WO2022036033A2

WO2022036033A2 - Solid state forms of an organic compound

Info

Publication number: WO2022036033A2
Application number: PCT/US2021/045656
Authority: WO
Inventors: Jose Luis RIOS LIZARRAGA; Kristopher Depew; Louis Grenier; Benjamin S. Lane; Eric Simone; Jacob Paul SIZEMORE
Original assignee: Servier Pharmaceuticals, Llc
Priority date: 2020-08-12
Filing date: 2021-08-12
Publication date: 2022-02-17
Also published as: TW202227446A; WO2022036033A3; WO2022036033A4; AR123228A1

Abstract

Provided herein are various solid state forms, including salts as well as various crystalline and amorphous forms, of Compound I which is represented by the structural formula: Also provided are pharmaceutical compositions comprising these materials, methods for their manufacture, uses thereof for treating conditions, including but not limited to conditions that would benefit from inhibition of methionine adenosyltransferase 2a (MAT2A).

Description

SOLID STATE FORMS OF AN ORGANIC COMPOUND

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/064,866, filed August 12, 2020, the disclosure of which is incorporated by reference herein.

BACKGROUND

[0002] Methionine adenosyltransferase (MAT) also known as S- adenosylmethionine synthetase is a cellular enzyme that catalyzes the synthesis of S-adenosyl methionine (SAM or AdoMet) from methionine and ATP and is considered the rate-limiting step of the methionine cycle. SAM is the propylamino donor in polyamine biosynthesis and the principal methyl donor for DNA methylation and is involved in gene transcription and cellular proliferation as well as the production of secondary metabolites.

[0003] Two genes, MAT1A and MAT2A, encode two distinct catalytic MAT isoforms. A third gene, MAT2B, encodes a MAT2A regulatory subunit. MAT1 A is specifically expressed in the adult liver, whereas MAT2A is widely distributed. Because MAT isoforms differ in catalytic kinetics and regulatory properties, MAT1 A-expressing cells have considerably higher SAM levels than do MAT2 A-expressing cells. It has been found that hypomethylation of the MAT2A promoter and histone acetylation causes upregulation of MAT2A expression.

[0004] Inhibitors of MAT2A have been found to possess wider applications as chemotherapeutic agents.

[0005] 3-(Cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-2- ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one, hereinafter also referred to as “Compound I” (structural formula shown below), has been characterized as an inhibitor of MAT2A. See e.g., International Patent Application Publication No. 2018-045071 the contents of which are incorporated herein by reference.

[0006] Compound I was developed to treat conditions and disorders that would benefit from inhibition of MAT2A. Given its therapeutic benefits, and the great promise for treating a plethora of different diseases, there is a need to develop various solid state forms of Compound I in an effort to facilitate isolation, manufacturing, and formulation development for various routes of administration, as well as to enhance storage stability.

SUMMARY

[0007] The disclosure is directed to solid state forms of Compound I including crystalline forms of Compound I, crystalline forms of pharmaceutically acceptable salts of Compound I, solvates of Compound I, crystalline solvates of Compound I, hydrates of Compound I, crystalline hydrates of Compound I, amorphous forms of Compound I, and combinations thereof. Pharmaceutical compositions comprising these solid state forms are also described, as well as methods for their preparation and use.

[0008] Also provided herein are pharmaceutical compositions comprising the various solid state forms of Compound I which include, solvated forms, salt forms, anhydrous forms and amorphous forms of Compound I, as well as methods for their manufacture, and uses thereof for treating conditions, including but not limited to conditions that would benefit from inhibition of MAT2A. Further provided are pharmaceutical compositions comprising a solid dispersion comprising one or more solid state forms of Compound I and a pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIG. 1 is the powder X-ray diffraction pattern for Form D of Compound I. [0010] FIG. 2 is the powder X-ray diffraction pattern for Form K of Compound I. [0011] FIG. 3 is the powder X-ray diffraction pattern for Form H of Compound I. [0012] FIG. 4 is the powder X-ray diffraction pattern for Form F of Compound I. [0013] FIG. 5 is the powder X-ray diffraction pattern for Form I of Compound I.

[0014] FIG. 6 is the powder X-ray diffraction pattern for Form L of Compound I.

[0015] FIG. 7 is the powder X-ray diffraction pattern for Form Q of Compound I.

[0016] FIG. 8 is the powder X-ray diffraction pattern for Form R of Compound I.

[0017] FIG. 9 is the powder X-ray diffraction pattern for Form S of Compound I.

[0018] FIG. 10 is the powder X-ray diffraction pattern for Form T of Compound I.

[0019] FIG. 11 is the powder X-ray diffraction pattern for Form U of Compound I.

[0020] FIG. 12 is the powder X-ray diffraction pattern for Form 17- A of Compound

I.

[0021] FIG. 13 is the powder X-ray diffraction pattern for Form 17-B of Compound I.

[0022] FIG. 14 is the powder X-ray diffraction pattern for Form 23 -A of Compound I.

[0023] FIG. 15 is the powder X-ray diffraction pattern for Form 23-B of Compound I.

[0024] FIG. 16 is the powder X-ray diffraction pattern for Form 23-C of Compound I.

[0025] FIGs. 17A-17E are the powder X-ray diffraction patterns for sodium salt Forms 20- A, 20-B, 20-C, 20-D, and 20-E of Compound I.

[0026] FIGs. 18A-18E are the powder X-ray diffraction patterns for potassium salt Forms 21-A, 21-B, 21-C, 21-D, and 21-E of Compound I. The spectra from the bottom to the top are Forms 21-A, 21-B, 21-C, 21-D, and 21-E, respectively.

[0027] FIGs. 19A-19F are the powder X-ray diffraction patterns for calcium salt Forms 22-A, 22-B, 22-C, 22 -D, 22-E, 22-F of Compound I.

[0028] FIG. 20 is the powder X-ray diffraction pattern for Form A of Compound I.

[0029] FIG. 21 is the DSC thermogram for Form D of Compound I.

[0030] FIG. 22 are the TGA/DSC chromatographs for Form D of Compound I.

[0031] FIG. 23 is the DVS spectrum for Form D of Compound I.

[0032] FIG. 24 are the TGA/DSC chromatographs for Form A of Compound I.

[0033] FIG. 25 are the TGA/DSC chromatographs for Form F of Compound I.

[0034] FIG. 26 are the TGA/DSC chromatographs for Form H of Compound I.

[0035] FIG. 27 are the TGA/DSC chromatographs for Form I of Compound I.

[0036] FIG. 28 are the TGA/DSC chromatographs for Form K of Compound I.

[0037] FIG. 29 are the TGA/DSC chromatographs for Form L of Compound I. [0038] FIG. 30 are the TGA/DSC chromatographs for Form Q of Compound I.

[0039] FIG. 31 are the TGA/DSC chromatographs for Form R of Compound I.

[0040] FIG. 32 are the TGA/DSC chromatographs for Form S of Compound I.

[0041] FIG. 33 are the TGA/DSC chromatographs for Form T of Compound I.

[0042] FIG. 34 are the TGA/DSC chromatographs for Form U of Compound I.

[0043] FIG. 35 are the TGA/DSC chromatographs for Form 17-A of Compound I.

[0044] FIG. 36 is the DSC thermogram of Form 17-A of Compound I.

[0045] FIG. 37 are the TGA/DSC chromatographs for Form 23-A of Compound I.

[0046] FIG. 38 is the DSC thermogram for Form 23-C of Compound I.

[0047] FIG. 39 are the TGA/DSC chromatographs for Form 23-C of Compound I.

[0048] FIG. 40 is the DVS spectrum of Form 17-B of Compound I.

[0049] FIG. 41 is DVS spectrum of Form 23-A of Compound I.

[0050] FIG. 42 is the DVS spectrum of Form 23-C of Compound I.

[0051] FIG. 43 are the DSC and DSC/TGA thermograms of Form 20-A of Compound I.

[0052] FIG. 44 are the DSC and DSC/TGA thermograms of sodium salt Form 20-B of Compound I.

[0053] FIG. 45 are the DSC and DSC/TGA thermograms of sodium salt Forms 20- C and 20-E of Compound I.

[0054] FIG. 46 is the DSC thermogram of sodium salt Form 20-D of Compound I.

[0055] FIG. 47 is the DSC thermogram of potassium salt Form 21 -A of Compound I.

[0056] FIG. 48 is the DSC thermogram of potassium salt Form 21 -B of Compound I.

[0057] FIG. 49 is the DSC thermogram of potassium salt Form 21 -C of Compound I.

[0058] FIG. 50 is the DSC thermogram of potassium salt Form 21 -D of Compound I.

[0059] FIG. 51 is the DSC thermogram of potassium salt Form 21 -E of Compound I.

[0060] FIG. 52 is the DSC thermogram of calcium salt Forms 22-A and 22-F of Compound I.

[0061] FIG. 53 is the DSC thermogram of calcium salt Form 22 -B of Compound I.

[0062] FIG. 54 is the DSC thermogram of calcium salt Form 22 -C of Compound I. [0063] FIG. 55 is the XRPD pattern of crystalline Form K-C of Compound I.

[0064] FIG. 56 is the DSC/TGA thermograms of crystalline Form K-C of Compound I.

[0065] FIG. 57 is the XRPD pattern of the lithium salt of Compound I (Form Li-W).

[0066] FIG. 58 is the DSC thermogram of the lithium salt of Compound I (Form Li- W).

[0067] FIG. 59 is the TGA thermogram of the lithium salt of Compound I (Form Li- W).

[0068] FIG. 60 the XRPD pattern of the sodium salt of Compound I (Form Na-W).

[0069] FIG. 61 is the DSC thermogram of the sodium salt of Compound I (Form Na-W).

[0070] FIG. 62 is the TGA thermogram of the sodium salt of Compound I (Form Na-W).

[0071] FIG. 63 the XRPD pattern of the potassium salt of Compound I (Form K- W).

[0072] FIG. 64 is the DSC thermogram of the potassium salt of Compound I (Form K-W).

[0073] FIG. 65 is the TGA thermogram of the potassium salt of Compound I (Form K-W).

[0074] FIG. 66 is the XRPD pattern of the calcium salt of Compound I (Form Ca- W).

[0075] FIG. 67 is a graph of the solubility of Compound I in dichloromethane and varying amounts of methanol at 35°C.

DETAILED DESCRIPTION

[0076] Definitions

[0077] When used alone, the terms, e.g., “Form A". “Form K”, “Form K-C”, “Form D”, “Form H”, “Form F”, “Form I”, “Form L”, “Form Q”, “Form R”, “Form S”, “Form T”, and “Form U” when describing Compound I, refer to the crystalline forms A, K, K-C, D, H, F, I, L, Q, R, S, T, U, and P of Compound I, respectively. Additionally, when describing various basic salts of Compound I, the terms “Form 20- A”, “Form 20-B”, “Form 20-C”, “Form 20-D”, “Form 20-E”, and “Form Na-W” refer to crystalline forms of the sodium salt of Compound I; the terms “Form 21-A”, “Form 21-B”, “Form 21-C”, “Form 21-D” “Form 21-E”, and “K-W” refer to crystalline forms of the potassium salt of Compound I; and the terms “Form 22- A”, “Form 22-B”, “Form 22-C”, “Form 22-D”, “Form 22-E”, “Form 22-G”, “Form 22 -H” and “Form Ca-W” refer to crystalline forms of the calcium salt of Compound I; and the term “Form Li-W” refers to a crystalline form of the lithium salt of Compound I. When describing various co-crystals of Compound I, the terms “Form 17-A”, “Form 17-B”, “Form 23-A”, “Form 23-B”, and “Form 23-C” refer to crystalline forms of co-crystals of Compound I.

[0078] The compound of Formula I as referenced herein refers to the compound that is 3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-2-ylamino)pyrazolo[l,5- a]pyrimidin-7(4H)-one. This compound has the following structure:

Compound I.

[0079] As used herein, “solid state form” refers to any of the solid forms of Compound I described herein, including solid forms of solvates of Compound I, solid forms of pharmaceutically acceptable salts of Compound I, solid forms of hydrate of Compound I, solid forms of anhydrous Compound I, solid forms of amorphous Compound I, as well as any combination thereof.

[0080] The term “amorphous” means solid state forms that are present in noncrystalline states or forms. Amorphous solids are disordered arrangements of molecules and therefore possess no distinguishable crystal lattice or unit cell and consequently have no definable long range ordering. Solid state ordering of solids may be determined by standard techniques known in the art, e.g., by X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC). Amorphous solids can also be differentiated from crystalline solids e.g., by birefringence using polarized light microscopy. Solid state forms that are “amorphous” are solids that are completely amorphous or substantially crystalline, and encompasses solids that are at least about 80% amorphous, about 85% amorphous, about 90% amorphous, about 95% amorphous, or about 99% amorphous, by weight (w/w%). In other embodiments, the solid is 100% amorphous, by weight.

[0081] As used herein, “crystalline” refers to solid state forms wherein there exists long-range atomic order in the positions of the atoms. Thus, “crystalline” includes all crystalline forms of Compound I, including salts thereof. The crystalline nature of solids can be confirmed, for example, by examination of the X-ray powder diffraction pattern. If the XRPD shows sharp intensity peaks in the XRPD, then the compound is crystalline. Solid state forms that are “crystalline” are solids that are completely crystalline or partially crystalline, and encompasses solids that are at least about 80% crystalline, about 85% crystalline, about 90% crystalline, about 95% crystalline, or about 99% crystalline, by weight (w/w%). In contrast to amorphous solids that have been defined above, crystalline solids are materials that exist in ordered arrangements of molecules that possess distinguishable crystal lattices or unit cells, and consequently have definable long range ordering.

[0082] The term “solvate” refers to solid state forms wherein a stoichiometric or non-stoichiometric amount of solvent, or mixture of solvents, is incorporated into the crystal structure. In some embodiments, the solvent is dichloromethane, methanol, acetone, acetonitrile, tetrahydrofuran, 2-methyl-tetrahydrofuran, benzyl alcohol, or cyclohexane, or mixtures thereof. In other embodiments, the solvent is dichloromethane. In further embodiments, the solvent is methanol. In still other embodiments, the solvent is acetone. In yet further embodiments, the solvent is acetonitrile. In other embodiments, the solvent is tetrahydrofuran. In further embodiments, the solvent is 2-methyl-tetrahydrofuran. In yet other embodiments, the solvent is benzyl alcohol. In still further embodiments, the solvent is cyclohexane. The term “solvates” also includes hydrates that are solid state forms where the solvent is water. In some embodiments, a hydrate is a solvate wherein a stoichiometric or non-stoichiometric amount of water is incorporated into the crystal structure.

[0083] The term “co-crystal” as used herein refers to a crystalline solid composed of Compound I and one or more additional neutral chemical components (coformers) in a defined stoichiometric ratio and possesses distinct crystallographic and spectroscopic properties when compared to each of the components individually. A co-crystal is distinct from a salt, which is made up of charged balanced, charged species. To contrast, the interactions between the species comprising a co-crystal are typically hydrogen bonds and other non-covalent and non-ionic interactions. The combinations of drug (or active pharmaceutical ingredient) and conformer(s) that will form pharmaceutically acceptable co- crystals are generally not predictable ab initio, and co-crystal formation typically affects the physiochemical properties of a drug in unpredictable ways.

[0084] The term “anhydrous” when used with respect to solid state forms means that substantially no water or other solvent incorporated into the crystal structure, e.g., less than about 0.1% by weight (w/w%) as determined by, for example, Karl Fisher analysis. Anhydrous solid state forms may also be referred to herein as “anhydrates”.

[0085] “Basic salt” or “basic addition salt” are used interchangeably and refer to pharmaceutically -acceptable salts having a positive counteranion. Basic addition salts may be formed by conventional means. For example, the basic addition salt may be prepared by reacting a free base form of a compound with one or more equivalents of an appropriate base or by exchanging a counter-ion of a compound in the form of a salt with another counter-ion, e.g. using a suitable ion exchange resin. In some embodiments, the basic addition salt is an alkali or earth alkaline metal salts, e.g., lithium, sodium, potassium, magnesium, or calcium salts. In some aspects, the salt is composed of a 1: 1 stoichiometry of Compound I to the counter cation, i.e., lithium, sodium, or potassium. In other aspects, the salt is composed of a 2: 1 stoichiometry of Compound I to the counter cation, i.e., calcium or magnesium. In some embodiments, the salts may be adducts, such as hydroxide or oxide adducts.

[0086] In one aspect, the solid state forms of the disclosure are present as single crystalline forms. In other aspects, the solid state forms are present as a plurality (i.e., mixture) of solid state forms, for example, a mixture of two or more crystalline forms, a mixture of amorphous forms, a mixture of a crystalline form and one or more amorphous forms, or a mixture of two or more crystalline forms and one or more amorphous forms. When a solid state form is defined herein as being a specified percentage of a single crystalline form, the remainder (i.e., the balance) of the solid state form may be made up of amorphous and/or other crystalline forms than the one solid state form. For example, in some aspects of the disclosure, the solid state form is 100 wt.% of a single crystalline form of Compound I. Also by way of example, in some aspects, the solid state form is 50 wt.% of a single crystalline form of Compound I. In these aspects, the remaining 50 wt.% can be one or more amorphous forms of Compound I and/or one or more other single crystalline forms of Compound I.

[0087] In one embodiment, the crystalline form is at least about 60 wt.% of a single crystalline form, at least about 70 wt.% of a single crystalline form, at least about 80 wt.% of a single crystalline form, at least about 90 wt.% of a single crystalline form, at least about 95 wt.% of a single crystalline form, or at least about 99 wt.% of a single crystalline form. Percent by weight of a particular crystal form is determined by the weight of the particular crystal form divided by the sum weight of the particular crystal, plus the weight of the other crystal forms present plus the weight of amorphous form present multiplied by 100% (w/w%).

[0088] The 2-theta values of the X-ray powder diffraction patterns for the crystalline forms described herein may vary slightly from one instrument to another and also depending on variations in sample preparation and batch to batch variation. Therefore, unless otherwise defined, the XRPD patterns and/or the 2-theta peak values recited herein are not to be construed as absolute and can vary by ± 0.2 degrees. The 2-theta values provided herein were obtained using Cu Kαi radiation.

[0089] Temperature values, e.g., for DSC peak temperatures and DSC onset temperatures herein may vary slightly from one instrument to another and also depending on variations in sample preparation, batch to batch variation, and environmental factors. Therefore, unless otherwise defined, temperature values recited herein are not to be construed as absolute and can vary by ± 5 degrees.

