 values.

[0255] (5)-4-((l-Benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol- 4-yl)benzenesulfonamide, when tested in the models of Examples 4-5, demonstrated the following IC50S provided in Table 5. “Flux” refers to the Sodium Influx Assay of example 5 and “EP” refers to the Electrophysiological Assay of example 4.

[0256] Table 5. Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patents, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.

Claims

WHAT IS CLAIMED IS:

1. A process, comprising reacting a compound of Formula II:II or a salt thereof, under a deprotection condition to afford a compound of Formula I:I or a salt thereof, wherein PG1is an amine protecting group.

2. The process of claim 1, wherein PG1is / ?-methoxybenzyl.

3. The process of claim 1 or 2, wherein the deprotection condition comprises reacting the compound of Formula II, or a salt thereof, with an organic acid.

4. The process of claim 3, wherein the organic acid is trifluoroacetic acid.

5. The process of any one of claims 1 to 4, wherein the deprotection is performed in a solvent comprising dichloromethane.

6. The process of any one of claims 3 to 5, wherein the deprotection is performed at a temperature of from about 35°C to about 45°C.

7. The process of any one of claims 1 to 6, further comprising reacting the compound of Formula I, or a salt thereof, with a strong base to form the free base form of the compound of Formula I.

8. The process of claim 7, wherein the strong base is sodium hydroxide.

9. The process any one of claims 1 to 8, wherein the compound of Formula II is a compound of Formula Ila:or a salt thereof.

10. The process of any one of claims 7 to 9, further comprising reacting the free base form of the compound of Formula I with / ?-toluenesulfonic acid to form a -toluenesulfonic acid salt of the compound of Formula I.

11. The process of claim 10, further comprising reacting the / ?-toluenesulfonic acid salt of the compound of Formula I with a base to form the free base form of the compound of Formula I.

12. The process of claim 11, wherein the base is sodium bicarbonate.

13. The process of claim 11 or 12, further comprising crystallizing the free base form of the compound of Formula I to afford crystalline (5)-4-((l- benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4- yl)benzenesulfonamide.

14. The process of claim 13, wherein the crystalline (5)-4-((l-benzylpyrrolidin-3- yl)(rnethyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide is crystallized from a solvent comprising ethanol.

15. The process of any one of claims 11 to 14, wherein the compound of Formula II, or a salt thereof, is prepared by reacting a compound of Formula III:III or a salt thereof, under a Suzuki coupling condition to form the compound of Formula II, or a salt thereof.

16. The process of claim 15, wherein the Suzuki coupling condition comprises heating a reaction mixture comprising the compound of Formula III, a Suzuki coupling catalyst, methylboronic acid, a base, and a solvent component.

17. The process of claim 16, wherein the Suzuki coupling catalyst comprises palladium (II) acetate and 2-dicyclohexylphosphino-2',6'- diisopropoxybiphenyl.

18. The process of claim 16 or 17, wherein the base is potassium phosphate.

19. The process of any one of claims 16 to 18, wherein the solvent comprises ethyl acetate.

20. The process of any one of claims 15 to 19, wherein the compound of FormulaIll is a compound of Formula Illa:Illa or a salt thereof.

21. The process of any one of claims 15 to 20, further comprising reacting the compound of Formula II, or a salt thereof, with 2,3-dibenzoyl-D-tartaric acid to form a 2,3-dibenzoyl-D-tartaric acid salt of the compound of Formula II.

22. The process of any one of claims 15 to 21, wherein the compound of Formula III, or a salt thereof, is prepared by reacting a compound of Formula IV:or a salt thereof, with a compound of Formula V:or a salt thereof, under a S\Ar reaction condition to afford the compound of Formula III, or a salt thereof.

23. The process of claim 22, wherein the S\Ar reaction conditions comprise reacting the compound of Formula IV and the compound of Formula V in the presence of a coupling agent and a solvent.

24. The process of claim 23, wherein the coupling agent is 1,4-diazabicyclo- [2.2.2]-octane.

25. The process of claim 23 or 24, wherein the solvent comprises dimethyl sulfoxide.

26. The process of any one of claims 22 to 25, wherein the S\Ar reaction is performed at a temperature of from about 65°C to about 75°C.

27. The process of any one of claims 22 to 26, wherein the compound of Formula IV is a compound of Formula IVa:IVa or a salt thereof.

28. The process of any one of claims 22 to 27, further comprising reacting the compound of Formula III, or a salt thereof, with 2,3-dibenzoyl-D-tartaric acid to form a 2,3-dibenzoyl-D-tartaric acid salt of the compound of Formula III.

