Dosage forms and crystalline forms of a NEK7 degrader

Abstract

Disclosed herein are dosage forms comprising a NEK7 degrader which is N-(3,5- dichloro-4-(2,6-dioxopiperidin-3-yl)benzyl)-2-methyl-2-(5-methylpyrimidin-2-yl)- propanamide or a pharmaceutically acceptable salt thereof. These dosage forms are useful, e.g., for treating a subject (e.g., a human subject) having a disorder or disease associated with NLRP3 inflammasome activation. Also disclosed herein are polymorphic forms of the NEK7 degrader. For instance, disclosed herein are crystalline forms of the NEK7 degrader N-(3,5- dichloro-4-(2,6-dioxopiperidin-3-yl)benzyl)-2-methyl-2-(5-methylpyrimidin-2-yl)- propanamide or a pharmaceutically acceptable salt thereof. These crystalline forms are useful, e.g., in the manufacturing and processing of drug products and / or for the preparation of dosage forms.

Description

[0001] DOSAGE FORMS AND CRYSTALLINE FORMS OF A NEK7 DEGRADER TECHNICAL FIELD

[0002] Disclosed herein are dosage forms comprising a chemical entity (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrades and / or otherwise inhibits NIMA Related Kinase 7 (NEK7). More specifically, disclosed herein are dosage forms comprising the NEK7 degrader JV-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)benzyl)-2-methyl-2-(5-methylpyrimidin-2-yl)-propanamide or a pharmaceutically acceptable salt thereof. These dosage forms are useful, e.g., for treating a subject (e.g., a human subject) having a disorder or disease associated with NLRP3 inflammasome activation.

[0003] Also disclosed herein are crystalline forms of a chemical entity (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrades and / or otherwise inhibits NIMA Related Kinase 7 (NEK7). More specifically, disclosed herein are crystalline forms of the NEK7 degrader JV-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)benzyl)-2-methyl-2-(5-methylpyrimidin-2-yl)-propanamide or a pharmaceutically acceptable salt thereof. These crystalline forms are useful, e.g., in the manufacturing and processing of drug products and / or for the preparation of dosage forms.

[0004] BACKGROUND

[0005] The ubiquitin proteasome system can be manipulated with different small molecules to trigger targeted degradation of specific proteins of interest. Promoting the targeted degradation of pathogenic proteins using small molecule degraders is emerging as a new modality in the treatment of diseases. One such modality relies on redirecting the activity of E3 ligases such as cereblon (a phenomenon known as E3 reprogramming) using low molecular weight compounds, which have been termed molecular glues to promote the poly-ubiquitination and ultimately proteasomal degradation of new protein substrates involved in the development of diseases. The molecular glues bind to both the E3 ligase and the target protein, thereby mediating an alteration of the ligase surface and enabling an interaction with the target protein. Particularly relevant compounds for the E3 ligase cereblon (CRBN) are the IMiD (immunomodulatory imide drugs) class including Thalidomide, Lenalidomide and Pomalidomide. These IMiDs have been approved by the FDA for use in hematological cancers. However, compounds for efficiently targeting other diseases are still required.

[0006] Inflammasomes are multi-protein complexes whose activation plays a central role in innate immunity and inflammation. NLR family pyrin domain containing 3 (NLRP3) inflammasome activation occurs in response to infectious or cell damage-related stress, and acts to initiate or amplify inflammation. The NLRP3 inflammasome is composed of NLRP3, ASC, and caspase-I, which, when activated forms an intracellular complex that cleaves gasdermin D and the cytokines IL-ip and IL- 18 to release their active forms1,2. Cleavedgasdermin D then forms pores in the cell membrane, which allows the release of active IL-ip and IL- 18 and, in most cases, the rupture of the cell membrane in a highly inflammatory process known as pyroptosis3. NLRP3 activation and the resultant IL-i produced is known to contribute to many settings of inappropriate or unwanted inflammation that is associated with autoinflammatory and autoimmune disease4,5. NEK7 is a serine / threonine kinase and a member of the family of NIMA-related kinases (NEKs) that are associated with mitotic entry, cell cycle progression, cell division, and mitotic progression. NEK7 is expressed in a variety of tissues and acts as an NLRP3 -binding protein to facilitate a conformational change that allows oligomerization and formation of the active NLRP3 inflammasome complex6.

[0007] The NEK7 -targeted molecular glue degrader (MGD) described herein, Compound A, induces an interaction between CRBN and NEK7 and the subsequent proteasome-mediated degradation of NEK7. Although NEK7 is a kinase, its role in the NLRP3 inflammasome is independent of its kinase activity7. The degradation of NEK7 allows for removal of the entire protein, thereby eliminating its key scaffolding function and leading to disruption of NLRP3 pathway activation.

[0008] References:

[0009] 1. Fu J & Wu H. Structural mechanisms of NLRP3 inflammasome assembly and activation. Ann Rev Immunol. 2023; 41:301-316

[0010] 2. McKee CM & Coll RC. NLRP3 inflammasome priming: A riddle wrapped in a mystery inside an enigma. J Leuk Biol. 2020; 108:937-952

[0011] 3. Devant P & Kagan JC. Molecular mechanisms of gasdermin D pore-forming activity.

[0012] Nat Immunol. 2023; 24:1064-1075

[0013] 4. Mangan MSJ, Olhava EJ, Roush WR, Seidl HM, Glick GD, Latz E. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov. 2018; 17:588-606

[0014] 5. Mullard A. NLRP3 inhibitors stoke anti-inflammatory ambitions. Nat Rev Drug Discov. 2019; 18:405-407

[0015] 6. Sharif H, Wang L, Wang WL, Magupalli VG, Andreeva L, Qiao Q, Hauenstein AV, Wu Z, Nunez G, Mao Y, Wu H. Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome. Nature 2019; 570(7761):338-343

[0016] 7. He, Y., Zeng M. Y., Yang D., Motro B., Nunez G. NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature. 2016 Feb 18 2016;530(7590):354-7. doi:10.1038 / naturel6959

[0017] PCT / US2024 / 039292 discloses chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrade and / or otherwise modulate (e.g., inhibit) NIMA Related Kinase 7 (NEK7). These chemical entities are useful, e.g., for treating a subject (e.g., a human subject) having one or more disorders or diseases associated withNLRP3 inflammasome activation. Said disorders or diseases include but are not limited to, autoinflammatory and autoimmune disorders (e.g., gout, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis), neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson’s disease), cardiovascular and metabolic disorders (eg. pericarditis, atherosclerosis, Type 2 diabetes, obesity and metabolic syndrome), fibrotic disorders (e.g. interstitial lung disease, chronic kidney disease), hematology (eg. anemia of inflammation) and eye disorders (eg. macular degeneration). In embodiments, and while not wishing to be bound by theory, it is believed that the chemical entities described therein directly target (e.g., directly bind to) NEK7, thereby altering (e.g., attenuating) the inflammatory response modulated by the NLRP3 inflammasome.

[0018] Amongst the chemical entities disclosed in PCT / US2024 / 039292 is A-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)benzyl)-2-methyl-2-(5-methylpyrimidin-2-yl)-propanamide. This compound is described herein as Compound A. Compound A has the following structure:

[0019]

[0020] There is a need for dosage forms of Compound A that can be used to administer Compound A to a subject. Ideally, such dosage forms will have advantageous characteristics such as long-term physical and chemical stability, uniformity, and suitability to facilitate delivery of the active ingredient to the target site in the subject to whom the dosage form is to be administered, for example a suitable dissolution profile. Dosage form design can also contribute to improved bioavailability of the active ingredient. There is also a need for crystalline forms of Compound A, and its pharmaceutically acceptable salts, that aid the preparation of dosage forms. Ideally, such crystalline forms will have advantageous characteristics such as a morphology that results in good filterability and ease of drying, high solubility in solvents used in the preparation of dosage forms, and acceptable stability and purity.

[0021] SUMMARY

[0022] The invention provides solid dosage forms comprising Compound A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein Compound A is a compound of the following formula:

[0023]

[0024] In some embodiments, the solid dosage form is for oral administration.

[0025] In some embodiments, the solid dosage form comprises a solid dispersion comprising Compound A and a polymer. In some embodiments, the polymer is hydroxy propyl methyl cellulose acetate succinate (HPMCAS). In some embodiments, the solid dispersion comprises Compound A and the polymer at a ratio of between 1:5 and 1:1 by weight, such as 1 :3 by weight. In some embodiments, the solid dispersion comprises Compound A and the polymer at a ratio of 1:3 by weight and the polymer is hydroxy propyl methyl cellulose acetate succinate (HPMCAS).

[0026] In some embodiments, the solid dosage form is a capsule, such as a hard capsule. In some embodiments, the capsule contains a fill composition comprising Compound A and a pharmaceutically acceptable excipient. In some embodiments, the fill composition comprises (i) Compound A, (ii) a filler, (iii) a disintegrant, and (iv) a lubricant.

[0027] In some embodiments, the amount of Compound A in the solid dosage form is between 0.1 mg and 500 mg, preferably between 1 mg and 100 mg, more preferably between 2 mg and 60 mg.

[0028] Also provided herein is a solid dispersion comprising Compound A, or a pharmaceutically acceptable salt thereof, and a polymer. In some embodiments, the polymer is hydroxy propyl methyl cellulose acetate succinate (HPMCAS). In some embodiments, the solid dispersion comprises Compound A and the polymer at a ratio of between 1:5 and 1:1 by weight, such as 1:3 by weight. In some embodiments, the solid dispersion comprises Compound A and the polymer at a ratio of 1 :3 by weight and the polymer is hydroxy propyl methyl cellulose acetate succinate (HPMCAS).

[0029] Also provided herein are processes for preparing the spray dried dispersion and processes for preparing the solid dosage form. In some embodiments, the process comprises spray drying a solution comprising Compound A, or a pharmaceutically acceptable salt thereof, to form a solid dispersion. In some embodiments, the solvent is a mixture of water and acetone, for example water and acetone at a ratio of between 1 : 6 to 1 : 12 (w / w).

[0030] Also provided herein are crystalline forms of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the crystalline form is selected from:

[0031] (i) Form I, characterised by a DSC profile comprising a major endotherm with peak temperature at around (±1.0) 192.7 °, and / or characterised by an XRPD pattern with atleast the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 7.0, 9.9, 16.6, 18.9, 26.5, and 28.0;

[0032] (ii) Form II, characterised by a DSC profile comprising a major endotherm with peak temperature at around (±1.0) 204.5 °, and / or characterised by an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 6.9, 9.8, 15.1, 16.6, 20.5, and 27.7;

[0033] (iii)Form III, characterised by an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 8.3, 9.0, 9.7, 13.2, 14.3, and 24.6;

[0034] (iv) Form IV, characterised by an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 9.0, 13.6, 14.5, 18.4, 20.2, and 21.1;

[0035] (v) Compound A HC1 co-Form V, characterised by an XRPD pattern with at least the following XRPD peaks at approximately (± 0.2): 20 (°) = 7.3, 11.3, 14.5, 18.3, 22.5, and 26.7; and

[0036] (vi) Compound A HC1 co-Form VI, characterised by an XRPD pattern with at least the following XRPD peaks at approximately (± 0.2): 20 (°) = 10.6, 12.0, 15.4, 21.3, 23.2, and 27.4.

[0037] In some embodiments, the crystalline form is further characterised by (i) its DSC profile, (ii) its TGA thermogram, (iii) its unit cell parameters, (iv) being obtainable from a certain solvent, and combinations of (i)-(iv).

[0038] In some embodiments, the crystalline form is Form III.

[0039] Also provided herein are methods of treating a disorder caused by or associated with NLRP3 inflammasome activation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a solid dosage form or a crystalline form described herein.

[0040] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1A depicts caspase-1 activity in the supernatant following treatment of human monocyte-derived macrophages with different doses of Compound A or selnoflast measured as a percentage relative to mean values in DMSO.

[0041] FIG. IB depicts IL-ip activity in the supernatant following treatment of human monocyte-derived macrophages with different doses of Compound A or selnoflast measured as a percentage relative to mean values in DMSO.

[0042] FIG. 2 depicts the spray dried dispersion (SDD) dissolution performance compared to Compound A (Form III).

[0043] FIG. 3 depicts the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) profiles of Form I.

[0044] FIG. 4 depicts the X-ray powder diffraction (XRPD) pattern of Form I.FIG. 5 depicts the DSC and TGA profiles of Form II.

[0045] FIG. 6 depicts the XRPD pattern of Form II.

[0046] FIG. 7 depicts the DSC and TGA profiles of Form III.

[0047] FIG. 8 depicts the XRPD pattern of Form III.

[0048] FIG. 9 depicts the DSC and TGA profiles of Form IV.

[0049] FIG. 10 depicts the XRPD pattern of Form IV.

[0050] FIG. 11 depicts the DSC and TGA profiles of Compound A HC1 co-Form V.

[0051] FIG. 12 depicts the XRPD pattern of Compound A HC1 co-Form V.

[0052] FIG. 13 depicts the DSC and TGA profiles of Compound A HC1 co-Form VI.

[0053] FIG. 14 depicts the XRPD pattern of Compound A HC1 co-Form VI.

[0054] FIG. 15 depicts polarised light microscopy (PLM) images of Form II and Form III.

[0055] DETAILED DESCRIPTION

[0056] Additional details of one or more embodiments of the invention are set forth in the description below. Other features and advantages of the dosage forms, crystalline forms, and methods featured herein will be apparent from the description and the claims.

[0057] All documents incorporated by reference in their entirety.

[0058] Definitions

[0059] As used herein, a “NEK7 degrader” refers to a chemical entity (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrades NIMA Related Kinase 7 protein (NEK7). A NEK7 degrader may bind to a specific amino acid sequence of a NEK7 protein and mediate the interaction of the NEK7 protein with an E3 ligase, thereby increasing degradation of the NEK7 protein. The NEK7 degrader is a therapeutically effective compound. The NEK7 degrader may be provided in any pharmaceutically acceptable form, for instance in free form, or as a pharmaceutically acceptable salt (including co-crystal), solvate, cocrystal, enantiomer, prodrug and / or metabolite thereof.

[0060] Compounds described herein may exist in one or more stereoisomeric forms. In some cases, such forms may be described through an assignment of absolute configuration, whereas other cases, stereochemistry is unknown and may be assigned arbitrarily to isolated stereoisomers. Isolation of stereoisomers may be conducted using chiral separation.

[0061] The disclosure of Compound A without its stereoisomeric form indicated encompasses the isolated enantiomer and a mixture, such as a racemic mixture. Specifically,

[0062]

[0063] mixture of the two stereoisomers.

[0064] Moreover, Compounds described herein having one enantiomeric form may epimerise into the other enantiomeric form if the chiral center is in a position susceptible to epimerization (for instance on the 3-position of the piperidine-2, 6-dione ring). Thus, unless it is specifically stated or the context indicates otherwise, disclosure of one stereoisomer with a chiral centre encompasses the isolated stereoisomer and a mixture, such as a racemic mixture, of the (R) and (S) stereoisomers if the stereoisomers epimerise. For example, a

[0065]

[0066] encompasses both isolated

[0067]

[0068] . As used herein, the term “comprising” is in inclusive term which indicates that certain elements are included in an embodiment, but does not exclude the presence of other elements. The terms “comprising”, “including”, and “containing” are used interchangeably herein. Conversely, the term “consisting of’ would exclude the presence of elements other than those recited. The term “consisting essentially of’ indicates that further elements may be included in the embodiment to the extent that these further elements do not materially alter the fundamental characteristics of the embodiment. Thus, the term “consisting essentially of’ allows for minor variations or additions that do not substantially alter the core functionality of the embodiment.

[0069] Where values are specified herein in the form of ranges, the range is always inclusive, i.e. it includes the endpoint stated. For example, up to 10% includes 10%, less than 10% also includes 10%, and between 10 % and 30% includes both 10% and 30%.

[0070] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate,glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0071] Pharmaceutically acceptable salts of Compound A include those derived from suitable inorganic and organic acids and bases. In particular, “pharmaceutically acceptable salts” encompasses any multicomponent form comprising Compound A and a suitable (in)organic acid or base, including salts in which the proton is completely transferred from the acid to the base, and cocrystals in which the proton remains in the acid molecule, and together the base and the acid form a unique crystal structure.

[0072] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g, a pediatric subject (e.g infant, child, adolescent) or adult subject (e.g, young adult, middle-aged adult or senior adult)) and / or a non-human animal, e.g, a mammal such as primates (e.g, cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein. Preferably, the subject is a human.

[0073] Disease, disorder, and condition are used interchangeably herein.

[0074] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic treatment”).

[0075] In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the present disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject.As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0076] A dosage form is the physical form in which a medication is administered to a subj ect, such as a capsule, tablet, or suspension.

[0077] A solid dispersion is a pharmaceutical formulation where an active pharmaceutical ingredient (API) is dispersed in a carrier, typically a water-soluble polymer. A solid dispersion may improve the dissolution of a dispersed API. In a solid dispersion, the solid API is typically in amorphous form.

[0078] A “crystalline” solid is a solid having a specific arrangement of atoms, ions, or molecules organized into a well-defined, repeating three-dimensional structure that has long-range order in the position of its molecules (a crystal lattice), whereas an “amorphous” solid is a solid that has no long-range order in the position of its molecules.

[0079] A crystalline form of Compound A is a crystalline solid comprising Compound A. Therefore, a “crystalline form of Compound A” may be a crystalline form of Compound A alone, or may be a co-form of Compound A, wherein a co-form of Compound A is a crystalline solid comprising Compound A and at least one other residue, which may be present in any physical association within the crystalline lattice, for instance as a salt, solvate, or cocrystal. For instance, the co-form may be Compound A and hydrochloric acid (“Compound A HC1”).

[0080] As used herein, a “filler” is an excipient that is added to a dosage form to add bulk or volume. Fillers may also aid processing, for example, by providing improved physical properties such as flow, compressibility, and hardness, e.g., of a tablet. The terms “filler” and “diluent” are used interchangeably.

[0081] As used herein, a “disintegrant” is an excipient that is added to a dosage form to promote the breakup or disintegration of the dosage form, for instance a tablet, after administration. The role of a disintegrant is to promote rapid dissolution of the drug by ensuring that the tablet or capsule disintegrates into smaller fragments in the gastrointestinal tract, allowing for faster release and absorption of the active pharmaceutical ingredient (API). Disintegrants work by swelling, wi eking, or through deformation, which disrupts the physical integrity of the dosage form. This process helps to ensure that the medication is effective and provides the intended therapeutic effect.As used herein, a “lubricant” is an excipient that is added to a dosage form to reduce adhesion of the dosage form to surfaces (such as filling or tableting equipment) and / or to reduce interparticle friction within dosage form, which can improve flowability of a powder to be filled into capsule or aid compression of tablets and ejection of tablets from the tableting equipment.

[0082] As used herein, a “glidant” is an excipient that is added to a dosage form to improve its flowability. A glidant can reduce interparticle friction and enhances the ability of the powder to flow more smoothly, which helps to ensure uniformity in the weight and content of tablets and capsules. By improving powder flow, glidants help to prevent issues such as sticking, clumping, and inconsistent dosing.

[0083] As used herein, a “binder” is an excipient that is added to a dosage form to hold together the active ingredient and excipients. A binder can improve the cohesion of a powder formulation and improve processability. It can also increase the mechanical strength of a tablet formulation, thereby reducing the risk of the tablet breaking.

[0084] As used herein, a “surfactant” is a substance that reduces the surface tension of a liquid, for example, by having a hydrophobic portion and a hydrophilic portion connected by one or more linkers. Surfactants may be added to a dosage form to improve solubility, stability, and / or bioavailability, due to their ability to modify interfacial properties.

[0085] As used herein to characterize certain types of hydroxypropylmethylcellulose (HPMC, also known as hypromellose), viscosity is determined as a 2 weight % solution in water at 20 °C as described in the United States Pharmacopeia (USP 35, "Hypromellose", pages 423-424 and 3467-3469). As described in USP 35, viscosities of up to 600 mPa-s are determined by Ubbelohde viscosity measurement and viscosities above 600 mPa-s are determined using a Brookfield viscometer. USP 35 provides descriptions of preparing the 2 wt. % HPMC solution and both Ubbelohde and Brookfield viscosity measurement conditions.

[0086] As used herein, “Cu Ka °20” indicates that XRPD pattern was measured with Cu Ka in the 20 region, wherein 20 is in degrees (°).

[0087] As used herein, terms such as “about”, “around”, “approximately”, and “substantially” would be understood by a person skilled in the art to account for the natural variation in a parameter or dataset. For example, a person skilled in the art comparing two spectra, such as two XRPD patterns, which are said to be "substantially the same" would focus on the maj or, characterising peaks and would not expect the two spectra to be identical. Similarly, a person skilled in the art comparing two thermoanalytical profiles, such as two DSC profiles, which are said to be "substantially the same" would focus on the peak temperature values and would not expect the two profiles to be identical. In other words, "substantially" is consistent with the degree of variation inherent in these characterisation techniques such as XRPD. The unit cell parameters, which are determined from the diffraction data, are similarly subject to variation. For example, "substantially","approximately", "about" etc. may be understood to refer to variation within the degree of significance reported. If not otherwise specified, the terms “about”, “around”, and “approximately” may encompass values within 10%, 5%, 2% or 1% of the stated value.

[0088] Unless otherwise specified, any percentage amounts or ratios are by weight.

[0089] Active ingredient

[0090] The dosage forms provided herein comprise, as the active ingredient, Compound A or a pharmaceutically acceptable salt thereof. The crystalline forms provided herein are crystalline forms of Compound A or a pharmaceutically acceptable salt thereof.

[0091] As explained above, Compound A is A-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)benzyl)-2-methyl-2-(5-methylpyrimidin-2-yl)-propanamide and has the following structure:

[0092]

[0093] The term “Compound A” is intended to encompass isotopically labelled compounds which are identical to Compound A as described above, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated in such compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F, and 36C1, respectively. For example, one or more H atoms (for example, all H atoms) may be replaced with deuterium.

[0094] In addition, the term “Compound A” is intended to encompass all tautomeric forms, or “tautomers”, of Compound A as described above. To give a non-limiting example, Compound A may be presented as the following tautomer:

[0095]

[0096] Furthermore, the term “Compound A” is intended to encompass all stereoisomeric forms, specifically all enantiomeric forms, unless it is specifically stated or the context indicates otherwise. Compound A may be present within the embodiments disclosed hereinas an isolated enantiomer (e.g. as the (R) enantiomer or (S) enantiomer) or a mixture of individual enantiomers, such as a racemate.

[0097] In some embodiments, Compound A is in the form of a single enantiomer, or a pharmaceutical acceptable salt thereof.

[0098] In some embodiments, Compound A is the following enantiomer:

[0099]

[0100] , or a pharmaceutical acceptable salt thereof.

[0101] In some embodiments, Compound A is the following enantiomer:

[0102]

[0103] pharmaceutical acceptable salt thereof.

[0104] Preferably, in the invention, Compound A, or a pharmaceutically salt thereof, exists in a mixture of the above enantiomeric forms, more preferably a racemic mixture.

[0105] In some aspects, Compound A is provided in an amorphous form.

[0106] In some aspects, Compound A is provided as crystalline Form I (Compound A in free form), wherein Form I is as defined below.

[0107] In some aspects, Compound A is provided as crystalline Form II (Compound A in free form), wherein Form II is as defined below.

[0108] In some aspects, Compound A is provided as crystalline Form III (Compound A in free form), wherein Form III is as defined below.

[0109] In some aspects, Compound A is provided as crystalline Form IV (Compound A in free form), wherein Form IV is as defined below.

[0110] In some aspects, Compound A is provided as crystalline Compound A HC1 co-Form V (a co-form of Compound A and hydrochloric acid), wherein Compound A HC1 co-Form V is as defined below.In some aspects, Compound A is provided as crystalline Compound A HC1 co-Form VI (a co-form of Compound A and hydrochloric acid), wherein Compound A HC1 co-Form VI is as defined below.