[0090] The term “substantially” as used herein refers to a first value or object that is at least about 90% similar to a second value or object, respectively. In some embodiments, the term “substantially” is used to describe likeness to the chemical structure of a chemical moiety (including the solid state forms described herein), analytical spectra, process parameters, a parameter of the chemical moiety (such as crystallinity, melting point, boiling point, melting point, etc.), amounts (such as dosages or amounts utilized in a process), among others. In other embodiments, “substantially” refers to a first value or object that is at least about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% similar to a second value or object, respectively.

[0091] One skilled in the art will understand that an XRPD pattern or diffractogram may be obtained which has one or more measurement errors depending on the recording conditions, such as the equipment or machine used. Similarly, it is generally known that intensities in an XRPD pattern may fluctuate depending on measurement conditions or sample preparation as a result of preferred orientation. Persons skilled in the art of XRPD will further realize that the relative intensity of peaks can also be affected by, for example, grains above 30 μm in size and non-unitary aspect ratios. The skilled person understands that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer, and also the zero calibration of the diffractometer. The surface planarity of the sample may also have a small effect. [0092] As a result of these considerations, the diffraction pattern data presented are not to be taken as absolute values (Jenkins, R & Snyder, R. L. ‘Introduction to X-Ray Powder Diffractometry’ John Wiley & Sons 1996; Bunn, C. W. (1948), ‘Chemical Crystallography’, Clarendon Press, London; Klug, H. P. & Alexander, L. E. (1974), ‘X-Ray Diffraction Procedures’). It should also be understood that the solid forms embodied herein are not limited to those that provide XRPD patterns that are identical to the XRPD pattern shown in the Figures, and any solid forms providing XRPD patterns substantially similar as those shown in the Figures fall within the scope of the corresponding embodiment. A person skilled in the art of XRPD is able to judge the substantial identity of XRPD patterns. Generally, a measurement error of a diffraction angle in an XRPD is approximately 2θ (±0.2°), and such degree of a measurement error should be taken into account when considering the X-ray powder diffraction pattern in the Figures and when reading data contained in the Tables included herein. In addition one of skill in the art would understand that when analysing a mixture of crystalline materials such as a drug product containing crystalline API (active pharmaceutical ingredient) as well as crystalline excipients, one or more of the XRPD peaks attributed to a particular crystalline form of Compound I can be swamped out or obscured by the XRPD peaks from at least one crystalline excipient, but that the obscured peaks characteristic of the particular crystalline form are still present in the XRPD pattern and that the particular crystalline form of Compound I can still be identified in such cases.

[0093] A person skilled in the art also understands that the value or range of values observed in a particular compound's DSC thermogram will show variation between batches of different purities. Therefore, whilst for one compound the range may be small, for others the range may be quite large. Generally, a measurement error of a diffraction angle in DSC thermal events is approximately plus or minus 5° C, and such degree of a measurement error should be taken into account when considering the DSC data included herein. TGA thermograms show similar variations, such that a person skilled in the art recognizes that measurement errors should be taken into account when judging substantial identity of TGA thermograms.

[0094] A “therapeutically effective amount” of a solid state form is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. The term “therapeutically effective amount” and “effective amount” are used interchangeably. In one aspect, 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 condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for eliciting therapeutic effects in the treatment of a cancer (including solid tumors, lymphomas, and mesothelioma as further described herein). In certain embodiments, a therapeutically effective amount is an amount sufficient for eliciting therapeutic effects in the treatment of a cancer (including solid tumors, lymphomas, and mesothelioma as further described herein), wherein the condition is responsive to inhibition of methionine adenosyltransferase 2a (MAT2A). In certain embodiments, a therapeutically effective amount is an amount sufficient for improving overall therapy, reducing or avoiding symptoms, signs, or causes of the condition.

[0095] In another embodiment, a therapeutically effective amount of a solid state form described herein is an amount that does not substantially interfere with the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount of a solid state form of Compound I is generally in the range from 0.1 to 200 mg/kg of body weight of the recipient (mammal) per day and particularly typically in the range from 1 to 10 mg/kg of body weight per day. Thus, according to such embodiments the actual amount per day for an adult mammal weighing 70 kg is usually about 70 to about 700 mg (for example, about 70, about 75, about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, or about 700 mg/day), where this amount can be administered as an individual dose per day or in a series of part-doses (such as, for example, two, three, four, five or six) per day, so that the total daily dose is the same. In other embodiments, for an adult mammal such as a human, a therapeutically effective amount of a solid state form of Compound I is generally in the range of about 10 mg to about 1000 mg which may be administered once or twice daily. In such embodiments, the adult mammal is administered about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg, of a solid state form of Compound I once or twice daily.

[0096] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, reducing the likelihood of developing, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to reduce the likelihood of or delay their recurrence.

[0097] As used herein, the terms “subject” and “patient” are used interchangeably, and mean a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment. In certain embodiments, the term “subject” refers to a human subject in need of treatment of a disease. In certain embodiments, the term “subject” refers to a human subject in need of treatment by inhibition of MAT2A. In certain embodiments, the term “subject” refers to a human adult that is 18 years old and older in need of treatment of a disease. In certain embodiments, the term “subject” refers to a human child no more than 18 years old in need of treatment of a disease. In certain embodiments, the patient is newly diagnosed with the disease. In other embodiments, the patient was previous diagnosed with the disease.

[0098] The term “pharmaceutically acceptable excipient” refers to a filler, diluent, carrier, adjuvant, or vehicle, that does not adversely affect the pharmacological activity of the compound with which it is formulated, and which the US Food and Drug Administration (or other regulatory authority) has approved for human use.

[0099] As used herein, the terms “about” and “approximately” when used in combination with a numeric value or range of values mean the value or range of values may deviate. In general, the term “about” or “approximately” indicates approximations that can vary depending on the desired properties sought to be obtained by the disclosed subject matter and is to be interpreted in the specific context in which it is used, based on its function. The person skilled in the art will be able to interpret this as a matter of routine. In some cases, the number of significant figures used for a particular value may be one non-limiting method of determining the extent of the word “about”. In other cases, the gradations used in a series of values may be used to determine the intended range available to the term “about” for each value. Where present, all ranges are inclusive and combinable. That is, references to values stated in ranges include every value within that range. The modifier “about” also may be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” In some embodiments, when used to modify a single number, the term “about” refers to plus or minus 10% of the indicated number and includes the indicated number. For example, “about 10%” indicates a range of 9% to 11%, and “about 1” means from 0.9-1.1. Further, within the context of X-ray diffraction patterns, “about” can also refer to two theta values that vary by about 0.2. By way of example, a two theta value of “about 1.0” is intended to include a two theta value of “0.8 to 1.2”.

[00100] In the present disclosure, “a”, “an”, and “the” include the plural reference, and reference to a particular numerical values includes at least that particular value, unless the context clearly indicates otherwise. Thus, for example, a reference to “a material” is a reference to at least one of such materials and equivalents thereof known to those skilled in the art.

[00101] Certain values provided herein may be rounded to avoid reporting insignificant figures. For example, the X-ray diffraction two theta values may rounded to the tenths. One of skill in the art would readily understand the use of rounding in significant figures. With respect to the number “5” or greater in the hundredth position, the number in the tenth position is rounded up. However, if a value has the number “4” or less in the hundredth position, the number in the tenth position is not changed.

[00102] Solid State Forms of Compound I

[00103] In a first embodiment, the present disclosure is drawn to solid state forms of Compound I or salts of Compound I or solvates of Compound I, wherein the Compound I is represented by the formula

[00104] The solid state forms may be substantially crystalline or substantially amorphous. In some embodiments, the solid state form is substantially crystalline. In other embodiments, the solid state form is substantially anhydrous. In further embodiments, the solid state form is a solvate of Compound I. In yet other embodiments, the solid state form is Compound I as a free base. In still further embodiments, the solid state form is a salt of Compound I. In other embodiments, the solid state form is a hydrate of Compound I.

[00105] The term “chemical purity” as used herein refers to the amount of Compound I that is present in a sample compared to other undesirable components (i.e., impurities) in the same sample, e.g., excipients, degradants, process impurities (e.g., unreacted starting materials, reagents, and the like), among others. In some embodiments, chemical purity refers to the extent to which the disclosed solid state forms of Compound I are free from other materials (crystalline or otherwise) that have chemical structures that are not Compound I. Chemical purity may be measured or assessed by any number of techniques including, e.g., high performance liquid chromatography (HPLC), melting point, mass spectral analysis, nuclear magnetic resonance (NMR - ¹H, ¹³C, etc.), or combinations thereof. In some embodiments, chemical purity may be measured using an HPLC C18 reverse phase column. Chemical purity in the disclosed solid state forms means the weight of the compound divided by the sum of the weight of the compound plus materials/impurities having different chemical structures multiplied by 100%, i.e., percent by weight (w/w%). Regardless of the specific form, the solid state form has a chemical purity is at least about 60 w/w%, at least about 70 w/w%, at least about 80 w/w%, at least about 90 w/w%, at least about 95 w/w%, or at least about 99 w/w%, as measured by HPLC. In some embodiments, the solid state form has a chemical purity of at least about 60 w/w%, as measured by HPLC. In other embodiments, the solid state form has a chemical purity of at least about 70 w/w%, as measured by HPLC. In further embodiments, the solid state form has a chemical purity of at least about 80 w/w%, as measured by HPLC. In yet other embodiments, the solid state form has a chemical purity of at least about 90 w/w%, as measured by HPLC. In still further embodiments, the solid state form has a chemical purity of at least about 95 w/w%, as measured by HPLC. In other embodiments, the solid state form has a chemical purity of at least about 98 w/w%, as measured by HPLC. In other embodiments, the solid state form has a chemical purity of at least about 99 w/w%, as measured by HPLC. In further embodiments, the solid state form has a chemical purity of about 100 w/w%, as measured by HPLC. In yet other embodiments, the solid state form has a chemical purity of about 95 to about 100 w/w%, as measured by HPLC. In still other embodiments, the solid state form has a chemical purity of between 95% and 105% (w/w%). In any of the foregoing embodiments the chemical purity of the solid state form of Compound I is measured as the w/w% on a solvent-free and anhydrous basis. [00106] In other embodiments, the present disclosure is directed to anhydrous solid state forms of Compound I. In some aspects, the anhydrous form is crystalline Forms D or K- C as described herein. Anhydrous Form D is characterized by two or more X-ray powder diffraction peaks at 2θ angles (± 0.2°) chosen from 7.6°, 10.7°, 19.0° and 23.7°. In other aspects, anhydrous Form D that is characterized by three or more X-ray powder diffraction peaks at 2θ angles (± 0.2°) chosen from 7.6°, 10.7°, 19.0° and 23.7°. In further aspects, anhydrous Form D is characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) 7.6°, 10.7°, 19.0° and 23.7°. In yet other aspects, anhydrous Form D is characterized by the X-ray powder diffraction peaks in Table 1.

Table 1

In still further aspects, anhydrous Form D is characterized by an X-ray powder diffraction pattern that is substantially similar to FIG. 1. In other aspects, anhydrous Form D contains a melting onset at about 329°C as analysed by differential scanning calorimetry. In further aspects, crystalline Form D is characterized by a DSC thermogram that is substantially similar to FIG. 21. In still other aspects, crystalline Form D is characterized by less than about 0.4 wt.% weight loss as measured by TGA. In yet further aspects, crystalline Form D is characterized by a TGA thermogram that is substantially similar to FIG. 22. In other aspects, crystalline Form D is characterized by a DVS spectrum that is substantially similar to FIG. 23. [00107] In further embodiments, the anhydrous form is crystalline Form K-C.

Crystalline Form K-C may be characterized by one or more X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 5.2, 10.4, and 26.3°. In some aspects, anhydrous Form K-C is characterized by two or more X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 5.2, 10.4, 11.7, and 26.3°. In other aspects, anhydrous Form K-C is characterized by three X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 5.2, 10.4, 11.7, or 26.3°. In further aspects, anhydrous Form K-C is characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 5.2, 10.4, 11.7, and 26.3°. In still other aspects, anhydrous Form K-C is characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 5.2, 10.4, 11.7, and 26.3°. Crystalline Form K-C may also be characterized by the X-ray powder diffraction peaks in Table 2.

Table 2

In still further aspects, crystalline Form K-C is characterized by an X-ray powder diffraction pattern that is substantially similar to FIG. 55. In other aspects, crystalline Form K-C is characterized by an DSC melting endotherm of about 331°C. In further aspects, crystalline Form K-C is characterized by an about 0.2 wt.% weight loss as measured by TGA. In still further aspects, crystalline Form K-C is characterized by DSC/TGA thermograms that are substantially similar to FIG. 56.

[00108] In further embodiments, the present disclosure provides basic salts of Compound I. In some aspects, the basic salt is a sodium salt of Compound I, a potassium salt of Compound I, a lithium salt of Compound I, or a calcium salt of Compound I. In certain embodiments, the basic salt of Compound I is amorphous. In other embodiments, the basic salt of Compound is crystalline. In further embodiments, the basic salt of Compound I is solvated. In further embodiments, the basic salt of Compound I is anhydrous.

[00109] In further embodiments, the basic salt is a crystalline sodium salt of Compound I. In some aspects, the basic salt is crystalline Form 20-A, Form 20-B, Form 20- C, Form 20-D, Form 20-D, or Form Na-W. In further aspects, the basic salt is a crystalline sodium salt Form 20-A. Crystalline Form 20-A is characterized by an X-ray powder diffraction peaks at 2θ angle (± 0.2°) 4.6. Crystalline Form 20-A may also be characterized by the X-ray powder diffraction peaks in Table 3.

Table 3

In some aspects, crystalline Form 20-A is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 17A. In other aspects, crystalline Form 20-A is characterized by at least one DSC thermal event at about 81 °C, about 183 °C, about 230 °C, and about 311 °C. In yet other aspects, crystalline Form 20-A is characterized by one DSC thermal event at about 81 °C, about 183 °C, about 230 °C, and about 311 °C. In further aspects, crystalline Form 20-A is characterized by two DSC thermal events at about 81 °C, about 183 °C, about 230 °C, and about 311 °C. In yet other aspects, crystalline Form 20-A is characterized by three DSC thermal events at about 81 °C, about 183 °C, about 230 °C, and about 311 °C. In still further aspects, crystalline Form 20-A is characterized by DSC thermal events at about 81 °C, about 183 °C, about 230 °C, and about 311 °C. In further aspects, crystalline Form 20-A is characterized by an about 10 wt.% weight loss as measured by TGA. In further aspects, Form 20-A is characterized by a DSC and DSC/TGA thermograms that are substantially similar to FIG. 43. [00110] In yet other aspects, the basic salt is a crystalline sodium salt Form 20-B. Crystalline Form 20-B is characterized by two or more X-ray powder diffraction peaks at 29 angles (± 0.2°) chosen from 6.2, 8.2, 14.8, and 18.8. Crystalline Form 20-B may also be characterized by the X-ray powder diffraction peaks in Table 4.

Table 4

In some aspects, crystalline Form 20-B is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 17B. In other aspects, crystalline Form 20-B is characterized by one or two DSC thermal events at about 87 °C and about 226 °C. In yet other aspects, crystalline Form 20-B is characterized by one DSC thermal event at about 87 °C and about 226 °C. In further aspects, crystalline Form 20-B is characterized DSC thermal events at about 87 °C and about 226 °C. In further aspects, crystalline Form 20-B is characterized by an about 6 wt.% weight loss as measured by TGA. In further aspects, Form 20-B is characterized by DSC and DSC/TGA thermograms that are substantially similar to FIG. 44.

[00111] In yet other aspects, the basic salt is a crystalline sodium salt Form 20-C. Crystalline Form 20-C is characterized by an X-ray powder diffraction peak at 2θ angles (± 0.2°) 4.9. Crystalline Form 20-C may also be characterized by the X-ray powder diffraction peaks in Table 5.

Table 5

In some aspects, crystalline Form 20-C is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 17C. In other aspects, crystalline Form 20-C is characterized by one or more DSC thermal events at about 79 °C, about 194 °C, about 254 °C, and about 333 °C. In yet other aspects, crystalline Form 20-C is characterized by one DSC thermal event at about 79 °C, about 194 °C, about 254 °C, and about 333 °C. In further aspects, crystalline Form 20-C is characterized by two DSC thermal events at about 79 °C, about 194 °C, about 254 °C, and about 333 °C. In still other aspects, crystalline Form 20-C is characterized by three DSC thermal events at about 79 °C, about 194 °C, about 254 °C, and about 333 °C. In yet further aspects, crystalline Form 20-C is characterized by DSC thermal events at about 79 °C, about 194 °C, about 254 °C, and about 333 °C. In further aspects, crystalline Form 20-C is characterized by an about 21 wt.% weight loss as measured by TGA. In yet other aspects, crystalline Form 20-C is characterizes d by DSC and DSC/TGA thermograms substantially similar to FIG. 45.

[00112] In yet other aspects, the basic salt is a crystalline sodium salt Form 20-E. Crystalline Form 20-E is characterized by an X-ray powder diffraction peak at 2θ angle (± 0.2°) 5.2. Crystalline Form 20-E may also be characterized by the X-ray powder diffraction peaks in Table 6. Table 6

In some aspects, crystalline Form 20-E is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 17E. In other aspects, crystalline Form 20-E is characterized by one or more DSC thermal events at about 79 °C, about 194 °C, about 254 °C, and about 333 °C. In yet other aspects, crystalline Form 20-E is characterized by one DSC thermal event at about 79 °C, about 194 °C, about 254 °C, and about 333 °C. In further aspects, crystalline Form 20-E is characterized by two DSC thermal events at about 79 °C, about 194 °C, about 254 °C, and about 333 °C. In still other aspects, crystalline Form 20-E is characterized by three DSC thermal events at about 79 °C, about 194 °C, about 254 °C, and about 333 °C. In yet further aspects, crystalline Form 20-E is characterized by DSC thermal events at about 79 °C, about 194 °C, about 254 °C, and about 333 °C. In further aspects, crystalline Form 20-E is characterized by an about 21 wt.% weight loss as measured by TGA. In yet other aspects, crystalline Form 20-E is characterizes d by DSC and DSC/TGA thermograms substantially similar to FIG. 45.

[00113] In yet other aspects, the basic salt is a crystalline sodium salt Form 20-D. Crystalline Form 20-D is characterized by two or more X-ray powder diffraction peaks at 2θ angles (± 0.2°) chosen from 6.1, 8.2, and 18.8. Crystalline Form 20-D may also be characterized by the X-ray powder diffraction peaks in Table 7. Table 7

In some aspects, crystalline Form 20-D is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 17D. In other aspects, crystalline Form 20-D is characterized by one or more DSC thermal events at about 80 °C, about 238 °C, about 314 °C, and about 338 °C. In still other aspects, crystalline Form 20-D is characterized by one DSC thermal event at about 80 °C, about 238 °C, about 314 °C, and about 338 °C. In further aspects, crystalline Form 20-D is characterized by two DSC thermal events at about 80 °C, about 238 °C, about 314 °C, and about 338 °C. In yet other aspects, crystalline Form 20-D is characterized by three DSC thermal events at about 80 °C, about 238 °C, about 314 °C, and about 338 °C. In still further aspects, crystalline Form 20-D is characterized by DSC thermal events at about 80 °C, about 238 °C, about 314 °C, and about 338 °C. In further aspects, Form 20-D is characterized by a DSC thermogram that is substantially similar to FIG. 46.