29. The process of any one of claims 22 to 28, wherein the compound of FormulaIV is prepared by reacting a compound of Formula VI:VI or a salt thereof, with 5-chloro-2,4-difluorobenzenesulfonyl chloride under a coupling condition to afford to the compound of Formula IV, or a salt thereof.

30. The process of claim 29, wherein the coupling condition comprises reacting the compound of Formula VI and 5-chloro-2,4-difluorobenzenesulfonyl chloride in the presence of a coupling agent and a solvent.

31. The process of claim 30, wherein the coupling agent is 1,4-diazabicyclo- [2.2.2]-octane.

32. The process of claim 30 or 31, wherein the solvent comprises acetonitrile.

33. The process of any one of claims 29 to 32, wherein the coupling is performed at a temperature of from about 0°C to about 30°C.

34. The process of any one of claims 29 to 33, wherein the compound of Formula VI is a compound of Formula Via:or a salt thereof.

5. A process comprising reacting a compound of Formula Via:with 5-chloro-2,4-difluorobenzenesulfonyl chloride under a coupling condition to afford a compound of Formula IVa:reacting the compound of Formula IVa with a compound of Formula V:or a salt thereof, under a S\Ar reaction condition to afford the compound of Formula Illa:or a salt thereof; reacting the compound of Formula Illa, or a salt thereof, under a Suzuki coupling condition to form a compound of Formula Ila:or a salt thereof; reacting the compound of Formula Ila, or a salt thereof, under a deprotection condition to afford the compound of Formula I:I or a salt thereof; reacting the compound of Formula I, or a salt thereof, with sodium hydroxide to form the free base form of the compound of Formula I; reacting the free base form of the compound of Formula I with p- toluenesulfonic acid to form a -toluenesulfonic acid salt of the compound of Formula I; reacting the -toluenesulfonic acid salt of the compound of Formula I with sodium bicarbonate to form the free base form of the compound of Formula I; and crystallizing the free base form of the compound of Formula I to afford crystalline (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl- N-(thiazol-4-yl)benzenesulfonamide.

36. The process of claim 35, wherein the crystallization is carried out in a solvent comprising ethanol.

37. A crystalline form of (S)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2- fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide (compound of Formula I) prepared by a process according to any one of claims 1 to 36.

38. A crystalline form of (S)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2- fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide (compound of Formula I).

39. The crystalline form of claim 37 or 38, characterized by a DSC thermogram having an endothermic peak at about 151°C.

40. The crystalline form of claim 37 or 38, characterized by a DSC thermogram substantially as shown in FIG. 1.

41. The crystalline form of any one of claims 37 to 40, characterized by a TGA thermogram with no substantial weight loss from room temperature to about 125 °C.

42. The crystalline form of any one of claims 37 to 40, characterized by a TGA thermogram with a weight loss of <0.3% up to about 170 °C.

43. The crystalline form of any one of claims 37 to 40, characterized by a TGA thermogram substantially as shown in FIG. 1.

44. The crystalline form of any one of claims 37 to 43, having at least one XRPD peak, in terms of 2-theta, selected from 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°.

45. The crystalline form of any one of claims 37 to 43, having at least two XRPD peaks, in terms of 2-theta, selected from 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°.

46. The crystalline form of any one of claims 37 to 43, having at least three XRPD peaks, in terms of 2-theta, selected from 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°.

47. The crystalline form of any one of claims 37 to 43, having three XRPD peaks, in terms of 2-theta, at 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°.

48. The crystalline form of any one of claims 37 to 43, having three XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°.

49. The crystalline form of any one of claims 37 to 43, having three XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, and 21.7°± 0.2°.

50. The crystalline form of any one of claims 37 to 43, having three XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, and 17.7°± 0.2°.

51. The crystalline form of any one of claims 37 to 43, having four XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°.

52. The crystalline form of any one of claims 37 to 43, having an XRPD profile substantially as shown in FIG. 3.

53. A crystalline form of (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2- fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide, having at least one characterization selected from the group consisting of:(1) an XRPD profile substantially as shown in FIG. 3,(2) a DSC thermogram substantially as shown in FIG. 1, and(3) a TGA thermogram substantially as shown in FIG. 1.

54. A crystalline form of (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2- fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide, having at least one characterization selected from the group consisting of:(1) at least one XRPD peak, in terms of 2-theta, selected from 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°,(2) a DSC thermogram having an endothermic peak at about 151°C, and(3) a TGA thermogram with no substantial weight loss from room temperature to about 125 °C.

55. A crystalline form of (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2- fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide, having at least one characterization selected from the group consisting of:(1) at least two XRPD peak, in terms of 2-theta, selected from 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°,(2) a DSC thermogram having an endothermic peak at about 151°C, and(3) a TGA thermogram with no substantial weight loss from room temperature to about 125 °C.