[0111] Solid dispersion

[0112] The solid dispersions of the invention provided herein comprise Compound A, or a pharmaceutically acceptable salt thereof, and a polymer. Preferably, the solid dispersion is a spray dried dispersion.

[0113] In some embodiments, the Compound A in the solid dispersion is substantially amorphous. In some embodiments, substantially amorphous means less than 15%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the Compound A in the dispersion is crystalline. In some embodiments, the Compound A in the solid dispersion is amorphous, i.e. the solid dispersion does not contain any crystalline Compound A.

[0114] The solid dispersion may also comprise a surfactant. The surfactant may be selected from the group consisting of: polyethylene-polypropylene glycol, lecithin, bile salt, and lauroyl polyoxyl-32 glycerides.

[0115] The particle size of Compound A in the solid dispersion may be reduced via co-micronisation. Compound A may be co-micronized with sodium lauryl sulfate or tocofersolan.

[0116] Polymer

[0117] In some embodiments, the polymer is selected from the group consisting of: enteric polymers (such as methacrylate polymers, hydroxypropyl methyl cellulose phthalate (HPMCP), and cellulose acetyate phthalate (CAP)), hydrophilic polymers (such as starch, sodium carboxymethyl cellulose, sodium alginate, polyethylene glycol (PEG), polyvinyl pyrrolidone (PVP), hydroxy propyl methyl cellulose (HPMC), polyvinyl alcohol (PVA), P-cyclodextrin, mannitol, chitosan, and carrageenan), and amphiphilic polymers (such as polyethylene oxides (PEO)Zpolypropylene glycol (PPG) copolymers, PEG-modified starches, vinyl acetate / vinylpyrrolidone random copolymers, polyacrylic acid, and polyacrylates), and a combination thereof. Examples of methacrylate polymers are Eudragit® E PO / 100, Eudragit® RLPO, Eudragit® LI 00, and Eudragit® SI 00. In some embodiments, the polymer is selected from the group consisting of: HPMCAS LG, HPMCAS MG, HPMC AS HG, HPMC E3, PVPVA 64, Eudragit LI 00, and combinations thereof. In preferred embodiments, the polymer is a hydroxypropylmethylcellulose (HPMC) derivative, such as hydroxypropylmethylcellulose acetate succinate (HPMCAS), for example: HPMCAS LG, HPMCAS MG, HPMCAS HG, HPMC E3, or a combination thereof. In some embodiments, the polymer is HPMCAS MG and / or HPMCAS HG. In some embodiments, the polymer is HPMCAS MG.In some embodiments, the solid dispersion comprises Compound A and a polymer at a ratio of between 1:5 and 1:1 by weight. In some embodiments, the solid dispersion comprises Compound A and the polymer at a ratio of between 1:3 and 2:3 by weight. In some embodiments, the solid dispersion comprises Compound A and the polymer at a ratio of 1:3 or 1 :2 by weight. In some embodiments, the solid dispersion comprises Compound A and the polymer at a ratio of 1 :3 by weight.

[0118] In some embodiments, the solid dispersion comprises Compound A and the polymer at a ratio of between 1:5 and 1:1 by weight, and the polymer is a hydroxypropylmethylcellulose (HPMC) derivative, such as hydroxypropylmethylcellulose acetate succinate (HPMCAS), for example: HPMCAS LG, HPMCAS MG, HPMCAS HG, HPMC E3, or a combination thereof. In some embodiments, the solid dispersion comprises Compound A and the polymer at a ratio of between 1:5 and 1 : 1 by weight, and the polymer is HPMCAS MG and / or HPMCAS HG. In some embodiments, the solid dispersion comprises Compound A and the polymer at a ratio of between 1:5 and 1: 1 by weight, and the polymer is HPMCAS MG.

[0119] In some embodiments, the solid dispersion comprises Compound A and the polymer at a ratio of 1:3 or 1:2 by weight, and the polymer is a hydroxypropylmethylcellulose (HPMC) derivative, such as hydroxypropylmethylcellulose acetate succinate (HPMCAS), for example: HPMCAS LG, HPMCAS MG, HPMCAS HG, HPMC E3, or a combination thereof. In some embodiments, the solid dispersion comprises Compound A and the polymer at a ratio of 1:3 or 1:2 by weight, and the polymer is HPMCAS MG and / or HPMCAS HG. In some embodiments, the solid dispersion comprises Compound A and the polymer at a ratio of 1 :3 or 1 :2 by weight, and the polymer is HPMCAS MG.

[0120] In some embodiments, the solid dispersion comprises Compound A and the polymer at a ratio of 1:3 by weight, and the polymer is a hydroxy propylmethylcellulose (HPMC) derivative, for example: HPMCAS LG, HPMCAS MG, HPMCAS HG, HPMC E3, or a combination thereof. In some embodiments, the solid dispersion comprises Compound A and the polymer at a ratio of 1:3 by weight, and the polymer is HPMCAS MG and / or HPMCAS HG. In some embodiments, the solid dispersion comprises Compound A and the polymer at a ratio of 1:3 by weight, and the polymer is HPMCAS MG.

[0121] In some embodiments, HPMCAS LG is characterized by one or more of the following properties: (i) an acetyl content of 5-9%; (ii) a succinoyl content of 14-18%; (iii) a methoxyl content of 20-24%; (iv) a hydroxypropoxy content of 5-9%; (v) solubility at a pH more than or equal to 5.5; (vi) a median particle size between about 300 pm and 1100 pm, for example between about 500 pm and 1000 pm; (vii) a viscosity in 2% w / w aqueous solution at 20 °C of 2.4-3.6 mPa»s. In some embodiments, HPMCAS LG is characterized by (i) and (ii). In some embodiments, HPMCAS LG is characterized by (i)-(iv). In some embodiments, HPMCAS LG is characterized by (i)-(v). In some embodiments, HPMCAS LG is characterized by (i)-(iv) and (vi). In some embodiments, HPMCAS LG is characterized by(i)-(iv) and (vii). In some embodiments, HPMCAS LG is characterized by (i)-(vi). In some embodiments, HPMCAS LG is characterized by all of (i)-(vii).

[0122] In some embodiments, HPMCAS MG is characterized by one or more of the following properties: (i) an acetyl content of 7-11%; (ii) a succinoyl content of 10-14%; (iii) a methoxyl content of 21-25%; (iv) a hydroxypropoxy content of 5-9%; (v) solubility at a pH more than or equal to 6.0; (vi) a median particle size between about 300 pm and 1100 pm, for example between about 500 pm and 1000 pm; (vii) a viscosity in 2% w / w aqueous solution at 20 °C of 2.4-3.6 mPa»s. In some embodiments, HPMCAS MG is characterized by (i) and (ii). In some embodiments, HPMCAS MG is characterized by (i)-(iv). In some embodiments, HPMCAS MG is characterized by (i)-(v). In some embodiments, HPMCAS MG is characterized by (i)-(iv) and (vi). In some embodiments, HPMCAS MG is characterized by (i)-(iv) and (vii). In some embodiments, HPMCAS MG is characterized by (i)-(vi). In some embodiments, HPMCAS MG is characterized by all of (i)-(vii).

[0123] In some embodiments, HPMCAS HG is characterized by one or more of the following properties: (i) an acetyl content of 10-14%; (ii) a succinoyl content of 4-8%; (iii) a methoxyl content of 22-26%; (iv) a hydroxypropoxy content of 6-10%; (v) solubility at a pH more than or equal to 6.5; (vi) a median particle size between about 300 pm and 1100 pm, for example between about 500 pm and 1000 pm; (vii) a viscosity in 2% w / w aqueous solution at 20 °C of 2.4-3.6 mPa»s. In some embodiments, HPMCAS HG is characterized by (i) and (ii). In some embodiments, HPMCAS HG is characterized by (i)-(iv). In some embodiments, HPMCAS HG is characterized by (i)-(v). In some embodiments, HPMCAS HG is characterized by (i)-(iv) and (vi). In some embodiments, HPMCAS HG is characterized by (i)-(iv) and (vii). In some embodiments, HPMCAS HG is characterized by (i)-(vi). In some embodiments, HPMCAS HG is characterized by all of (i)-(vii).

[0124] In some embodiments, HPMCAS E3 is characterized by one or more of the following properties: (i) a methoxyl content of 28.0-30.0%, for example a methoxyl content of 29%; (ii) a hydroxy propyl content of 7.0-12.0%, for example a hydroxy propyl content of 10%; (iii) a viscosity in 2% w / w aqueous solution at 20 °C of 3 mPa»s. In some embodiments, HPMCAS E3 is characterized by (i) and (ii). In some embodiments, HPMCAS E3 is characterized by all of (i)-(iii).

[0125] Process of preparing solid dispersion

[0126] The invention provides a process of preparing a solid dispersion of Compound A, or a pharmaceutically acceptable salt thereof, and a polymer, comprising spray drying a solution comprising Compound A, or a pharmaceutically acceptable salt thereof, to form a solid dispersion.

[0127] Spray drying is a process that is commonly used to prepare solid dispersions from a liquid suspension or solution, and the skilled person will be able to readily prepare solid dispersions as provided herein, for example using commercial spray drying equipment. Techniques and methods for spray drying may be found in Perry’s Chemical EngineeringHandbook, 6th Ed., R. H. Perry, D. W. Green & J. O. Maloney, eds.), McGraw-Hill book co. (1984); and Marshall "Atomization and Spray Drying" 50, Chem. Eng. Prog. Monogr. Series 2 (1954).

[0128] Some conventional spray drying process parameters are as follows. The load of solid material (i.e., drug and excipients) in the liquid starting material is generally from about 3% to about 30% by weight. The inlet temperature is generally from about 60 °C to about 200 °C. The outlet temperature is generally from about 30 °C to about 90 °C. The atomization gas flow rate is generally from about 4 kg / h to about 12 kg / h. The solution feed flow rate is generally from about 1 kg / h to about 25 kg / h, such as from about 1 kg / h to about 14 kg / h. The atomization ratio is generally from about 0.1 to 2.5.

[0129] The solvent in the liquid starting material may be selected from an aqueous solvent, a polar aprotic solvent, a polar protic solvent, and combinations thereof. In some embodiments, the solvent has a boiling point of about 100 °C or less.

[0130] In some embodiments, the solvent is selected from acetone, cyclohexane, dichloromethane, N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide (DMSO), dioxane, ethyl acetate, ethyl ether, glacial acetic acid (HAc), methyl ethyl ketone (MEK), N-methyl-2-pyrrolidinone (NMP), methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), pentane, acetonitrile, methanol, ethanol, isopropyl alcohol, isopropyl acetate, toluene, or a mixture thereof, for example acetone / DMSO, acetone / DMF, acetone / water, MEK / water, THF / water, or dioxane / water. In some embodiments, the solvent may be selected from water, acetone, acetic acid, methanol, ethanol, isopropanol, dichloromethane, tetrahydrofuran (THF), and combinations thereof. In a preferred embodiment, the solvent is acetone / water. In some embodiment, the water and acetone are present at a ratio of between 1 : 6 to 1 : 12 (w / w), preferably a ratio of between 1 : 8 to 1 : 10 (w / w), more preferably a ratio of 1 : 9 (w / w).

[0131] In some embodiments, the load of solid material in the solvent is between about 1% to about 25% by weight. In some embodiments, the load of solid material in the solvent is between about 2% to about 15% by weight. In some embodiments, the load of solid material in the solvent is between about 3% to about 10% by weight.

[0132] The solid dispersion of Compound A, or a pharmaceutically acceptable salt thereof, is as described above. In particular, the polymer may be a polymer according to the solid dispersion described above.

[0133] Dosage forms

[0134] The dosage forms provided herein comprise Compound A, or a pharmaceutically acceptable salt thereof.The dosage form can contain Compound A or its pharmaceutically acceptable salt in any form, for instance in a crystalline form, including any of the crystalline forms described herein, or, more preferably, in an amorphous form.

[0135] In addition to Compound A, the dosage forms provided herein comprise a pharmaceutically acceptable excipient. In some embodiments, the dosage form comprises two or more pharmaceutically acceptable excipients. In some embodiments, the dosage form comprises three or more pharmaceutically acceptable excipients. In some embodiments, the dosage form comprises four or more pharmaceutically acceptable excipients. In some embodiments, the dosage form comprises five or more pharmaceutically acceptable excipients.

[0136] In some embodiments, the dosage form is a unit dosage form. The term “unit dosage form” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect. Thus, unit dosage forms are useful for facilitating accurate dosing. Typical unit dosage forms include pills, tablets, capsules or the like in the case of solid compositions.

[0137] Amount of Compound A

[0138] The dosage forms provided herein comprise an amount of Compound A in a therapeutically effective amount. This amount may be, for instance, between 0.1 mg and 1.0 g. As would be apparent to the skilled person, if using a pharmaceutically acceptable salt of Compound A, the amount will need to be adjusted in order to provide the requisite amount of Compound A, i.e. the free form equivalent. All amounts of Compound A herein are given as the amount of Compound A in free form, unless it is specified otherwise.

[0139] In some embodiments, the amount of Compound A is between 0.1 mg and 500 mg. In some embodiments, the amount of Compound A is between 0.1 mg and 300 mg. In some embodiments, the amount of Compound A is between 0.1 mg and 250 mg. In some embodiments, the amount of Compound A is between 0.1 mg and 200 mg. In some embodiments, the amount of Compound A is between 0.1 mg and 150 mg. In some embodiments, the amount of Compound A is between 0.1 mg and 100 mg. In some embodiments, the amount of Compound A is between 0. mg and 80 mg. In some embodiments, the amount of Compound A is between 0.1 mg and 60 mg.

[0140] In some embodiments, the amount of Compound A is between 0.5 mg and 500 mg. In some embodiments, the amount of Compound A is between 0.5 mg and 300 mg. In some embodiments, the amount of Compound A is between 0.5 mg and 250 mg. In some embodiments, the amount of Compound A is between 0.5 mg and 200 mg. In some embodiments, the amount of Compound A is between 0.5 mg and 150 mg. In some embodiments, the amount of Compound A is between 0.5 mg and 100 mg. In some embodiments, the amount of Compound A is between 0.; mg and 80 mg. In some embodiments, the amount of Compound A is between 0.5 mg and 60 mg.In some embodiments, the amount of Compound A is between 1 mg and 500 mg. In some embodiments, the amount of Compound A is between 1 mg and 300 mg. In some embodiments, the amount of Compound A is between 1 mg and 250 mg. In some embodiments, the amount of Compound A is between 1 mg and 200 mg. In some embodiments, the amount of Compound A is between 1 mg and 150 mg. In some embodiments, the amount of Compound A is between 1 mg and 100 mg. In some embodiments, the amount of Compound A is between 1 mg and 80 mg. In some embodiments, the amount of Compound A is between 1 mg and 60 mg.

[0141] In some embodiments, the amount of Compound A is between 2 mg and 500 mg. In some embodiments, the amount of Compound A is between 2 mg and 300 mg. In some embodiments, the amount of Compound A is between 2 mg and 250 mg In some embodiments, the amount of Compound A is between 2 mg and 200 mg In some embodiments, the amount of Compound A is between 2 mg and 150 mg In some embodiments, the amount of Compound A is between 2 mg and 100 mg In some embodiments, the amount of Compound A is between 2 mg and 80 mg. In some embodiments, the amount of Compound A is between 2 mg and 60 mg.

[0142] In some embodiments, the amount of Compound A is between 0.05 mg and 10 mg. In some embodiments, the amount of Compound A is between 0.1 mg and 5 mg. In some embodiments, the amount of Compound A is between 0.2 mg and 5 mg. In some embodiments, the amount of Compound A is between 0.4 mg and 2 mg. In some embodiments, the amount of Compound A is between 0.5 mg and 1.5 mg. In some embodiments, the amount of Compound A is 1 mg.

[0143] In some embodiments, the amount of Compound A is between 0.1 mg and 20 mg. In some embodiments, the amount of Compound A is between 0.1 mg and 10 mg. In some embodiments, the amount of Compound A is between 1 mg and 10 mg. In some embodiments, the amount of Compound A is between 2 mg and 8 mg. In some embodiments, the amount of Compound A is between 4 mg and 6 mg. In some embodiments, the amount of Compound A is 5 mg.

[0144] In some embodiments, the amount of Compound A is between 0.1 mg and 40 mg. In some embodiments, the amount of Compound A is between 1 mg and 20 mg. In some embodiments, the amount of Compound A is between 5 mg and 15 mg. In some embodiments, the amount of Compound A is between 8 mg and 12 mg. In some embodiments, the amount of Compound A is 10 mg.

[0145] In some embodiments, the amount of Compound A is between 0.1 mg and 50 mg. In some embodiments, the amount of Compound A is between 1 mg and 40 mg. In some embodiments, the amount of Compound A is between 5 mg and 40 mg. In some embodiments, the amount of Compound A is between 10 mg and 30 mg. In some embodiments, the amount of Compound A is between 15 mg and 25 mg. In some embodiments, the amount of Compound A is 20 mg.In some embodiments, the amount of Compound A is between 1 mg and 80 mg. In some embodiments, the amount of Compound A is between 5 mg and 75 mg. In some embodiments, the amount of Compound A is between 20 mg and 60 mg. In some embodiments, the amount of Compound A is between 30 mg and 50 mg. In some embodiments, the amount of Compound A is between 35 mg and 45 mg. In some embodiments, the amount of Compound A is 40 mg.

[0146] In some embodiments, the amount of Compound A is between 1 mg and 100 mg. In some embodiments, the amount of Compound A is between 5 mg and 100 mg. In some embodiments, the amount of Compound A is between 10 mg and 10 mg. In some embodiments, the amount of Compound A is between 25 mg and 75 mg. In some embodiments, the amount of Compound A is between 40 mg and 60 mg. In some embodiments, the amount of Compound A is 50 mg.

[0147] In some embodiments, the amount of Compound A is between 1 mg and 150 mg. In some embodiments, the amount of Compound A is between 10 mg and 150 mg. In some embodiments, the amount of Compound A is between 50 mg and 120 mg. In some embodiments, the amount of Compound A is between 60 mg and 100 mg. In some embodiments, the amount of Compound A is between 70 mg and 90 mg. In some embodiments, the amount of Compound A is 80 mg.

[0148] In some embodiments, the amount of Compound A is between 1 mg and 200 mg. In some embodiments, the amount of Compound A is between 10 mg and 200 mg. In some embodiments, the amount of Compound A is between 50 mg and 150 mg. In some embodiments, the amount of Compound A is between 80 mg and 120 mg. In some embodiments, the amount of Compound A is between 90 mg and 100 mg. In some embodiments, the amount of Compound A is 100 mg.

[0149] Preferably, the amount of Compound A is between 1 mg and 100 mg. More preferably, the amount of Compound A is between 2 mg and 80 mg. Most preferably, the amount of Compound A is between 2 mg and 60 mg.

[0150] In some embodiments, the amount of Compound A is selected from 1 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 80 mg, and 100 mg.

[0151] In some embodiments, the amount of Compound A is selected from 5 mg, 20 mg, and 50 mg.

[0152] In some embodiments, the dosage form comprises less than 50% by weight of Compound A. In some embodiments, the dosage form comprises less than 40% by weight of Compound A. In some embodiments, the dosage form comprises less than 30% by weight of Compound A. In some embodiments, the dosage form comprises less than 20% by weight of Compound A. In some embodiments, the dosage form comprises less than 10% by weight of Compound A.In some embodiments, the total weight of the dosage form is between 5 and 2000 mg. In some embodiments, the total weight of the dosage form is between 5 and 1500 mg. In some embodiments, the total weight of the dosage form is between 5 and 1000 mg. In some embodiments, the total weight of the dosage form is between 5 and 900 mg. In some embodiments, the total weight of the dosage form is between 5 and 800 mg. In some embodiments, the total weight of the dosage form is between 5 and 700 mg. In some embodiments, the total weight of the dosage form is between 5 and 600 mg.

[0153] In some embodiments, the total weight of the dosage form is between 50 and 2000 mg. In some embodiments, the total weight of the dosage form is between 50 and 1500 mg. In some embodiments, the total weight of the dosage form is between 50 and 1000 mg. In some embodiments, the total weight of the dosage form is between 50 and 900 mg. In some embodiments, the total weight of the dosage form is between 50 and 800 mg. In some embodiments, the total weight of the dosage form is between 50 and 700 mg. In some embodiments, the total weight of the dosage form is between 50 and 600 mg.

[0154] In some embodiments, the total weight of the dosage form is between 100 and 2000 mg. In some embodiments, the total weight of the dosage form is between 100 and 1500 mg. In some embodiments, the total weight of the dosage form is between 100 and 1000 mg. In some embodiments, the total weight of the dosage form is between 100 and 900 mg. In some embodiments, the total weight of the dosage form is between 100 and 800 mg. In some embodiments, the total weight of the dosage form is between 100 and 700 mg. In some embodiments, the total weight of the dosage form is between 100 and 600 mg.

[0155] In some embodiments, the total weight of the dosage form is between 1 and 2000 mg. In some embodiments, the total weight of the dosage form is between 1 and 1000 mg. In some embodiments, the total weight of the dosage form is between 5 and 1000 mg. In some embodiments, the total weight of the dosage form is between 10 and 900 mg. In some embodiments, the total weight of the dosage form is between 50 and 800 mg. In some embodiments, the total weight of the dosage form is between 100 and 700 mg. In some embodiments, the total weight of the dosage form is between 150 and 600 mg.

[0156] In some embodiments, the amount of Compound A, its percentage by weight of the dosage form, and the total weight of the dosage form are as defined herein. For example: the amount of Compound A in the dosage form may be between 0.1 mg and 500 mg, between 0.5 mg and 250 mg, between 1 mg and 100 mg, between 2 mg and 80 mg, or between 2 mg and 60 mg; the dosage form may comprise less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% by weight of Compound A; and / or the total weight of the dosage form may be between 1 and 2000 mg, between 5 and 1000 mg, between 10 and 900 mg, between 50 and 800 mg, between 100 and 700 mg, or between 150 and 600 mg. The skilled person knows how to make dosage forms according to these embodiments, e.g. by selecting amounts of Compound A and various excipients which do not exceed the stated total weight of the dosage form.Solid dosage forms

[0157] Preferably, the dosage form is a solid dosage form. As used herein, solid dosage forms are dosage forms that have a solid exterior. Thus, dosage forms that comprise a solid outer shell but have a liquid or semisolid interior (as is the case for softgel capsules), or that are hollow, are encompassed by the term “solid dosage form”. In some embodiments, the dosage form is a pill, tablet, capsule, or lozenge. In some embodiments, the dosage form is a pill, tablet, or capsule. In some embodiments, the dosage form is a tablet or a capsule.

[0158] Solid dosage forms can be advantageous as, in general, solid dosage forms have a longer shelflife than liquid dosage forms, since drugs are generally more stable in the solid state and microbial growth is hindered. Solid dosage forms are also generally less bulky than liquid dosage forms, which is beneficial for transport, storage, and ease of administration.

[0159] Capsules

[0160] The solid dosage form of the invention may be a capsule. The capsule contains a fill composition comprising Compound A, or a pharmaceutically acceptable salt thereof.

[0161] Preferably, the fill composition comprises a solid dispersion as described above. In some embodiments, the solid dispersion makes up less than 70% by weight of the fill composition. In some embodiments, the solid dispersion makes up less than 60% by weight of the fill composition. In some embodiments, the solid dispersion makes up less than 50% by weight of the fill composition. In some embodiments, the solid dispersion makes up less than 45% by weight of the fill composition. In some embodiments, the solid dispersion makes up less than 20% by weight of the fill composition.

[0162] Capsule excipients

[0163] In some embodiments, the fill composition comprises a pharmaceutically acceptable excipient. In some embodiments, the fill composition comprises two or more pharmaceutically acceptable excipients. In some embodiments, the fill composition comprises three or more pharmaceutically acceptable excipients.