[00114] In still other aspects, the basic salt is crystalline sodium salt FormNa-W. In some aspects, crystalline Form Na-W may be characterized by the X-ray powder diffraction peaks in Table 8.

Table 8

In some aspects, Form Na-W has aXRPD pattern that is substantially similar to FIG. 60. In other aspects, Form Na-W has a DSC thermogram that is substantially similar to FIG. 61. In further aspects, Form Na-W has a DSC thermogram that is substantially similar to FIG. 62.

[00115] In yet other embodiments, the basic salt is a potassium salt of Compound I. In some aspects, the basic salt is crystalline potassium Form 21-A, Form 21-B, Form 21-C, Form 21-D or Form 21-E. In further aspects, the basic salt is crystalline potassium salt Form 21-A. Crystalline Form 21-A is characterized by two X-ray powder diffraction peaks at 29 angles (± 0.2°) 5.8 and 7.9. Crystalline Form 21-A may also be characterized by the X-ray powder diffraction peaks in Table 9. Table 9

In some aspects, crystalline Form 21-A is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 18 A. In other aspects, crystalline Form 21-A is characterized by one DSC thermal event at about 263 °C or about 354 °C. In further aspects, crystalline Form 21-A is characterized by DSC thermal events at about 263 °C and about 354 °C. In further aspects, Form 21-A is characterized by a DSC thermogram substantially that is similar to FIG. 47.

[00116] In further aspects, the basic salt is crystalline potassium salt Form 21 -B. Crystalline Form 21-B is characterized by two or more X-ray powder diffraction peaks at 29 angles (± 0.2°) chosen from 6.0, 7.8, 8.1, 19.1, and 23.7. Crystalline Form 21-B may also be characterized by the X-ray powder diffraction peaks in Table 10.

Table 10

In some aspects, crystalline Form 21 -B is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 18B. In other aspects, crystalline Form 21-B is characterized by DSC thermal events at about 285 °C and about 350 °C. In further aspects, crystalline Form 21-B is characterized by a DSC thermal event at about 350 °C. In further aspects, Form 21-B is characterized by a DSC thermogram that is substantially similar to FIG. 48.

[00117] In further aspects, the basic salt is crystalline potassium salt Form 21 -C.

Crystalline Form 21-C is characterized by two or more X-ray powder diffraction peaks at 29 angles (± 0.2°) chosen from 6.0, 7.7, and 19.1. Crystalline Form 21-C may also be characterized by the X-ray powder diffraction peaks in Table 11.

Table 11

In some aspects, crystalline Form 21 -C is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 18C. In other aspects, crystalline Form 21-C is characterized by one DSC thermal event at about 285 °C. In further aspects, Form 21-C is characterized by a DSC thermogram that is substantially similar to FIG. 49.

[00118] In further aspects, the basic salt is crystalline potassium salt Form 21 -D.

Crystalline Form 21-D is characterized by two or more X-ray powder diffraction peaks at 2θ angles (± 0.2°) chosen from 6.5, 7.7, 19.1, 19.8, and 25.6. Crystalline Form 21-D may also be characterized by the X-ray powder diffraction peaks in Table 12.

Table 12

In some aspects, crystalline Form 21-D is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 18D. In other aspects, crystalline Form 21-D is characterized by one or more DSC thermal events at about 257 °C, about 275 °C, and about 290 °C, provided that the when the DSC thermal event is at about 257 °C, another peak thermal event is present. In further aspects, crystalline Form 21-D is characterized by two DSC thermal events at about 257 °C, about 275 °C, and about 290 °C. In yet other aspects, crystalline Form 21-D is characterized by DSC thermal events at about 257 °C, about 275 °C, and about 290 °C. In further aspects, Form 21-D is characterized by a DSC thermogram substantially that is similar to FIG. 50.

[00119] In further aspects, the basic salt is crystalline potassium salt Form 21-E. Crystalline Form 21-E is characterized by two or more X-ray powder diffraction peaks at 2θ angles (± 0.2°) chosen from 6.4, 7.0, 7.7, 9.5, 11.9, 15.7, 19.7, and 25.6. Crystalline Form 21- E may also be characterized by the X-ray powder diffraction peaks in Table 13.

Table 13

In some aspects, crystalline Form 21-E is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 18E. In other aspects, crystalline Form 21-E is characterized by one or more DSC thermal events at 110 °C, about 171 °C, about 189 °C, about 247 °C, about 257 °C, about 277 °C, and about 289 °C, provided that the when the DSC thermal event is at about 257 °C, another peak thermal event is present. In yet other aspects, crystalline Form 21-E is characterized by one DSC thermal events at 110 °C, about 171 °C, about 189 °C, about 247 °C, about 277 °C, and about 289 °C. In further aspects, crystalline Form 21-E is characterized by two DSC thermal events at 110 °C, about 171 °C, about 189 °C, about 247 °C, about 257 °C, about 277 °C, and about 289 °C. In yet other aspects, crystalline Form 21-E is characterized by three DSC thermal events at 110 °C, about 171 °C, about 189 °C, about 247 °C, about 257 °C, about 277 °C, and about 289 °C. In still further aspects, crystalline Form 21-E is characterized by four DSC thermal events at 110 °C, about 171 °C, about 189 °C, about 247 °C, about 257 °C, about 277 °C, and about 289 °C. In other aspects, crystalline Form 21-E is characterized by five DSC thermal events at 110 °C, about 171 °C, about 189 °C, about 247 °C, about 257 °C, about 277 °C, and about 289 °C. In further aspects, crystalline Form 21-E is characterized by six DSC thermal events at 110 °C, about 171 °C, about 189 °C, about 247 °C, about 257 °C, about 277 °C, and about 289 °C. In other aspects, crystalline Form 21-E is characterized by DSC thermal events at 110 °C, about 171 °C, about 189 °C, about 247 °C, about 257 °C, about 277 °C, and about 289 °C. In further aspects, Form 21-E is characterized by a DSC thermogram that is substantially similar to FIG. 51.

[00120] In still other aspects, the basic salt is crystalline potassium salt Form K-W. In certain aspects, Form K-W is characterized by a DSC thermal event at 381.3 °C. In other aspects, Form K-W is characterized by the X-ray powder diffraction peaks in Table 14.

Table 14

In some aspects, Form K-W has a XRPD pattern that is substantially similar to FIG. 63. In other aspects, Form K-W has a DSC thermogram that is substantially similar to FIG. 64. In further aspects, Form K-W has a TGA thermogram that is substantially similar to FIG. 65.

[00121] In still further embodiments, the basic salt is a calcium salt of Compound I. In some aspects, the basic salt is crystalline calcium Form 22-A, Form 22-B, Form 22-C, Form 22-D or Form 22 -E. In further aspects, the basic salt is crystalline calcium salt Form 22-A. Crystalline Form 22-A is characterized by two or more X-ray powder diffraction peaks at 2θ angles (± 0.2°) chosen from 6.5, 7.1, and 12.0. Crystalline Form 22-A may also be characterized by the X-ray powder diffraction peaks in Table 15.

Table 15

In some aspects, crystalline Form 22-A is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 19A. In other aspects, crystalline Form 22-A is characterized by one or more DSC thermal events at about 92 °C, 183 °C, and about 262 °C. In yet other aspects, crystalline Form 22-A is characterized by one DSC thermal event at about 92 °C, 183 °C, and about 262 °C. In further aspects, crystalline Form 22-A is characterized by two DSC thermal events at about 92 °C, 183 °C, and about 262 °C. In other aspects, crystalline Form 22 -A is characterized by DSC thermal events at about 92 °C, 183 °C, and about 262 °C. In further aspects, Form 22-A is characterized by a DSC thermogram substantially similar to FIG. 52.

[00122] In other aspects, the basic salt is crystalline calcium salt Form 22-F.

Crystalline Form 22-F is characterized by two or more X-ray powder diffraction peaks at 2θ angles (± 0.2°) chosen from 6.5, 7.2, and 12.1. Crystalline Form 22-F may also be characterized by the X-ray powder diffraction peaks in Table 16.

Table 16

In some aspects, crystalline Form 22-F is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 19F. In other aspects, crystalline Form 22-F is characterized by one or more DSC thermal events at about 92 °C, about 183 °C, and about 262 °C. In further aspects, crystalline Form 22-F is characterized by one DSC thermal event at about 92 °C, about 183 °C, and about 262 °C. In further aspects, crystalline Form 22-F is characterized by two DSC thermal events at about 92 °C, about 183 °C, and about 262 °C. In other aspects, crystalline Form 22-F is characterized by DSC thermal events at about 92 °C, 183 °C, and about 262 °C. In further aspects, Form 22-F is characterized by a DSC thermogram substantially similar to FIG. 52.

[00123] In further aspects, the basic salt is crystalline calcium salt Form 22-B. Crystalline Form 22-B is characterized by two or more X-ray powder diffraction peaks at 29 angles (± 0.2°) chosen from 6.0, 7.8, and 18.8. Crystalline Form 22-B may also be characterized by the X-ray powder diffraction peaks in Table 17. Table 17

In some aspects, crystalline Form 22-B is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 19B. In other aspects, crystalline Form 22-B is characterized by a DSC thermal event at about 168 °C. In further aspects, Form 22-B is characterized by a DSC thermogram that is substantially similar to FIG. 53.

[00124] In still other aspects, the basic salt is crystalline calcium salt Form 22-C.

Crystalline Form 22-C is characterized by two or more X-ray powder diffraction peaks at 29 angle (± 0.2°) 4.6. Crystalline Form 22-C may also be characterized by the X-ray powder diffraction peaks in Table 18.

Table 18

In some aspects, crystalline Form 22-C is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 19C. In further aspects, Form 22-C is characterized by a DSC thermogram that is substantially similar to FIG. 54.

[00125] In yet further aspects, the basic salt is crystalline calcium salt Form 22 -D. Crystalline Form 22-D is characterized by two or more X-ray powder diffraction peaks at 2θ angles (± 0.2°) chosen from 7.1 and 7.7 Crystalline Form 22 -D may also be characterized by the X-ray powder diffraction peaks in Table 19.

Table 19

In some aspects, crystalline Form 22-D is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 19D. In other aspects, crystalline Form 22-D is characterized by one or two DSC thermal events at about 82 °C or about 250 °C. In further aspects, crystalline Form 22-D is characterized by one DSC thermal event at about 82 °C or about 250 °C. In yet other aspects, crystalline Form 22-D is characterized by DSC thermal events at about 82 °C and about 250 °C.

[00126] In other aspects, the basic salt is crystalline calcium salt Form 22-G. In some aspects, crystalline Form 22-G is characterized by one or two DSC thermal event at about 82 °C or about 250 °C. In further aspects, crystalline Form 22-G is characterized by one DSC thermal event at about 82 °C or about 250 °C. In yet other aspects, crystalline Form 22-G is characterized by DSC thermal events at about 82 °C and about 250 °C.

[00127] In further aspects, the basic salt is crystalline calcium salt Form 22-E.

Crystalline Form 22-E is characterized by two or more X-ray powder diffraction peaks at 2θ angles (± 0.2°) chosen from 6.4, 6.6, 8.5, and 20.5. Crystalline Form 22-E may also be characterized by the X-ray powder diffraction peaks in Table 20. Table 20

In some aspects, crystalline Form 22-E is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 19E. In other aspects, crystalline Form 22-E is characterized by one or more DSC thermal events at about 94 °C, about 122 °C, about 185 °C, and about 271 °C. In further aspects, crystalline Form 22-E is characterized by one DSC thermal event at about 94 °C, about 122 °C, about 185 °C, and about 271 °C. In yet other aspects, crystalline Form 22-E is characterized by two DSC thermal events at about 94 °C, about 122 °C, about 185 °C, and about 271 °C. In still further aspects, crystalline Form 22-E is characterized by three DSC thermal events at about 94 °C, about 122 °C, about 185 °C, and about 271 °C. In other aspects, crystalline Form 22-E is characterized by DSC thermal events at about 94 °C, about 122 °C, about 185 °C, and about 271 °C.

[00128] In still other aspects, the basic salt is crystalline calcium salt Form Ca-W. In some aspects, crystalline Form Ca-W is characterized by the X-ray powder diffraction peaks in Table 21. Table 21

In some aspects, Form Ca-W has aXRPD patern that is substantially similar to FIG. 66.

[00129] In still further embodiments, the basic salt is crystalline lithium salt Form Li-W. In some aspects, crystalline Form Li-W is characterized by the X-ray powder diffraction peaks in Table 22.

Table 22

In some aspects, Form Li-W has a XRPD pattern that is substantially similar to FIG. 57. In other aspects, Form Li-W has a DSC thermogram that is substantially similar to FIG. 58. In further aspects, Form Li-W has a DSC thermogram that is substantially similar to FIG. 59.

[00130] In yet other embodiments, the disclosure provides solid state forms of solvates of Compound I. The solid state solvate of Compound I is a dichloromethane solvate, methanol solvate, acetone solvate, acetonitrile solvent, dichloromethane solvate, tetrahydrofuran solvate, 2-methyl-tetrahydrofuran solvate, benzyl alcohol solvate, or cyclohexane solvate.

[00131] In some aspects, the solid state solvate of Compound I is a dichloromethane solvate. For example, the dichloromethane solvate of Compound I is selected from crystalline Form H, crystalline Form R, crystalline Form T, or crystalline Form U. In certain embodiments, the solid state form is crystalline Form H. Crystalline Form H may be characterized by two or more X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 7.1°, 7.5° and 11.7°. In some aspects, crystall ine Form H is characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 7.1°, 7.5° and 11.7°. In yet other aspects, crystalline Form H is characterized by the X-ray powder diffraction peaks in Table 23.

Table 23

In still further aspects, crystalline Form H is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 3. In other aspects, crystalline Form H is characterized by an DSC onset temperature of about 113 °C. In further aspects, crystalline Form H is characterized by an about 14 wt.% weight loss as measured by TGA. In further aspects, crystalline Form H is characterized by a DSC/TGA thermogram that is substantially similar to FIG. 26.

[00132] In other embodiments, the dichloromethane solvate is crystalline Form R. Crystalline Form R may be characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 5.0 and 9.9°. Crystalline Form R may also be characterized by the X-ray powder diffraction peaks in Table 24.

Table 24

In still further aspects, crystalline Form R is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 8. In yet other aspects, crystalline Form R is characterized by an DSC onset temperature of about 70 °C. In further aspects, crystalline Form R is characterized by an about 3 wt.% weight loss as measured by TGA. In further aspects, crystalline Form R is characterized by a DSC/TGA thermogram that is substantially similar to FIG. 31.

[00133] In further embodiments, the dichloromethane solvate is crystalline Form T. Crystalline Form T may be characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 7.0 and 7.8°. Crystalline Form T may also be characterized by the X-ray powder diffraction peaks in Table 25.

Table 25

In still further aspects, crystalline Form T is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 10. In other aspects, crystalline Form T is characterized by an DSC onset temperature of about 119 °C. In further aspects, crystalline Form T is characterized by an about 5 wt.% weight loss as measured by TGA. In further aspects, crystalline Form T is characterized by a DSC/TGA thermogram that is substantially similar to FIG. 33.

[00134] In yet other embodiments, the di chloromethane solvate is crystalline Form U. Crystalline Form U may be characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 4.8 and 9.8°. Crystalline Form U may also be characterized by the X-ray powder diffraction peaks in Table 26.

Table 26

In still further aspects, crystalline Form U is characterized by an X-ray powder diffraction pattern that is substantially similar to FIG. 11. In other aspects, crystalline Form U is characterized by an DSC onset temperature of about 59 °C. In further aspects, crystalline Form U is characterized by an about 2 wt.% weight loss as measured by TGA. In further aspects, crystalline Form U is characterized by a DSC/TGA that is thermogram substantially similar to FIG. 34.

[00135] In other embodiments, the solid state solvate of Compound I is a methanol solvate. In some aspects, the methanol solvate is crystalline Form K or L as described herein. In some aspects, the methanol solvate is Form K. In other aspects, the methanol solvate is Form L.

[00136] Form K is characterized by two or more X-ray powder diffraction peaks at 2θ angles (± 0.2°) chosen from 7.5°, 8.4°, 10.0°, 22.4° and 24.2°. In other aspects, anhydrous Form K that is characterized by three or more X-ray powder diffraction peaks at 2θ angles (± 0.2°) chosen from 7.5°, 8.4°, 10.0°, 22.4° and 24.2°. In further aspects, anhydrous Form K is characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) 7.5°, 8.4°, 10.0°, 22.4° and 24.2°. In yet other aspects, anhydrous Form K is characterized by the X-ray powder diffraction peaks in Table 27. Table 27

In still further aspects, Form K is characterized by an X-ray powder diffraction pattern that is substantially similar to FIG. 2. In other aspects, crystalline Form K is characterized by an DSC onset temperature of about 173 °C. In further aspects, crystalline Form K is characterized by an about 5 wt.% weight loss as measured by TGA. In further aspects, crystalline Form K is characterized by a DSC/TGA thermogram that is substantially similar to FIG. 28.

[00137] Form L is characterized by two or more X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 7.5, 18.6, and 24.2°. In certain aspects, Form L is characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 7.5, 18.6, and 24.2°. In other aspects, Form L is characterized by the X-ray powder diffraction peaks in Table 28.

Table 28

In still further aspects, Form L is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 6. In other aspects, crystalline Form L is characterized by an DSC onset temperature of about 171 °C. In further aspects, crystalline Form L is characterized by an about 3 wt.% weight loss as measured by TGA. In further aspects, crystalline Form L is characterized by a DSC/TGA that is substantially similar to FIG. 29.

[00138] In further embodiments, the solid state form is an acetonitrile solvate. In some aspects, the acetonitrile solvate is crystalline Form F as described herein. Form F that is characterized by two or three X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 6.6, 11.5, and 18.5°. In some aspects, Form F that is characterized by two X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 6.6, 11.5, and 18.5°. In other aspects, Form F is characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 6.6, 11.5, and 18.5°. In other aspects, Form F is characterized by the X-ray powder diffraction peaks in Table 29. Table 29

In still further aspects, Form F is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 4. In other aspects, crystalline Form F is characterized by an DSC onset temperature of about 135 °C. In further aspects, crystalline Form F is characterized by an about 5 wt.% weight loss as measured by TGA. In further aspects, crystalline Form F is characterized by a DSC thermogram that is substantially similar to FIG. 25.