56. A crystalline form of (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2- fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide, having at least one characterization selected from the group consisting of:(1) at least two XRPD peaks, in terms of 2-theta, selected from 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°,(2) a DSC thermogram having an endothermic peak at about 151°C, and(3) a TGA thermogram with a weight loss <0.3% up to about 170 °C.

57. A crystalline form of (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2- fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide, having at least one characterization selected from the group consisting of:(1) at least three XRPD peaks, in terms of 2-theta, selected from 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°,(2) a DSC thermogram having an endothermic peak at about 151°C, and(3) a TGA thermogram with no substantial weight loss from room temperature to about 125 °C.

58. A crystalline form of (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2- fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide, having at least one characterization selected from the group consisting of:(1) three XRPD peaks, in terms of 2-theta, at 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°,(2) a DSC thermogram having an endothermic peak at about 151°C, and(3) a TGA thermogram with no substantial weight loss from room temperature to about 125 °C.

59. A crystalline form of (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2- fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide, having at least one characterization selected from the group consisting of:(1) three XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°,(2) a DSC thermogram having an endothermic peak at about 151°C, and(3) a TGA thermogram with no substantial weight loss from room temperature to about 125 °C.

60. A crystalline form of (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2- fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide, having at least one characterization selected from the group consisting of:(1) three XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, and 17.7°± 0.2°,(2) a DSC thermogram having an endothermic peak at about 151°C, and(3) a TGA thermogram with no substantial weight loss from room temperature to about 125 °C.

61. A crystalline form of (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2- fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide, having at least one characterization selected from the group consisting of:(1) three XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, and 21.7°± 0.2°,(2) a DSC thermogram having an endothermic peak at about 151°C, and(3) a TGA thermogram with no substantial weight loss from room temperature to about 125 °C.

62. A crystalline form of (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2- fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide, having at least one characterization selected from the group consisting of:(1) four XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°,(2) a DSC thermogram having an endothermic peak at about 151°C, and(3) a TGA thermogram with no substantial weight loss from room temperature to about 125 °C.

63. The crystalline form according to any one of claims 53 to 62, wherein the crystalline form has characterization (1).

64. The crystalline form according to any one of claims 53 to 62, wherein the crystalline form has characterization (2).

65. The crystalline form according to any one of claims 53 to 62, wherein the crystalline form has characterization (3).

66. The crystalline form according to any one of claims 53 to 62, wherein the crystalline form has characterizations (1) and (2).

67. The crystalline form according to any one of claims 53 to 62, wherein the crystalline form has characterizations (1) and (3).

68. The crystalline form according to any one of claims 53 to 62, wherein the crystalline form has characterization (2) and (3).

69. The crystalline form according to any one of claims 53 to 62, wherein the crystalline form has characterizations (1), (2) and (3).

70. The crystalline form of any one of claims 37 to 69, having at least 97% purity of (S)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N- (thiazol-4-yl)benzenesulfonamide as determined by HPLC.

71. The crystalline form of any one of claims 37 to 69, having at least 98% purity of (S)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N- (thiazol-4-yl)benzenesulfonamide as determined by HPLC.

72. The crystalline form of any one of claims 37 to 69, having at least 99% purity of (S)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N- (thiazol-4-yl)benzenesulfonamide as determined by HPLC.

73. The crystalline form of any one of claims 37 to 72, further comprising impurity A, represented by the following structural formula:Impurity A in an amount of no more than about 0.5%.

74. The crystalline form of claim 73, comprising at least about 0.1% of impurityA.

75. The crystalline form of claim 73 or 74, comprising about 0.4% of impurity A.

76. The crystalline form of any one of claims 37 to 75, further comprising no more than about 0.5% of impurity B, represented by the following structural formula:

77. The crystalline form of claim 76, comprising an undetectable level of impurityB.

78. The crystalline form of any one of claims 37 to 77, further comprising impurity C, wherein impurity C has an exact mass of 904, in an amount of no more than about 0.5%.

79. The crystalline form of claim 78, comprising at least about 0.05% of impurityC.

80. The crystalline form of claim 78 or 79, comprising about 0.1% of impurity C.

81. The crystalline form of any one of claims 73 to 80, wherein the level of impurity is determined by HPLC by comparing the peak area of said impurity to the total peak area.