[0164] In some embodiments, the fill composition comprises a filler. In some embodiments, the filler is present at from about 40 to about 95 wt %, or from about 50 to about 85 wt %. In some embodiments, the filler is selected from the group consisting of: celluloses, modified celluloses (such as sodium carboxymethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropylcellulose, cellulose acetate, microcrystalline cellulose, and silicified microcrystalline cellulose), calcium phosphates (such as dibasic calcium phosphate), starches (such as com starch, and potato starch), sugars (such as mannitol, sorbitol, lactose, and sucrose), and combinations thereof. In some embodiments, the filler is mannitol and / or microcrystalline cellulose. Preferably, the filler is mannitol and microcrystalline cellulose. In some embodiments, the filler is mannitol and microcrystalline cellulose in a ratio of between 6 : 1 and 2 : 1 by weight, for example a ratio of 4 : 1 by weight. In some embodiments, the filler is mannitol and microcrystalline cellulose, and the filler is present at from about 40 toabout 95 wt %. In some embodiments, the filler is mannitol and microcrystalline cellulose in a ratio of between 6 : 1 and 2 : 1 by weight, and the filler is present at from about 50 to about 85 wt %.

[0165] In some embodiments, the fill composition comprises a disintegrant. In some embodiments, the disintegrant is present at from about 1 to about 10 wt %, or from about 4 to about 6 wt %. In some embodiments, the disintegrant is selected from the group consisting of: starches (such as com starch or potato starch), modified starches (such as pregelatinized starch, sodium starch glycolate, and starch 1500), cellulose derivatives (such as microcrystalline cellulose, croscarmellose sodium, sodium carboxymethyl cellulose, and hydroxypropyl methylcellulose), natural gums (such as guar gum, xanthan gum, and locust bean gum), ion exchange resins (such as polacrilin potassium and Amberlite IRP69), calcium silicates (dicalcium phosphate and tricalcium phosphate), sodium alginate, cross-linked polyvinylpyrrolidone, chitosan, and combinations thereof. Preferably, the disintegrant is sodium croscarmellose. In some embodiments, the disintegrant is sodium croscarmellose, and the disintegrant is present at from about 1 to about 10 wt %.

[0166] In some embodiments, the fill composition comprises a lubricant. In some embodiments, the lubricant is present at from about 0.1 to about 5 wt %, or from about 0.5 to about 1.5 wt %. In some embodiments, the lubricant is selected from the group consisting of: sodium stearate, magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, polyethylene glycols, beeswax, hydrogenated vegetable oil, and combinations thereof. Preferably, the lubricant is magnesium stearate. In some embodiments, the lubricant is magnesium stearate, and the disintegrant is present at from about 0.1 to about 5 wt %.

[0167] In some embodiments, the fill composition comprises a glidant. In some embodiments, the glidant is present at from about 0.1 to about 5 wt %, or from about 0.25 to about 2 wt %. In some embodiments, the glidant is selected from the list consisting of colloidal silicon dioxide, talc, magnesium stearate, calcium stearate, com starch, stearic acid, magnesium silicate, aluminium silicate, and combinations thereof.

[0168] In some embodiments, the fill composition comprises a binder. In some embodiments, the binder is present at from about 1 to about 10 wt %, or from about 2 to about 5 wt %. In some embodiments, the binder is selected from the list consisting of starch, acacia, tragacanth, gelatin, guar gum, xanthan gum, pectin, alginates, carrageenan, polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), methylcellulose, carboxymethylcellulose (CMC), ethylcellulose, microcrystalline cellulose, polyethylene glycol, sorbitol, sucrose, lactose, mannitol, and combinations thereof.

[0169] In some embodiments, the fill composition comprises a surfactant. In some embodiments, the surfactant is present at from about 0.1 to about 2 wt %, or from about 0.25 to about 1.5 wt %. In some embodiments, the surfactant is selected from the list consisting of polysorbates, sorbitan esters, polyethylene glycol, poloxamers, cetomacrogol, lecithin, sodium lauryl sulfate, bile salts, lauroyl polyoxyl-32 glycerides, and combinations thereof.In some embodiments, the fill composition comprises one or more of: (i) a filler; (ii) a disintegrant; (iii) a lubricant; (iv) a glidant; (v) a binder; and (vi) a surfactant. In some embodiments, the fill composition comprises two or more of: (i), (ii), (iii), (iv), (v), and (vi). In some embodiments, the fill composition comprises (i) and (ii), (i) and (iii), or (ii) and (iii). In some embodiments, the fill composition comprises three or more of: (i), (ii), (iii), (iv), (v), and (vi). Preferably, the fill composition comprises (i), (ii), and (iii). In some embodiments, the fill composition further comprises one or more of: (iv), (v), or (vi).

[0170] In some embodiments, the fill composition comprises (i) a filler at from about 40 to about 95 wt %; (ii) a disintegrant at from about 1 to about 10 wt %; and (iii) a lubricant at from about 0.1 to about 5 wt %. In some embodiments, the fill composition comprises (i) a filler at from about 50 to about 85 wt %; (ii) a disintegrant at from about 4 to about 6 wt %; and (iii) a lubricant at from about 0.5 to about 1.5 wt %.

[0171] In some embodiments, the fill composition has the following composition:

[0172]

[0173] In some embodiments, the fill compositions described above comprise between 1 mg and 10 mg of Compound A, preferably 5 mg of Compound A. In some embodiments, the fill compositions described above comprise 1 mg of Compound A. In some embodiments, the fill compositions described above comprise 10 mg of Compound A.

[0174] In some embodiments, the fill composition has the following composition:

[0175]

[0176] In some embodiments, the fill compositions described above comprise between 10 mg and 30 mg of Compound A, preferably 20 mg of Compound A. In some embodiments,the fill compositions described above comprise 10 mg of Compound A. In some embodiments, the fill compositions described above comprise between 40 mg and 60 mg, preferably 50 mg of Compound A. In some embodiments, the fill compositions described above comprise 40 mg of Compound A. In some embodiments, the fill compositions described above comprise 80 mg of Compound A. In some embodiments, the fill compositions described above comprise 100 mg of Compound A.

[0177] Capsule types

[0178] The capsule may be a hard capsule or a soft capsule. The skilled practitioner will be familiar with conventional methods of preparing capsules.

[0179] Preferably, the capsule is a hard capsule. Hard capsules may be made from gelatin, or HPMC (hydroxypropylmethyl cellulose), with the latter being preferred due to a reduction in capsule leakage compared to gelatin capsules. Hard capsules are typically produced from two halves that are sealed together after the active ingredient and any excipients are added. Hard capsules can be filled manually (e.g. with a pipette), or automatically (e.g. with an automated filling machine such as a Capsugel CFS 1000).

[0180] In some embodiments, the capsule is a soft capsule, such as a softgel capsule. Softgels have a gelatin-based shell surrounding a liquid or semi-solid fill. Many patients prefer softgel capsules to hard capsules as they can be easier to swallow. In addition, it is straightforward to prepare a uniform lipid solution of Compound A for inclusion as the softgel fill, which facilitates highly accurate dosing. Softgels are produced using a sotfgel encapsulation machine, which uses a pump to deliver the softgel fill into the gelatin shell.

[0181] Tablets

[0182] The solid dosage form of the invention may be a tablet. In some embodiments, the tablet comprises a solid dispersion as described above.

[0183] Tablets typically contain one or more excipients selected from fillers / diluents, disintegrants, surfactants, binders, glidants, lubricants, colorants, and fragrances.

[0184] Tablets may be prepared using conventional methods known to those skilled in the field of pharmaceutical formulation, for example as described in textbooks such as Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins, Baltimore, Md. (2003); Ansel et al., Pharmaceutical Dosage Forms And Drug Delivery Systems, 7th Edition, Lippincott Williams & Wilkins, (1999); The Handbook of Pharmaceutical Excipients, 4th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003); Gibson, Pharmaceutical Preformulation And Formulation, CRC Press (2001).

[0185] For example, tablets can be prepared by compressing a powder or granular formulation, e.g. using a die punch.A granular formulation may be prepared by techniques that are well known to any person skilled in the art of pharmaceutical formulation, such as by wet granulation or dry granulation. Formulation of the API into granules can help to enhance the uniformity, flow, and compactability of the formulation.

[0186] In some embodiments, the tablet comprises a filler. In some embodiments, the filler is present at from about 40 to about 95 wt %, or from about 50 to about 85 wt %. In some embodiments, the filler is selected from the group consisting of: celluloses, modified celluloses (such as sodium carboxymethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropylcellulose, cellulose acetate, microcrystalline cellulose, and silicified microcrystalline cellulose), calcium phosphates (such as dibasic calcium phosphate), starches (such as com starch, and potato starch), sugars (such as mannitol, sorbitol, lactose, and sucrose), and combinations thereof. In some embodiments, the filler is mannitol and / or microcrystalline cellulose. Preferably, the filler is mannitol and microcrystalline cellulose. In some embodiments, the filler is mannitol and microcrystalline cellulose in a ratio of between 6 : 1 and 2 : 1 by weight, for example a ratio of 4 : 1 by weight. In some embodiments, the filler is mannitol and microcrystalline cellulose, and the filler is present at from about 40 to about 95 wt %. In some embodiments, the filler is mannitol and microcrystalline cellulose in a ratio of between 6 : 1 and 2 : 1 by weight, and the filler is present at from about 50 to about 85 wt %.

[0187] In some embodiments, the tablet comprises a disintegrant. In some embodiments, the disintegrant is present at from about 1 to about 10 wt %, or from about 4 to about 6 wt %. In some embodiments, the disintegrant is selected from the group consisting of: starches (such as com starch or potato starch), modified starches (such as pregelatinized starch, sodium starch glycolate, and starch 1500), cellulose derivatives (such as microcrystalline cellulose, croscarmellose sodium, sodium carboxymethyl cellulose, and hydroxypropyl methylcellulose), natural gums (such as guar gum, xanthan gum, and locust bean gum), ion exchange resins (such as polacrilin potassium and Amberlite IRP69), calcium silicates (dicalcium phosphate and tricalcium phosphate), sodium alginate, cross-linked polyvinylpyrrolidone, chitosan, and combinations thereof. Preferably, the disintegrant is sodium croscarmellose. In some embodiments, the disintegrant is sodium croscarmellose, and the disintegrant is present at from about 1 to about 10 wt %.

[0188] In some embodiments, the tablet comprises a lubricant. In some embodiments, the lubricant is present at from about 0.1 to about 5 wt %, or from about 0.5 to about 1.5 wt %. In some embodiments, the lubricant is selected from the group consisting of: sodium stearate, magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, polyethylene glycols, beeswax, hydrogenated vegetable oil, and combinations thereof. Preferably, the lubricant is magnesium stearate. In some embodiments, the lubricant is magnesium stearate, and the disintegrant is present at from about 0.1 to about 5 wt %.In some embodiments, the tablet comprises a glidant. In some embodiments, the glidant is present at from about 0.1 to about 5 wt %, or from about 0.25 to about 2 wt %. In some embodiments, the glidant is selected from the list consisting of colloidal silicon dioxide, talc, magnesium stearate, calcium stearate, com starch, stearic acid, magnesium silicate, aluminium silicate, and combinations thereof.

[0189] In some embodiments, the tablet comprises a binder. In some embodiments, the binder is present at from about 1 to about 10 wt %, or from about 2 to about 5 wt %. In some embodiments, the binder is selected from the list consisting of starch, acacia, tragacanth, gelatin, guar gum, xanthan gum, pectin, alginates, carrageenan, polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), methylcellulose, carboxymethylcellulose (CMC), ethylcellulose, microcrystalline cellulose, polyethylene glycol, sorbitol, sucrose, lactose, mannitol, and combinations thereof.

[0190] In some embodiments, the tablet comprises a surfactant. In some embodiments, the surfactant is present at from about 0.1 to about 2 wt %, or from about 0.25 to about 1.5 wt %. In some embodiments, the surfactant is selected from the list consisting of polysorbates, sorbitan esters, polyethylene glycol, poloxamers, cetomacrogol, lecithin, sodium lauryl sulfate, bile salts, lauroyl polyoxyl-32 glycerides, and combinations thereof.

[0191] In some embodiments, the tablet comprises one or more of: (i) a filler; (ii) a disintegrant; (iii) a lubricant; (iv) a glidant; (v) a binder; and (vi) a surfactant. In some embodiments, the tablet comprises two or more of: (i), (ii), (iii), (iv), (v), and (vi). In some embodiments, the tablet comprises (i) and (ii), (i) and (iii), or (ii) and (iii). In some embodiments, the tablet comprises three or more of: (i), (ii), (iii), (iv), (v), and (vi). Preferably, the tablet comprises (i), (ii), and (iii). In some embodiments, the tablet further comprises one or more of: (iv), (v), or (vi).

[0192] In some embodiments, the tablet comprises (i) a filler at from about 40 to about 95 wt %; (ii) a disintegrant at from about 1 to about 10 wt %; and (iii) a lubricant at from about 0.1 to about 5 wt %. In some embodiments, the tablet comprises (i) a filler at from about 50 to about 85 wt %; (ii) a disintegrant at from about 4 to about 6 wt %; and (iii) a lubricant at from about 0.5 to about 1.5 wt %.

[0193] Liquid formulations

[0194] In some embodiments, the dosage form is a liquid dosage form. The liquid dosage form may be a solution, suspension, emulsion, elixir, syrup, spirit, tincture, liniment, spray, aromatic water, or aerosol. Liquid dosage forms comprise a vehicle and the active ingredient, and may also include excipients such as co-solvents, preservatives, sweeteners, and flavours. The skilled practitioner will be able to prepare a variety of liquid dosage forms on the basis of methods of manufacture that are commonly known in the art.Advantages of liquid dosage forms include flexibility of dosing and ease of swallowing.

[0195] In some embodiments, the vehicle is water.

[0196] In some embodiments, the liquid dosage form comprises a polymer. In some embodiments, the polymer is selected from the group consisting of: a P-cyclodextrin, carboxymethyl cellulose, polyethylene glycol, and combinations thereof. In some embodiments, the P-cyclodextrin is a hydroxy propyl modified P-cyclodextrin.

[0197] Inclusion of a polymer can help to solubilize Compound A. Techniques to improve solubility include complexation, use of co-solvents, chemical modifications, particle size reduction, and pH control.

[0198] In some embodiment, the liquid dosage form is a suspension. In some embodiments, the suspension comprises a solid dispersion of Compound A, or a pharmaceutically acceptable salt, as described above, and a solvent. In some embodiments, the solid dispersion of Compound A, or a pharmaceutically acceptable salt, is suspended in water.

[0199] Process of preparing dosage form

[0200] Provided herein is a process for preparing a dosage form described above, such as a solid dosage form.

[0201] In some embodiments, the process comprises spray drying a solution comprising Compound A, or a pharmaceutically acceptable salt thereof, to form a solid dispersion. In some embodiments, the solution further comprises a polymer. Preferably, the solid dispersion is the solid dispersion comprising Compound A, or a pharmaceutically acceptable salt thereof, and a polymer described above. In particular, the polymer may be a polymer according to the embodiments described above, such as HPMC. Further preferably, the process of preparing the solid dispersion is the process described above.

[0202] In some embodiments, the process comprises blending the solid dispersion with one or more pharmaceutical excipients, and filling the blend into capsules. In some embodiments, the process further comprises dry granulating the blend before it is filled into capsules. In some embodiments, a lubricant is added before and / or after the dry granulation step.

[0203] In some embodiments, the process comprises the following steps:

[0204] (a) blending the solid dispersion with one or more pharmaceutical excipients;

[0205] (b) adding lubricant and blending;

[0206] (c) dry granulating;

[0207] (d) adding further lubricant and blending; and

[0208] (e) filling the blend into capsules.In some embodiments, the one or more pharmaceutical excipients comprises a filler and a disintegrant. In some embodiments, the filler is mannitol and microcrystalline cellulose, optionally mannitol and microcrystalline cellulose in a ratio of between 6 : 1 and 2 : 1 by weight, for example a ratio of 4 : 1 by weight, and / or the filler is present at from about 40 to about 95 wt %, or from about 50 to about 85 wt%. In some embodiments, the disintegrant is sodium croscarmellose, and / or the disintegrant is present at from about 1 to about 10 wt %, or from about 4 to about 6 wt %. In some embodiments, the lubricant is magnesium stearate, and / or the lubricant at from about 0.1 to about 5 wt %, or from about 0.5 to about 1.5 wt %.

[0209] In some embodiments, the process is a process for preparing a capsule containing a fill composition comprising (i) a solid dispersion comprising Compound A, or a pharmaceutically acceptable salt thereof, and a polymer, (ii) a filler, (iii) a disintegrant, and (iv) a lubricant. The process comprises one or more of the following steps:

[0210] (1) Measuring out each of the ingredients onto a weight boat or the like;

[0211] (2) Adding filler, disintegrant, and solid dispersion to a blender to form a pre-mix 1;

[0212] preferably in the following order: 50-70 wt% of the filler, the disintegrant, the solid dispersion, and the 30-50 wt% of the filler;

[0213] (3) Blending the pre-mix 1, optionally for about 5-15 minutes (for example about 10 minutes), and optionally wherein the pre-mix 1 is blended at about 15-25 RPM (for example at about 20 RPM)

[0214] (4) Adding a first portion of the lubricant to form pre-mix 2, optionally lubricant previously sieved through a 0.630 mm manual sieve

[0215] (5) Blending the pre-mix 2, optionally for about 3-7 minutes (for example about 5 minutes), and optionally wherein the pre-mix 2 is blended at about 15-25 RPM (for example at about 20 RPM)

[0216] (6) Dry granulating pre-mix 2, optionally wherein the dry granulation is roller compaction

[0217] (7) Adding a second portion of the lubricant to form the final blend, optionally lubricant previously sieved through a 0.630 mm manual sieve, and optionally wherein the amount of the second portion of the lubricant is recalculated based on the intragranular yield obtained

[0218] (8) Blending the final blend, optionally for about 3-7 minutes (for example about 5 minutes), and optionally wherein the final blend is blended at about 15-25 RPM (for example at about 20 RPM)

[0219] (9) Filling the final blend into capsules

[0220] In some embodiments, the process comprises all of steps (l)-(9).

[0221] In some embodiments, the capsule prepared has one or more of the following features: (i) the polymer is a hydroxypropylmethylcellulose (HPMC) derivative, for example hydroxypropylmethylcellulose (HPMCAS), for example HPMCAS MG;(ii) the filler is mannitol and microcrystalline cellulose, optionally mannitol and microcrystalline cellulose in a ratio of between 6 : 1 and 2 : 1 by weight, for example a ratio of 4 : 1 by weight;

[0222] (iii) the disintegrant is sodium croscarmellose;

[0223] (iv) the lubricant is magnesium stearate;

[0224] (v) the solid dispersion makes up less than 15% by weight of the fill composition; (vi) the fill composition comprises the filler at from about 40 to about 95 wt %, or from about 50 to about 85 wt%;

[0225] (vii) the fill composition comprises the disintegrant at from about 1 to about 10 wt %, or from about 4 to about 6 wt %;

[0226] (viii) the fill composition comprises the lubricant at from about 0.1 to about 5 wt %, or from about 0.5 to about 1.5 wt %;

[0227] (ix) the fill composition comprises 5 mg of Compound A;

[0228] (x) the fill composition comprises 20 mg of Compound A; and

[0229] (xi) the fill composition comprises 50 mg of Compound A.

[0230] In some embodiments, the tablet prepared has features (i)-(iv). In some embodiments, the tablet prepared has features (v)-(viii). In some embodiments, the tablet prepared has features (i)-(viii). In some embodiments, the tablet prepared has features (i)-(v) and (ix). In some embodiments, the tablet prepared has features (i)-(v) and (x). In some embodiments, the tablet prepared has features (i)-(v) and (xi). In some embodiments, the tablet prepared has features (i)-(viii) and (ix). In some embodiments, the tablet prepared has features (i)-(viii) and (x). In some embodiments, the tablet prepared has features (i)-(viii) and (xi).

[0231] In some embodiments, the fill composition has the following composition:

[0232]

[0233] In some embodiments, the fill compositions described above comprise between 1 mg and 10 mg of Compound A, preferably 5 mg of Compound A.

[0234] In some embodiments, the composition has the following composition:

[0235]

[0236] In some embodiments, the fill compositions described above comprise between 10 mg and 30 mg of Compound A, preferably 20 mg of Compound A. In some embodiments, the fill compositions described above comprise between 40 mg and 60 mg, preferably 50 mg of Compound A.

[0237] Crystalline forms

[0238] Provided herein are crystalline forms of Compound A or a pharmaceutically acceptable salt thereof.

[0239] The crystalline forms are characterised by X-ray powder diffraction (XRPD) using Cu Ka radiation in the 20 region. Each crystalline form has an XRPD pattern with XRPD peaks at approximately (± 0.2) the listed 20 (°) values, preferably at approximately (± 0.1) the listed 20 (°) values. The crystalline forms are also characterised by unit cell parameters, which are determined from the diffraction data.

[0240] The crystalline forms are also characterised by differential scanning calorimetry (DSC) and thermogravimetric analysis at a heating rate of 10°C / min.

[0241] The crystalline forms are also characterised by being obtainable from certain solvents. It will be understood that “being obtainable from” means that the crystalline form may be prepared in the listed solvent.

[0242] Crystalline forms of Compound A (free form)

[0243] In some embodiments, the crystalline form is a crystalline form of the free form of Compound A. Preferably, crystalline Compound A is provided as a mixture of enantiomers, preferably a racemic mixture.

[0244] Form I

[0245] The crystalline form may be Form I of Compound A. Form I is characterised by one or more of the following properties:

[0246] a) a DSC profile comprising a major endotherm with peak temperature at around (±1.0) 192.7 °C;b) a DSC profile that is substantially the same as shown in Figure 3;

[0247] c) an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 7.0, 9.9, 16.6, 18.9, 26.5, and 28.0;

[0248] d) an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 7.0, 9.9, 12.1, 15.4, 16.6, 17.1, 18.9, 21.0, 26.5, and 28.0;

[0249] e) an XRPD pattern that is substantially the same as shown in Figure 4;

[0250] f) a TGA thermogram that is substantially the same as shown in Figure 3;

[0251] g) the following unit cell parameters at 296 K: a is 6.65 ± 0.01 A, b is 22.14 ± 0.01 A, c is 15.79 ± 0.01 A, a = y = 90°, and is 96.95 ± 0.10 °;

[0252] h) a unit cell volume at 296 K of approximately (± 5) 2308 A3; and

[0253] i) being obtainable from isopropyl acetate.

[0254] Form I may be characterised by at least a). Form I may be characterised by at least b). Form I may be characterised by at least c). Form I may be characterised by at least d). Form I may be characterised by at least e). Form I may be characterised by at least f). Form I may be characterised by at least g). Form I may be characterised by at least h). Form I may be characterised by at least i). Preferably, Form I is characterised by at least a).

[0255] Form I may be characterised by at least a) and c). Form I may be characterised by at least a) and d). Form I may be characterised by at least a), c), and g). Form I may be characterised by at least a), d), and g). Form I may be characterised by at least a), c), and i). Form I may be characterised by at least a), d), and i). Preferably, Form I may be characterised by at least a) and c).

[0256] Form I is a non-hygroscopic anhydrate of irregular shape and high crystallinity. The XRPD pattern for Form I is shown in Figure 4. Form I has characterising peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 7.0, 9.9, 16.6, 18.9, 26.5, and 28.0. Form I may have characterising peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 7.0, 9.9, 12.1, 15.4, 16.6, 17.1, 18.9, 21.0, 26.5, and 28.0. Form I may have characterising peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 7.0, 9.9, 12.1, 13.9, 15.4, 16.6, 17.1, 17.5, 18.9, 21.0, 22.8, 23.2, 26.5, and 28.0.