[00139] In yet other embodiments, the solid state form is a tetrahydrofuran solvate. In some aspects, the tetrahydrofuran solvate is crystalline Form I as described herein. Form I that is characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 4.7 and 5.0°. In other aspects, Form I is characterized by the X-ray powder diffraction peaks in Table 30.

Table 30

In further aspects, Form I is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 5. In other aspects, crystalline Form I is characterized by an DSC onset temperature of about 165 °C. In further aspects, crystalline Form I is characterized by an about 2 wt.% weight loss as measured by TGA. In further aspects, crystalline Form I is characterized by a DSC/TGA thermogram that is substantially similar to FIG. 27.

[00140] In still further embodiments, the solid state form is a 2-methyl- tetrahydrofuran solvate. In some aspects, the 2-methyl -tetrahydrofuran solvate is crystalline Form Q as described herein. Form Q that is characterized by two or more X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 5.1, 5.9, 8.7, and 9.2°. In some aspects, Form Q is characterized by three or more X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 5. 1, 5.9, 8.7, and 9.2°. In other aspects, Form Q is characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 5.1, 5.9, 8.7, and 9.2°. In other aspects, Form Q is characterized by the X-ray powder diffraction peaks in Table 31. Table 31

In further aspects, Form Q is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 7. In other aspects, crystalline Form Q is characterized by an DSC onset temperature of about 172 °C. In further aspects, crystalline Form Q is characterized by an about 2 wt.% weight loss as measured by TGA. In further aspects, crystalline Form Q is characterized by a DSC/TGA that is thermogram substantially similar to FIG 30.

[00141] In other embodiments, the solid state form is a benzyl alcohol solvate. In some aspects, the benzyl alcohol solvate is crystalline Form S as described herein. Form S that is characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 5.0 and 9.9°. In other aspects, Form S is characterized by the X-ray powder diffraction peaks in Table 32.

Table 32

In further aspects, Form S is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 9. In other aspects, crystalline Form S is characterized by two DSC thermal events at about 101 and 152 °C. In further aspects, crystalline Form S is characterized by an about 8 wt.% weight loss as measured by TGA. In further aspects, crystalline Form S is characterized by a DSC/TGA thermogram that is substantially similar to FIG. 32.

[00142] In further embodiments, the solid state form is a hydrate of Compound I.

[00143] In still other embodiments, the solid state form of Compound I is a cocrystal. In some aspects, the solid state form of Compound I is a co-crystal of 4- hydroxybenzoic acid and Compound I or a co-crystal of 3,4-dihydroxybenzoic acid and Compound I.

[00144] In further embodiments, the solid state form of Compound I is a co-crystal of 4-hydroxybenzoic acid and Compound I. In some aspects, the solid state form is a cocrystal of 4-hydroxybenzoic acid and Compound I that is Form 17-A or 17-B. In further aspects, the solid state form is a co-crystal of Compound I that is Form 17-A. In other aspects, the solid state form is a co-crystal of Compound I that is Form 17B. Form 17-A is characterized by two or three X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 5.0, 9.8, and 11.3°. In some aspects, Form 17-A is characterized by two X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 5.0, 9.8, and 11.3°. In other aspects, Form 17-A is characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 5.0, 9.8, and 11.3°. In further aspects, Form 17-A is characterized by the X-ray powder diffraction peaks in Table 33.

Table 33

In yet other aspects, Form 17-A is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 12. In further aspects, crystalline Form 17-A is characterized by a DSC/TGA thermogram that is substantially similar to FIG. 35 or 36.

[00145] In other aspects, the solid state form is a co-crystal of Compound I that is Form 17-B. Form 17-B is characterized by two or three X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 6.1, 12.0, and 18.9°. In some aspects, Form 17-B is characterized by two X- ray powder diffraction peaks at 2θ angles (± 0.2°) at 6.1, 12.0, and 18.9°. In other aspects, Form 17-B is characterized by three X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 6.1, 12.0, and 18.9°. In further aspects, Form 17-B is characterized by the X-ray powder diffraction peaks in Table 34. Table 34

In further aspects, Form 17-B is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 13. In further aspects, Form 17-B is characterized by a DVS spectrum that is substantially similar to FIG. 40.

[00146] In further embodiments, the solid state form of Compound I is a co-crystal of 3,4-dihydroxybenzoic acid and Compound I. In some aspects, the solid state form is a cocrystal of 3,4-dihydroxybenzoic acid and Compound I that is Form 23-A, 23-B, or 23-C. In other aspects, the solid state form is a co-crystal of 3,4-dihydroxybenzoic acid and Compound I that is Form 23-A. Form 23-A is characterized by two or three X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 5.6, 12.8 and 17.8°. In some aspects, Form 23-A is characterized by two X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 5.6, 12.8 and 17.8°. In other aspects, Form 23-A is characterized by two or three X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 5.6, 12.8 and 17.8°. In further aspects, Form 23-A is characterized by the X-ray powder diffraction peaks in Table 35. Table 35

In yet other aspects, Form 23-A is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 14. In further aspects, crystalline Form 23-A is characterized by a DSC/TGA thermogram that is substantially similar to FIG. 37. In further aspects, Form 23- A is characterized by a DV S spectrum that is substantially similar to FIG. 41.

[00147] In other aspects, the solid state form is a co-crystal of 3,4-dihydroxybenzoic acid and Compound I that is Form 23-B. Form 23-B is characterized by two or three X-ray powder diffraction peaks at 29 angles (± 0.2°) at 4.9, 9.8, and 11.2°. In some aspects, Form 23-B is characterized by two X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 5.6, 12.8 and 4.9, 9.8, and 11.2°. In other aspects, Form 23-B is characterized by three X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 4.9, 9.8, and 11.2°. In further aspects, Form 23-B is characterized by the X-ray powder diffraction peaks in Table 36. Table 36

In yet other aspects, Form 23-B is characterized by an X-ray powder diffraction pattern that is substantially similar to FIG. 15.

[00148] In further aspects, the solid state form is a co-crystal of 3,4- dihydroxybenzoic acid and Compound I that is Form 23-C. Form 23-C is characterized by two or three X-ray powder diffraction peaks at 2θ angles (± 0.2°) 5.6, 6.2, and 12.0°. In some aspects, Form 23-A is characterized by two X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 5.6, 6.2, and 12.0°. In other aspects, Form 23-C is characterized by three X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 5.6, 6.2, and 12.0°. In further aspects, Form 23-C is characterized by the X-ray powder diffraction peaks in Table 37.

Table 37

In yet other aspects, Form 23-C is characterized by an X-ray powder diffraction pattern that is substantially similar to FIG. 16. In further aspects, crystalline Form 23-C is characterized by a DSC/TGA thermogram that is substantially similar to FIG. 38 or 39. In further aspects, Form 23-C is characterized by a DVS spectrum that is substantially similar to FIG. 42.

[00149] In still other embodiments, the solid state form of Compound I is Form A. Crystalline Form A may be characterized by two X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 7.1° and 12°. In other aspects, crystalline Form A is characterized by the X-ray powder diffraction peaks in Table 38. Table 38

In further aspects, Form A is characterized by an X-ray powder diffraction pattern that is substantially similar to FIG. 20. In other aspects, crystalline Form A is characterized by a DSC thermal event at about 186°C. In further aspects, crystalline Form A is characterized by an about 2 wt.% weight loss as measured by TGA. In other aspects, crystalline Form A is characterized by a DSC/TGA thermogram that is substantially similar to FIG. 24.

[00150] Another embodiment of the present disclosure is drawn to a solid state form of Compound I that is amorphous.

[00151] The amorphous form of Compound I may be prepared using any one of the crystalline forms described herein. One process for preparing the amorphous solid state form of Compound I comprises dissolving a crystalline form of Compound I in a solvent to form a solution and producing the solid state form that is amorphous Compound I from the solution. In some embodiments, the solvent is an alcohol such as benzyl alcohol. The solution may be heated to a temperature that is above about 20 °C. In some embodiments, the solution is heated to a temperature of about 50 to about 70°C. In other embodiments, the solution is heated to a temperature of about 60°C. Amorphous Compound I may be produced from the solution using techniques such as precipitating the amorphous form from the solution. In some embodiments, the precipitation is performed at a solution temperature that is about room temperature or lower. In other embodiments, the precipitation is performed at about -20 to about 15°C. In further embodiments, the precipitation is performed at about 5°C.

[00152] Another process for preparing the amorphous solid state form of Compound I comprises milling a crystalline form of Compound I in the presence of a solvent for a time sufficient to produce the amorphous solid state form. In some embodiments, the solvent is an ether. In further embodiments, the solvent is tetrahydrofuran, 2-methyl- tetrahydrofuran, ethyl ether, diethyl ether, methyl ethyl ether, dimethyl ether, dipropyl ether, diisopropyl ether, 1,2-dimethoxy ethane, methyl phenyl ether, furan, 1,4-dioxane, diphenyl ether, or methyl t-butyl ether. In other embodiments, the solvent is tetrahydrofuran or methyl t-butyl ether. The milling may be performed using techniques in the art. In some embodiments, milling is performed in a ball milling container. In other embodiments, milling is performed in a ball milling capsule.

[00153] Solid Dispersions

[00154] The term "dispersion" refers to a disperse system in which one substance, the dispersed phase, is distributed, in discrete units, throughout a second substance (the continuous phase or vehicle). The size of the dispersed phase can vary considerably (e.g., colloidal particles of nanometer dimension, to multiple microns in size). In general, the dispersed phases can be solids, liquids, or gases. In the case of a solid dispersion, the dispersed and continuous phases are both solids. In pharmaceutical applications, a solid dispersion can include a crystalline therapeutically active compound (dispersed phase) in an amorphous polymer(s) (continuous phase), or alternatively, an amorphous therapeutically active compound (dispersed phase) in an amorphous polymer (continuous phase).

[00155] The term "amorphous solid dispersion" generally refers to a solid dispersion of two or more components, usually a therapeutically active compound and polymer (or plurality of polymers), but possibly containing other components such as surfactants or other pharmaceutical excipients, where the therapeutically active compound is in the amorphous phase, and the physical stability and/or dissolution and/or solubility of the amorphous therapeutically active compound is enhanced by the other components. In some embodiments, an amorphous solid dispersion includes the polymer(s) (and optionally a surfactant) constituting the dispersed phase, and the therapeutically active compound constitutes the continuous phase. In some embodiments, an amorphous solid dispersion includes the polymer(s) (and optionally a surfactant) constituting the continuous phase, and the therapeutically active compound constitutes the dispersed phase.

[00156] An exemplary solid dispersion is a co-precipitate or a co-melt of a particular therapeutically active compound with one or more polymer(s). A "co-precipitate" is produced after dissolving a therapeutically active compound and one or more polymer(s) in a solvent or solvent mixture followed by the removal of the solvent or solvent mixture. Sometimes the one or more polymer(s) can be suspended in the solvent or solvent mixture. The solvent or solvent mixture includes organic solvents and supercritical fluids. The solvent or solvent mixture can also contain anon-volatile solvent. A "co-melt" is produced after heating a therapeutically active compound and one or more polymer(s) to melt, optionally in the presence of a solvent or solvent mixture, followed by mixing, removal of at least a portion of the solvent if applicable, and cooling to room temperature at a selected rate. In some cases, solid dispersions are prepared by adding a solution of a therapeutically active compound and solid polymers followed by mixing and removal of the solvent or solvent mixture. To remove the solvent or solvent mixture, vacuum drying, spray drying, tray drying, lyophilization, and other drying procedures may be applied. Applying any of these methods using appropriate processing parameters, according to this disclosure, would provide the particular therapeutically active compound in an amorphous state in the final solid dispersion product.

[00157] Processes for preparing solid dispersions

[00158] In some embodiments, the solid dispersion may be prepared according to a process described herein. In some embodiments, a solid state form as described herein may be used as the starting material in a process to prepare the solid dispersion. In some embodiments, the solid state form used as a starting material in the process to prepare the solid dispersion is one of the crystalline forms described herein. In some embodiments, where the solid state form is a basic salt, the process to prepare the solid state dispersion includes an optional de-salting step, whereby the basic salt is converted to the free base or neutral form prior to preparing the dispersion.

[00159] In general, methods that could be used include those that involve rapid removal of solvent or solvent mixture from a mixture or cooling a molten sample. See, e.g. , International Patent Publication Nos. WO-2019/090059 and WO-2015/138837, which are incorporated herein by reference. Such methods include, but are not limited to, rotational evaporation, freeze-drying (i.e., lyophilization), vacuum drying, melt congealing, and melt extrusion. One embodiment of this disclosure involves solid dispersion obtained by spraydrying. In one embodiment, the product obtained by spray drying is dried to remove the solvent or solvent mixture.

[00160] Preparations disclosed herein, e.g. , a pharmaceutical composition, can be obtained by spray-drying a mixture comprising Compound I, or a pharmaceutically acceptable salt thereof, one or more polymer(s), and an appropriate solvent or solvent mixture. Spray drying involves atomization of a liquid mixture containing, e.g., a solid and a solvent or solvent mixture, and removal of the solvent or solvent mixture. The solvent or solvent mixture can also contain a non-volatile solvent. Atomization may be done, for example, through a two-fluid or pressure or electrosonic nozzle or on a rotating disk.

[00161] Spray Precipitation for Substances

[00162] Spray-dry ing is a technique that involves spraying an atomized solution of a substance into a drying chamber under a heated gas flow, which evaporates the solvent and precipitates the substance as solid particles that are collected in a collection vessel. The technique is used to generate amorphous dispersions of a particular substance, e.g., an API, with a stabilizing polymer for the purpose of increasing the bioavailability of that substance, especially one that may be highly crystalline or has poor water solubility. Lab-based spraydryers are expensive (prices starting at $100k) and are not meant to be single use equipment. Their high cost precludes spray -drying radioactive substances as this would foul the spraydryer for future use as later batches would be contaminated with radioactive material. One inexpensive workaround for radioactive substances involves concentrating the solution of a substance/polymer mixture in a round-bottom flask using a rotary evaporator. The concentrate is removed with manual scraping using a metal spatula. Oftentimes the scraped material requires grinding with a mortar and pestle followed by sieving to ensure the particles are of a sufficiently small size to enhance their bioavailability. The downsides to this workaround are that scraping is an intensely manual process, can cause the flask to break, is not easily scalable and results in low recoveries (<50%).

[00163] An alternative to spray-drying is a method called herein as spray precipitation, which involves spraying an atomized solution into an anti-solvent at ambient pressure. As rapid precipitation is the driving parameter leading to particle formation, as opposed to rapid drying under heated gas flow, no spray-drying equipment is required. The solution is sprayed directly into an inexpensive vessel (e.g., a glass bottle) filled with a rapidly-stirring anti-solvent. The stirring rate is modulated with a magnetic stir bar and a stirrer. The anti-solvent is chosen to favor precipitation of the substance/polymer mixture and can be tuned to minimize loss of the substance in that anti-solvent and to favor a precipitate amenable to sieving. Once the spraying is complete, the suspension is filtered without need for scraping. Recovery yields are >90% by mass.

[00164] This technique is safe and inexpensive, especially for preparing amorphous dispersions of radioactive substances, because only the atomizing spray nozzle, tubing and vessel are exposed to the radioactive material. After the filtration, the inexpensive vessel and tubing can be discarded. The spray nozzle can be cleaned. [00165] Spray drying converts a liquid feed to a dried particulate form. Spray drying generally involves the atomization of a liquid feed solution into a spray of droplets and contacting the droplets with hot air or gas in a drying chamber. The sprays are generally produced by either rotary (wheel) or nozzle atomizers. Evaporation of moisture from the droplets and formation of dry particles proceed under controlled temperature and airflow conditions.

[00166] Optionally, a secondary drying process such as fluidized bed drying or vacuum drying, may be used to reduce residual solvents (and other additives, such as glacial acetic acid) to pharmaceutically acceptable levels. Typically, spray-drying involves contacting a highly dispersed liquid suspension or solution (e.g., atomized solution), and a sufficient volume of hot air or gas (e.g., nitrogen, e.g., pure nitrogen) to produce evaporation and drying of the liquid droplets. The preparation to be spray dried can be any solution, coarse suspension, slurry, colloidal dispersion, or paste that may be atomized using the selected spray-drying apparatus. In a standard procedure, the preparation is sprayed into a current of warm filtered air (or into gas, e.g., nitrogen) that evaporates the solvent and conveys the dried product to a collector (e.g., a cyclone). The spent air or gas is then exhausted with the solvent (or solvent mixture including any additives such as glacial acetic acid), (e.g., then filtered) or alternatively the spent air or gas is sent to a condenser to capture and potentially recycle the solvent or solvent mixture. For example, if a gas (e.g., nitrogen) is used, the gas is then optionally recycled, heated again and returned to the unit in a closed loop system. Commercially available types of apparatus may be used to conduct the spraydrying. For example, commercial spray dryers are manufactured by Buchi Ltd. and Niro (e.g., the PSD line of spray driers manufactured by Niro).

[00167] Spray-dry ing typically employs solids loads of material from about 1% to about 30% or up to about 50% (i.e., therapeutically active compound plus and excipients), preferably at least about 10%. In some embodiments, solids loads of less than 10% may result in poor yields and unacceptably long run-times. In general, the upper limit of solids loads is governed by the viscosity of (e.g., the ability to pump) the resulting solution and the solubility of the components in the solution. Generally, the viscosity of the solution can determine the size of the particle in the resulting powder product.

[00168] Techniques and methods for spray-drying may be found in Perry's Chemical Engineering Handbook, 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). In general, the spray-drying is conducted with an inlet temperature of from about 40°C to about 200°C, for example, from about 70°C to about 150°C, preferably from about 40°C to about 60°C, about 50°C to about 55°C, or about 80°C to about 110°C, e.g., about 90°C. The spray-drying is generally conducted with an outlet temperature of from about 20 °C to about 100°C, for example from about 25°C to about 30°C (e.g., about 26°C), about 40°C to about 50°C, about 50°C to about 65°C, e.g., about 56°C to about 58°C.

[00169] Removal of the solvent or solvent mixture may require a subsequent drying step, such as tray drying, fluid bed drying (e.g., from about room temperature to about 100°C), vacuum dr ing, micro wave drying, rotary drum drying or biconical vacuum drying (e.g., from about room temperature to about 200°C).