82. The crystalline form of any one of claims 37 to 81, comprising less than 30 ppm of dichloromethane.

83. The crystalline form of any one of claims 37 to 82, comprising less than 72 ppm of tetrahydrofuran.

84. The crystalline form of any one of claims 37 to 83, comprising about 1% by weight of ethanol.

85. The crystalline form of any one of claims 37 to 84, comprising about 1% by weight of solvent.

86. A composition comprising: (S)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol- 4-yl)benzenesulfonamide; and at least one impurity selected from the group consisting of impurities A, B, and C; wherein impurities A and B are represented by formulae:and wherein impurity C has an exact mass of 904.

87. The composition of claim 86, wherein (S)-4-((l-benzylpyrrolidin-3- yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide is crystalline.

88. The composition of claim 87, wherein the crystalline form is characterized by a DSC thermogram having an endothermic peak at about 151°C.

89. The composition of any one of claims 87 or 88, wherein the crystalline form is characterized by a TGA thermogram with a weight loss of <0.3% at about 170 °C.

90. The composition of any one of claims 87-89, wherein the crystalline form is characterized by at least one XRPD peak, in terms of 2-theta, selected from 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°.

91. The composition of any one of claims 87-89, wherein the crystalline form is characterized by at least two XRPD peaks, in terms of 2-theta, selected from 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°.

92. The composition of any one of claims 87-89, wherein the crystalline form is characterized by at least three XRPD peaks, in terms of 2-theta, selected from 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°.

93. The composition of any one of claims 87-89, wherein the crystalline form is characterized by four XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°.

94. The composition of any one of claims 87-89, wherein the crystalline form is characterized by three XRPD peaks, in terms of 2-theta, at 16.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°.

95. The composition of any one of claims 87-89, wherein the crystalline form is characterized by three XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 17.7°± 0.2°, and 21.7°± 0.2°.

96. The composition of any one of claims 87-89, wherein the crystalline form is characterized by three XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, and 21.7°± 0.2°.

97. The composition of any one of claims 87-89, wherein the crystalline form is characterized by three XRPD peaks, in terms of 2-theta, at 13.4°± 0.2°, 16.4°± 0.2°, and 17.7°± 0.2°.

98. The composition of claim 86, wherein (S)-4-((l-benzylpyrrolidin-3- yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide is amorphous.

99. The composition of any one of claims 86 to 98, comprising about 0.4% of impurity A as determined by HPLC by comparing the peak area of impurity A to the total peak area.

100. The composition of any one of claims 86 to 98, comprising an undetectable level of impurity B by HPLC.

101. The composition of any one of claims 86 to 98, comprising about 0.1% of impurity C as determined by HPLC by comparing the peak area of impurity C to the total peak area.

102. A pharmaceutical composition comprising a composition according to any one of claims 86 to 101 and at least one pharmaceutically acceptable excipient.

103. A compound or a salt of Formula IIIHI, wherein PG1is an amine protecting group.

104. A dibenzoyl-D-tartaric acid (D-DBTA) salt of Formula IllaIlla.

105. A compound or a salt of Formula IIwherein PG1is an amine protecting group.

106. A dibenzoyl-D-tartaric acid (D-DBTA) salt of Formula Ila107. Use of a compound or a salt according to any one of claims 103 to 106 for the preparation of a compound of Formula I.

108. A method of treating a disease or a condition associated with NapT.6 activity in a subject, comprising administering to the subject a crystalline form of any one of claims 37 to 85, or a composition according to any one of claims 86 to 101, or a pharmaceutical composition according to claim 102.

109. Use of a crystalline form of (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2- fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide according to any one of claims 37 to 85 for the manufacture of a medicament for the treatment of a disease or a condition associated with Najzl.6 activity in a subject.

110. A crystalline form of (5)-4-((l-benzylpyrrolidin-3-yl)(methyl)amino)-2- fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide according to any one of claims 37 to 85 or a composition comprising (5)-4-((l-benzylpyrrolidin-3- yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide according to any one of claims 84 to 101 , or a pharmaceutical composition according to claim 102 for use in the treatment of a disease or a condition associated with Najzl.6 activity in a subject.

111. The method or use of any one of claims 107 to 110, wherein the disease or condition is epilepsy or epileptic seizure disorder.

112. The method or use of any one of claims 107 to 110, wherein the disease or condition is epilepsy.

113. The method or use of any one of claims 107 to 110, wherein the disease or condition is epileptic seizure disorder.

114. The method or use of any one of claims 107 to 110, wherein the disease or condition is SCN8A developmental and epileptic encephalopathy (SCN8A- DEE).

115. The method of or use of any one of claims 107 to 110, wherein the disease or condition is focal onset seizure.

116. The method or use of claim 115, wherein the focal onset seizure is adult focal onset seizure.

117. The method of or use of any one of claims 107 to 110, wherein the disease or condition is a bipolar disorder.

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