[0257] The DSC profile for Form I is shown in Figure 3. It shows a major endothermic peak at 192.7 °C (onset at 188.4 °C) relating to the melting of Form I, an exothermic peak at 198.1 °C (onset at 196.5 °C) relating to the crystallisation into Form III, and a major endothermic peak at 212.9 °C (onset at 210.7 °C) relating to the melting of Form III.

[0258] The TGA profile for Form I is shown in Figure 3. It shows no significant weight loss before 120 °C, and a small weight loss of 0.252 wt% from 120 °C to 210 °C.

[0259] Form II

[0260] The crystalline form may be Form II of Compound A. Form II is characterised by one or more of the following properties:a) a DSC profile comprising a major endotherm with peak temperature at around (±1.0) 204.5 °C;

[0261] b) a DSC profile that is substantially the same as shown in Figure 5;

[0262] c) an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 6.9, 9.8, 15.1, 16.6, 20.5, and 27.7;

[0263] d) an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 6.9, 9.8, 11.915.1, 16.6, 19.2, 20.5, 22.5, and 27.7; e) an XRPD pattern that is substantially the same as shown in Figure 6;

[0264] f) a TGA thermogram that is substantially the same as shown in Figure 5;

[0265] g) the following unit cell parameters at 296 K: a is 6.12 ± 0.01 A, b is 22.20 ± 0.01 A, c is 15.85 ± 0.01 A, a = y = 90°, and is 92.90 ± 0.10 °;

[0266] h) a unit cell volume at 296 K of approximately (± 5) 2150 A3; and

[0267] i) being obtainable from acetone.

[0268] Form II may be characterised by at least a). Form II may be characterised by at least b). Form II may be characterised by at least c). Form II may be characterised by at least d). Form II may be characterised by at least e). Form II may be characterised by at least I). Form II may be characterised by at least g). Form II may be characterised by at least h). Form I may be characterised by at least i). Preferably, Form II is characterised by at least a).

[0269] Form II may be characterised by at least a) and c). Form II may be characterised by at least a) and d). Form II may be characterised by at least a), c), and g). Form II may be characterised by at least a), d), and g). Form II may be characterised by at least a), c), and i). Form II may be characterised by at least a), d), and i).

[0270] Form II is a non-hygroscopic anhydrate of irregular shape and high crystallinity. Figure 15 shows that Form II exists as fine needles, which reduces filterability and ease of drying.

[0271] The XRPD pattern for Form II is shown in Figure 6. Form II has characterising peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 6.9, 9.8, 15.1, 16.6, 20.5, and 27.7. Form II may have characterising peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 6.9, 9.8, 11.9 15.1, 16.6, 19.2, 20.5, 22.5, and 27.7. Form II may have characterising peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 6.9, 9.8, 11.9 15.1, 16.6, 17.0, 19.2, 19.6, 20.5, 22.5, 23.2, and 27.7.

[0272] The DSC profile for Form II is shown in Figure 5. It shows a major endothermic peak at 202.0 °C (onset at 204.5 °C) relating to the melting of Form II.

[0273] The TGA profile for Form II is shown in Figure 5. It shows no significant weight loss before the melting of Form II.

[0274] Form III

[0275] Preferably, the crystalline form is Form III of Compound A. Form III is characterised by one or more of the following properties:a) a DSC profile comprising a major endotherm with peak temperature at around (±1.0) 213.2 °C;

[0276] b) a DSC profile that is substantially the same as shown in Figure 7;

[0277] c) an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 8.3, 9.0, 9.7, 13.2, 14.3, and 24.6;

[0278] d) an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 8.3, 9.0, 9.7, 13.2, 14.3, 23.0, 24.6, 25.7, and 27.5; e) an XRPD pattern that is substantially the same as shown in Figure 8;

[0279] f) a TGA thermogram that is substantially the same as shown in Figure 7;

[0280] g) the following unit cell parameters at 296 K: a is 11.59 ± 0.01 A, b is 9.94 ± 0.01 A, c is 20.02 ± 0.01 A, a = y = 90°, and is 100.41 ± 0.10 °;

[0281] h) a unit cell volume at 296 K of approximately (± 5) 2268 A3; and

[0282] i) being obtainable from dimethylformamide.

[0283] Form III may be characterised by at least a). Form III may be characterised by at least b). Form III may be characterised by at least c). Form III may be characterised by at least d). Form III may be characterised by at least e). Form III may be characterised by at least f). Form III may be characterised by at least g). Form III may be characterised by at least h). Form III may be characterised by at least i). Preferably, Form III is characterised by at least c).

[0284] Form III may be characterised by at least a) and c). Form III may be characterised by at least a) and d). Form III may be characterised by at least c) and g). Form III may be characterised by at least d) and g). Form III may be characterised by at least c) and i). Form III may be characterised by at least d) and i). Form III may be characterised by at least a), c), and g). Form III may be characterised by at least a), d), and g). Form III may be characterised by at least a), c), and i). Form III may be characterised by at least a), d), and i). Form III may be characterised by at least c), g) and i). Form III may be characterised by at least d), g) and i).

[0285] Form III is a stable non-hygroscopic anhydrate of irregular shape and high crystallinity. Figure 15 shows that Form III exists as grain-like particles, which improves filterability and ease of drying compared to other forms of Compound A. Form III is polymorphically stable, in particular with respect to Forms I and IV and Compound A HC1 co-Forms V and VI. Form III also has good solubility in polar solvents such as water / acetone, in particular compared to Form II.

[0286] The XRPD pattern for Form III is shown in Figure 8. Form III has characterising peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 8.3, 9.0, 9.7, 13.2, 14.3, and 24.6. Form III may have characterising peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 8.3, 9.0, 9.7, 13.2, 14.3, 23.0, 24.6, 25.7, and 27.5. Form III may have characterising peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 8.3, 9.0, 9.7, 13.2, 14.3, 16.9, 20.4, 22.5, 23.0, 24.6, 25.7, and 27.5.The DSC profile for Form III is shown in Figure 7. It shows a major endothermic peak at 213.2 °C (onset at 211.5 °C) relating to the melting of Form III.

[0287] The TGA profile for Form III is shown in Figure 7. It shows no significant weight loss before the melting of Form III.

[0288] Form IV

[0289] The crystalline form may be Form IV of Compound A. Form IV is characterised by one or more of the following properties:

[0290] a) a DSC profile comprising an endotherm with peak temperature at around (±1.0) 169.3 °C;

[0291] b) a DSC profile that is substantially the same as shown in Figure 9;

[0292] c) an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 9.0, 13.6, 14.5, 18.4, 20.2, and 21.1; d) an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 9.0, 13.6, 14.5, 18.4, 20.2, 21.1, 22.7, 24.3, and 30.6;

[0293] e) an XRPD pattern that is substantially the same as shown in Figure 10;

[0294] 1) a TGA thermogram that is substantially the same as shown in Figure 9; and g) being obtainable from acetic acid and water in a volume ratio of 1 :21.

[0295] Form IV may be characterised by at least a). Form IV may be characterised by at least b). Form IV may be characterised by at least c). Form IV may be characterised by at least d). Form IV may be characterised by at least e). Form IV may be characterised by at least 1). Form IV may be characterised by at least g). Preferably, Form IV is characterised by at least c).

[0296] Form IV may be characterised by at least a) and c). Form IV may be characterised by at least a) and d). Form IV may be characterised by at least c) and g). Form IV may be characterised by at least d) and g). Form IV may be characterised by at least a), c), and g). Form IV may be characterised by at least a), d), and g).

[0297] The XRPD pattern for Form IV is shown in Figure 10. Form III has characterising peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 9.0, 13.6, 14.5, 18.4, 20.2, and 21.1. Form III may have characterising peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 9.0, 13.6, 14.5, 18.4, 20.2, 21.1, 22.7, 24.3, and 30.6. Form III may have characterising peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 9.0, 13.6, 14.5, 18.4, 18.7, 20.2, 21.1, 22.7, 24.3, 27.4, 30.6, 36.2, and 37.4.

[0298] The DSC profile for Form IV is shown in Figure 9. It shows an endothermic peak at 169.3 °C (onset at 159.8 °C), and a major endothermic peak at 210.8 °C (onset at 209.0 °C) relating to the melting of Form III.The TGA profile for Form IV is shown in Figure 9. It shows weight loss of 0.429 wt% from 30 °C to 188 °C.

[0299] Crystalline co-forms of Compound A HC1

[0300] In some embodiments, the crystalline form is a crystalline co-form of Compound A and a different compound. In a preferred embodiment, the crystalline form is a crystalline coform of Compound A and hydrochloric acid.

[0301] Compound A HCl co-Form V

[0302] The crystalline form may be Compound A HCl co-Form V of Compound A. Compound A HCl co-Form V is characterised by one or more of the following properties:

[0303] a) a DSC profile comprising a major endotherm with peak temperature at around (±1.0) 176.8 °C;

[0304] b) a DSC profile that is substantially the same as shown in Figure 11;

[0305] c) an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 7.3, 11.3, 14.5, 18.3, 22.5, and 26.7; d) an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 7.3, 11.3, 14.5, 18.0, 18.3, 22.5, 26.7, 29.6, and 30.9;

[0306] e) an XRPD pattern that is substantially the same as shown in Figure 12;

[0307] 1) a TGA thermogram that is substantially the same as shown in Figure 11 ; g) a free base to hydrochloric acid stoichiometric ratio of 1 : 0.88; and

[0308] h) being obtainable from 1.05 equivalents of hydrochloric acid in acetonitrile solvent.

[0309] Compound A HCl co-Form V may be characterised by at least a). Compound A HCl co-Form V may be characterised by at least b). Compound A HCl co-Form V may be characterised by at least c). Compound A HCl co-Form V may be characterised by at least d). Compound A HCl co-Form V may be characterised by at least e). Compound A HCl coForm V may be characterised by at least 1). Compound A HCl co-Form V may be characterised by at least g). Compound A HCl co-Form V may be characterised by at least h). Preferably, Compound A HCl co-Form V is characterised by at least c).

[0310] Compound A HCl co-Form V may be characterised by at least a) and c). Compound A HCl co-Form V may be characterised by at least a) and d). Compound A HCl co-Form V may be characterised by at least c) and g). Compound A HCl co-Form V may be characterised by at least d) and g). Compound A HCl co-Form V may be characterised by at least c) and h). Compound A HCl co-Form V may be characterised by at least d) and h). Compound A HCl co-Form V may be characterised by at least a), c), and g). Compound A HCl co-Form V may be characterised by at least a), d), and g). Compound A HCl co-Form V may be characterised by at least a), c), and h). Compound A HCl co-Form V may be characterisedby at least a), d), and h). Compound A HC1 co-Form V may be characterised by at least c), g) and h). Compound A HC1 co-Form V may be characterised by at least d), g) and h).

[0311] The XRPD pattern for Compound A HC1 co-Form V is shown in Figure 12. Compound A HC1 co-Form V has characterising peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 7.3, 11.3, 14.5, 18.3, 22.5, and 26.7. Compound A HC1 co-Form V may have characterising peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 7.3, 11.3, 14.5, 18.0, 18.3, 22.5, 26.7, 29.6, and 30.9. Compound A HC1 co-Form V may have characterising peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 7.3, 11.3, 14.5, 18.0, 18.3, 21.8, 22.5, 24.1, 26.4, 26.7, 29.6, and 30.9.

[0312] The DSC profile for Compound A HC1 co-Form V is shown in Figure 11. It shows a major endothermic peak at 176.8 °C (onset at 157.7 °C), and a further major endothermic peak at 212.6 °C (onset at 211.1 °C) relating to the melting of Form III.

[0313] The TGA profile for Compound A HC1 co-Form V is shown in Figure 11. It shows weight loss of 4.644 wt% from 60 °C to 160 °C and weight loss of 2.113 wt% from 165 °C to 225 °C.

[0314] Compound A HCl co-Form VI

[0315] The crystalline form may be Compound A HCl co-Form VI of Compound A. Compound A HCl co-Form VI is characterised by one or more of the following properties:

[0316] a) a DSC profile comprising an endotherm with peak temperature at around (±1.0) 171.9 °C;

[0317] b) a DSC profile that is substantially the same as shown in Figure 13;

[0318] c) an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 10.6, 12.0, 15.4, 21.3, 23.2, and 27.4; d) an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 10.6, 12.0, 13.5, 15.4, 16.1, 19.4, 21.3, 23.2, and 27.4;

[0319] e) an XRPD pattern that is substantially the same as shown in Figure 14;

[0320] 1) a TGA thermogram that is substantially the same as shown in Figure 13; g) a free base to hydrochloric acid stoichiometric ratio of 1 : 1.02; and

[0321] h) being obtainable from 2.05 equivalents of hydrochloric acid in 2- methyltetrahydrofuran solvent.

[0322] Compound A HCl co-Form VI may be characterised by at least a). Compound A HCl co-Form VI may be characterised by at least b). Compound A HCl co-Form VI may be characterised by at least c). Compound A HCl co-Form VI may be characterised by at least d). Compound A HCl co-Form VI may be characterised by at least e). Compound A HCl coForm VI may be characterised by at least 1). Compound A HCl co-Form VI may be characterised by at least g). Compound A HCl co-Form VI may be characterised by at least h). Preferably, Compound A HCl co-Form VI is characterised by at least c).Compound A HC1 co-Form VI may be characterised by at least a) and c). Compound A HC1 co-Form VI may be characterised by at least a) and d). Compound A HC1 co-Form VI may be characterised by at least c) and g). Compound A HC1 co-Form VI may be characterised by at least d) and g). Compound A HC1 co-Form VI may be characterised by at least c) and h). Compound A HC1 co-Form VI may be characterised by at least d) and h). Compound A HC1 co-Form VI may be characterised by at least a), c), and g). Compound A HC1 co-Form VI may be characterised by at least a), d), and g). Compound A HC1 co-Form VI may be characterised by at least a), c), and h). Compound A HC1 co-Form VI may be characterised by at least a), d), and i). Compound A HC1 co-Form VI may be characterised by at least c), g) and h). Compound A HC1 co-Form VI may be characterised by at least d), g) and h).

[0323] The XRPD pattern for Compound A HC1 co-Form VI is shown in Figure 14. Compound A HC1 co-Form VI has characterising peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 10.6, 12.0, 15.4, 21.3, 23.2, and 27.4. Compound A HC1 co-Form VI may have characterising peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 10.6, 12.0, 13.5, 15.4, 16.1, 19.4, 21.3, 23.2, and 27.4. Compound A HC1 co-Form VI may have characterising peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 10.6, 12.0, 13.5, 15.4, 16.1, 17.8, 19.4, 21.3, 23.2, 25.5, 27.4, and 31.2.

[0324] The DSC profile for Compound A HC1 co-Form VI is shown in Figure 13. It shows an endothermic peak at 171.9 °C (onset at 166.7 °C), and a further major endothermic peak at 212.8 °C (onset at 211.3 °C) relating to the melting of Form III.

[0325] The TGA profile for Compound A HC1 co-Form VI is shown in Figure 13. It shows weight loss of 4.150 wt% from 90 °C to 165 °C and weight loss of 3.134 wt% from 195 °C to 240 °C.

[0326] In some embodiments, the crystalline form is selected from Form I, Form II, Form III, and Form VI. In some embodiments, the crystalline form is selected from Form II and Form III. In some embodiments, the crystalline form is selected from Compound A HC1 coForm V and Compound A HC1 co-Form VI.

[0327] In some embodiments, the crystalline form is Form I. In some embodiments, the crystalline form is Form II. In some embodiments, the crystalline form is Form III. In some embodiments, the crystalline form is Form IV. In some embodiments, the crystalline form is Compound A HC1 co-Form V. In some embodiments, the crystalline form is Compound A HC1 co-Form VI. Preferably, the crystalline form is Form III.

[0328] Alternatively, provided herein are amorphous forms of Compound A or a pharmaceutically acceptable salt thereof. Preferably, the invention provides amorphous Compound A in free form.Methods of use

[0329] The solid dispersions, dosage forms, crystalline forms, and amorphous forms provided herein can be used in the treatment of disorders in subjects in need thereof. Said disorders include, but are not limited to, those disorders caused by or associated with NLRP3 inflammasome activation.

[0330] Compound A can act as a degrader of NIMA-Related Kinase 7 (NEK7). NEK7 is an activator of the NLRP3 inflammasome, a central regulator of cellular inflammatory responses to pathogens, damage and stress. The NLRP3 inflammasome is a multiprotein complex that serves as a central node to integrate cellular signals generated by pathogens, damage and stress, and triggers the generation of pro-inflammatory cytokines. The assembly of NLRP3 / NEK7 with ASC and pro-caspase 1 in a multi-protein complex induces cleavage of pro-caspase 1, which then activates multiple inflammatory responses including secretion or release of the cytokines interleukin- ip and interleukin- 18 and induction of pyroptosis. Additionally, multiple activating NLRP3 mutations have been shown to be associated with Cryopyrin-associated periodic syndromes.

[0331] NEK7, a serine / threonine-protein kinase, activates the NLRP3 inflammasome in a kinase independent manner. Increased (e.g., excessive) NLRP3 inflammasome activation has been implicated in the pathogenesis of several of the disorders described herein (e.g., disorders of the immune system, hematopeoitic systemjoints, renal system, gastro-intestinal tract, skin, eye, respiratory system, central nervous system, cardiovascular system, hepatic system, and / or endocrine system). In certain embodiments, the increased (e.g., excessive) NLRP3 inflammasome activation is chronically increased (e.g., excessive) NLRP3 inflammasome activation. In certain embodiments, the NLRP3 / NEK7 inflammasome activation is occurring in the brain or central nervous system (CNS), thereby requiring CNS penetration and exposure of any therapeutic agent targeting this inflammasome. NEK7 binding to NLRP3 has been shown to be involved in promoting the assembly of the NLRP3 inflammasome. While not wishing to be bound by theory, by being able to degrade NEK7, the compounds described herein may be used to treat disorders caused by or associated with increased (e.g., excessive) NLRP3 inflammasome activation.

[0332] Accordingly, in one embodiment, described herein is a method of treating a disorder caused by or associated with NLRP3 inflammasome activation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of (i) a solid dispersion described herein, (ii) a dosage form described herein, such as a solid dosage form, (iii) a crystalline form of Compound A, or a pharmaceutically acceptable salt thereof, described herein, or (iv) an amorphous form of Compound A, or a pharmaceutically acceptable salt thereof, described herein.

[0333] Preferably, the disorder is gout.

[0334] In some embodiments, the disorder is pericarditis.In some embodiments, the disorder is Wilson disease, also known as Wilson’s disease.

[0335] In some embodiments, the disorder is a disorder of the immune system, hematopeoitic system, joints, renal system, gastro-intestinal tract, skin, eye, respiratory system, central nervous system, cardiovascular system, hepatic system, and / or endocrine system.

[0336] In some embodiments, the disorder is an autoinflammatory or autoimmune disorder. In certain of these embodiments, the disorder is gout (e.g., acute and chronic gout, tophaceous gout, or pseudo-gout).

[0337] In certain of these embodiments, the disorder is inflammatory bowel disease.

[0338] In certain of these embodiments, the disorder is rheumatoid arthritis.

[0339] In certain of these embodiments, the disorder is multiple sclerosis.

[0340] In some embodiments, the disorder is a neurodegenerative disorder (e.g., Alzheimer's disease).

[0341] Preferably, the disorder is a cardiovascular or metabolic disorder (e.g., pericarditis, atherosclerosis, Type 2 diabetes, obesity or metabolic syndrome).

[0342] In some embodiments, the disorder is a fibrotic disorder (e.g., interstitial lung disease or chronic kidney disease).

[0343] In some embodiments, the disorder is a disorder associated with hematology (e.g., anemia of inflammation).

[0344] In some embodiments, the disorder is an eye disorder (e.g., macular degeneration). In some embodiments, the disorder is a disorder of the immune system, hematopeoitic system, joints, renal system, gastro-intestinal tract, skin, eye, respiratory system, central nervous system, cardiovascular system, hepatic system, and / or endocrine system.

[0345] In some embodiments, the disorder is a cancer, tumour or other malignancy.

[0346] In some embodiments, the disorder is selected from the group consisting of

[0347] (i) inflammatory reactions in the joints including acute and chronic gout, tophaceous gout, pseudo-gout, osteoarthritis, psoriatic arthritis, systemic juvenile idiopathic arthritis, adult-onset Still’s disease, relapsing polychondritis, tendonitis, frozen shoulder and pyogenic arthritis;

[0348] (ii) hyperactive inflammation with underlying genetic mutations, including autoinflammatory diseases such as cryopyrin-associated periodic syndrome (CAPS): Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS) and neonatal-onset multisystem inflammatory disease (NOMID); familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MVK), hyperimmunoglobuliemia D and periodic fever syndrome (HIDS), deficiency of interleukin1 receptor (DIRA) antagonist), VEXAS syndrome, Majeed syndrome, pyoderma gangrenosum, acne and hidradenitis suppurative syndrome, haploinsufficency of A20, pediatric granulomatous arthritis (PGA), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD), Sweet’s syndrome, chronic non-bacterial osteomyelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO) and any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3 orNEK7

[0349] (iii) autoimmune diseases including multiple sclerosis (MS), rheumatoid arthritis, Behcet’s disease, Sjogren’s syndrome, systemic sclerosis, mixed connective tissue disease, myositis, vasculitis, lupus, including systemic and cutaneous forms, lupus nephritis, type-1 diabetes, psoriasis and Schnitzler’s syndrome, Grave’s disease, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, microscopic polyangiitis, inflammatory bowel disease, colitis, Crohn’s disease;

[0350] (iv) respiratory diseases including chronic obstructive pulmonary disorder (COPD), acute respiratory distress syndrome (ARDS), steroid-resistant asthma, asbestosis, silicosis, sarcoidosis, cystic fibrosis and interstitial lung disease (ILD), including, but not limited to idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis, rheumatoid arthritis-associated ILD, autoimmune myositis-associated ILD, systemic sclerosis-associated ILD, idiopathic interstitial pneumonia and progressive fibrosing ILD;

[0351] (v) kidney disease including chronic kidney disease (CKD), including CKD associated with high uric acid, APOL1 mutations, complement-mediated kidney diseases such as C3 glomerulopathy, IgA nephropathy, atypical hemalytic uremic syndrome and membranous nepropathy, idiopathic nephrotic syndrome, oxalate nephropathy and diabetic nephropathy;

[0352] (vi) central nervous system diseases including Parkinson’s disease, Alzheimer’s disease, motor neuron disease, Huntington’s disease, cerebral malaria, post-traumatic brain injury, sub-arachnoid hemorrhage and brain injury from pneumococcal meningitis, cerebral amyloid angiopathy, migraine, depression, psychological stress;

[0353] (vii) ocular diseases including those of the ocular epithelium, age-related macular degeneration (AMD), comeal infection, uveitis and dry eye;

[0354] (viii) cardiovascular diseases including myocarditis, inflammatory cardiomyopathy, atherosclerosis, stroke, myocardial infarction, hypertension, abdominal aortic aneurism, pericarditis including Dressier’s syndrome, thromboembolism, ischemia reperfusion injury, transthyretin amyloidosis, vasculitis;(ix) viral infections and subsequent immune hyperactivation including alphavirus including Chikungunya and Ross River virus, and flavivirus including Dengue and Zika viruses, COVID-19 / SARS-CoV-2, influenza, HIV;;

[0355] (x) diseases of the hematopoietic system including anemia of inflammation (anemia of chronic disease), paroxysmal nocturnal hemaglobinuria (PNH), sickle cell disease;

[0356] (xi) liver disease including non-alcoholic steatohepatitis, alcoholic liver disease and drug-induced liver injury;

[0357] (xii) inflammatory reactions in the skin including contact hypersensitivity and sunbum, psoriasis, hidradenitis suppurativa (HS) and other cyst-causing skin diseases, dermatomyositis, pemphigus, pyoderma gangrenosum;

[0358] (xiii) metabolic diseases including obesity, metabolic syndrome, and Type 2 diabetes and related morbidities including diabetic foot ulcers, atherosclerosis, obesity, diabetic cardiomyopathy, Wilson disease, and diabetic retinopathy;

[0359] (xiv) cancers including lung cancer and lung cancer metastasis, pancreatic cancers, gastric cancers, myelodysplastic syndrome, leukemia and melanoma; polymyositis; graft-versus-host disease and transplant rejection;

[0360] (xv) infectious diseases including bacterial infections, including Clostridium species, viral infections, helminth infections; wound healing; sepsis; gangrene; and

[0361] (xvi) allergic diseases and Type 2 inflammation-associated diseases including asthma, atopic dermatitis, eosinophilic esophagitis, chronic obstructive pulmonary disease, chronic sinusitis, nasal polyps.