[00170] In one embodiment, the spray-drying is fluidized spray drying (FSD). The steps in FSD can include, for example: preparing a liquid feed solution (e.g., containing Compound I or a pharmaceutically acceptable salt thereof, and optionally a polymer(s) and/or surfactant(s), dissolved or suspended in solvent(s)); atomizing (e.g., with a pressure nozzle, a rotary atomizer or disk, two-fluid nozzle or other atomizing methods) the feed solution upon delivery into the drying chamber of a spray dryer, e.g., operating in FSD mode; drying the feed solution in the drying chamber with heated air or a heated gas (e.g., nitrogen) to obtain a product, wherein larger particles of product separate out, e.g., drop out, while fines are carried by a stream of air or gas up to the top of the dr ing chamber (e.g., by natural convection) and to a cyclone, and re-introducing (e.g., at the top of the drying chamber or axially to the middle of the chamber) the fines into the drying chamber, wherein the reintroduced fines can agglomerate with newly formed product to generate an agglomerated product, wherein if the agglomerated product is large enough, it will separate out, if it is not large enough to separate out, the agglomerated product will be carried by convection to the top of the chamber and to the cyclone and re-introduced into the chamber. This process repeats until an agglomerated product that is large enough to drop out is formed. The fines can be re-introduced from the cyclone to the drying chamber via a feed pipe.

[00171] In some embodiments, there is an optional step of de-salting the pharmaceutically acceptable salt of Compound I (so as to form the free base of Compound I) prior to preparing the liquid feed solution.

[00172] In some embodiments, rather than drying the feed solution with heated air or a heated gas, the feed solution can instead be spray congealed, e.g. , the chamber is at room temperature (e.g., 21 ± 4 °C) or is cooled, e.g., cooled gas (e.g., nitrogen) is used for the process. [00173] FSD can further include collecting the agglomerated product in a first fluidizing chamber; which can be followed by discharging the agglomerated product from the first fluidizing chamber to a second fluidizing chamber, wherein a post-drying process can occur.

[00174] The agglomerated product (e.g., that separates out in the dry ing chamber) can then be transferred from the second fluidizing chamber to a third fluidizing chamber, where the agglomerated product is cooled. The agglomerated product (e.g., a solid dispersion of an amorphous compound) can then be further processed. For example, the product can be directly compressed. The product can optionally be blended with a surfactant, excipient, or pharmaceutically acceptable carrier, e.g., prior to direct compression. The product can optionally be further processed, e.g., milled, granulated, blended, and/or mixed with a melt granulate, surfactant, excipient, and/or pharmaceutically acceptable carrier.

[00175] FSD can be performed in a commercial spray dryer operating in fluidized spray dryer mode (FSD mode). FSD can be accomplished in either open cycle mode or closed cycle mode (e.g., the drying gas, e.g., nitrogen, is recycled). Examples of suitable spray dryers for use in FSD include dryers from Niro (e.g., the PSD line of spray driers manufactured by Niro: PHARMASD™; Chemical or SD line dryers). FSD can essentially be performed in any spray dryer that is configured to allow for the re-introduction of fines into the drying chamber.

[00176] Additional post drying, e.g., in a vacuum or fluidized bed dryer or a double cone or biconical post-dryer or a tumble dryer, can be performed if needed/ applicable to remove further solvents. In some embodiments, a post-drying step is performed.

[00177] To remove the solvent or solvent mixture, vacuum dry ing, spray drying, fluidized spray drying, tray drying, lyophilization, rotovapping, and other drying procedures may be applied. Applying any of these methods using appropnate processing parameters, according to this disclosure, would provide Compound I, or a pharmaceutically acceptable salt thereof in an amorphous state in the final solid dispersion product. Upon use of appropriate conditions (e.g., low outlet temperatures in the spray dryer, use of low boiling point solvents, use of heated gas) that result in a dispersion, e.g., powder, with desirable properties (e.g., median particle size (d₅₀) of 40-200 microns, e.g., 40-150 microns), powder bulk density of >0.2 g/ml (e.g., 0.2 to 0.5 g/ml), or > 0.25 g/ml, improved powder flowability (e.g., low cohesion forces, low interparticle internal friction); and/or dry powder with low OVIs (Organic Volatile Impurities), e.g., below ICH limits and/or user specifications), the dispersion can be directly compressed into a dosage form. [00178] In some embodiments, the inlet temperature is about 50°C to about 200°C, e.g., about 60°C to about 150°C, about 70°C to about 100°C, about 60°C to about 95°C, about 65°C to about 85°C, about 70°C to about 90°C, about 85°C to about 95°C, or about 70°C to about 85°C.

[00179] In some embodiments, the outlet temperature is about room temperature (e.g., USP room temperature (e.g., 21 ± 4°C)) to about 80°C, e.g., about 25°C to about 75°C, about 30°C to about 65°C, about 35°C to about 70°C, about 40°C to about 65°C, about 45°C to about 60°C, about 35°C to about 45°C, about 35°C to about 40°C, or about 37°C to about 40°C.

[00180] In some embodiments, the temperature set points of the fluidized beds (the temperature for each bed being selected independently from the temperature selected for another bed) is about room temperature (e.g., USP room temperature (e.g., 21±4°C)) to about 100°C, e.g., about 30°C to about 95°C, about 40°C to about 90°C, about 50°C to about 80°C, about 60°C to about 85°C, about 65°C to about 95°C, or about 80°C to about 95°C.

[00181] FSD can be performed on a mixture containing a compound of interest (e.g., a therapeutically active compound or API such as Compound I, or a pharmaceutically acceptable salt thereof). For example, FSD can be performed on a mixture containing Compound I, or a pharmaceutically acceptable salt thereof and one or more polymer(s), and optionally one or more surfactant(s), and optionally one or more additional excipients(s)) to obtain a solid dispersion of amorphous Compound I, or a pharmaceutically acceptable salt thereof that can be directly compressed into an oral dosage form e.g., tablet). Alternatively, the dispersion can be blended with one or more excipients prior to compression.

[00182] In one embodiment, the process for preparing a solid dispersion of compound I comprises:

[00183] a) forming a mixture of Compound I, or a pharmaceutically acceptable salt thereof, one or more polymer(s), and one or more solvent(s); and

[00184] b) rapidly removing the solvent(s) from the solution to form a solid amorphous dispersion comprising Compound I, or a pharmaceutically acceptable salt thereof, and the one or more polymer(s). The one or more polymer(s) and one or more solvent(s) may be any of those disclosed herein.

[00185] In some embodiments, the process includes an optional step of de-salting the pharmaceutically acceptable salt of Compound I (so as to form the free base of Compound I) prior to preparing a solid dispersion. [00186] In some embodiments, the solvent is removed by spray drying. In other embodiments the solid dispersion is tray dried using a convection tray dryer. In further embodiments, the solid dispersion is screened.

[00187] In one embodiment, Compound I, or a pharmaceutically acceptable salt thereof, is crystalline. In another embodiment, Compound I, or a pharmaceutically acceptable salt thereof, is amorphous.

[00188] As would be appreciated by one of skill in the art, spray drying may be done and is often done in the presence of an inert gas such as nitrogen. In certain embodiments, processes that involve spray drying may be done in the presence of a supercritical fluid involving carbon dioxide or a mixture including carbon dioxide.

[00189] In another embodiment, the process for preparing a solid dispersion of Compound I, or a pharmaceutically acceptable salt thereof, comprises:

[00190] a) forming a mixture of Compound I, or a pharmaceutically acceptable salt thereof, at least one polymer, and a solvent; and

[00191] b) spray-drying the mixture to form a solid dispersion comprising Compound I, or a pharmaceutically acceptable salt thereof, and the polymer.

[00192] In some embodiments, the process for preparing a solid dispersion of a pharmaceutically acceptable salt of Compound I includes an optional step of de-salting the pharmaceutically acceptable salt of Compound I (so as to form the free base of Compound I) prior to forming a mixture with the at least one polymer and the solvent.

[00193] Post-drying and/or polishing the wet spray dried dispersion to below ICH or given specifications for residual solvents can optionally be performed.

[00194] These processes may be used to prepare the pharmaceutical compositions disclosed herein. The amounts and the features of the components used in the processes may be as disclosed herein.

[00195] In some embodiments, the solvent comprises one or more volatile solvent(s) to dissolve or suspend Compound I, or a pharmaceutically acceptable salt thereof, and the polymer(s). In other embodiments, the one or more solvent(s) completely dissolves Compound I, or a pharmaceutically acceptable salt thereof, and the polymer(s). Solvents suitable for use in spray-drying processes will tend to be those that are volatile at the temperature and pressure of the drying process to facilitate removal of the solvent from the dispersion.

[00196] In some embodiments, the solvent is a volatile solvent. In other embodiments the solvent is a mixture of two or more volatile solvents. Examples of suitable volatile solvents include those that dissolve or suspend the therapeutically active compound either alone or in combination with another co-solvent. In other embodiments, the solvent(s) completely dissolves the therapeutically active compound.

[00197] In some embodiments, the solvent is anon-volatile solvent. In other embodiments the non-volatile solvent is water. In other embodiments, a non-volatile solvent is a component in a mixture comprising two or more solvents in any ratio. For example the non-volatile solvent may be present as a component in a mixture of solvents from about 1% to about 20% w/w (e.g., from about 3% w/w to about 15% w/w, from about 4% w/w to about 12% w/w, or from about 5% w/w to about 10% w/w).

[00198] In some embodiments, the solvent is a mixture of solvents. For example, the solvent mixture can include from about 0% to about 30% of solvent A and from about 70% to about 100% of solvent B, or the solvent mixture can include from about 0% to about 40% solvent A and from about 60% to about 100% solvent B. Other exemplary ratios of various solvents may include 80:20, 75:25, 70:30, 60:40, 55:45, and 50:50.

[00199] In some embodiments, the solvent is a mixture of solvents including at least one non-volatile solvent. For example, the solvent is a combination of components that includes both a volatile solvent and a non-volatile solvent.

[00200] In some embodiments, the solvent is a mixture of two or more volatile solvents and a non-volatile solvent. For example, the solvent mixture may comprise from about 40% to about 80% of one volatile solvent, from about 20% to about 35% of a second volatile solvent, and from about 0.1% to about 15% a non-volatile solvent (e.g., from about 50% to about 70% one volatile solvent, from about 25% to about 30% of another volatile solvent, and from about 1% to about 5% of anon-volatile solvent).

[00201] Compositions and Administration

[00202] Provided herein are pharmaceutical compositions comprising at least one solid state form as described herein, which may be optionally in admixture with a pharmaceutically acceptable or excipient. In some embodiments, the pharmaceutical composition comprises an amorphous form of Compound I and an optional pharmaceutically acceptable or excipient. In other embodiments, the pharmaceutical composition comprises one or more crystalline forms of Compound I and an optional pharmaceutically acceptable or excipient. In further embodiments, the pharmaceutical composition comprises one or more crystalline salts of Compound I and an optional pharmaceutically acceptable or excipient. In still other embodiments, the pharmaceutical composition comprises one or more co-crystals of Compound I and an optional pharmaceutically acceptable or excipient. Further provided are pharmaceutical compositions comprising a solid dispersion comprising one or more solid state forms as described herein, and a pharmaceutically acceptable excipient.

[00203] In some embodiments, the pharmaceutical composition comprises an anhydrous form of Compound I that is Form D. In other embodiments, the pharmaceutical composition comprises a basic salt of Compound I that is a sodium salt, a potassium salt, a lithium salt, or a calcium salt. In further embodiments, the pharmaceutical composition comprises a solvate of Compound I that is a dichloromethane solvate, e.g., Form H, R, T, or U. In yet other embodiments, the pharmaceutical composition comprises a methanol solvate of Compound I, e.g., Form K or L. In other embodiments, the pharmaceutical composition comprises an acetonitrile solvate of Compound I, e.g., Form F. In further embodiments, the pharmaceutical composition comprises a tetrahydrofuran solvate of Compound I, e.g., Form I. In still other embodiments, the pharmaceutical composition comprises a 2-methyl- tetrahydrofuran solvate of Compound I, e.g., Form Q. In yet further embodiments, the pharmaceutical composition comprises a benzyl alcohol solvate of Compound I, e.g., Form S. In further embodiments, the pharmaceutical composition comprises a hydrate of Compound I. In yet other embodiments, the pharmaceutical composition comprises a co-crystal of 4- hydroxy benzoic acid with the Compound I, e.g., Forms 17-A and 17-B. In still further embodiments, the pharmaceutical composition comprises a co-crystal of Compound I and 3,4-dihydroxy benzoic acid, e.g., Forms 23-A, 23-B, or 23-C. In other embodiments, the pharmaceutical composition comprises amorphous Compound I.

[00204] Compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, transmucosally, or in an ophthalmic preparation. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In one aspect, the pharmaceutical compositions provided herewith are orally administered in an orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.

[00205] The amount of a specified solid state form that may be combined with one or more excipients to produce a composition in a single dosage form will vary depending upon the subject to be treated and the particular mode of administration.

[00206] In another embodiment, a pharmaceutical composition comprises: i) Compound I or a pharmaceutically acceptable salt thereof as a component of a solid dispersion; and optionally one or more of the following ii) a filler; iii) a disintegrant; and iv) a lubricant.

[00207] In one aspect the solid dispersion comprising Compound I (or a pharmaceutically acceptable salt thereof) includes a polymer. In another embodiment, the solid dispersion may contain one or more additional excipients.

[00208] In another embodiment, a pharmaceutical composition comprises: i) Compound I or a pharmaceutically acceptable salt thereof as a component of a solid dispersion; and optionally one or more of the following ii) a filler; iii) a disintegrant; and iv) a lubricant.

[00209] In another embodiment, the pharmaceutical composition of the disclosure is in the form of a capsule. In a further embodiment, the pharmaceutical composition is in the form of a tablet. In still other embodiments the tablet is film-coated tablet.

[00210] Exemplary fillers include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, com starch, powdered sugar, and mixtures thereof.

[00211] Exemplary disintegrating agents include potato starch, com starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[00212] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, sodium stearyl fumarate, and mixtures thereof.

[00213] Another embodiment of the invention is a liquid formulation comprising the sodium salt of Compound I that is suitable for administration orally or parenterally. Typically, the liquid formulation is aqueous. For oral administration, certain sweetening and/or flavoring and/or coloring agents may be added. [00214] As used herein, the term "solid dispersion” generally refers to a solid dispersion of two or more components, usually a therapeutically active compound and a polymer (or plurality of polymers). In some embodiments, the solid dispersion may contain other components such as surfactants or other pharmaceutical excipients. In further embodiments, the therapeutically active compound is in the amorphous phase. In certain embodiments, the solid dispersion includes the polymer(s) (and optionally a surfactant) constituting the dispersed phase, and the therapeutically active compound constitutes the continuous phase. In some embodiments, an amorphous solid dispersion includes the polymer(s) (and optionally a surfactant) constituting the continuous phase, and the therapeutically active compound constitutes the dispersed phase. In some embodiments, the therapeutically active compound is substantially amorphous. In other embodiments, the therapeutically active compound is substantially crystalline.

[00215] In some embodiments, the solid dispersion or pharmaceutical composition containing the solid dispersion comprises a solid state form and one or more polymer(s). In other embodiments, the solid dispersion is a spray dried dispersion. In some embodiments, the solid dispersion comprises a solid state form, one or more polymer(s), and one or more surfactant(s). In some embodiments, the solid dispersion or pharmaceutical composition containing the solid dispersion comprises a solid state form and one polymer. In some embodiments, the solid dispersion or pharmaceutical composition containing the solid dispersion comprises a solid state form of, one polymer, and a surfactant.

[00216] In certain embodiments, the free form of Compound I is used to make the solid dispersion or pharmaceutical composition containing the solid dispersion. In other embodiments, a pharmaceutically acceptable salt of Compound I is used to make the solid dispersion or pharmaceutical composition containing the solid dispersion. In certain embodiments, the amorphous form of Compound I is used to make the solid dispersion or pharmaceutical composition containing the solid dispersion. In other embodiments, the pharmaceutically acceptable salt of Compound I is used to make the solid dispersion or pharmaceutical composition containing the solid dispersion is the sodium salt of Compound I. In further embodiments, the pharmaceutically acceptable salt of Compound I is used to make solid dispersion or pharmaceutical composition containing the solid dispersion is the lithium salt of Compound I. In yet other embodiments, the pharmaceutically acceptable salt of Compound I is used to make solid dispersion or pharmaceutical composition containing the solid dispersion is the potassium salt of Compound I. In still further embodiments, the pharmaceutically acceptable salt of Compound I is used to make solid dispersion or pharmaceutical composition containing the solid dispersion is the calcium salt of Compound I.

[00217] In some embodiments, the polymer present in the solid dispersion is a water-soluble polymer. In other embodiments, the polymer is a cellulosic polymer. In further embodiments, the polymer is a cellulose ether, cellulose ester, cellulose co-carboxy ester, cellulose phthalate, cellulose succinate, or mixtures thereof. In yet other embodiments, methylcellulose (MC); ethylcellulose (EC); hydroxyethylcellulose (HEC); hydroxypropyl methyl cellulose (HPMC) such as HPMC 606 or HPMC E5; hydroxypropyl cellulose (HPC); carboxymethyl ethyl cellulose (CMEC); hydroxypropyl methyl cellulose acetosuccinate (HPMCAS) such as HPMCAS/SLS, HPMCAS AS-MF, HPMCAS-HF, HPMCAS-H, HPMCAS-L, HPMCAS-M, HPMCAS 912 HP, HPMCAS 912, or HPMCAS HP-55; hydroxypropyl methyl cellulose phthalate (HPMCP); cellulose acetate phthalate (CAP); cellulose acetate groups having at least a half of cellulose acetate in hydrolyzed form; polyvinylpyrrolidone such as PVP K-12, PVPVA, PVP K 29/32, or PVPVA 64; polyoxyethylene-polyoxypropylene copolymers; polyvinylacetate (PVAc); poly(2 -vinyl pyridine) (P2VP), TPGS, copovidone; cellulose acetate (CA); cellulose acetate butyrate (CAB); 5-carboxypentyl hydroxypropyl cellulose (CHC); polyacrylic acid (PAA); carboxymethylcellulose derivatives such as carboxymethyl cellulose (CMC) or carboxymethyl cellulose acetate butyrate (CMCAB); hydroxypropylmethylphthalate (HPMP); hydroxypropylmethylphthalate acetate succinate (HP MP AS); Eudragit EPO; Eudragit E-100; cellulose acetate adipate (CAAdP); cellulose acetate suberate (CASub); methylcellulose adipate (MCAd); cellulose acetate butyrate sebacate (CAB Seb); cellulose acetate butyrate suberate (CAB Sub); cellulose acetate sebacate (CASeb); cellulose acetate phthalate (CAPhth); cellulose succinate (CS); cellulose acetate butyrate suberate (CABSu); HPCPenl06-AA-H-hydroxypropyl pent-4-enyl cellulose; HPC-SSL; HP-β-CD; or mixtures thereof. In still further embodiments, the polymer is HPMCAS. In other embodiments, the polymer is HPMCAS-M. In further embodiments, the polymer is HPMCAS 912 HP. In still other embodiments, the polymer is HPMCAS 912. In yet further embodiments, the polymer is HPMCAS-L. In other embodiments, the polymer is HPMCAS-H. In further embodiments, the polymer is HPMCAS HP-55. In further embodiments, the polymer is a PVP such as PVP VA64. PVP VA64 is available in the art as, e.g., Kollidon® VA64, which is a co-polymer of N-vinylpyrrolidone and vinyl acetate. In certain aspects, PVP VA64 has the following structure, wherein the molar ratio of N-vinylpyrrolidone and vinyl acetate groups is about 6 to about 4, and m and p are integers such as to provide an average molecular weight of about 45,000 to about 70,000.