[0362] In another embodiment, described herein is a method of degrading NIMA Related Kinase 7 (NEK7) in a subject suffering from any one or more of the disorders described herein, comprising administering to the subject an effective amount of (i) a solid dispersion described herein, (ii) a dosage form described herein, such as a solid dosage form, (iii) a crystalline form of Compound A, or a pharmaceutically acceptable salt thereof, described herein, or (iv) an amorphous form of Compound A, or a pharmaceutically acceptable salt thereof, described herein.

[0363] In an aspect, the disclosure provides (i) a solid dispersion described herein, (ii) a dosage form described herein, such as a solid dosage form, (iii) a crystalline form of Compound A, or a pharmaceutically acceptable salt thereof, described herein, or (iv) an amorphous form of Compound A, or a pharmaceutically acceptable salt thereof, described herein for use in any of the above-recited methods of treatment. In some embodiments, the disclosure provides a dosage form described herein, such as a solid dosage form, for use in any of the above-recited methods of treatment. In some embodiments, the disclosure provides a solid dispersion described herein for use in any of the above-recited methods of treatment. In some embodiments, the disclosure provides a crystalline form of Compound A, or apharmaceutically acceptable salt thereof, described herein for use in any of the above-recited methods of treatment. In some embodiments, the disclosure provides an amorphous form of Compound A, or a pharmaceutically acceptable salt thereof, described herein for use in any of the above-recited methods of treatment.

[0364] In a further aspect, the disclosure provides the use of (i) a solid dispersion described herein, (ii) a dosage form described herein, such as a solid dosage form, (iii) a crystalline form of Compound A, or a pharmaceutically acceptable salt thereof, described herein, or (iv) an amorphous form of Compound A, or a pharmaceutically acceptable salt thereof, described herein for the manufacture of a medicament for any of the above-recited methods of treatment.

[0365] Accordingly, in one embodiment, described herein is a method of treating a disorder caused by or associated with NLRP3 inflammasome activation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of (i) a solid dispersion described herein, (ii) a dosage form described herein, such as a solid dosage form, (iii) a crystalline form of Compound A, or a pharmaceutically acceptable salt thereof, described herein, or (iv) an amorphous form of Compound A, or a pharmaceutically acceptable salt thereof, described herein.

[0366] NUMBERED EMBODIMENTS

[0367] The invention can be described further by the following enumerated embodiments.

[0368] Embodiments

[0369] 1. A solid dosage form comprising Compound A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein Compound A is a compound of the following formula:

[0370]

[0371] 2. The solid dosage form of embodiment 1, wherein the solid dosage form is for oral administration.

[0372] 3. The solid dosage form of embodiment 1 or embodiment 2, wherein the solid dosage form comprises a solid dispersion comprising Compound A and a polymer.

[0373] 4. The solid dosage form of embodiment 3, wherein the polymer is selected from the group consisting of: enteric polymers (such as methacrylate polymers, hydroxypropyl methyl cellulose phthalate (HPMCP), and cellulose acetyate phthalate (CAP)), hydrophilic polymers (such as starch, sodium carboxymethyl cellulose, sodiumalginate, polyethylene glycol (PEG), polyvinyl pyrrolidone (PVP), hydroxy propyl methyl cellulose (HPMC), polyvinyl alcohol (PVA), P-cyclodextrin, mannitol, chitosan, and carrageenan), and amphiphilic polymers (such as polyethylene oxides (PEO)Zpolypropylene glycol (PPG) copolymers, PEG-modified starches, vinyl acetate / vinylpyrrolidone random copolymers, polyacrylic acid, and polyacrylates), and a combination thereof.

[0374] 5. The solid dosage form of embodiment 3 or embodiment 4, wherein the polymer is hydroxy propyl methyl cellulose acetate succinate (HPMCAS).

[0375] 6. The solid dosage form of any one of embodiments 3-5, wherein the polymer is medium grade hydroxy propyl methyl cellulose acetate succinate (HPMCAS MG) and / or high grade hydroxy propyl methyl cellulose acetate succinate (HPMCAS HG).

[0376] 7. The solid dosage form of any one of embodiments 3-6, wherein the polymer is medium grade hydroxy propyl methyl cellulose acetate succinate (HPMCAS MG).

[0377] 8. The solid dosage form of any one of embodiments 3-7, wherein the solid dispersion comprises Compound A and the polymer at a ratio of between 1:5 and 1 : 1 by weight.

[0378] 9. The solid dosage form of any one of embodiments 3-8, wherein the solid dispersion comprises Compound A and the polymer at a ratio of 1 :3 or 1 :2 by weight.

[0379] 10. The solid dosage form of any one of embodiments 3-9, wherein the solid dispersion comprises Compound A and the polymer at a ratio of 1 :3 by weight.

[0380] 11. The solid dosage form of any one of embodiments 3-10, wherein the solid dispersion makes up less than 50% by weight of the dosage form.

[0381] 12. The solid dosage form of any one of the preceding embodiments, wherein the amount of Compound A is:

[0382] (i) between 0.1 mg and 500 mg;

[0383] (ii) between 0.1 mg and 300 mg;

[0384] (iii) between 0.1 mg and 250 mg;

[0385] (iv) between 0.1 mg and 200 mg;

[0386] (v) between 0.1 mg and 150 mg;

[0387] (vi) between 0.1 mg and 100 mg;

[0388] (vii) between 0.1 mg and 80 mg;

[0389] (viii) between 0.1 mg and 60 mg;

[0390] (ix) between 1 mg and 250 mg

[0391] (x) between 1 mg and 200 mg;

[0392] (xi) between 1 mg and 150 mg;

[0393] (xii) between 1 mg and 100 mg;

[0394] (xiii) between 1 mg and 80 mg;

[0395] (xiv) between 1 mg and 60 mg;

[0396] (xv) between 2 mg and 250 mg

[0397] (xvi) between 2 mg and 200 mg;

[0398] (xvii) between 2 mg and 150 mg;

[0399] (xviii) between 2 mg and 100 mg;(xix) between 2 mg and 80 mg;

[0400] (xx) between 2 mg and 60 mg; or

[0401] (xxi) between 2 mg and 25 mg.

[0402] 13. The solid dosage form of any one of the preceding embodiments, wherein the amount of Compound A is between 2 mg and 100 mg, for example, wherein the amount of Compound A is selected from 1 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 80 mg, and 100 mg.

[0403] 14. The solid dosage form of any one of the preceding embodiments, wherein the amount of Compound A is between 2 mg and 80 mg.

[0404] 15. The solid dosage form of any one of the preceding embodiments, wherein the amount of Compound A is between 2 mg and 60 mg.

[0405] 16. The solid dosage form of any one of the preceding embodiments, wherein the amount of Compound A is selected from 5 mg, 20 mg, and 50 mg.

[0406] 17. The solid dosage form of any one of the preceding embodiments, wherein the dosage form comprises:

[0407] (i) less than 50% by weight of Compound A;

[0408] (ii) less than 40% by weight of Compound A;

[0409] (iii) less than 30% by weight of Compound A;

[0410] (iv) less than 20% by weight of Compound A; or

[0411] (v) less than 10% by weight of Compound A.

[0412] 18. The solid dosage form of any one of the preceding embodiments, wherein the total weight of the dosage form is:

[0413] (i) between 5 and 1000 mg;

[0414] (ii) between 50 and 800 mg; or

[0415] (ii) between 100 and 700 mg.

[0416] 19. The solid dosage form of any one of the preceding embodiments, wherein the dosage form comprises:

[0417] (i) two or more pharmaceutically acceptable excipients;

[0418] (ii) three or more pharmaceutically acceptable excipients;

[0419] (iii) four or more pharmaceutically acceptable excipients; or

[0420] (iv) five or more pharmaceutically acceptable excipients.

[0421] 20. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form is a tablet or a capsule.

[0422] 21. The solid dosage form of any one of the preceding embodiments, wherein the solid dosage form is a capsule.

[0423] 22. The solid dosage form of embodiment 20 or embodiment 21, wherein the capsule is a hard capsule.

[0424] 23. The solid dosage form of any one of embodiments 20-22, wherein the capsule is made from hydroxy propyl methyl cellulose (HPMC).The solid dosage form of any one of embodiments 20-23, wherein the capsule contains a fill composition comprising Compound A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0425] The solid dosage form of any one of embodiments 20-24, wherein the tablet or fill composition comprises:

[0426] (i) less than 50% by weight of Compound A;

[0427] (iii) less than 30% by weight of Compound A; or

[0428] (iii) less than 15% by weight of Compound A.

[0429] The solid dosage form of any one of embodiments 20-25, wherein the tablet or fill composition comprises at least one of:

[0430] (i) a filler;

[0431] (ii) a disintegrant;

[0432] (iii) a lubricant;

[0433] (iv) a glidant;

[0434] (v) a binder; and

[0435] (vi) a surfactant.

[0436] The solid dosage form of any one of embodiments 20-26, wherein the tablet or fill composition comprises:

[0437] (i) a filler;

[0438] (ii) a disintegrant; and

[0439] (iii) a lubricant.

[0440] The solid dosage form of embodiment 27, wherein the tablet or fill composition further comprises at least one of:

[0441] (iv) a glidant;

[0442] (v) a binder; and

[0443] (vi) a surfactant.

[0444] The solid dosage form of any one of embodiments 26-28, wherein the filler is present at from about 40 to about 95 wt %, or from about 50 to about 85 wt %.

[0445] The solid dosage form of any one of embodiments 26-29, wherein the filler is selected from the group consisting of: celluloses, modified celluloses (such as sodium carboxymethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropylcellulose, cellulose acetate, microcrystalline cellulose, and silicified microcrystalline cellulose), calcium phosphates (such as dibasic calcium phosphate), starches (such as com starch, and potato starch), sugars (such as mannitol, sorbitol, lactose, and sucrose), and combinations thereof.

[0446] The solid dosage form of any one of embodiments 26-30, wherein the filler is mannitol and microcrystalline cellulose.

[0447] The solid dosage form of any one of embodiments 26-31, wherein the filler is mannitol and microcrystalline cellulose in a ratio of between 6 : 1 and 2 : 1 by weight, for example a ratio of 4 : 1 by weight.33. The solid dosage form of any one of embodiments 26-32, wherein the disintegrant is present at from about 1 to about 10 wt %, or from about 4 to about 6 wt %.

[0448] 34. The solid dosage form of any one of embodiments 26-33, wherein the disintegrant is selected from the group consisting of: starches (such as com starch or potato starch), modified starches (such as pregelatinized starch, sodium starch glycolate, and starch 1500), cellulose derivatives (such as microcrystalline cellulose, sodium croscarmellose, sodium carboxymethyl cellulose, and hydroxypropyl methylcellulose), natural gums (such as guar gum, xanthan gum, and locust bean gum), ion exchange resins (such as polacrilin potassium and Amberlite IRP69), calcium silicates (dicalcium phosphate and tricalcium phosphate), sodium alginate, cross-linked polyvinylpyrrolidone, chitosan, and combinations thereof.

[0449] 35. The solid dosage form of any one of embodiments 26-34, wherein the disintegrant is sodium croscarmellose.

[0450] 36. The solid dosage form of any one of embodiments 26-35, wherein the lubricant is present at from about 0.1 to about 5 wt %, or from about 0.5 to about 1.5 wt %. 37. The solid dosage form of any one of embodiments 26-36, wherein the lubricant is selected from the group consisting of: sodium stearate, magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, polyethylene glycols, beeswax, hydrogenated vegetable oil, and combinations thereof.

[0451] 38. The solid dosage form of any one of embodiments 26-37, wherein the lubricant is magnesium stearate.

[0452] 39. The solid dosage form of any one of embodiments 26-38, wherein the filler is present at from about 40 to about 95 wt %, the disintegrant is present at from about 1 to about 10 wt %, and the lubricant is present at from about 0.1 to about 5 wt %.

[0453] 40. The solid dosage form of any one of embodiments 26-39, wherein the filler is present at from about 50 to about 85 wt %, the disintegrant is present at from about 4 to about 6 wt %, and the lubricant is present from about 0.5 to about 1.5 wt %.

[0454] 41. The solid dosage form of any one of embodiments 26-40, wherein the glidant is selected from the list consisting of colloidal silicon dioxide, talc, magnesium stearate, calcium stearate, com starch, stearic acid, magnesium silicate, aluminium silicate, and combinations thereof.

[0455] 42. The solid dosage form of any one of embodiments 26-41, wherein the binder is selected from the list consisting of starch, acacia, tragacanth, gelatin, guar gum, xanthan gum, pectin, alginates, carrageenan, polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), methylcellulose, carboxymethylcellulose (CMC), ethylcellulose, microcrystalline cellulose, polyethylene glycol, sorbitol, sucrose, lactose, mannitol, and combinations thereof.

[0456] 43. The solid dosage form of any one of embodiments 26-42, wherein the surfactant is selected from the list consisting of polysorbates, sorbitan esters, polyethylene glycol, poloxamers, cetomacrogol, lecithin, sodium lauryl sulfate, bile salts, lauroyl polyoxyl-32 glycerides, and combinations thereof.44. The solid dosage form of any one of embodiments 24-43, wherein the fill composition is selected from one of the following compositions:

[0457] (a)

[0458]

[0459] and

[0460] (b)

[0461]

[0462] 45. The solid dosage form of embodiment 44, wherein composition (a) comprises 5 mg of Compound A.

[0463] 46. The solid dosage form of embodiment 44 or embodiment 45, wherein composition (b) comprises 20 mg of Compound A.

[0464] 47. The solid dosage form of embodiment 44 or embodiment 45, wherein composition (b) comprises 50 mg of Compound A.

[0465] 48. The solid dosage form of any one of the preceding embodiments, wherein Compound A, or its pharmaceutically acceptable salt thereof, is in amorphous form.

[0466] 49. A solid dispersion comprising Compound A, or a pharmaceutically acceptable salt thereof, and a polymer, wherein Compound A is a compound of the following formula:

[0467]

[0468] 50. The solid dispersion of embodiment 49, wherein the polymer is selected from the group consisting of: enteric polymers (such as methacrylate polymers, hydroxypropyl methyl cellulose phthalate (HPMCP), and cellulose acetyate phthalate (CAP)), hydrophilic polymers (such as starch, sodium carboxymethyl cellulose, sodium alginate, polyethylene glycol (PEG), polyvinyl pyrrolidone (PVP), hydroxy propyl methyl cellulose (HPMC), polyvinyl alcohol (PVA), P-cyclodextrin, mannitol, chitosan, and carrageenan), and amphiphilic polymers (such as polyethylene oxides (PEO)Zpolypropylene glycol (PPG) copolymers, PEG-modified starches, vinyl acetate / vinylpyrrolidone random copolymers, polyacrylic acid, and polyacrylates), and a combination thereof.

[0469] 51. The solid dispersion of embodiment 49 or embodiment 50, wherein the polymer is hydroxy propyl methyl cellulose acetate succinate (HPMCAS).

[0470] 52. The solid dispersion of any one of embodiments 49-51, wherein the polymer is medium grade hydroxy propyl methyl cellulose acetate succinate (HPMCAS MG) and / or high grade hydroxy propyl methyl cellulose acetate succinate (HPMCAS HG).

[0471] 53. The solid dispersion of any one of embodiments 49-52, wherein the polymer is medium grade hydroxy propyl methyl cellulose acetate succinate (HPMCAS MG).

[0472] 54. The solid dispersion of any one of embodiments 49-53, wherein the solid dispersion comprises Compound A and the polymer at a ratio of between 1:5 and 1 : 1 by weight.

[0473] 55. The solid dispersion of any one of embodiments 49-54, wherein the solid dispersion comprises Compound A and the polymer at a ratio of 1 :3 or 1 :2.

[0474] 56. The solid dispersion of any one of embodiments 49-55, wherein the solid dispersion comprises Compound A and the polymer at a ratio of 1 :3.

[0475] 57. The solid dispersion of any one of embodiments 49-56, wherein the solid dispersion is a spray dried dispersion.

[0476] 58. The solid dispersion of any one of embodiments 49-57, wherein Compound A, or its pharmaceutically acceptable salt thereof, is in amorphous form.

[0477] 59. A process for preparing a solid dosage form according to any one of embodiments 1- 48, or a solid dispersion according to any one of embodiments 49-58, comprising spray drying a solution comprising Compound A, or a pharmaceutically acceptable salt thereof, to form a solid dispersion.

[0478] 60. The process of embodiment 59, wherein the solution further comprises a polymer.

[0479] 61. The process of embodiment 60, wherein the polymer is selected from the group consisting of: enteric polymers (such as methacrylate polymers, hydroxypropylmethyl cellulose phthalate (HPMCP), and cellulose acetyate phthalate (CAP)), hydrophilic polymers (such as starch, sodium carboxymethyl cellulose, sodium alginate, polyethylene glycol (PEG), polyvinyl pyrrolidone (PVP), hydroxy propyl methyl cellulose (HPMC), polyvinyl alcohol (PVA), P-cyclodextrin, mannitol, chitosan, and carrageenan), and amphiphilic polymers (such as polyethylene oxides (PEO)Zpolypropylene glycol (PPG) copolymers, PEG-modified starches, vinyl acetate / vinylpyrrolidone random copolymers, polyacrylic acid, and polyacrylates), and a combination thereof.

[0480] 62. The process of embodiment 60 or embodiment 61, wherein the polymer is hydroxy propyl methyl cellulose acetate succinate (HPMCAS).

[0481] 63. The process of any one of embodiments 60-62, wherein the polymer is medium grade hydroxy propyl methyl cellulose acetate succinate (HPMCAS MG) and / or high grade hydroxy propyl methyl cellulose acetate succinate (HPMCAS HG).

[0482] 64. The process of any one of embodiments 60-63, wherein the polymer is medium grade hydroxy propyl methyl cellulose acetate succinate (HPMCAS MG).

[0483] 65. The process of any one of embodiments 59-64, wherein the solvent is selected from an aqueous solvent, a polar aprotic solvent, a polar protic solvent, and combinations thereof.

[0484] 66. The process of any one of embodiments 59-65, wherein the solvent has a boiling point of about 100 °C or less.

[0485] 67. The process of any one of embodiments 59-66, wherein the solvent is selected from acetone, cyclohexane, dichloromethane, N,N-dimethylacetamide (DMA), N,N- dimethylformamide (DMF), l,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide (DMSO), dioxane, ethyl acetate, ethyl ether, glacial acetic acid (HAc), methyl ethyl ketone (MEK), N-methyl-2-pyrrolidinone (NMP), methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), pentane, acetonitrile, methanol, ethanol, isopropyl alcohol, isopropyl acetate, toluene, and combinations thereof.

[0486] 68. The process of any one of embodiments 59-67, wherein the solvent is selected from water, acetone, acetic acid, methanol, ethanol, isopropanol, dichloromethane, tetrahydrofuran, and combinations thereof.

[0487] 69. The process of any one of embodiments 59-68, wherein the solvent is a mixture of water and acetone.

[0488] 70. The process of any one of embodiments 59-69, wherein the water and acetone are present at a ratio of between 1 : 6 to 1 : 12 (w / w).

[0489] 71. The process of any one of embodiments 59-70, wherein the water and acetone are present at a ratio of between 1 : 8 to 1 : 10 (w / w), such as a ratio of 1 : 9 (w / w). 72. The process of any one of embodiments 59-71, wherein the load of solid material in the solvent is between about 3% to about 25% by weight.

[0490] 73. The process of preparing a solid dosage form of any one of embodiments 59-72, further comprising the steps of blending the solid dispersion with one or more pharmaceutical excipients, and filling the blend into capsules.74. The process of embodiment 73, further comprising dry granulating the blend before it is filled into capsules.

[0491] 75. The process of embodiment 74, further comprising adding a lubricant to the blend before and / or after dry granulation.

[0492] 76. The process of preparing a solid dosage form of any one of embodiments 59-75, wherein the process comprises:

[0493] (a) blending the solid dispersion with one or more pharmaceutical excipients;

[0494] (b) adding lubricant and blending;

[0495] (c) dry granulating;

[0496] (d) adding further lubricant and blending; and

[0497] (e) filling the blend into capsules.

[0498] 77. The process of any one of embodiments 73-76, wherein the one or more pharmaceutical excipients comprise a filler and a disintegrant.

[0499] 78. A crystalline form of Compound A, or a pharmaceutically acceptable salt thereof, wherein Compound A is a compound of the following formula:

[0500]

[0501] 79. The crystalline form of embodiment 78, wherein the crystalline form is selected from:

[0502] (i) Form I, characterised by a DSC profile comprising a major endotherm with peak temperature at around (±1.0) 192.7 °C, and / or characterised by an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 7.0, 9.9, 16.6, 18.9, 26.5, and 28.0;

[0503] (ii) Form II, characterised by a DSC profile comprising a major endotherm with peak temperature at around (±1.0) 204.5 °C, and / or characterised by an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 6.9, 9.8, 15.1, 16.6, 20.5, and 27.7;

[0504] (iii)Form III, characterised by an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 8.3, 9.0, 9.7, 13.2, 14.3, and 24.6; (iv)Form IV, characterised by an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 9.0, 13.6, 14.5, 18.4, 20.2, and 21.1; (v) Compound A HC1 co-Form V, characterised by an XRPD pattern with at least the following XRPD peaks at approximately (± 0.2): 20 (°) = 7.3, 11.3, 14.5, 18.3, 22.5, and 26.7; and

[0505] (vi)Compound A HC1 co-Form VI, characterised by an XRPD pattern with at least the following XRPD peaks at approximately (± 0.2): 20 (°) = 10.6, 12.0, 15.4, 21.3, 23.2, and 27.4.80. The crystalline form of embodiment 79, wherein Form I is characterised by an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 7.0, 9.9, 16.6, 18.9, 26.5, and 28.0.

[0506] 81. The crystalline form of embodiment 79 or embodiment 80, wherein Form I is characterised by an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 7.0, 9.9, 12.1, 15.4, 16.6, 17.1, 18.9, 21.0, 26.5, and 28.0.

[0507] 82. The crystalline form of any one of embodiments 79-81, wherein Form I is characterised by an XRPD pattern that is substantially the same as shown in Figure 4.

[0508] 83. The crystalline form of any one of embodiments 79-82, wherein Form I is characterised by a DSC profile comprising a major endotherm with peak temperature at around (±1.0) 192.7 °C.

[0509] 84. The crystalline form of any one of embodiments 79-83, wherein Form I is further characterised by a DSC profile that is substantially the same as shown in Figure 3.

[0510] 85. The crystalline form of any one of embodiments 79-84, wherein Form I is further characterised by TGA thermogram that is substantially the same as shown in Figure 3.

[0511] 86. The crystalline form of any one of embodiments 79-85, wherein Form I is further characterised by the following unit cell parameters at 296 K a is 6.65 ± 0.01 A, b is 22.14 ± 0.01 A, c is 15.79 ± 0.01 A, a = y = 90°, and p is 96.95 ± 0.10 °.

[0512] 87. The crystalline form of any one of embodiments 79-86, wherein Form I is further characterised by a unit cell volume at 296 K of approximately (± 5) 2308 A3.

[0513] 88. The crystalline form of any one of embodiments 79-87, wherein Form I is obtainable from isopropyl acetate.

[0514] 89. The crystalline form of any one of embodiments 79-88, wherein Form II is characterised by an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 6.9, 9.8, 15.1, 16.6, 20.5, and 27.7.

[0515] 90. The crystalline form of any one of embodiments 79-89, wherein Form II is characterised by an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (±0.2): 6.9, 9.8, 11.9 15.1, 16.6, 19.2, 20.5, 22.5, and 27.7. 91. The crystalline form of any one of embodiments 79-90, wherein Form II is characterised by an XRPD pattern that is substantially the same as shown in Figure 6.

[0516] 92. The crystalline form of any one of embodiments 79-91, wherein Form II is further characterised by a DSC profile comprising a major endotherm with peak temperature at around (±1.0) 204.5 °C.

[0517] 93. The crystalline form of any one of embodiments 79-92, wherein Form II is further characterised by a DSC profile that is substantially the same as shown in Figure 5.

[0518] 94. The crystalline form of any one of embodiments 79-93, wherein Form II is further characterised by TGA thermogram that is substantially the same as shown in Figure 5.

[0519] 95. The crystalline form of any one of embodiments 79-94, wherein Form II is further characterised by the following unit cell parameters at 296 K: a is 6.12 ± 0.01 A, b is 22.20 ± 0.01 A, c is 15.85 ± 0.01 A, a = y = 90°, and p is 92.90 ± 0.10 °.96. The crystalline form of any one of embodiments 79-95, wherein Form II is further characterised by a unit cell volume at 296 K of approximately (± 5) 2150 A3.

[0520] 97. The crystalline form of any one of embodiments 79-96, wherein Form II is obtainable from acetone.

[0521] 98. The crystalline form of any one of embodiments 79-97, wherein Form III is characterised by an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (±0.2): 8.3, 9.0, 9.7, 13.2, 14.3, 23.0, 24.6, 25.7, and 27.5. 99. The crystalline form of any one of embodiments 79-98, wherein Form III is characterised by an XRPD pattern that is substantially the same as shown in Figure 8.

[0522] 100. The crystalline form of any one of embodiments 79-99, wherein Form III is further characterised by a DSC profile comprising a major endotherm with peak temperature at around (±1.0) 213.2 °C.

[0523] 101. The crystalline form of any one of embodiments 79-100, wherein Form III is further characterised by a DSC profile that is substantially the same as shown in Figure 7.

[0524] 102. The crystalline form of any one of embodiments 79-101, wherein Form III is further characterised by TGA thermogram that is substantially the same as shown in Figure 7.

[0525] 103. The crystalline form of any one of embodiments 79-102, wherein Form III is further characterised by the following unit cell parameters at 296 K: a is 11.59 ± 0.01 A, b is 9.94 ± 0.01 A, c is 20.02 ± 0.01 A, a = y = 90°, and is 100.41 ± 0.10 °. 104. The crystalline form of any one of embodiments 79-103, wherein Form III is further characterised by a unit cell volume at 296 K of approximately (± 5) 2268 A3.

[0526] 105. The crystalline form of any one of embodiments 79-104, wherein Form III is obtainable from dimethylformamide.

[0527] 106. The crystalline form of any one of embodiments 79-105, wherein Form IV is characterised by an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (±0.2): 9.0, 13.6, 14.5, 18.4, 20.2, 21.1, 22.7, 24.3, and 30.6.

[0528] 107. The crystalline form of any one of embodiments 79-106, wherein Form IV is characterised by an XRPD pattern that is substantially the same as shown in Figure 10.

[0529] 108. The crystalline form of any one of embodiments 79-107, wherein Form IV is further characterised by a DSC profile comprising an endotherm with peak temperature at around (±1.0) 169.3 °C.

[0530] 109. The crystalline form of any one of embodiments 79-108, wherein Form IV is further characterised by a DSC profile that is substantially the same as shown in Figure 9.

[0531] 110. The crystalline form of any one of embodiments 79-109, wherein Form IV is further characterised by TGA thermogram that is substantially the same as shown in Figure 9.111. The crystalline form of any one of embodiments 79-110, wherein Form IV is obtainable from acetic acid and water in a volume ratio of 1 :21.

[0532] 112. The crystalline form of any one of embodiments 79-111, wherein Compound A HC1 co-Form V is characterised by an XRPD pattern with at least the following XRPD peaks at approximately (± 0.2): 20 (°) = 7.3, 11.3, 14.5, 18.0, 18.3, 22.5, 26.7, 29.6, and 30.9.

[0533] 113. The crystalline form of any one of embodiments 79-112, wherein Compound A HC1 co-Form V is characterised by an XRPD pattern that is substantially the same as shown in Figure 12.

[0534] 114. The crystalline form of any one of embodiments 79-113, wherein Compound A HC1 co-Form V is further characterised by a DSC profile comprising a major endotherm with peak temperature at around (±1.0) 176.8°C.

[0535] 115. The crystalline form of any one of embodiments 79-114, wherein Compound A HC1 co-Form V is further characterised by a DSC profile that is substantially the same as shown in Figure 11.

[0536] 116. The crystalline form of any one of embodiments 79-115, wherein Compound A HC1 co-Form V is further characterised by TGA thermogram that is substantially the same as shown in Figure 11.

[0537] 117. The crystalline form of any one of embodiments 79-116, wherein Compound A HC1 co-Form V has a free base to hydrochloric acid stoichiometric ratio of 1 : 0.88.

[0538] 118. The crystalline form of any one of embodiments 79-117, wherein Compound A HC1 co-Form V is obtainable from 1.05 equivalents of hydrochloric acid in acetonitrile solvent.

[0539] 119. The crystalline form of any one of embodiments 79-118, wherein Compound A HC1 co-Form VI is characterised by an XRPD pattern with at least the following XRPD peaks at approximately (±0.2): 20 (°)= 10.6, 12.0, 13.5, 15.4, 16.1, 19.4, 21.3, 23.2, and 27.4.

[0540] 120. The crystalline form of any one of embodiments 79-119, wherein Compound A HC1 co-Form VI is characterised by an XRPD pattern that is substantially the same as shown in Figure 14.

[0541] 121. The crystalline form of any one of embodiments 79-120, wherein Compound A HC1 co-Form VI is further characterised by a DSC profile comprising an endotherm with peak temperature at around (±1.0) 171.9 °C.

[0542] 122. The crystalline form of any one of embodiments 79-121, wherein Compound A HC1 co-Form VI is further characterised by a DSC profile that is substantially the same as shown in Figure 13.

[0543] 123. The crystalline form of any one of embodiments 79-122, wherein Compound A HC1 co-Form VI is further characterised by TGA thermogram that is substantially the same as shown in Figure 13.

[0544] 124. The crystalline form of any one of embodiments 79-123, wherein Compound AHC1 co-Form VI has a free base to hydrochloric acid stoichiometric ratio of 1 : 1.02.125. The crystalline form of any one of embodiments 79-124, wherein Compound A HC1 co-Form VI is obtainable from 2.05 equivalents of hydrochloric acid in 2-methyltetrahydrofuran solvent.

[0545] 126. The crystalline form of any one of embodiments 78-125, wherein the crystalline form is a crystalline form of the free form of Compound A.

[0546] 127. The crystalline form of any one of embodiments 79-126, wherein the crystalline form is selected from Form I, Form II, Form III, and Form VI.

[0547] 128. The crystalline form of any one of embodiments 79-126, wherein the crystalline form is selected from Form I, Form II, and Form III.

[0548] 129. The crystalline form of any one of embodiments 79-126, wherein the crystalline form is Form I or Form II.

[0549] 130. The crystalline form of any one of embodiments 79-126, wherein the crystalline form is Form I or Form III.

[0550] 131. The crystalline form of any one of embodiments 79-126, wherein the crystalline form is Form II or Form III.

[0551] 132. The crystalline form of any one of embodiments 79-126, wherein the crystalline form is Form I.

[0552] 133. The crystalline form of any one of embodiments 79-126, wherein the crystalline form is Form II.

[0553] 134. The crystalline form of any one of embodiments 79-126, wherein the crystalline form is Form III.

[0554] 135. The crystalline form of any one of embodiments 78-126, wherein the crystalline form is a co-form of Compound A and hydrochloric acid.

[0555] 136. The crystalline form of any one of embodiments 79-126 and 135, wherein the crystalline form is selected from Compound A HC1 co-Form V and Compound A HC1 co-Form VI.

[0556] 137. The crystalline form of any one of embodiments 79-126 and 135, wherein the crystalline form is Compound A HC1 co-Form V.

[0557] 138. The crystalline form of any one of embodiments 79-126 and 135, wherein the crystalline form is Compound A HC1 co-Form VI.

[0558] 139. An amorphous form of Compound A, or a pharmaceutically acceptable salt thereof, wherein Compound A is a compound of the following formula:

[0559]

[0560] 140. The solid dosage form of embodiments 1-48, the solid dispersion of embodiments 49-58, the crystalline form of embodiments 78-138, or the amorphousform of embodiment 139, wherein Compound A or its pharmaceutically acceptable

[0561]

[0562] or a pharmaceutically acceptable salt. . The solid dosage form of embodiments 1-48, the solid dispersion of embodiments 49-58, the crystalline form of embodiments 78-138, or the amorphous form of embodiment 139, wherein Compound A or its pharmaceutically acceptable

[0563]

[0564] . A solid dosage form according to embodiments 1-48, a solid dispersion according to embodiments 49-58, a crystalline form according to embodiments 78- 138, or an amorphous form according to embodiment 139, for use in therapy.

[0565] . A method of treating a disorder caused by or associated with NLRP3 inflammasome activation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a solid dispersion according to embodiments 1-48, a solid dispersion according to embodiments 49-58, a crystalline form according to embodiments 78-138, or an amorphous form according to embodiment 139.

[0566] . The method of embodiment 143, wherein the disorder is selected from the group consisting of:

[0567] (i) inflammatory reactions in the joints;

[0568] (ii) hyperactive inflammation with underlying genetic mutations;

[0569] (iii) autoimmune diseases;

[0570] (iv) respiratory diseases;

[0571] (v) kidney diseases;

[0572] (vi) central nervous system diseases;

[0573] (vii) ocular diseases;

[0574] (viii) cardiovascular diseases;

[0575] (ix) viral infections and subsequent immune hyperactivation;(x) diseases of the hematopoietic system;

[0576] (xi) liver disease;

[0577] (xii) inflammatory reactions in the skin;

[0578] (xiii) metabolic diseases;

[0579] (xiv) cancers;

[0580] (xv) infectious diseases; and

[0581] (xvi) allergic disease.

[0582] 145. The method of embodiment 143 or embodiment 144, wherein the disorder is selected from the group consisting of cardiovascular diseases and metabolic diseases.

[0583] 146. The method of embodiment 143 or embodiment 144, wherein the disorder is gout, for example wherein the disorder is a) acute or chronic gout, b) tophaceous gout or c) pseudo-gout.

[0584] 147. The method of any one of embodiments 143-145, wherein the disorder is pericarditis, for example Dressier’s syndrome.

[0585] 148. The method of any one of embodiments 143-145, wherein the disorder is Wilson disease.EXAMPLES

[0586] Abbreviations: AcOH: acetic acid; API: active pharmaceutical ingredient; Boc: tertbutyloxy carbonyl; brd: broad doublet; brdd: broad doublet of doublet; brs: broad singlet; brt: broad triplet; CRBN: cereblon; d: doublet; dd: doublet of doublet; ddd: doublet of doublet of doublet; dba: dibenzylideneacetone; DCM: dichloromethane; DIEA: diisopropylethylamine; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; DPPF: 1,1'-bis(diphenylphosphino)ferrocene; DSC: differential scanning calorimetry; EDCI: l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide; EDTA: ethylenediaminetetraacetic acid; eq: equivalents; ESI: electrospray ionization; EtOAc: ethyl acetate; EtOH: ethanol; FASSIF: fasted state simulated intestinal fluid; h: hours; HEPES: 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid; HOBt: 1 -hydroxy benzotriazole; HPLC: high-performance liquid chromatography; HPMCAS MG: hydroxy propylmethylcellulose acetate succinate medium grade; IB: intestinal buffer; IPAC: isopropyl acetate; LCMS: liquid chromatography-mass spectrometry; LDV; low dead volume: LiHMDS: lithium bis(trimethylsilyl)amide; LPS: lipopolysaccharide; m: multiplet; M-CSF: macrophage colony-stimulating factor; MeOH: methanol; MGD: molecular glue degrader; MS: mass spectrometry; MSU: monosodium urate crystals; MTBE: methyl tert-butyl ether; NMR: nuclear magnetic resonance; NMP: JV-methyl-2-pyrrolidone; PBS: phosphate-buffered saline; q: quartet; rpm: revolutions per minute; s: singlet; SDD: spray dried dispersion; SGF: simulated gastric fluid; SIF: simulated intestinal fluid; PE: petroleum ether; quin: quintet; RH: relative humidity; t: triplet; td: triplet of doublet; THF: tetrahydrofuran; tt: triplet of triplet; XRPD: X-ray powder diffraction.

[0587] EXAMPLE 1: SYNTHESIS OF COMPOUND A

[0588] An example of a route to synthesize Compound A is described below. This route (and other routes) may be used to prepare Compound A for the purpose of affording material suitable for crystallization.

[0589]

[0590] Step 1. The reaction was performed as 2 batches in parallel. NMP (18.0 L, 5 V) was added into a 50.0 L reactor at 15 ~ 25 °C. 5-bromo-l,3-dichloro-2 -fluorobenzene (4.50 kg, 18.4 mol, 1.00 eq.) was added into the reactor followed by K2CO3 (7.65 kg, 55.3 mol, 2.00 eq.) at 15 - 25 °C. Lastly, ethyl 2-cyanoacetate (2.71 kg, 24.0 mol, 2.56 L, 1.30 eq.) was added into the reactor at 15 - 25 °C. The mixture was heated to 115 °C and stirred at that temperature for 15 h under nitrogen atmosphere. The reaction was sampled and analysed for completion (HPLC). The mixture was cooled to 25 °C and divided into four batches. Each batch was poured into water (5 V, 22.5 L) and extracted with petroleum ether (4.50 L x 3). The aqueous phase was adjusted to pH = 3 - 4 with citric acid (solid) and stirred at 20 - 25 °C for 0.5 h. The mixture was filtered, and the four filter cakes of each batch were combined and washed with water (3.00 L). The products of the two batches of reaction were combined. Ethyl 2-(4-bromo-2,6-dichlorophenyl)-2-cyanoacetate (4.50 kg, 13.1 mol, 71.1% yield, 98.2% purity) was obtained as a white solid.

[0591] Step 2. The reaction was performed as 2 batches in parallel. NMP (14.0 L, 3.33 V) was added into a 50.0 L reactor at 15 ~ 25 °C. Ethyl 2-(4-bromo-2,6-dichlorophenyl)-2-cyanoacetate (4.30 kg, 12.8 mol, 1.00 eq.) followed by LiCl (1.35 kg, 31.9 mol, 654 mL, 2.50 eq.) in ice-water (7.00 L, 1.67 V) was added, and the reaction was heated to 100 °C and stirred at that temperature for 15 h under nitrogen atmosphere. The reaction was sampled andanalysed for completion (HPLC). The reaction was cooled to 25 °C and divided into two batches. Water (28.0 L) was added to each batch, and the mixtures were stirred at 15 ~ 25 °C for 0.5 h. The mixtures were filtered, and the filter cakes were combined and washed with water (4.3 L). The products of the two reaction batches were combined and dried under vacuum at 45°C. 2-(4-bromo-2,6-dichlorophenyl)acetonitrile (6.46 kg, 24.2 mol, 94.8% yield, 99.2% purity) was obtained as a white solid.

[0592] Step 3. The reaction was performed as 2 batches in parallel. THF (16.2 L, 5.00 V) was added into a 50.0 L reactor at 20 °C. 2-(4-bromo-2,6-dichlorophenyl)acetonitrile (3.24 kg, 12.2 mol, 1.00 eq.) was added at 20 ~ 25 °C. Tert-butyl acrylate (1.57 kg, 12.2 mol, 1.78 L, 1.00 eq.) was added into the reactor at 0 ~ 5 °C under nitrogen atmosphere. NaOMe (66.1 g, 1.22 mol, 0.10 eq.) was added at 0 ~ 5°C under nitrogen atmosphere. The reaction was stirred at 20 ~ 25 °C for 2 h. The reaction was sampled and analysed for completion (HPLC). The mixture was divided into two batches for work-up, each of which was poured into ice water (16.5 L) at 0 ~ 5 °C. The mixtures were extracted with EtOAc (2 x 9.90 L, 3.00 V). The combined organic layers of each batch were washed with 10.0% NaCl solution (2 x 9.90 L, 3.00 V). The organic phases of both batches were combined, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. Tert-butyl 4-(4-bromo-2,6-dichlorophenyl)-4-cyanobutanoate (9.20 kg, 22.9 mol, 93.7% yield, 97.9% purity) was obtained as an off-white solid.

[0593] Step 4. The reaction was performed as 2 batches in parallel. AcOH (23.1 L, 5.00 V, 24.2 kg) was charged into a 50.0 L reactor at 20 °C. Tert-butyl 4-(4-bromo-2,6-dichlorophenyl)-4-cyanobutanoate (4.62 kg, 11.8 mol, 1.00 eq.) was added at 20 ~ 25 °C. H2SO4 (8.50 kg, 86.7 mol, 4.62 L, 7.37 eq.) was added at 20 °C. The reaction was stirred at 80 ~ 90 °C for 2 h under nitrogen atmosphere. The reaction was sampled and analysed for completion (HPLC). The mixture was divided into two batches for work-up, each of which was cooled to 0 ~ 10°C, poured into ice water (50.0 L) at 0 ~ 10 °C, and filtered. The filter cakes were combined and washed with water (200 L). The solid was combined and freeze-dried. 3-(4-bromo-2,6-dichlorophenyl)piperidine-2, 6-dione (7.52 kg, 22.2 mol, 94.3% yield, 99.3% purity) was obtained as a white solid.

[0594] Step 5. Six reactions were carried out in parallel. To a solution of 3-(4-bromo-2,6-di chi orophenyl)piperidine-2, 6-dione (600 g, 1.78 mol, 1.00 eq.) inNMP (3.00 L) were added Zn(CN)2(223 g, 1.90 mol, 121 mL, 1.07 eq.), DPPF (19.2 g, 34.6 mmol, 0.02 eq.), and Pd2(dba)s (32.4 g, 35.4 mmol, 0.02 eq.) under nitrogen atmosphere. The reaction was stirred at 100 °C for 12 h. The reaction was sampled and analysed for completion (HPLC). The reaction mixture was poured into water (3.00 L) at 25 °C and filtered. The filter cakes of all six reactions were washed with H2O (2 x 5.00 L) at 25 °C and combined. The solid was dissolved in THF (45 L) and the solution was filtered through a diatomaceous earth (Celite) pad. The filtrate was concentrated under reduced pressure to afford crude 3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)benzonitrile (2.93 kg, 83.2% purity) as a yellow solid.Step 6. Twenty reactions were carried out in parallel. Raney Nickel (33.5 g, 391 mmol, 1.65 eq.) was washed with THF:DMF = 1:1 (6 x 200 mL). DMF (350 mL), THF (350 mL), 3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)benzonitrile (67.0 g, 236 mmol, 1.00 eq.) and BOC2O (103 g, 473 mmol, 109 mL, 2.00 eq.) were added at 25 °C under nitrogen atmosphere. The reaction was stirred at 60 °C under H2 (15 psi) for 12 h. The reaction was sampled and analysed for completion (HPLC). 10 batches of the reactions were combined for workup. The reaction mixture was filtered through a Celite pad. The Celite pad was washed with THF (3 x 1.00 L) and the filtrate was concentrated under reduced pressure. The reaction mixture was poured into H2O (1.00 L) and extracted with EtOAc (3 x 1.00 L). The organic layers of all batches were washed with brine (2.00 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, 20 kg, Petroleum ether: Ethyl acetate = 5:1 to 1:1) to afford tert-butyl (3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)benzyl)carbamate (864 g, 47.1% yield, 95.0% purity) as yellow solid.

[0595] Step 7. To a solution of HC12M in EtOAc (2.50 L, 2 M, 3.85 eq.) at 0 °C was added tertbutyl (3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)benzyl)carbamate (500 g, 1.29 mol, 1.00 eq.). The reaction was stirred at 25 °C for 3 h. The reaction was sampled and analysed for completion (HPLC). The reaction mixture was filtered at 25 °C, and the filter cake was washed with ethyl acetate (500 ml x 3) to afford 3-(4-(aminomethyl)-2,6-dichlorophenyl)piperidine-2, 6-dione hydrochloride (430 g, 1.13 mol, 99.0% yield, 96.2% purity, HC1 salt) as a white solid.

[0596] ‘H-NMR (400 MHz, DMSO- e) 11.0 (s, 1H), 8.63 (br s, 3H), 7.75 - 7.68 (m, 2H), 4.62 (dd, J= 5.60, 12.8 Hz, 1H), 4.05 - 4.00 (m, 2H), 2.89 - 2.87 (m, 1H), 2.57 (br dd, J= 2.00, 16.8 Hz, 1H), 2.37 (dq, J = 4.40, 13.2 Hz, 1H), 1.93 - 1.91 (m, 1H). LCMSm / z 287.1 [M+H]+Step 8. The reaction was performed in three batches in parallel. To a solution of ethyl 2-(5-bromopyrimidin-2-yl)acetate (160 g, 653 mmol, 1.00 eq) in THF (1.60 L) was slowly added LiHMDS (1 M, 1310 mL, 2.00 eq) at -10 °C under nitrogen atmosphere over 1 h. The mixture was stirred at -10 °C for 30 min. Mel (324 g, 2.29 mol, 142 mL, 3.50 eq) was slowly added at -10 °C over 30 min, and the reaction mixture was allowed to warm to 20 °C and stirred for 1 hr. More LiHMDS (1 M, 326 mL, 0.50 eq) was slowly added at -10 °C under nitrogen atmosphere over 1 h. The mixture was stirred at -10 °C for 30 min. Mel (46.3 g, 326 mmol, 20.3 mL, 0.50 eq) was slowly added at -10 °C over 15 min, and the reaction mixture was allowed to warm to 20 °C and stirred for 3 hrs. The reaction was quenched with sat. NH4CI (3 x 1.60 L) at 25 °C, then extracted with EtOAc (3 x 2.40 L). Three batches in parallel were combined, and the organic layer washed with brine (2 x 2.40 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford ethyl 2-(5-bromopyrimidin-2-yl)-2-methylpropanoate (480 g, 1.72 mol, 87.7% yield, 97.7% purity) as a brown oil.

[0597] Step 9. A mixture of ethyl 2-(5-bromopyrimidin-2-yl)-2-methylpropanoate (240 g, 879 mmol, 1.00 eq), MeB(OH)2 (263 g, 4.39 mol, 5.00 eq), K3PO4 (560 g, 2.64 mol, 3.00 eq) andPd(dppf)Ch (32.2 g, 43.9 mmol, 0.05 eq) in dioxane (2.40 L) was degassed by purging with nitrogen (3 x), then the reaction was stirred at 85 °C for 4 h under nitrogen. The reaction mixture was diluted with water (2.40 L) and extracted with EtOAc (3 x 1.20 L). The combined organic layers were washed with brine (2 x 1.20 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE : EtOAc = 100:1 to 5:1) to afford ethyl 2-methyl-2-(5-methylpyrimidin-2-yl)propanoate (149 g, 680 mmol, 77.4% yield, 97.0% purity) as a brown oil.