In yet other embodiments, the polymer is a HPMC polymer such as HPMC-E3LV. HPMC- E3LV is available in the art, e.g., Methocel® E3, containing about 85 to about 99% of HPMC, about 0.5 to about 5% of sodium chloride, and about 1 to about 10% of water. In certain aspects, the HPMC-E3LV has the following structure, wherein k is an integer to provide a number average molecular weight (M_n) of about 10,000 to about 220,000:

HPMC-E3LV comprises about 26 to about 30 wt% of methoxy groups, preferably about 29wt%, and about 7 to about 12 wt% of hydroxy propyl groups, preferably about 8.5 wt%. In still further embodiments, the polymer is a methacrylic acid and ethyl acry late polymer such as Eudragit L 100-55. Eudragit L 100-55 is available in the art and, in certain aspects, has an average molecular weight of about 100,000 to about 130,000 g/mol, acid number of about 315, an about 1:1 molar ratio of methacrylic acid and ethyl acrylate groups, and the following structure. In certain aspects, v is an integer so as to provide an average molecular weight of about 100,000 to about 130,000 g/mol.

In still further embodiments, the polymer is the Soluplus® polymer. The Soluplus® polymer is available in the art and refers to polyvinyl caprolactam-polyvinyl acetate4- polyethylene glycol graft copolymer of the following structure:

In this structure, a, b, and c are integers such that the average molecular weight of the polymer is about 90,000 to about 140,000 g/mol, preferably about 118,000 g/mol. In certain aspects, the ratio of a:b:c is about 57: about 30: about 13.

[00218] As known in the art, HPMCAS refers to a cellulose polymer chain comprising acetyl (-C(O)CH₃), succinoyl (-C(O)CH₂CH₂C(O)OH), methoxy (-OCH₃), and hydroxypropoxy (-OCH₂CH(CH₃)OH) groups. In some aspects, the HPMCAS contains varying levels of the acetyl, succinoyl, methoxy, and hydroxypropoxy groups. In other aspects, the HPMCAS has the following structure:

In Formula A, each of the “R” groups are, independently, H, C(O)CH₃, C(O)CH₂CH₂C(O)OH, CH₃, or [CH₂CH(CH₃)O]mR’, wherein R’ is H, C(O)CH₃, C(O)CH₂CH₂C(O)OH, or CH₃ and m is 1 to 3, and n is an integer that results in a molecular weight of about 10,000 to about 500,000 daltons.

[00219] HPMCAS is available in the art as products such as AquaSolve™, Affinisol™, and Aqoat® from suppliers such as Dow, Ashland, and Shin-Etsu. In certain aspects, HPMCAS-M contains about 7 to about 11 wt% of acetyl groups, about 10 to about 14 wt% of succinoyl groups, about 12 to about 25 wt% of methoxy groups, and about 5 to about 9 wt% of hydroxy propoxy groups. In other aspects, HPMCAS-M contains about 9 wt% of acetyl groups and about 11 wt% of succinoyl groups. In further aspects, HPMCAS-L contains about 5 to about 9 wt% of acetyl groups, about 14 to about 18 wt% of succinoyl, groups, about 20 to about 24 wt% of methoxy groups, and about 5 to about 9 wt% of hydroxypropoxy groups. In yet other aspects, HPMCAS-L contains about 8 wt% of acetyl groups and about 15 wt% of succinoyl, groups. In still further aspects, HPMCAS -H contains about 10 to about 14 wt% of acetyl groups, about 4 to about 8 wt% of succinoyl groups, about 22 to about 26 wt% of methoxy groups, and about 6 to about 10 wt% of hydroxypropoxy groups. In other aspects, HPMCAS-H contains about 12 wt% of acetyl groups and about 7 wt% of succinoyl groups. In further aspects, HPMCAS-912 and HPMCAS-912 HP (high productivity) contain about 5 to about 9 wt% of hydroxypropyl groups, about 21 to about 25 wt% of methoxy groups, about 7 to about 11 wt% of acetate groups, about 10 to about 14 wt% of succinate groups, and about 0.5 wt% of acetic acid groups. One of skill in the art would understand that all HPMCAS references to wt% are based on the weight of the polymer.

[00220] In some embodiments, the polymer is present in the solid dispersion in an amount of about 10% w/w to 90% w/w (e.g., about 20% w/w to about 80% w/w; about 30% w/w to about 70% w/w; about 40% w/w to about 60% w/w; or about 15% w/w to about 35% w/w). In some embodiments, the polymer is (or the one or more polymers are) present in the solid dispersion in an amount of from about 10% w/w to about 80% w/w, for example from about 30% w/w to about 75% w/w, or from about 40% w/w to about 65% w/w, or from about 45% w/w to about 55% w/w, for example, about 46% w/w, about 47% w/w, about 48% w/w, about 49% w/w, about 50% w/w, about 51% w/w, about 52% w/w, about 53% w/w, or about 54% w/w.

[00221] In certain embodiments, the molar ratio of Compound I to the polymer is about 25:75 to about 50:50. In some aspects, the molar ratio of Compound I to the polymer is about 25:75, about 30:70, about 35:65, about 40:60, about 45:55, or about 50:50. In other aspects, the molar ratio of Compound I to the polymer is about 25:75. In further aspects, the molar ratio of Compound I to the polymer is about 30:70. In yet other aspects, the molar ratio of Compound I to the polymer is about 35:65. In still further aspects, the molar ratio of Compound I to the polymer is about 40:60. In other aspects, the molar ratio of Compound I to the polymer is about 45:55. In further aspects, the molar ratio of Compound I to the polymer is about 50:50.In some embodiments, the solid state form is present in the solid dispersion in an amount of from about 10% w/w and 90% w/w (equivalent to the amount of Compound I). In some embodiments, the solid state form is present in the solid dispersion in an amount of from about 10% w/w to about 90% w/w, for example from about 20% w/w to about 80% w/w, or from about 30% w/w to about 70% w/w or from about 40% w/w to about 60% w/w; or from about 15% w/w to about 35% w/w.

[00222] In some embodiments, the solid dispersion further comprises a surfactant. In some embodiments, the surfactant is selected from sodium lauryl sulfate (SLS), vitamin E or a derivative thereof (e.g., vitamin E TPGS), docusate sodium, sodium dodecyl sulfate, polysorbates (such as Tween 20 and Tween 80), poloxamers (such as Poloxamer 335 and Poloxamer 407), glyceryl monooleate, Span 65, Span 25, Capryol 90, pluronic copolymers (e.g., Pluronic F108, Pluronic P-123), and mixtures thereof. In some embodiments, the surfactant is SLS. In other embodiments, the surfactant is vitamin E or a derivative thereof (e.g., vitamin E TPGS).

[00223] In some embodiments, the surfactant is present in the solid dispersion in an amount of from about 0. 1% w/w to about 10% w/w, for example from about 0.5% w/w to about 2% w/w, or from about 1% w/w to about 3% w/w, from about 1% w/w to about 4% w/w, or from about 1% w/w to about 5% w/w. In some embodiments, the surfactant is present in the solid dispersion in an amount of about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, or about 1% w/w. In some embodiments, the surfactant is present in the solid dispersion in an amount of about 0.5% w/w, about 1% w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, or about 5% w/w.

[00224] Methods of Treatment, Uses for Manufacture of Medicament, Salts or Crystalline Forms for Use in Disease Treatment

[00225] In one aspect, the solid state forms described herein and the compositions thereof are inhibitors of MAT2A, and are generally useful for treating a disease or disorder that would be responsive to inhibition of MAT2A. The term “solid state form” described in the following paragraphs includes any of the solid state forms in accordance with any one of embodiments described herein.

[00226] The methods described herein may be performed at any stage of diagnosis or treatment of the patient. In some embodiments, the methods of the application are the first line of treatment, i.e., administered to treatment naive patients or newly diagnosed patients. In other embodiments, the methods of the application are the second or more lines of treatment, i.e., administered to patients who have already received or are receiving treatment with another therapeutic agent, i.e., in patients where the disease has relapsed or is refractory. In one aspect, the present disclosure relates to a method of treating cancer in a subject, comprising administering to the subject an effective amount of a solid state form or a pharmaceutical composition as described herein. In another aspect, the present disclosure relates to use of a solid state form for the manufacture of a medicament for treating cancer. In yet another aspect, the present disclosure relates to the use of a solid state form or a pharmaceutical composition comprising a disclosed solid state form for treating cancer. In some embodiments the solid state form is a crystalline form. In other embodiments the crystalline form is a salt of Compound I. In other embodiments the crystalline form is a free base of Compound I. In still other embodiments the crystalline form of Compound I is a hydrate, a solvate, or an anhydrate. In yet other embodiments the crystalline form of Compound I is an anhydrous crystalline free base form of Compound I. In additional embodiments the solid state form of Compound I is an amorphous form of Compound I.

[00227] In further embodiments, the methods comprising administering an anhydrous form of Compound I that is Form D.

[00228] In other embodiments, the methods comprise administering a basic salt of Compound I that is a sodium salt, a potassium salt, a lithium salt, or a calcium salt.

[00229] In further embodiments, the methods comprise administering a solvate of Compound I that is a dichloromethane solvate, e.g., Form H, R, T, or U.

[00230] In yet other embodiments, the methods comprise administering a methanol solvate of Compound I, e.g., Form K or L.

[00231] In other embodiments, the methods comprise administering an acetonitrile solvate of Compound I, e.g., Form F.

[00232] In further embodiments, the methods comprise administering a tetrahydrofuran solvate of Compound I, e.g., Form I. [00233] In still other embodiments, the methods comprise administering a 2- methyl -tetrahydrofuran solvate of Compound I, e.g., Form Q.

[00234] In yet further embodiments, the methods comprise administering a benzyl alcohol solvate of Compound I, e.g., Form S.

[00235] In further embodiments, the methods comprise administering a hydrate of Compound I.

[00236] In yet other embodiments, the methods comprise administering a co-crystal of 4-hydroxy benzoic acid with the Compound I, e.g., Forms 17-A and 17-B.

[00237] In still further embodiments, the methods comprise administering a cocrystal of Compound I and 3,4-dihydroxy benzoic acid, e.g., Forms 23-A, 23-B, or 23-C.

[00238] In other embodiments, the methods comprise administering amorphous Compound I.

[00239] In some embodiments, the cancer comprises a solid tumor. In some embodiments, the cancer is selected from lung cancer, pancreatic cancer, or cancer of the esophagus. In other embodiments, the cancer is lung cancer. In further embodiments, the cancer is pancreatic cancer. In still other embodiments, the cancer is cancer of the esophagus. In yet further embodiments, the cancer is lymphoma. In other embodiments, the lymphoma is follicular lymphoma, diffuse large B cell lymphoma, anaplastic large cell lymphoma, mantle cell lymphoma, lymphocytic lymphoma cancer of the bladder, primary CNS lymphoma, T- cell lymphoma, or mesothelioma. In other embodiments, the is diffuse mixed cell lymphoma, primary effusion lymphoma, double hit diffuse large B cell lymphoma, or triple hit diffuse large B cell lymphoma. In further embodiments, the cancer is angioimmunoblastic lymphoma, Burkit's lymphoma, Burkitt-like lymphoma, blastic NK-cell lymphoma, cutaneous T-cell lymphoma, lymphoblastic lymphoma, MALT lymphoma, mediastinal large B-cell lymphoma, nodal marginal zone B-cell lymphoma, small lymphocytic lymphoma, thyroid lymphoma, or follicular lymphoma. In yet other embodiments, the cancer is mesothelioma.

[00240] In other aspects, the present disclosure relates to methods of treating a disease or disorder that would be responsive to inhibition of MAT2A, comprising administering to the subject an effective amount of a solid state form or a pharmaceutical composition comprising a disclosed solid state form. In another aspect, the disclosure relates to use of a solid state form or a pharmaceutical composition comprising a disclosed solid state form for the manufacture of a medicament for a disease or disorder that would be responsive to inhibition of MAT2A. In some embodiments the disease or disorder that would be responsive to MAT2A inhibition is a MTAP null cancer. In other embodiments the disease or disorder that would be responsive to MAT2A inhibition is a CDKN2A null cancer. In other embodiments the disease or disorder that would be responsive to MAT2A inhibition is a MTAP wild type cancer. In still further embodiments the disease or disorder that would be responsive to MAT2A inhibition is a disease or disorder that would benefit from a reduction of s-adenosylmethionine (SAM).

[00241] In a further aspect, the present disclosure relates to a method of treating cancer in a subject, wherein the cancer is responsive to inhibition of MAT2A, comprising administering to the subject an effective amount of a solid state form or a pharmaceutical composition comprising a disclosed solid state form. In another aspect, the disclosure relates to use of a solid state form or a pharmaceutical composition comprising a disclosed solid state form for the manufacture of a medicament for treating cancer, wherein the cancer is responsive to inhibition of MAT2A. In yet another aspect, the present disclosure relates to a solid state form or a pharmaceutical composition comprising a disclosed solid state form for treating cancer, wherein the cancer is responsive to inhibition of MAT2A. In other aspects, the present disclosure relates to a solid state form or a pharmaceutical composition comprising a disclosed solid state form for treating a disease that would benefit from a reduction in SAM. In further aspects, the present disclosure relates to a solid state form or a pharmaceutical composition comprising a disclosed solid state form for treating a MTAP null (deleted) cancer. In other aspects, the present disclosure relates to a solid state form or a pharmaceutical composition comprising a disclosed solid state form for treating a CDKN2A null cancer. In still further aspects, the present disclosure relates to a solid state form or a pharmaceutical composition comprising a disclosed solid state form for treating a MTAP wild type cancer. In one embodiment, the cancer may be selected from the list of cancers described above. In another embodiment, the solid state from may be selected from any of the solid state forms disclosed herein.

[00242] In further embodiments, the methods of treating cancer comprise administering an anhydrous form of Compound I that is Form D. In other embodiments, the methods of treating cancer comprise administering a basic salt of Compound I that is a sodium salt, a potassium salt, a lithium salt, or a calcium salt. In further embodiments, the methods of treating cancer comprise administering a solvate of Compound I that is a dichloromethane solvate, e.g., Form H, R, T, or U. In yet other embodiments, the methods of treating cancer comprise administering a methanol solvate of Compound I, e.g., Form K or L. In other embodiments, the methods of treating cancer comprise administering an acetonitrile solvate of Compound I, e.g., Form F. In further embodiments, the methods of treating cancer comprise administering a tetrahydrofuran solvate of Compound I, e.g., Form I. In still other embodiments, the methods of treating cancer comprise administering a 2-methyl- tetrahydrofuran solvate of Compound I, e.g., Form Q. In yet further embodiments, the methods of treating cancer comprise administering a benzyl alcohol solvate of Compound I, e.g., Form S. In further embodiments, the methods of treating cancer comprise administering a hydrate of Compound I. In yet other embodiments, the methods of treating cancer comprise administering a co-crystal of 4-hydroxy benzoic acid with the Compound I, e.g., Forms 17-A and 17-B. In still further embodiments, the methods of treating cancer comprise administering a co-crystal of Compound I and 3,4-dihydroxy benzoic acid, e.g., Forms 23-A, 23-B, or 23 -C. In other embodiments, the methods of treating cancer comprise administering amorphous Compound I.

[00243] In a further aspect, the present disclosure relates to a method of treating cancer in a subject, comprising administering to the subject an effective amount of a solid state form of Compound I or a pharmaceutical composition comprising a solid state form of Compound I and an additional therapeutic agent. In another aspect, the present disclosure relates to use of a solid state form of Compound I or a pharmaceutical composition of a solid state form of Compound I and an additional therapeutic agent for the manufacture of a medicament for treating cancer. In yet another aspect, the present disclosure relates to a solid state form or a pharmaceutical composition comprising a disclosed solid state form and an additional therapeutic agent for treating cancer. In some embodiments the cancer is a MTAP null cancer. In other embodiments the cancer is a CDKN2A null cancer. In other embodiments the cancer is a MTAP wild type cancer. In still further embodiments the cancer is a cancer that would benefit from a reduction of s-adenosylmethionine (SAM).

[00244] In some aspects, the methods of the disclosure are directed to treating cancer in a subject wherein a solid state form of the disclosure, or a pharmaceutical composition comprising a disclosure solid state form, is administered to the subject as an initial treatment, i.e., a “first line” treatment. In other aspects, the methods are directed to treating cancer in a subject wherein a solid state form of the disclosure, or a pharmaceutical composition comprising a disclosure solid state form, is administered to the subject as a second line treatment. In other aspects, the methods are directed to treating cancer in a subject wherein a solid state form of the disclosure, or a pharmaceutical composition comprising a disclosure solid state form, is administered to the subject as a third line treatment. In other aspects, the methods are directed to treating cancer in a subject wherein a solid state form of the disclosure, or a pharmaceutical composition comprising a disclosure solid state form, is administered to a subject wherein the subject’s cancer is refractory to one or more prior cancer treatments.

[00245] In another aspect, the present disclosure relates to a method of inhibiting growth and/or metastasis of tumor cells in a subject wherein the tumor cells are responsive to inhibition of MAT2A, comprising administering to the subject an effective amount of a solid state form or a pharmaceutical composition comprising a disclosed solid state form.

[00246] In another aspect, the present disclosure relates to a method of inhibiting MAT2A in a subject wherein the tumor cells are responsive to inhibition of MAT2A, comprising administering to the subject an effective amount of a solid state form or a pharmaceutical composition comprising an effective amount of a disclosed solid state form.

[00247] In yet another aspect, the present disclosure relates to a method of treating an MTAP deleted cancer in a subject, comprising administering to the subject an effective amount of a solid state form or a pharmaceutical composition comprising an effective amount of a disclosed solid state form, as described herein wherein one of the dosing regimens described in the following paragraphs is implemented.