[0598] Step 10. To a solution of ethyl 2-methyl-2-(5-methylpyrimidin-2-yl)propanoate (300 g, 1.40 mol, 1.00 eq) in MeOH (1.50 L) was added a solution ofNaOH (279 g, 6.99 mol, 5.00 eq) in H2O (1.50 L) dropwise over 30 min at 25 °C. The reaction mixture was stirred at 25 °C for 3 h. The mixture was adjusted to pH = 2 ~ 3 with HC1 (12 M aq., 700 mL), then it was extracted with DCM (3 x 3.00 L). The combined organic layers were washed with brine (2 x 1.00 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with PE (3.00 L) at 25 °C for 30 min to afford 2-methyl-2-(5-methylpyrimidin-2-yl)propanoic acid (205 g, 1.11 mol, 79.7% yield, 97.9% purity) as a brown solid.

[0599] Step 11. To a mixture of 2-methyl-2-(5-methylpyrimidin-2-yl)propanoic acid (200 g, 1.11 mol, 1.00 eq) in DCM (1.60 L) were added DMF (8.11 g, 111 mmol, 0.10 eq) and (COC1)2 (211 g, 1.66 mol, 1.50 eq) dropwise at 0 °C over 30 min. The reaction was stirred at 20 °C for 1 h, then it was concentrated under reduced pressure to afford 2-methyl-2-(5-methylpyrimidin-2-yl)propanoyl chloride (220 g, 1.10 mol, 98.7% yield, 98.7% purity) as a yellow solid.

[0600] Step 12. To a solution of 3-(4-(aminomethyl)-2,6-dichlorophenyl)piperidine-2, 6-dione hydrochloride (257 g, 794 mmol, 1.00 eq) in DCM (2.50 mL) were slowly added DIEA (308 g, 2.38 mol, 415 mL, 3.00 eq) and 2-methyl-2-(5-methylpyrimidin-2-yl)propanoyl chloride (158 g, 794 mmol, 1.00 eq) in DCM (790 mL) over 1 h at 25 °C. The reaction was stirred at 25 °C for 2 h. The reaction mixture was diluted with H2O (2500 mL) and extracted with DCM (3 x 1.00 L). The combined organic layers were washed with brine (2 x 1.00 L), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was triturated with MTBE (2.50 L) at 25 °C for 30 min. The crude product was further purified by reversed-phase HPLC to afford Compound A (218 g, 485 mmol, 99.4% purity, 60.0% yield over two steps) as a white solid.

[0601] ‘H-NMR (400 MHz, DMSO- L) 810.97 (s, 1H), 8.64 (s, 2H), 8.04 (t, J= 6.00 Hz, 1H), 7.40 (s, 1H), 7.34 (s, 1H), 4.56 (dd, J= 5.60 Hz, 12.8 Hz, 1H), 4.25 (d, J= 6.00 Hz, 2H), 2.85 -2.84 (m, 1H), 2.56 - 2.55 (m, 1H), 2.38 - 2.33 (m, 1H), 2.27 (s, 3H), 1.90 - 1.89 (m, 1H), 1.53 (s, 6H). LCMS m / z 499.1 [M+H]+

[0602] This synthesis route for Compound A could be performed with larger quantities, for example, to yield Compound A on a multi-gram scale.Chiral separation of Compound A enantiomers

[0603]

[0604] Note: for these enantiomers, their absolute configuration was not determined and was assigned arbitrarily.

[0605] JV-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)benzyl)-2-methyl-2-(5-methylpyrimidin-2-yl)propanamide (Compound A, 600 mg, 1.34 mmol, 1.00 eq.) was separated by Chiral SFC (column: DAICEL CHIRALCEL OX (250 mm x 30 mm, 10 pm); mobile phase: [carbon dioxide - isopropanol / acetonitrile / acetonitrile]; B%: 62.5%, isocratic elution mode) to give two peaks.

[0606] Peak one was diluted with water (10 mL) and lyophilized to give (S)-JV-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)benzyl)-2-methyl-2-(5-methylpyrimidin-2-yl)propanamide (248 mg, 546 / / mol, 40% yield) as a white solid.

[0607] H NMR (400 MHz, DMSO-z / e) S = 10.94 (s, 1H), 8.64 (s, 2H), 8.02 (t, J= 6.0 Hz, 1H), 7.40 (s, 1H), 7.34 (s, 1H), 4.56 (dd, J= 5.6, 12.8 Hz, 1H), 4.25 (d, J = 6.0 Hz, 2H), 2.86 (ddd, J = 5.6, 14.0, 16.8 Hz, 1H), 2.60 - 2.52 (m, 1H), 2.44 - 2.31 (m, 1H), 2.27 (s, 3H), 1.95 - 1.84 (m, 1H), 1.53 (s, 6H). MS (ESI) m / z 449.1 [M+H]+

[0608] Peak two was diluted with water (10 mL) and lyophilized to give (7?)-V-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)benzyl)-2-methyl-2-(5-methylpyrimidin-2-yl)propanamide (232 mg, 513 / / mol, 38% yield) as a white solid.

[0609] H NMR (400 MHz, DMSO-z / e) d = 10.95 (s, 1H), 8.64 (s, 2H), 8.03 (t, J= 6.0 Hz, 1H), 7.40 (s, 1H), 7.34 (s, 1H), 4.56 (dd, J= 5.6, 12.8 Hz, 1H), 4.25 (d, J= 6.0 Hz, 2H), 2.94 - 2.78 (m, 1H), 2.56 (s, 1H), 2.45 - 2.32 (m, 1H), 2.27 (s, 3H), 1.96 - 1.82 (m, 1H), 1.53 (s, 6H). MS (ESI) m / z 449.1 [M+H]+EXAMPLE 2: BIOLOGICAL ACTIVITY DATA FOR COMPOUND A

[0610] Example 2.1: Compound A binding to CRBN by HTRF assay:

[0611] The activity of Compound A was monitored in a Homogenous Time-Resolved Fluorescence (HTRF) assay using l-[5-({2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl]oxy}acetamido)ethoxy]ethyl}carbamoyl)pentyl]-3,3-dimethyl-2-[(lE,3E)-5-[(2E)-l,3,3-trimethyl-5-sulfo-2,3-dihydro-lH-indol-2-ylidene]penta-l,3-dien-l-yl]-3H-indol-l-ium-5 -sulfonate as a fluorescent probe. Biochemical assays were conducted in Greiner white 384 well HiBase plates (Cat. No 784075-25) in 20 pL total volume. A one pot detection solution of CRBN-DDB1 (2.5 nM), Anti-His Terbium Cryptate Gold (IX, PerkinElmer Cat.#: 61HI2TLB), and Cy5-Thalidomide (lOOnM, Tenova Cat.: T52461) was prepared in 20 mM HEPES, 20 mM NaCl, 0.2 mM TCEP, 0.2 mM EDTA, and 0.005% Tween20 was dispensed to each assay plate. Compound A was stored in dry, ambient temperatures at 10 mM. An 11 -point, 1:3 dilution series was prepared from 10 mM stock concentrations in Echo-compatible LDV plates. lOnL of each compound dilution series was dispensed into assays wells using an Echo 650 (Labcyte inc. USA). 20 nL of 10 mM Lenalidomide was transferred into the active-control wells for the assay and 20 nL of DMSO was transferred into the neutral-control wells. The assay was then allowed to incubate for 30 min at ambient temperature after transferring compound. Plate measurements were taken on a Pherastar FSX (BMG Labtech, Germany) using the HTRF Red filter (Ex. 337 nm, eml: 620 nm, em2: 665 nm) (Flashes: 50, Integration time: 60-400 us, Z-height: 10 mm, Ratio-multipler: 10,000). The HTRF signal was then subsequently normalized to the neutral and active controls. Analysis and ECso values were derived using KNIME analytics (KNIME Zurich) transformation and fitting within Collaborative Drug Discovery (Collaborative Drug Discovery USA). Ki was derived from the geometric mean of the ECso values using the Cheng-Prustoff transformation.

[0612] Example 2.2; Experimental for NanoBiT

[0613] Cal51 NEK7 NanoBiT cell line was generated via CRISPR Knock-In of the HiBiT tag in NEK7 gene and stable infection with a lentivirus carrying LgBiT protein. The cell line was generated in house. For the experiment, cells were plated in 384-well white flat bottom plates (Coming, 3570BC) at 2500 cells per well using Multiflo (BioTek / Agilent) and in 25 jil volume in DMEM experimental medium: DMEM (DMEM, high glucose, HEPES, no phenol red (ThermoFisher Scientific, 21063029) supplemented with 10% FBS (Coming, 35-075-CV), 1% Penicillin / Streptomycin ((ThermoFisher Scientific, 15140-122), and 1% Endurazine (Nano-Gio Endurazine Live Cell Substrate (Promega, N2571)). Cells were incubated for 16 hours at 37 °C, 5% CO2 before compound addition. For dose response determination, 2.5nL of Compound A at different concentrations (stock compound concentration range: lOmM to 0.5pM. final concentration range inside cell plate: IpM to 0.05nM) was dispensed into the plate using an Echo® 650 liquid handling device (BackmanCoulter / Labcyte). Cells were incubated at 37 °C, 5% CO2 for 24 hours and then signal was read on a Pherastar FSX using “LUM plus” optic module with 4095 gain and measurement interval time 0.2 seconds.

[0614] Analysis was performed in Genedata Screener (Genedata, Basel, CH). Luminescence response (R) was calculated by the formula: response = 100 * (S - N) / (P-N) where S is the signal of the well, N and P the mean negative and positive control values respectively of the same plate. The luminescence response was then fitted in Genedata using a 4-parameter antagonist logistic fit (hill slope unconstrained, ECso > 0, top / bottom unconstrained).

[0615] The results are shown in Table 1.

[0616] Table 1: HTRF Binding of Compound A to CRBN and Activity forNEK7 degradation.

[0617]

[0618] Example 2.3: Functional assay for caspase-1 activity and IL-IP release in human monocyte-derived macrophages in response to inflammasome stimulation

[0619] Human monocytes were enriched and isolated from a huffy coat of healthy donor whole blood with a RosetteSep™ Human Monocyte Enrichment Cocktail (Cat.No. 15068, StemCell) and Ficoll-Plaque PLUS (Cat.No. H8889, Sigma). Monocytes were differentiated into macrophages by treatment with 100 ng / mL M-CSF for 6 days at 37 °C, 5% CO2. Differentiated macrophages were seeded overnight (50,000 cells / well) in 100 pL of medium in a 96-well, white-bottom plate at 37 °C, 5% CO2. Cells were treated with a concentration range of MGD for 24 hours prior to stimulation with nigericin. Macrophages were primed with 1 pg / mL LPS for 3 h followed by 1 h stimulation with 10 pM nigericin. Media of stimulated macrophages were collected and assayed for caspase 1 activity directly (Promega G9951), according to manufacturer’s instructions. For IL-ip release assay, media of stimulated macrophages were collected and stored at -20°C, then thawed at 4°C before assaying for IL-ip activity (Promega W6011), according to manufacturer’s instructions. Compound A exhibited dose-dependent inhibition of caspase- 1 activity and IL-ip release in this assay of NLRP3 inflammasome activation (Table 2).

[0620] Table 2: Functional assay for caspase-1 activity and IL-ip release in human monocyte-derived macrophages in response to inflammasome stimulation.

[0621]

[0622] In Table 2, ICso values (concentration at which inhibition of 50% is achieved) for Compound A in caspase- 1 and IL-ip assays are shown. Compound A was tested in 3 monocyte donors.

[0623] Example 2.4: Functional assay of inflammasome activation in human monocyte-derived macrophages using LPS / MSU stimulation

[0624] Human monocytes were enriched and isolated from a huffy coat of whole blood with a RosetteSep™ Human Monocyte Enrichment Cocktail (Cat.No. 15068, StemCell) and Ficoll-Plaque PLUS (Cat.No. H8889, Sigma). Monocytes were differentiated into macrophages by treatment with 100 ng / mL M-CSF for 6 days at 37 °C, 5% CO2. Differentiated macrophages were seeded overnight (50,000 cells / well) in 100 pL of medium in a 96-well white-bottom plate at 37°C, 5% CO2. Cells were treated with a concentration range of MGD or the NLRP3 inhibitor selnoflast (Cat.No. HY- 132831, MedChemExpress) for 24 h prior to stimulation with monosodium urate crystals (MSU). Macrophages were stimulated with 1 pg / mL lipopolysaccharide (LPS) and 0.2 mg / mL MSU for 6 h. Medium of stimulated macrophages were collected and assayed for caspase-1 activity directly (Promega G9951) as well as IL-ip (Promega W6010), according to manufacturer’s instructions.

[0625] Compound A exhibited dose-dependent inhibition of NLRP3-driven activation of human macrophages in this assay (Figure 1). The MSU crystal stimulus used in this assay is relevant to the setting of gout, where MSU crystals activate NLRP3 inflammasome of jointresident cells and consequently trigger painful flares of the disease. These data support the therapeutic application of a NEK7 MGD in gout.

[0626] As shown in Figure 1, Compound A inhibits NLRP3-mediated inflammasome stimulation in primary human monocyte-derived macrophages, (a, b) Human monocyte-derived macrophages pre-treated with a dose-response of Compound A or selnoflast (NLRP3 inhibitor) for 24 h and stimulated with a combination of lipopolysaccharide (LPS) and monosodium urate crystals (MSU) for 6 h prior to supernatant collection. Monocytes were isolated from eight human donors. Caspase- 1 (a) and IL-ip (b) in the supernatant are measured and data are expressed as percentage relative to mean values of DMSO conditions for each donor (technical triplicates). Means of eight donors are plotted and analyzed using a four-parameter logistic regression model.

[0627] Table 3. Comparison of half-maximal inhibitory concentration (IC50) and maximal inhibition (Imax) for Compound A and selnoflast in both assays.

[0628]

[0629] Example 2.5. Multiple-dose study with Compound A induces NEK7 degradation and inhibits NLRP3 inflammasome activation in vivo in non-human primates

[0630] Non-naive male and female non-human primate (NHP) cynomolgus monkeys were orally administered with 5 consecutive daily doses of Compound A at 5 mg / kg, n=2 per dose group, 1 male and 1 female. Compound formulation was prepared on the day of administration in 0.5% methyl cellulose (4000 cps) in water and animals were fasted overnight. Plasma collected post dose were analyzed using a non GLP LC / MS / MS bioanalytical method to evaluate the compound concentration. Whole blood collected post dose were processed to PBMC and were analyzed using western blot method. Plasma pharmacokinetics and PMBC pharmacodynamics were assessed longitudinally throughout dosing and following dosing cessation.

[0631] Within 0.5 h of blood collection from animals that received vehicle or Compound A at 5 mg / kg, whole blood was aliquoted into two 0.25 mL aliquots. One aliquot was used as baseline, and the other as the ex vivo stimulated condition. For stimulation, whole blood was incubated with 100 ng / mL Lipopolysaccharide from Escherichia coli 0111 :B4 (LPS-EB) for 3 h, followed by 10 pM nigericin for 2 h. Plasma was then isolated and concentrations of IL-ip in plasma isolated from ex vivo whole blood stimulation were measured using the IL-i ELISA R&D Systems kit (Cat. # DY1318), with 50 pL per sample diluted with 50 pL reagent diluent / well. After reading absorbance on plate reader, standard curve and sample IL-ip levels were analyzed using 4PL method. Percent decrease in IL-i was quantified based on IL-ip levels from whole blood of Compound A-dosed animals relative to those from the vehicle group at each timepoint.

[0632] At 6 h after the final dose, a single oral gavage of Compound A at 5 mg / kg showed similar mean plasma concentration in comparison to 5 consecutive days of dosing (Table 4).

[0633] Table 4. Mean Plasma Concentration (ng / mL) of Compound A dosed orally at 5 mg / kg.

[0634]

[0635] In Table 4, plasma was isolated 6 h after final dose (dosed once or over five consecutive days), n=2. Plasma collected post dose were analyzed using a non GLP LC / MS / MS bioanalytical method to evaluate the compound concentration.

[0636] PBMC NEK7 degradation showed reduction to 44% of pre-dose levels on day 1, that was further reduced to 15% by day 5 (Table 5).

[0637] Table 5. NEK7 level from PBMC of NHP

[0638]

[0639] In Table 5, Compound A induces NEK7 degradation in vivo. NEK7 protein levels were assessed in PBMC isolated from NHP after oral administration for 5 consecutive days of Compound A at 5 mg / kg, n=2 per dose group. NEK7 levels were normalized to P-actin, as determined by JESS, at the indicated time points. NEK7 level at pre dose was normalized to 100%. Days 10 and 15 correspond to recovery period, 5 or 10 days after drug administration, respectively.

[0640] Commensurate with NEK7 levels, production of IL-1 was inhibited in an ex vivo whole blood stimulation assay (Table 6). The deep and sustained inhibition of IL-1 p release in the ex vivo assay after oral administration over five consecutive days suggests that Compound A can control inflammation driven by NLRP3 inflammasome. The inhibition of IL-ip in this ex vivo stimulation assay by NEK7 MGD dosed in NHP serves as a proof-of-concept for the therapeutic use of NEK7 MGD for the treatment of multiple inflammatory diseases in which IL-ip plays a pathogenic role. Such diseases include, but are not limited to gout, pericarditis, arthritis, and Still's disease.

[0641] Table 6. Percent decrease in IL-ip relative to predose

[0642]

[0643] In Table 6, suppression of ex vivo inflammasome activation following degradation of NEK7 in NHP is reported. Whole blood was isolated at the indicated time points from NHP dosed orally 5 mg / kg of Compound A over 5 days (day 1 through 5), n=2. Days 10 and 15 correspond to recovery period, 5 or 10 days after drug administration, respectively. Whole blood was stimulated ex vivo with 100 ng / mL LPS for 3 h and 10 pM nigericin for 2 h. Plasma was isolated and IL-ip was measured by ELISA. Percent decrease in IL-ip was quantified based on IL-ip levels from whole blood of Compound A-dosed animals relative to those from the vehicle group.

[0644] Example 2.6. Analysis of central nervous system penetrance in NHP

[0645] Naive NHP were orally administered with 7 consecutive daily dose of Compound A at 30 mg / kg, n=4 per dose group, 2 male and 2 female. Compound formulation was prepared on the day of administration in 0.5% methyl cellulose (4000 cps) in water and animals were fed twice a day; water was available ad libitum. Plasma collected posted dose on Day 1 and Day 7 were analyzed using a non GLP LC / MS / MS bioanalytical method to evaluate the compound concentration. Brain samples were harvested 24 h after final dose. Lysates for different brain regions (hippocampus, frontal cortex, and cerebellum) were prepared in M-PER lysis buffer and diluted at total protein concentration of 0.4 mg / mL in 0.1X sample buffer (12-230 kDa detection module; Protein Simple). The anti-NEK7 rabbit mAb (Abeam #AB133514) was used at 1:100 and anti-P-actin rabbit mAb (CST #5125) was used at 1:500. Samples were probed for NEK7 and -actin protein levels by JESS, and quantified relative to vehicle control.

[0646] NHPs dosed with Compound A at 30 mg / kg for 7 days showed oral bioavailability and favorable pharmacokinetic profile, with Cmax of 6600 ng / mL at 1.75 h after the final dose (Table 7). The brains of NHPs dosed with Compound A showed around 80% degradation of NEK7 across three different brain regions profiled (Table 8). These data support that certain NEK7 MGD may be suitable for applications that require exposure of CNS cells to the compound. These include diseases of the CNS, but may also extend to other diseases, such as obesity, where some component of pathology is driven by cells within the CNS.

[0647] Table 7. Plasma pharmacokinetics of Compound A after oral dosing for 7 days

[0648]

[0649] In Table 7, concentration of Compound A in NHP plasma following administration via oral gavage after 7 days post dose at 30 mg / kg is reported. NHP received daily oral administration of 30 mg / kg of Compound A for 7 days, n=2. Cmax, tmax, hast, AUCtiast, and AUCo-24hr were calculated based on the average of the group, n=4 (2 male and 2 female).Table 8. NEK7 degradation in the brain of NHP.

[0650]

[0651] In Table 8, NEK7 protein degradation in brains of NHP following oral dosing of Compound A is reported. NHP received daily oral administration of 30 mg / kg of Compound A or vehicle for 7 days. For Compound A group, n=4 (two male and two female); for vehicle, n=2; samples taken 24 h post-final dose. Brains were harvested 24 h after final dose, sectioned by region (hippocampus, frontal cortex, cerebellum), and analyzed for NEK7 and beta-actin protein levels by JESS. The average percent of NEK7 was quantified by brain region and normalized to P-actin.

[0652] EXAMPLE 3: CRYSTALLINE FORMS

[0653] The preparation and characterisation of five distinct crystalline forms of Compound A and two distinct forms of the co-form of Compound A HC1 is presented below, including XRPD and DSC data. The XRPD measurements used monochromatic Cu Ka radiation in the 20 region, and the DSC measurements are based on a heating rate of 10°C / min. Form II is the most thermodynamically stable, and Form III has favourable properties for processing, including improved filterability, purity, ease of drying, and solubility in typical solvents for forming spray dried dispersions.

[0654] The synthesis routes for the following crystalline forms of Compound A and the co-form of Compound A HC1 could be performed with smaller quantities, for example by starting with amounts of Compound A on the milligram scale, or with larger quantities, for example by starting with amounts of Compound A on the multi-gram scale.

[0655] Example 3.1: Form I

[0656] Preparation and Characterization of Form I

[0657] 1000.92 mg of Compound A was weighed in a 40 mL vial. Isopropyl acetate (IP AC) (15 mL) was added, and the mixture was stirred at 50 °C for 24 h. The suspension was filtered, and the filter cake was dried under vacuum at 50 °C for 6 h to give 963.65 mg (96.3% yield) of Compound A (Form I).

[0658] Tests showed that Form I is a non-hygroscopic anhydrate of irregular shape and high crystallinity. Form I converts to Form III upon heating above 200 °C. The XRPD and DSC data of Form I are summarized in Table 9.Table 9. Characterisation of Form I

[0659] > <> >

[0660]

[0661]

[0662] *This peak is characteristic of Form III. Form III appears upon heating.

[0663] Example 3.2: Form II

[0664] Preparation and Characterization of Form II

[0665] 1000.39 mg of Compound A was weighed in a 40 mL vial. Acetone (15 mL) was added, and the mixture was stirred at 50 °C for 24 h. The suspension was filtered, and the filter cake was dried under vacuum at 50 °C for 6 h to give 880.44 mg (88.0% yield) of Compound A (Form II).

[0666] Tests showed that Form II is a non-hygroscopic anhydrate of irregular shape and high crystallinity. The XRPD and DSC data of Form II are summarized in Table 10.

[0667] Table 10. Characterisation of Form II

[0668]

[0669]

[0670] Preparation of Form II from seed crystals

[0671] Compound A (1000.1 mg) was dissolved in THF / water 87.5 / 12.5 (13 mL). The solution was filtered through a syringe filter (0.2 pm) into a 50 mL reactor. Water (1.2 mL) was added to reach a THF / water ratio of 80 / 20. Seed crystals (Form II, 10.17 mg, as prepared above) suspended in THF / water 29 / 71 (400 pL) were added. A thin suspension was obtained. Water (12.4 mL) was added using a syringe pump within 30 minutes. The suspension was aged at 20 °C for 1 h, then it was heated to 50 °C within 1 h, and allowed to age for 1 h at 50 °C. More water (12.4 mL) was added and the suspension was stirred for 8 h at 50 °C, then it was cooled to 5 °C over 8 h. The solids were filtered and washed twice with water, then dried overnight under vacuum at 50 °C to obtain Compound A (Form II, 70 % yield).Example 3.3: Form III

[0672] Preparation and Characterization of Form III

[0673] 2000.85 mg of Compound A was weighed in a 250 mL round-bottom flask. DMF (20 mL) was added to dissolve the solid at 25 °C, then H2O (70 mL) was added dropwise with stirring. The resulting suspension was stirred at 25 °C for 24 h. The suspension was filtered, and the filter cake was dried under vacuum at 50 °C for 6 h to give 1887.41 mg (94.3% yield) of Compound A (Form III).