[00248] In one embodiment, the subject treated for the MTAP deleted cancer is treated by administering an effective amount of a solid state form of salt of Compound I. In some embodiments, an effective amount of sodium salt Form 20- A of Compound I is administered. In other embodiments, an effective amount of sodium salt Form 20-B of Compound I is administered. In further embodiments, an effective amount of sodium salt Form 20-C of Compound I is administered. In still other embodiments, an effective amount of sodium salt Form 20-D of Compound I is administered. In yet further embodiments, an effective amount of sodium salt Form 20-E of Compound I is administered. In other embodiments, an effective amount of potassium salt Form 21 -A of Compound I is administered. In further embodiments, an effective amount of potassium salt Form 21-B of Compound I is administered. In still other embodiments, an effective amount of potassium salt Form 21 -C of Compound I is administered. In yet further embodiments, an effective amount of potassium salt Form 21 -D of Compound I is administered. In other embodiments, an effective amount of potassium salt Form 21-E of Compound I is administered. In further embodiments, an effective amount of calcium salt Form 22 -A of Compound I is administered. In yet other embodiments, an effective amount of calcium salt Form 22 -B of Compound I is administered. In still further embodiments, an effective amount of calcium salt Form 22-C of Compound I is administered. In other embodiments, an effective amount of calcium salt Form 22-D of Compound I is administered. In further embodiments, an effective amount of calcium salt Form 22-E of Compound I is administered. In still other embodiments, an effective amount of calcium salt Form 22-G of Compound I is administered. In yet embodiments, an effective amount of calcium salt 22-H is administered. In some embodiments, an effective amount of Form D of Compound I is administered. In other embodiments, an effective amount of Form K of Compound I is administered. In further embodiments, an effective amount of Form H of Compound I is administered. In yet further embodiments, an effective amount of Form F of Compound I is administered. In other embodiments, an effective amount of Form I is administered. In further embodiments, an effective amount of Form L of Compound I is administered. In yet other embodiments, an effective amount of Form Q of Compound I is administered. In still further embodiments, an effective amount of Form R of Compound I is administered. In other embodiments, an effective amount of Form S of Compound I is administered. In still other embodiments, an effective amount of Form I is administered. In yet further embodiments, an effective amount of Form U of Compound I is administered. In some embodiments, the subject is treated by administering an effective amount of a solid state form of amorphous Compound I. In one particular embodiment, the solid state form of amorphous Compound I is the unsolvated or anhydrous non-salt of Compound I. In another particular embodiment, the subject is treated by administering an effective amount of amorphous Compound I as part of a solid dispersion.

[00249] In one embodiment, the dosing regimen for the cancer treatment method described in the foregoing paragraphs comprises orally administering an effective amount of a solid state form or a pharmaceutical composition comprising an effective amount of a disclosed solid state form. In some embodiments, the dosing regimen comprises administering an anhydrous form of Compound I that is Form D. In other embodiments, the dosing regimen comprises administering a basic salt of Compound I that is a sodium salt, a potassium salt, a lithium salt, or a calcium salt. In further embodiments, the dosing regimen comprises administering a solvate of Compound I that is a di chloromethane solvate, e.g., Form H, R, T, or U. In yet other embodiments, the dosing regimen comprises administering a methanol solvate of Compound I, e.g., Form K or L. In other embodiments, the dosing regimen comprises administering an acetonitrile solvate of Compound I, e.g., Form F. In further embodiments, the dosing regimen comprises administering a tetrahydrofuran solvate of Compound I, e.g., Form I. In still other embodiments, the dosing regimen comprises comprise administering a 2-methyl-tetrahydrofuran solvate of Compound I, e.g., Form Q. In yet further embodiments, the dosing regimen comprises administering a benzyl alcohol solvate of Compound I, e.g., Form S. In further embodiments, the dosing regimen comprises administering a hydrate of Compound I. In yet other embodiments, the dosing regimen comprises administering a co-crystal of 4-hydroxy benzoic acid with the Compound I, e.g., Forms 17-A and 17-B. In still further embodiments, the dosing regimen comprises administering a co-crystal of Compound I and 3,4-dihydroxy benzoic acid, e.g., Forms 23-A, 23-B, or 23 -C. In other embodiments, the dosing regimen comprises administering amorphous Compound I.

[00250] In one embodiment, the orally administered solid state form or pharmaceutical composition including a disclosed solid state form is administered as an oral capsule. In another embodiment, the orally administered solid state form or pharmaceutical composition including a disclosed solid state form is administered as an oral tablet. In some of the embodiments, the oral tablet has an optional film coating. In some embodiments, the orally administered solid state form or pharmaceutical composition including a disclosed solid state form is administered as a component of a solid dispersion. In other embodiments, a solid dispersion that is administered orally is in the form of a tablet or capsule.

[00251] In still other embodiments, the dosing regimen for the aforementioned cancer treatment methods includes an additional therapeutic agent.

[00252] The additional therapeutic agent may be selected by one skilled the in art depending on factors such as the patient’s disease state, among others. In some aspects, the second therapeutic agent is a taxane. In further aspects, the additional therapeutic agent is a taxane that is docetaxel, paclitaxel, or nab-paclitaxel, or alternative formulations thereof. In yet other aspects, the taxane is docetaxel. In still further aspects, the additional therapeutic agent is a platinum-based chemotherapeutic. In other aspects, the platinum-based chemotherapeutic is cisplatin, carboplatin, oxaplatin, nedaplatin, triplatin tetra nitrate, phenanthriplatin, picoplatin, or satraplatin. In further aspects, the platinum-based chemotherapeutic is carboplatin or cisplatin. In still other aspects, the second therapeutic agent is a DNA synthesis inhibitor. In yet further aspects, the DNA synthesis inhibitor is gemcitabine. In some embodiments, the solid state form and the additional therapeutic agent are administered concurrently. In other embodiments, the solid state form and the additional therapeutic agent are administered sequentially.

[00253] In one embodiment, a dosing regimen for the cancer treatment described in the foregoing paragraphs comprises administering an effective amount of a solid state form once daily (QD). In another embodiment, the dosing regimen described in the foregoing paragraphs comprises administering an effective amount of a solid state form disclosed herein twice daily (BID).

[00254] In one embodiment, the cancer treated in the methods described in foregoing paragraphs is selected from the lists of solid tumors, lymphomas, or mesothelioma provided elsewhere herein. In another embodiment, the cancer treated in the methods described herein is an MTAP deleted cancer.

[00255] Processes of Preparation

[00256] The disclosure also provide processes for preparing Compound I. These processes advantageously lack any palladium reagents, thereby resulting in fewer palladium side products and fewer steps, since not additional purification steps are not required to remove the palladium reagents and palladium side-products. The processes also are high yielding. In some embodiments, the yield of Compound I is at least about 90%. In other embodiments, the yield of Compound I is at least about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, or about 99%. In further embodiments, the yield of Compound I is about 100%.

[00257] The processes include converting compound INT-15 to ketenimine compound INT-15K. The structures for compounds INT-15 and INT-15K are the following:

Compound INT-15K is prepared by reacting compound INT-15 with triphenylphosphine chloride or triphenylphosphine bromide. In some embodiments, compound INT-15 is reacted with triphenylphosphine chloride. In other embodiments, compound INT-15 is reacted with triphenylphosphine chloride. Triphenylphosphine chloride may be prepared by reacting triphenylphosphine oxide and oxalyl chloride. In some embodiments, triphenylphosphine oxide and oxalyl chloride are combined before contacting with compound INT-15. The preparation of ketenimine compound INT-15K may be prepared at reduced temperatures. The term “reduced temperature” as used herein refers to a temperature that is below about room temperature. In some embodiments, “reduced temperature” refer to a temperature that is below about 22°C. The reduced temperatures utilized to prepare ketenimine INT-15K is about -10 to about 20°C. In some aspects, the reduced temperature to prepare compound INT-15K is about -10, about -5, about 0, about 5, about 10, about 15, or about 20°C. In further aspects, the reduced temperature to prepare compound INT-15K is about -10 to about 15, about -10 to about 10, about -10 to about 5, about -10 to about 0, about -10 to about -5, about -5 to about 20, about -5 to about 15, about -5 to about 10, about -5 to about 5, about -5 to about 0, about 0 to about 20, about 0 to about 15, about 0 to about 10, about 0 to about 5, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 20, about 10 to about 15, or about 15 to about 20°C. In other aspects, the reduced temperature utilized to prepare compound INT-15K is about 10°C.

[00258] A base is then added to the reduced temperature solution. In some embodiments, the base is an amine base such as N-methylmorpholine, triethyl amine, 2,6- lutidine, pyridine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, or 1,4- diazabicyclo[2.2.2]octane. In certain aspects, the base is N-methylmorpholine. In other aspects, the base is triethyl amine. In further aspects, the base is 2,6-lutidine. In still other aspects, the base is pyridine. In yet further aspects, the base is 4-dimethylaminopyridine. In other aspects, the base is N,N-diisopropylethylamine. In further aspects, the base is 1,4- diazabicyclo[2.2.2]octane. In other embodiments, an excess of the base is utilized. In certain aspects, more than about 1 equivalents of the base is utilized. In other aspects, at least about 1.5 equivalents of the base are utilized. In further aspects, at least about 2 equivalents of the base are utilized. In yet other aspects, at least about 2.5 equivalents of the base are utilized. In still further aspects, at least about 3 equivalents of the base are utilized.

[00259] Compound INT-15K is then converted to compound INT-12A. This conversion is performed by reacting compound INT-15K with compound INT-12. The structures for compounds INT-12 and INT-12A are the following

In some embodiments, compound INT-12 is reacted with compound INT-15K at reduced temperatures. In certain aspects, the reduced temperature used to prepare compound INT-12A is about -25 to about 20°C. In other aspects, the reduced temperature used to prepare compound INT-12A is about -25, about -20, about -15, about -10, about -5, about 0, about 5, about 10, about 15, or about 20°C. In further aspects, the reduced temperature used to prepare compound INT-12A is about -25 to about 15, about -25 to about 10, about -25 to about 5, about -25 to about 0, about -25 to about -5, about -25 to about -10, about -25 to about -15, about -25 to about -20, about -20 to about 20, about -20 to about 15, about -20 to about 10, about -20 to about 5, about -20 to about 0, about -20 to about -5, about -20 to about -10, about -20 to about -15, about -15 to about 20, about -15 to about 15, about -15 to about 10, about - 15 to about 5, about -15 to about 0, about -15 to about -5, about -15 to about -10, about -10 to about 20, about -10 to about 15, about -10 to about 10, about -10 to about 5, about -10 to about 0, about -10 to about -5, about -5 to about 20, about -5 to about 15, about -5 to about 10, about -5 to about 5, about -5 to about -25, about 0 to about 20, about 0 to about 15, about 0 to about 10, about 0 to about 5, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 20, about 10 to about 15, or about 15 to about 20°C. In yet other aspects, the reduced temperature to prepare compound INT-12A is about 0°C.

[00260] The reduced temperature is then raised using skill in the art. In some embodiments, the temperature is raised to an elevated temperature. In certain aspects, the elevated temperature is about 25 to about 45°C. In other aspects, the elevated temperature is about 25, about 30, about 35, about 40, or about 45°C. In further aspects, the elevated temperature is about 25 to about 40, about 25 to about 35, about 25 to about 30, about 30 to about 45, about 30 to about 40, about 30 to about 35, about 35 to about 45, about 35 to about 40, or about 40 to about 45°C. In still other aspects, the elevated temperature is about 35°C. In other embodiments, a molar excess of compound INT-15K relative to compound INT-12 is used. As used herein, the term “molar excess” refers to an amount in moles of INT-15K that is greater than INT-12. In certain aspects, the molar excess of compound INT-15 is at least about 1.1 equivalents relative to 1 equivalent of compound INT-12. In other aspects, the molar excess of compound INT-15 is at least 1.2 equivalents of compound INT-15 relative to 1 equivalent of compound INT-12. In further aspects, the molar excess of compound INT-15 is at least 1.25 equivalents of compound INT-15 relative to 1 equivalent of compound INT- 12. In still other aspects, the molar excess of compound INT-15 is at least 1.3 equivalents of compound INT-15 relative to 1 equivalent of compound INT-12. In yet further aspects, the molar excess is at least 1.5 equivalents of compound INT-15 relative to 1 equivalent of compound INT-12.

[00261] Following preparation of compound INT-12A, it is then deprotected to form compound INT-12B. The structure for compound INT-12B is as follows:

One skilled in the art would be able to determine suitable deprotection conditions. In some embodiments, the deprotecting is performed using an acid or a base. In other embodiments, the deprotecting is performed using an acid. In certain aspects, the acid is a strong acid. In other aspects, the acid is HC1 or methanesulfonic acid. In further aspects, the acid is HC1. In yet other aspects, the acid is methanesulfonic acid. In further embodiments, the deprotecting is performed using a base. In certain aspects, the base is potassium tert-butoxide. The deprotecting may be performed at a temperature that provides compound INT-12B. The deprotecting is performed at a reduced temperature. In certain aspects, the reduced temperature used to prepare compound INT-12B is about -25 to about 20°C. In other aspects, the reduced temperature used to prepare compound INT-12B is about -25, about -20, about - 15, about -10, about -5, about 0, about 5, about 10, about 15, or about 20°C. In further aspects, the reduced temperature used to prepare compound INT-12B is about -25 to about 15, about -25 to about 10, about -25 to about 5, about -25 to about 0, about -25 to about -5, about -25 to about -10, about -25 to about -15, about -25 to about -20, about -20 to about 20, about -20 to about 15, about -20 to about 10, about -20 to about 5, about -20 to about 0, about -20 to about -5, about -20 to about -10, about -20 to about -15, about -15 to about 20, about - 15 to about 15, about -15 to about 10, about -15 to about 5, about -15 to about 0, about -15 to about -5, about -15 to about -10, about -10 to about 20, about -10 to about 15, about -10 to about 10, about -10 to about 5, about -10 to about 0, about -10 to about -5, about -5 to about 20, about -5 to about 15, about -5 to about 10, about -5 to about 5, about -5 to about -25, about 0 to about 20, about 0 to about 15, about 0 to about 10, about 0 to about 5, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 20, about 10 to about 15, or about 15 to about 20°C. In yet other aspects, the reduced temperature is about 0°C. The solvent utilized to prepare compound INT-12B may be selected by one skill in the art. In some embodiments, the organic solvent is an organic solvent, such as an aqueous organic solvent. In certain aspects, the organic solvent is an ether, alcohol, or ethyl acetate. In other aspects, the organic solvent is an ether such as dioxane or cyclopentyl methyl ether. In further aspects, the organic solvent is dioxane. In still other aspects, the organic solvent is an alcohol such as isopropyl alcohol. In yet further aspects, the organic solvent is ethyl acetate.

[00262] Compound INT-12B is then cyclized to form Compound I. One skilled in the art would be able to determine a suitable temperature to perform the cyclization. In some embodiments, the cyclization temperature is at least about 30°C. In other embodiments, the cyclization temperature is about 30 to about 50°C. In further embodiments, the cyclization temperature is about 30, about 35, about 40, about 45, or about 50°C. In other embodiments, the cyclization temperature is about 30 to about 45, about 30 to about 40, about 30 to about 35, about 35 to about 50, about 35 to about 45, about 35 to about 40, about 40 to about 50, about 40 to about 45, or about 45 to about 50°C. In further embodiments, the cyclization temperature is about 25 to about 45°C.

[00263] Compound INT-15 may be prepared by coupling compound INT-14 with 2-aminopyridine. The structure of compound INT-14 is shown below.

The coupling may be performed using a coupling agent that may be selected by one skilled in the art. In some embodiments, the coupling agent is l,l'-carbonyldiimidazole (CDI), 1 -ethyl - 3-(3-dimethylaminopropyl)carbodiimide (EDC), 2,2-dichloro-5-(2-phenylethyl)-4- (trimethylsilyl)-3-furanone (DPTF), 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methyl- morpholin-4-ium chloride (DMT-MM), (l-cyano-2-ethoxy-2- oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), or N,N’-diisopropylcarbodiimide (DIC). In certain aspects, the coupling agent is CDI. In other aspects, the coupling agent is EDC. In further aspects, the coupling agent is DPTF. In yet other aspects, the coupling agent is DMT-MM. In still further aspects, the coupling agent is COMU. In still further aspects, the coupling agent is DIC. The coupling is performed at a reduced temperature that may be selected by one skilled in the art. In some embodiments, the coupling is performed at a temperature of about -25 to about 20°C. In certain aspects, the coupling temperature is about -25, about -20, about -15, about -10, about - 5, about 0, about 5, about 10, about 15, or about 20°C. In further aspects, the coupling temperature is about -25 to about 15, about -25 to about 10, about -25 to about 5, about -25 to about 0, about -25 to about -5, about -25 to about -10, about -25 to about -15, about -25 to about -20, about -20 to about 20, about -20 to about 15, about -20 to about 10, about -20 to about 5, about -20 to about 0, about -20 to about -5, about -20 to about -10, about -20 to about -15, about -15 to about 20, about -15 to about 15, about -15 to about 10, about -15 to about 5, about -15 to about 0, about -15 to about -5, about -15 to about -10, about -10 to about 20, about -10 to about 15, about -10 to about 10, about -10 to about 5, about -10 to about 0, about -10 to about -5, about -5 to about 20, about -5 to about 15, about -5 to about 10, about -5 to about 5, about -5 to about -25, about 0 to about 20, about 0 to about 15, about 0 to about 10, about 0 to about 5, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 20, about 10 to about 15, or about 15 to about 20°C. In yet other aspects, the coupling temperature is about 0°C. The coupling compound may be added to INT-14 or INT-14 may be added to the coupling compound. In some aspects, compound INT-14 is added to a solution comprising the coupling compound.