[0674] Tests showed that Form III is a stable non-hygroscopic anhydrate of irregular shape and high crystallinity. It is polymorphically stable, in particular with respect to Forms I and IV and Compound A HC1 co-Forms V and VI, and has good solubility in polar solvents such as water / acetone, in particular compared to Form II. The XRPD and DSC data of Form III are summarized in Table 11.

[0675] Table 11. Characterisation of Form III

[0676]

[0677]

[0678] Large scale preparation of Form III with seed crystals - Method I

[0679] Compound A (30 g) was dissolved in acetic acid / water 90 / 10 v / v (6 V, 180 mL) at 25 °C to give a dark brown solution. It was filtered into a 1 L reactor at 25 °C. The filter was washed with acetic acid / water 90 / 10% v / v (1 V, 30 mL). An overhead stirrer with a stirring speed of 500 rpm was used throughout the process. Water (3.7 V, 111 mL) was added at 25 °C. 5 minutes after the addition of water, seed crystals (Form III, 1% w / w, 300 mg, as prepared above) were added to the solution. A pale slurry was obtained. After 5 minutes, the remaining anti solvent (13.3V, 399 mL of water) was added at once to the suspension. A brown suspension was obtained, which turned into a suspension with white solids approximately 90 minutes after adding the seeds. This suspension remained unchanged for the rest of the aging. The suspension was kept for 2.5 h in total at 25 °C, then it was filtered rapidly, and washed twice with water (1.3 V, 39 mL). The resulting solid was vacuum dried to afford Compound A (Form III, 16.8 g, 56% yield, 99.6% purity).Large scale preparation of Form III with seed crystals - Method II

[0680] Reactor 1 was inertized with nitrogen. AcOH (24.32 kg, 3.5 V) was charged into Reactor 1 and heated to 50-70 °C. Compound A (6.60 kg, 1 eq.) was added into the reactor in portions to obtain a clear solution. Reactor 2 was inertized with nitrogen. The mixture from Reactor 1 was filtered into Reactor 2 through Ultrafilter. AcOH (3.47 kg, 0.5 V) was charged into Reactor 1 to wash the reactor wall, keeping the internal temperature of Reactor 1 at 50-60 °C. The acetic acid was stirred for 10-30 min, then it was filtered into Reactor 2 through Ultrafilter. Reactor 3 was inertized with nitrogen. Water (69.30 kg, 10.5 V) was charged into Reactor 3, followed by seed crystals of Compound A (Form III, 66 g, 1.00 wt%, as prepared above). The internal temperature of Reactor 2 was cooled to 45-55 °C, and the mixture was slowly transferred into Reactor 3 at 45-55 °C over 2-4 hours. The mixture in Reactor 3 was cooled to 15-25 °C and stirred for 6-8 h, then it was filtered. The filter cake was washed with anhydrous ethanol (2 V) and dried at 40-50 °C for 12-24 h to afford crystalline Compound A (Form III, 5.90 kg, 91.5% yield, 99.9% purity) as a white solid.

[0681] Example 3.4: Comparison of filtration speeds Form II and Form III

[0682] The crystal forms II and III were of different shapes (fine needles for Form II versus more grain-like for Form III, see Figure 15 in the appendix), which had a significant impact on the purging of the mother and washing liquor, filtration time, and ease of drying. While the purging efficiency can have a direct impact on product quality, the filtration time and ease of drying are important parameters for the batch cycle time (Table 12). These effects are mainly seen on larger scale and therefore, Form III is the preferred form for large scale crystallization processes.

[0683] Table 12. Differences in filtration times for Form II and Form III

[0684]

[0685] Example 3.5: Form IV

[0686] Preparation and Characterization of Form IV

[0687] In a glass vial, Compound A (1.0 g) was dissolved in acetic acid (3.0 V). The mixture was heated to 60 °C to obtain a clear solution. The solution was filtered, and the filter unit was washed with acetic acid (0.5 V). The Compound A / acetic acid solution was slowly added into a 50 mL glass vial containing water (10.5 V) over 2 h. The resulting suspension was filtered to afford Compound A (Form IV, 85-90% yield).Form IV can be converted to Form III by heating to 75 °C in acetic acid / water 1 / 3 (14 V) for 2.5 h, or by stirring at 20 °C in acid / water 1 / 2 (15.75 V) for 2.5 h. The XRPD and DSC data of Form IV are summarized in Table 13.

[0688] Table 13. Characterisation of Form IV

[0689] > <> >

[0690]

[0691]

[0692] Example 3.6: Compound A HC1 co-Form V

[0693] Preparation and Characterization of Compound A HC1 co-Form V

[0694] 1298.96 mg of Compound A was weighed in a 40 mL vial. Acetonitrile (26 mL) and HC1 (1.05 eq.) were added, and the mixture was stirred at 50 °C for 24 h, then at 25 °C for 48 h. The suspension was filtered, and the filter cake was dried under vacuum at 50 °C for 2 h to give 929.1 mg (65.9% yield) of Compound A (Compound A HC1 co-Form V).

[0695] The XRPD and DSC data of Compound A HC1 Form V are summarized in Table 14.Table 14. Characterisation of Compound A HC1 Form V

[0696] > <> >

[0697]

[0698]

[0699] *This peak is characteristic of Form III. Form III appears upon heating.

[0700] Example 3.7: Compound A HC1 co-Form VI

[0701] Preparation and Characterization of Compound A HC1 co-Form VI

[0702] 1298.98 mg of Compound A was weighed in a 40 mL vial. Methyl THF (26 mL) and HC1 (2.05 eq.) were added, and the mixture was stirred at 50 °C for 1 h, then at 25 °C for 48 h. The suspension was filtered, and the filter cake was dried under vacuum at 50 °C for 2 h to give 1226.9 mg (87.0% yield) of Compound A (Compound A HC1 co-Form VI).

[0703] The XRPD and DSC data of Compound A HC1 Form VI are summarized in Table 15.

[0704] Table 15. Characterisation of Compound A HC1 Form VI

[0705] >

[0706] > > >

[0707]

[0708]

[0709]

[0710] *This peak is characteristic of Form III. Form III appears upon heating.

[0711] Example 3.8: Solubility studies of Compound A: Amorphous Form and Crystalline Forms I- VI

[0712] Solubility of Compound A (amorphous form) in Biorelevant Aqueous Media

[0713] A stock solution of Compound A in 95 / 5 THF / water at 50 mg / mL was loaded into 1 mL syringes and dosed into 10 mL of aqueous media. The solutions were dosed using a syringe pump at 100 pL / min for a final concentration of 2500 pg / mL. UV-Vis spectral data was recorded using fibre optic probes from 200 - 720 nm. The concentration was determined by monitoring the second derivative of the absorbance at 255-265 nm. The results are summarized in Table 16.

[0714] Table 16. Solubility of Compound A (amorphous) in biorelevant aqueous media.

[0715]

[0716] Solubility of Compound A (amorphous form) in various solvents

[0717] The solubility of Compound A was assessed in potential spray solvent systems by serial addition of Compound A into 1 mL of solvent with stirring. The reported solubility is the point at which Compound A no longer completely dissolves by visual assessment. The results are summarized in Table 17.

[0718] Table 17. Solubility of Compound A (amorphous) in various solvents.

[0719]

[0720]

[0721] The acetone / water 9 / 1 solvent mixture was chosen as the preferred spray solvent system, and the solubility of the crystalline forms was tested in this mixture as well as in aqueous media.

[0722] Solubility of Crystalline Forms II and III in Acetone / Water 9 / 1

[0723] 10 mg of the crystalline sample was charged into a 2 mL glass vial at room temperature (20 - 25 °C). Solvent was added into the vial in doses of 20 pL every 10 minutes until a total volume of 100 pL, then in doses of 50 pL until a total volume of 1.8 mL, with continual stirring at 500 rpm. After each dose of solvent, the solution was checked to see if the solid had dissolved. When a clear solution was obtained, the approximate solubility of the crystalline form was calculated. The results are summarized in Table 18.

[0724] Table 18. Solubility of Crystalline Forms II and III in Acetone / Water 9 / 1

[0725]

[0726] Form III showed better solubility in acetone / water 9 / 1 than other forms. Acetone / water 9 / 1 is the favoured solvent mixture for creating spray-dried dispersions (SDD) of Compound A in order to formulate Compound A into capsules or tablets. Therefore, Form III is particularly useful for the preparation of SDDs due to its higher solubility.

[0727] Solubility of Crystalline Forms II and III in Aqueous Biorelevant Media

[0728] Compound A (Form II, III, co-Form V, or co-Form VI) was weighed into a glass vial, and the biorelevant medium was added to create a target concentration of 5 mg / mL. The resulting suspension was stirred at 37 °C (600 rpm) for 24 h. The suspensions were filtered through a 0.45 pm nylon membrane, and the filtrates were analysed by HPLC for solubility at 0.5 h, 2 h and 24 h. Results are summarized in Table 19.

[0729] Table 19. Solubility Results in Aqueous Biorelevant Media

[0730]

[0731] <>

[0732]

[0733] The HPLC results were the mean values of three parallel batches.

[0734] Example 3.9; Stability studies

[0735] Compound A (Form I or II, or Compound A HC1 co-Form V or VI) was stored for 7 days at various temperatures and relative humidities. The samples were characterized by XRPD and HPLC and inspected for colour change. No changes in crystal form were observed for Form I, II and III. For Compound A HC1 co-Forms V and VI, small amounts of Form III were observed under high humidity conditions. The results are summarized in Table 20.

[0736] Table 20. Short Term Stability Results

[0737] " " " " < " <

[0738]

[0739] 2HC1 co-Forms V and VI were also stored at 2-8 °C, and no change in purity from the initial conditions was observed.

[0740] 3Traces of Compound A Form III were observed in XRPD.Example 3.10: Competitive slurry studies

[0741] Preparation of the saturated solutions

[0742] The relevant form of Compound A was added into a 1 mL vial. 1 mL of the selected solvent was added, and the mixture was stirred at the temperature used for the competitive slurry test (25, 50, 75 or 85 °C) to make saturated solutions. If all of Compound A was solubilized, more Compound A was added until a suspension was obtained. The suspensions were stirred for 2 h, then filtered through a 0.45 pM membrane. The filtrates were used as the competitive slurry solvent.

[0743] Competitive slurry of Form I, Form II and Form III

[0744] Slurry preparation

[0745] ~20 mg each of Form I, Form II and Form III were placed together in a 2 mL vial. 1 mL of a saturated solution of Compound A (amorphous form) prepared as above was added, and the mixture was stirred at the specified temperature (25, 50 or 75 °C). The residual solids were characterized after 24 h and again after 7 days. The results are shown in Table 21.

[0746] Table 21. Result of competitive slurry of Form I, Form II and Form III

[0747]

[0748] Competitive slurry of Form II and Form III

[0749] Slurry preparation

[0750] ~50 mg of Form III and 0.5 mg of Form II were placed in a 2 mL vial. 1 mL of a saturated solution of Compound A (Form III) prepared as above was added, and the mixture was stirredat 25 °C. The residual solids were characterized after a specified time. The results are shown in Table 22.

[0751] Table 22. Result of competitive slurry of Form III and Form II (approx. l%w / w)

[0752]

[0753] Competitive slurry of Compound A HC1 co-Form V and Compound A HC1 co-Form VI ~20 mg each of Compound A HC1 co-Form V and Compound A HC1 co-Form VI were placed together in a 2 mL vial. 1 mL of a saturated solution of Compound A (Compound A HC1 coForm VI) prepared as above was added, and the mixture was stirred at 25 °C. The residual solids were characterized after 24 h and again after 7 days. The results are shown in Table 23.

[0754] Table 23. Results of the competitive slurry of Compound A HC1 co-Form V and Compound A HC1 co-Form VI

[0755]

[0756] EXAMPLE 4: FORMULATION

[0757] Example 4.1: Solid Dispersion Comprising Compound A

[0758] SDD Ingredients and Preparation

[0759] To improve the bioavailability of Compound A, a spray-dried dispersion (SDD) of Compound A in hydroxypropylmethylcellulose acetate succinate medium grade (HPMCAS MG) as the polymeric carrier in a 25 / 75 ratio was prepared. The total batch size of the SDD was split into 3 equal sub-batches, which were combined after drying. The following materials and equipment were used (Table 24):

[0760] Table 24. Spray dried dispersion solution ingredients and process information

[0761]

[0762] The spray drying process was carried out as follows:

[0763] Purified water and acetone were mixed in a 15 L stainless steel container and heated to 25 °C using a recirculator bath. Compound A was added to the solvent mixture under constant stirring, and the mixture was stirred until it was completely dissolved. The HPMCAS MG was added to the mixture, and stirring was continued until it was completely dissolved. Once all of the solids had dissolved (confirmed by visual inspection), the solution was dried by spray drying. The setup of the atomization device was as follows:

[0764] - Two-fluid nozzle

[0765] - Nozzle cap: 5 mm

[0766] - Nozzle insert: 1 mm

[0767] Spacer ring: 3 mmThe process was carried out in closed cycle mode using nitrogen as a drying gas. After the spray drying process, the obtained product was subjected to a secondary drying process in a vacuum oven. The product was dried at 10 mbar (40 °C) for 45 min, then at 960 mbar (40 °C) for 5 min. This was repeated five times until the product was dry. The batches were combined by blending manually in a double PE bag for 4 min. The cumulative yield was 83.7%.

[0768] SDD Dissolution Performance

[0769] A gastric to intestinal transfer non-sink dissolution test was used to measure the supersaturation of Compound A in the SDD compared to bulk Compound A when dosed as a powder. A concentration of 2.5 mgA / mL was used as the dosing concentration to ensure non-sink conditions were reached. The SDD was first dosed into 10 mL of media at a low pH value to imitate a fasted stomach. Then after 30 minutes, 10 mL of concentrated simulated intestinal buffer was added to reach a final composition of 0.5% SIF in phosphate buffer pH 6.5. Drug concentration was measured over time using Pion UV-Vis probes as well as manual pulls for HPLC measurement. The SDD outperformed the API at supersaturated conditions, reaching a maximum concentration of around 2300 pg / mL in the IB portion of the test (the API reached a maximum concentration of approximately 120 pg / mL). The SDD achieves a plateau of dissolution before 60 minutes (Figure 2).

[0770] Example 4.2: Capsules 5, 20, 50 mg strength

[0771] The 5, 20 and 50 mg formulations of Compound A were prepared from a spray-dried dispersion of Compound A and a mannitol / cellulose 80 / 20 filler. The three dosages all contain the same excipients. The 5 mg strength blend is an independent blend, while the 20 and 50 mg strengths use a common blend but two different capsule sizes.

[0772] Materials

[0773] Table 25. Materials and quantities used for the capsule formulation

[0774]

[0775] Capsule formulation composition

[0776] Table 26. Composition of the 5, 20 and 50 mg capsule formulations

[0777] <

[0778]

[0779] Blending and encapsulation procedure

[0780] 1. One-half the amount of mannitol, the solid dispersion, the microcrystalline cellulose, the rest of the mannitol, and the sodium croscarmellose were added (in this order) to a 10 L bin.

[0781] 2. A 10-minute blending process was performed at 20 rpm.

[0782] 3. Then, the intragranular magnesium stearate previously sieved through a 0.630 mm manual sieve was added to the bin.

[0783] 4. A 5 -minute blending process was performed at 20 rpm.

[0784] 5. The roller compaction (dry granulation) process was performed.

[0785] 6. Once compacted, the extragranular magnesium stearate was recalculated based on the intragranular yield obtained.

[0786] 7. The extragranular magnesium stearate previously sieved through a 0.630 mm manual sieve was added to the granulated product.

[0787] 8. A 5-minute blending process was performed at 20 rpm to give the final blend.

[0788] 9. The capsules were manually filled using the Profille 3600 capsule filler machine, with different size capsules for the different dosage blends (5 mg: size 4 capsules; 20 mg: size 3 capsules; 50 mg: size 0 capsules). The capsules were made from hydroxy propyl methyl cellulose (HPMC).Capsule dissolution profiles

[0789] The dissolution rate of the capsules (5, 20 and 50 mg strength) was tested at pH 6.8 with paddle stirring at 75 rpm (900 ml volume, N = 6). At all dosage strengths, dissolution was complete within 30 minutes (Table 27).

[0790] Table 27. Dissolution rates of 5 mg, 20 mg and 50 mg capsules.

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[0792]

[0793] 1time (minutes);2dissolution (%);3coefficient of variation (%)

[0794] Stability Study

[0795] The chromatographic purity and assay uniformity of the capsules (5 mg and 50 mg strength) were evaluated in open and closed bottles, showing that the capsules are stable for 1 month under accelerated stability testing conditions (40°C / 75% RH). The data is summarized in Table 28.

[0796] Table 28. Chromatographic purih and a sa uniformih of (he capsules (N 3)

[0797]

[0798] 1Average assay uniformity;2average chromatographic impurities (% area under peaks).

[0799] EQUIVALENTS

[0800] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

CLAIMS1. A solid dosage form comprising Compound A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein Compound A is a compound of the following formula:

2. The solid dosage form of claim 1, wherein the solid dosage form comprises a solid dispersion comprising Compound A and a polymer.

3. The solid dosage form of claim 2, wherein the polymer is hydroxy propyl methyl cellulose acetate succinate (HPMCAS).

4. The solid dosage form of claim 2 or claim 3, wherein the solid dispersion comprises Compound A and the polymer at a ratio of between 1:5 and 1 : 1 by weight.

5. The solid dosage form of any one of the preceding claims, wherein the amount of Compound A is:(i) between 0.1 mg and 500 mg;(ii) between 0.1 mg and 300 mg;(iii) between 0.1 mg and 250 mg;(iv) between 0.1 mg and 200 mg;(v) between 0.1 mg and 150 mg;(vi) between 0.1 mg and 100 mg;(vii) between 0.1 mg and 80 mg;(viii) between 0.1 mg and 60 mg;(ix) between 1 mg and 250 mg(x) between 1 mg and 200 mg;(xi) between 1 mg and 150 mg;(xii) between 1 mg and 100 mg;(xiii) between 1 mg and 80 mg;(xiv) between 1 mg and 60 mg;(xv) between 2 mg and 250 mg(xvi) between 2 mg and 200 mg;(xvii) between 2 mg and 150 mg;(xviii) between 2 mg and 100 mg;(xix) between 2 mg and 80 mg;(xx) between 2 mg and 60 mg; or(xxi) between 2 mg and 25 mg.

6. The solid dosage form of any one of the preceding claims, wherein the amount of Compound A is between 2 mg and 100 mg, between 2 mg and 80 mg, or between 2 mg and 60 mg.

7. The solid dosage form of any one of the preceding claims, wherein the amount of Compound A is selected from 1 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 80 mg, and 100 mg8. The solid dosage form of any one of the preceding claims, wherein the amount of Compound A is between 2 mg and 60 mg.

9. The solid dosage form of any one of the preceding claims, wherein the amount of Compound A is selected from 5 mg, 20 mg, and 50 mg.

10. The solid dosage form of any one of the preceding claims, wherein the solid dosage form is a tablet or a capsule.

11. The solid dosage form of any one of the preceding claims, wherein the solid dosage form is a capsule.

12. The solid dosage form of any one of the preceding claims, wherein the solid dosage form is a hard capsule, for example, wherein the solid dosage form is a capsule made from hydroxypropylmethyl cellulose (HPMC).

13. The solid dosage form of any one of claims 10-12, wherein the capsule contains a fill composition comprising Compound A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

14. The solid dosage form of claim 13, wherein the tablet or fill composition comprises:(i) a filler;(ii) a disintegrant; and(iii) a lubricant.

15. The solid dosage form of claim 14, wherein the filler is present at from about 40 to about 95 wt %.

16. The solid dosage form of claim 14 or claim 15, wherein the disintegrant is present at from about 1 to about 10 wt %.

17. The solid dosage form of any one of claims 14-16, wherein the lubricant is present at from about 0.1 to about 5 wt %.

18. A solid dispersion comprising Compound A, or a pharmaceutically acceptable salt thereof, and a polymer, wherein Compound A is a compound of the following formula:

19. The solid dispersion of claim 18, wherein the polymer is hydroxy propyl methyl cellulose acetate succinate (HPMCAS).

20. The solid dispersion of claim 19, wherein the polymer is medium grade hydroxy propyl methyl cellulose acetate succinate (HPMCAS MG).

21. The solid dispersion of any one of claims 18-20, wherein the solid dispersion comprises Compound A and the polymer at a ratio of between 1:5 and 1 : 1 by weight.

22. A process for preparing a solid dosage form according to any one of claims 1-17, or a solid dispersion according to any one of claims 18-21, comprising spray drying a solution comprising Compound A, or a pharmaceutically acceptable salt thereof, to form a solid dispersion.

23. A crystalline form of Compound A, or a pharmaceutically acceptable salt thereof, wherein Compound A is a compound of the following formula:

24. The crystalline form of claim 23, wherein the crystalline form is selected from:(i) Form I, characterised by a DSC profile comprising a major endotherm with peak temperature at around (±1.0) 192.7 °C, and / or characterised by an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 7.0, 9.9, 16.6, 18.9, 26.5, and 28.0;(ii) Form II, characterised by a DSC profile comprising a major endotherm with peak temperature at around (±1.0) 204.5 °C, and / or characterised by an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 20 (°) = 6.9, 9.8, 15.1, 16.6, 20.5, and 27.7;(iii) Form III, characterised by an XRPD pattern with at least the following XRPD peaks (CuKa°20) at approximately (± 0.2): 8.3, 9.0, 9.7, 13.2, 14.3, and 24.6; (iv) Form IV, characterised by an XRPD pattern with at least the following XRPD peaks (Cu Ka °20) at approximately (± 0.2): 9.0, 13.6, 14.5, 18.4, 20.2, and 21.1;(v) Compound A HC1 co-Form V, characterised by an XRPD pattern with at least the following XRPD peaks at approximately (± 0.2): 20 (°) = 7.3, 11.3, 14.5, 18.3, 22.5, and 26.7; and(vi) Compound A HC1 co-Form VI, characterised by an XRPD pattern with at least the following XRPD peaks at approximately (± 0.2): 20 (°) = 10.6, 12.0, 15.4, 21.3, 23.2, and 27.4.

25. The crystalline form of claim 24, wherein the crystalline form is selected from Form I, Form II, Form III, and Form IV.

26. The crystalline form of claim 24, wherein the crystalline form is Form III.

27. The crystalline form of claim 24, wherein the crystalline form is selected from Compound A HC1 co-Form V and Compound A HC1 co-Form VI.

28. A method of treating a disorder caused by or associated with NLRP3 inflammasome activation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a solid dosage form according to claims 1-17, a solid dispersion according to claims 18-21, or a crystalline form according to claims 23-27.

29. The method of claim 28, wherein the disorder is selected from the group consisting of:(i) inflammatory reactions in the joints;(ii) hyperactive inflammation with underlying genetic mutations;(iii) autoimmune diseases;(iv) respiratory diseases;(v) kidney diseases;(vi) central nervous system diseases;(vii) ocular diseases;(viii) cardiovascular diseases;(ix) viral infections and subsequent immune hyperactivation;(x) diseases of the hematopoietic system;(xi) liver disease;(xii) inflammatory reactions in the skin;(xiii) metabolic diseases;(xiv) cancers;(xv) infectious diseases; and(xvi) allergic disease.

30. The method of claim 28 or claim 29, wherein the disorder is selected from the group consisting of cardiovascular diseases and metabolic diseases.

31. The method of any one of claims 28-30, wherein the disorder is (i) gout, for example wherein the disorder is a) acute or chronic gout, b) tophaceous gout or c) pseudogout, (ii) pericarditis, for example Dressier’s syndrome, or (iii) Wilson disease.

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