[00264] Compound INT-14 may be prepared by carboxylating methyl 4- methoxyphenylacetate (INT-13) to form compound INT-14. Compound INT-13 has the following structure:

[00265] The carboxylation is performed using carbon dioxide. In certain aspects, the carboxylation is performed using carbon dioxide gas or solid carbon dioxide. In other aspects, the carboxy lation is performed using carbon dioxide gas. In further aspects, the carboxylation is performed using solid carbon dioxide, i.e., dry ice. In some embodiments, the carboxylation is performed in the presence of a base. In certain aspects, the base is a strong non-nucleophilic base. In other aspects, the base is sodium hexamethyldisilazide, lithium hexamethyldisilazide, or potassium hexamethyldisilazide. In further aspects, the base is sodium hexamethyldisilazide. In yet other aspects, the base is lithium hexamethyldisilazide. In still further aspects, the base is potassium hexamethyldisilazide. In other embodiments, the carboxylation is performed at reduced temperature. In certain aspects, the carboxylation is performed at about -100 to about 0°C. In other aspects, the carboxylation is performed at about -100, about -90, about -80, about -70, about -60, about -50, about -40, about -30, about -20, about -10, or about 0°C. In further aspects, the carboxylation is performed at about -100 to about -10, about -100 to about -20, about -100 to about -30, about -100 to about -40, about -100 to about -50, about -100 to about -60, about -100 to about -70, about -100 to about -80, about -100 to about -90, about -90 to about 0, about -90 to about -10, about -90 to about -20, about -90 to about -30, about -90 to about -40, about -90 to about -50, about -90 to about -60, about -90 to about -70, about -90 to about -80, about -80 to about 0, about -80 to about -10, about -80 to about -20, about -80 to about -30, about -80 to about -40, about -80 to about -50, about -80 to about -60, about -80 to about -70, about -70 to about 0, about -70 to about -10, about -70 to about -20, about -70 to about -30, about -70 to about -40, about -70 to about -50, about -70 to about -60, about -60 to about 0, about -60 to about -10, about -60 to about -20, about -60 to about -30, about -60 to about -40, about -60 to about -50, about -50 to about 0, about -50 to about -10, about -50 to about -20, about -50 to about -30, about -50 to about -40, about -40 to about 0, about -40 to about -10, about -40 to about -20, about -40 to about -30, about -30 to about 0, about -30 to about -10, about -30 to about -20, about -20 to about 0, about -20 to about -10, or about -10 to about 0. In further aspects, the carboxylation is performed at about -90 to about -50°C. In other aspects, the carboxylation is performed at about -50 to about -70°C.

[00266] In further embodiments, the carboxylation solution is then warmed via one or more warming steps. In certain aspects, the warming is performed using at least one, two, three, four, five, or six warming steps. In other aspects, the warming is performed in two steps. In further aspects, the warming is performed in three steps. In yet other aspects, the wanning is performed in four steps. In still other embodiments, at least one wanning step comprises warming to a temperature of about -35 to about -15°C. In certain aspects, the one warming step temperature is about -35 to about -20, about -35 to about -25, about -35 to about -30, about -30 to about -15, about -30 to about -20, about -30 to about -25, about -25 to about -15, about -25 to about -20, or about -20 to about -15°C. In other aspects, the one warming temperature is about -30 to about -20°C. In further aspects, the one warming temperature is about -25°C. In yet further embodiments, a second warming step comprises warming to about -15 to about 5°C. In certain aspects, the second warming step temperature is about -15 to about 0, about -15 to about -5, about -15 to about -10, about -10 to about 5, about -10 to about 0, about -10 to about -5, about -5 to about 5, about -5 to about 0, or about 0 to about 5°C. In other embodiments, the second warming step temperature is about -5°C. In other embodiments, a third warming step comprises warming to about room temperature, i.e., about 20 to about 25°C. An excess of the base may be utilized. In certain aspects, more than one equivalents of base is used. In other aspects, at least about 1.5 equivalents of base are utilized. In further aspects, about 1 to about 4 equivalents of the base are utilized. In still other aspects, about 1.1 to about 3.5 equivalents of the base are utilized. In yet further aspects, about 1.1 to about 3.3 equivalents, of the base are utilized. In other aspects, 1.5 equivalents of the base are utilized. [00267] Compound INT-15 may be prepared by reacting compound INT-25 with methanesulfonic acid. Compound INT-25 has the following structure.

In some embodiments, compound INT-25 is reacted with methanesulfonic acid at an elevated temperature. In certain aspects, the elevated temperature is about 50 to about 80°C. In other aspects, the temperature is about 50 to about 70, about 50 about 60, about 60 to about 80, about 60 to about 70, or about 70 to about 80°C. In further aspects, the temperature is about 60 to about 70°C. In yet other aspects, the temperature is about 65 to about 70°C.

[00268] Alternatively, compound INT-15 may be prepared by reacting compound INT-2 with 2-aminopyridine to provide compound INT-15. This reaction may also result in the preparation of compound INT-25 or a combination of compounds INT-15 and INT-25. The structures for INT-2 and INT-25 are shown below.

Compound INT-2 may be reacted with 2-aminopyridine in an organic solvent. Examples of suitable organic solvents include those with a high boiling point. In certain aspects, the organic solvent is toluene or the like. The reaction is performed at an elevated temperature. In certain aspects, the reaction is performed at a temperature of about 90 to about 120°C. In other aspects, the reaction is performed at a temperature of about 90, about 95, about 100, about 105, about 110, about 115, or about 120°C. In further aspects, the reaction is performed at about 90 to about 110, about 90 to about 100, about 100 to about 120, about 100 to about 110, or about 110 to about 120°C. In yet other aspects, the reaction nis performed about 100 to about 110°C. In further aspects, the reaction is performed at about 110°C.

[00269] Compound INT-12 may be prepared by reacting compound INT-11 with cyclohexanone. The structure of compound INT-11 is shown below.

The reaction of INT-11 with cyclohexanone may be performed at a reduced temperature. In certain aspects, the reduced temperature is about 0 to about 20°C. In other aspects, the reduced temperature is about 0, about 5, about 10, about 15, or about 20°C. In further aspects, the reduced temperature is about 0 to about 15, about 0 to about 10, about 0 to about 5, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 20, about 10 to about 15, or about 15 to about 20°C. In further aspects, the reduced temperature is about 15°C. In some embodiments, an excess of cyclohexanone utilized. In certain aspects, at least about 1.5 equivalents of cyclohexanone are utilized. In other aspects, at least about 2 equivalents of cyclohexanone are utilized. In further aspects, at least about 2.5 equivalents of cyclohexanone are utilized. In other embodiments, cyclohexanone is reacted with INT-11 in the presence of a strong organic acid. In some aspects, the strong organic acid is p- toluenesulfonic acid. In further embodiments, a catalytic amount of the strong organic acid is utilized. In certain aspects, the catalytic amount of the strong organic acid is about 0.01 to about 0.1 equivalents. In other aspects, the catalytic amount is about 0.01, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, or about 1 equivalents. In further aspects, the catalytic amount is about 0.01 to about 0.09, about 0.01 to about 0.08, about 0.01 to about 0.07, about 0.01 to about 0.06, about 0.01 to about 0.05, about 0.01 to about 0.04, about 0.01 to about 0.03, about 0.01 to about 0.02, about 0.02 to about 0.1, about 0.02 to about 0.09, about 0.02 to about 0.08, about 0.02 to about 0.07, about 0.02 to about 0.06, about 0.02 to about 0.05, about 0.02 to about 0.04, about 0.02 to about 0.03, about 0.03 to about 0.1, about 0.03 to about 0.09, about 0.03 to about 0.08, about 0.03 to about 0.07, about 0.03 to about 0.06, about 0.03 to about 0.05, about 0.03 to about 0.04, about 0.04 to about 0.1, about 0.04 to about 0.09, about 0.04 to about 0.08, about 0.04 to about 0.07, about 0.04 to about 0.06, about 0.04 to about 0.05, about 0.05 to about 0.1, about 0.05 to about 0.09 about 0.05 to about 0.08, about 0.05 to about 0.07, about 0.05 to about 0.06, about 0.06 to about 0.1, about 0.06 to about 0.09, about 0.06 to about 0.08, about 0.06 to about 0.07, about 0.07 to about 0.1, about 0.07 to about 0.09, about 0.07 to about 0.08, about 0.08 to about 0.1, about 0.08 to about 0.09, or about 0.09 to about 0.1 equivalents. In yet other aspects, the catalytic amount is about 0.03 to about 0.07 equivalents. In still further aspects, the catalytic amount is about 0.04 equivalents.

[00270] Compound INT-11 may be prepared by protecting the pyrazole group of compound INT-10. The structure of compound INT-10 is shown below.

In some embodiments, the pyrazole is protected with a pivalyl group. The protection may be performed using a group comprising a pivaloyl moiety. In certain aspects, the protecting is performed using pivalic anhydride or pivalic chloride. In other aspects, the protecting is performed using pivalic anhydride. In further aspects, the protecting is performed using pivalic chloride. In other embodiments, the protecting further includes an alkali t-butoxide. In certain aspects, the alkali t-butoxide is lithium t-butoxide, sodium t-butoxide, or potassium t- butoxide. In other aspects, the alkali t-butoxide is lithium t-butoxide. In further aspects, the alkali t-butoxide is sodium t-butoxide. In still other aspects, the alkali t-butoxide is potassium t-butoxide. The alkali t-butoxide may be added to compound INT-10 or compound INT-10 is added to the alkali t-butoxide. In some aspects, one or more of the alkali t-butoxide, pivalic chloride or pivalic anhydride is added to compound INT-10. In other aspects, compound INT-10 is added to one or more of the alkali t-butoxide, pivalic chloride or pivalic anhydride. In certain embodiments, portions of the total amount of the pivalic anhydride or pivalic chloride are added to compound INT-10. In some aspects, the pivalic anhydride or pivalic chloride are added to compound INT-10 in at least two options. In other aspects, the pivalic anhydride or pivalic chloride are added to compound INT-10 in three portions. In further aspects, the pivalic anhydride or pivalic chloride are added to compound INT-10 in four portions. In yet other aspects, the pivalic anhydride or pivalic chloride are added to compound INT-10 in five portions. In still further aspects, the first portion comprises at least about 0.50 equivalents of the pivalic anhydride or pivalic chloride. In other aspects, the first portion comprises about 0.50 equivalents of the pivalic anhydride or pivalic chloride. In further aspects, the second portion comprises at least about 0.30 equivalents of the pivalic anhydride or pivalic chloride. In still other aspects, the second portion comprises about 0.35 equivalents of the pivalic anhydride or pivalic chloride. In yet further aspects, the third portion comprises at least about 0.20 equivalents of the pivalic anhydride or pivalic chloride. In other aspects, the third portion comprises about 0.1 equivalents of the pivalic anhydride or pivalic chloride. In further aspects, the fourth portion comprises at least about 0. 10 equivalents of the pivalic anhydride or pivalic chloride. In yet other aspects, the fourth portion comprises about 0.05 equivalents of the pivalic anhydride or pivalic chloride. The protecting may further contain a base. In certain aspects, the base utilized in the protecting step is an alkali hydroxide. In further aspects, the base utilized in the protecting step is sodium hydroxide, lithium hydroxide, or potassium hydroxide. In yet other aspects, the base utilized in the protecting step is potassium hydroxide. In still further aspects, the base utilized in the protecting step is sodium hydroxide. In other aspects, the base utilized in the protecting step is lithium hydroxide. In further aspects, the base utilized in the protecting step is an amine. In yet other aspects, the base is triethylamine.

[00271] Aspects

[00272] Aspect 1. A solid state form of Compound I or a salt thereof or a solvate thereof, wherein the Compound I is represented by the formula:

[00273] Aspect 2. The solid state form according to Aspect 1 wherein the solid state form is substantially crystalline.

[00274] Aspect 3. The solid state form according to Aspect 2 wherein the solid state form is substantially anhydrous.

[00275] Aspect 4. The solid state form according to Aspect 1 or 2, wherein the solid state form is of a solvate of Compound I.

[00276] Aspect 5. The solid state form according to any one of Aspects 1-4, wherein the solid state form is of Compound I as a free base.

[00277] Aspect 6. The solid state form according to Aspect 1, wherein the solid state form is of a salt of Compound I.

[00278] Aspect 7. The solid state form according to any one of Aspects 1-6, wherein the solid state form is at least 60 wt.% of a single crystalline form, at least 70 wt.% of a single crystalline form, at least 80 wt.% of a single crystall ine form, at least 90 wt.% of a single crystalline form, at least 95 wt.% of a single crystalline form, or at least 99 wt.% of a single crystalline form. [00279] Aspect 8. The solid state form according to any one of Aspects 1-6, wherein the solid state form has a chemical purity of at least 60 wt.%, at least 70 wt.%, at least 80 wt.%, at least 90 wt.%, at least 95wt.%, or at least 99 wt.%, as measured by HPLC.

[00280] Aspect 9. An anhydrous solid state form of Compound I that is represented by the formula:

[00281] Aspect 10. The solid state form according to Aspect 9 that is crystall ine Form D that is characterized by two or more X-ray powder diffraction peaks at 2θ angles (± 0.2°) chosen from 7.6°, 10.7°, 19.0° and 23.7°.

[00282] Aspect 11. The solid state form according to Aspect 10 characterized by an X-ray powder diffraction pattern substantially similar to FIG. 1.

[00283] Aspect 12. A basic salt of Compound I or a solvate thereof, wherein Compound I is represented by the formula:

[00284] Aspect 13. The basic salt or a solvate thereof according to Aspect 12, wherein the salt is a sodium salt, a potassium salt, a lithium salt, or a calcium salt.

[00285] Aspect 14. The basic salt according to Aspect 12 or 13, wherein the salt is crystalline or amorphous. [00286] Aspect 15. A solid state form of a solvate of Compound I, wherein Compound I is represented by the formula:

Compound I.

[00287] Aspect 16. The solid state form according to Aspect 15 that is a dichloromethane solvate.

[00288] Aspect 17. The solid state form according to Aspect 16 that is crystalline Form H that is characterized by two or more X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 7.1°, 7.5° and 11.7°.

[00289] Aspect 18. The solid state form according to Aspect 17 characterized by an X-ray powder diffraction pattern substantially similar to FIG. 3.

[00290] Aspect 19. The solid state form according to Aspect 16 that is crystalline Form R that is characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 5.0 and 9.9°.

[00291] Aspect 20. The solid state form according to Aspect 19 characterized by an X-ray powder diffraction pattern substantially similar to FIG. 8.

[00292] Aspect 21. The solid state form according to Aspect 16 that is crystalline Form T that is characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 7.0 and 7.8°.

[00293] Aspect 22. The solid state form according to Aspect 21 characterized by an X-ray powder diffraction pattern substantially similar to FIG. 10.

[00294] Aspect 23. The solid state form according to Aspect 16 that is crystalline Form U that is characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 4.8 and 9.8°.

[00295] Aspect 24. The solid state form according to Aspect 23 characterized by an X-ray powder diffraction pattern substantially similar to FIG. 11. [00296] Aspect 25. The solid state form according to Aspect 15 that is a methanol solvate.

[00297] Aspect 26. The solid state form according to Aspect 25 that is crystalline Form K that is characterized by two or more X-ray powder diffraction peaks at 2θ angles (± 0.2°) chosen from 7.5°, 8.4°, 10.0°, 22.4° and 24.2°.

[00298] Aspect 27. The solid state form according to Aspect 26 characterized by an X-ray powder diffraction pattern substantially similar to FIG. 2.

[00299] Aspect 28. The solid state form according to Aspect 25 that is crystalline Form L that is characterized by two or more X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 7.5, 18.6, and 24.2°.

[00300] Aspect 29. The solid state form according to Aspect 28 characterized by an X-ray powder diffraction pattern substantially similar to FIG. 6.

[00301] Aspect 30. The solid state form according to Aspect 15 that is an acetonitrile solvate.

[00302] Aspect 31. The solid state form according to Aspect 30 that is crystalline Form F that is characterized by two or three X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 6.6, 11.5, and 18.5°.

[00303] Aspect 32. The solid state form according to Aspect 31 characterized by an X-ray powder diffraction pattern substantially similar to FIG. 4.

[00304] Aspect 33. The solid state form according to Aspect 15 that is a tetrahydrofuran solvate.

[00305] Aspect 34. The solid state form according to Aspect 33 that is crystalline Form I that is characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 4.7 and 5.0°.

[00306] Aspect 35. The solid state form according to Aspect 34 characterized by an X-ray powder diffraction pattern substantially similar to FIG. 5.

[00307] Aspect 36. The solid state form according to Aspect 15 that is a 2-methyl- tetrahydrofuran solvate.

[00308] Aspect 37. The solid state form according to Aspect 33 that is crystalline Form Q that is characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 5.1, 5.9, 8.7, and 9.2°.

[00309] Aspect 38. The solid state form according to Aspect 37 characterized by an X-ray powder diffraction pattern substantially similar to FIG. 7. [00310] Aspect 39. The solid state form according to Aspect 15 that is a benzy l alcohol solvate.

[00311] Aspect 40. The solid state form according to Aspect 39 that is crystalline Form S that is characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 5.0 and 9.9°.

[00312] Aspect 41. The solid state form according to Aspect 40 characterized by an X-ray powder diffraction pattern substantially similar to FIG. 9.

[00313] Aspect 42. A solid state form of a hydrate of Compound I, wherein Compound I is represented by the formula:

[00314] Aspect 43. The solid state form according to Aspect 1 that is a co-crystal of 4-hydroxy benzoic acid and Compound I.

[00315] Aspect 44. The solid state form according to Aspect 43 that is crystalline Form 17- A that is characterized by X-ray powder diffraction peaks at two or three 2θ angles (± 0.2°) at 5.0, 9.8, and 11.3°.

[00316] Aspect 45. The solid state form according to Aspect 44 characterized by an X-ray powder diffraction pattern substantially similar to FIG. 12.

[00317] Aspect 46. The solid state form according to Aspect 43 that is crystalline Form 17-B that is characterized by two or three X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 6.1, 12.0, and 18.9°.

[00318] Aspect 47. The solid state form according to Aspect 46 characterized by an X-ray powder diffraction pattern substantially similar to FIG. 13.

[00319] Aspect 48. The solid state form according to Aspect 1 that is a co-crystal of 3,4-dihydroxy benzoic acid and Compound I. [00320] Aspect 49. The solid state form according to Aspect 48 that is crystalline Form 23 -A that is characterized by two or three X-ray powder diffract on peaks at 2θ angles (± 0.2°) at 5.6, 12.8 and 17.8°.

[00321] Aspect 50. The solid state form according to Aspect 49 characterized by an X-ray powder diffraction patern substantially similar to FIG. 14.

[00322] Aspect 51. The solid state form according to Aspect 48 that is crystalline Form 23-B that is characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 4.9, 9.8, and 11.2°.

[00323] Aspect 52. The solid state form according to Aspect 51 characterized by an X-ray powder diffraction patern substantially similar to FIG. 15.

[00324] Aspect 53. The solid state form according to Aspect 48 that is crystalline Form 23-C that is characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) at 5.6, 6.2, and 12.0°.

[00325] Aspect 54. The solid state form according to Aspect 53 characterized by an X-ray powder diffraction patern substantially similar to FIG. 16.

[00326] Aspect 55. The solid state form of any one of Aspects 1-54, wherein the solid state form is at least 60 wt.% a single crystalline form, at least 70 wt.% a single crystalline form, at least 80 wt.% a single crystalline form, at least 90 wt.% a single crystalline form, at least 95 wt.% a single crystalline form, or at least 99 wt.% a single crystalline form.

[00327] Aspect 56. The solid state form of any one of Aspects 9-55, wherein solid state form has a chemical purity of at least 60 wt.%, at least 70 wt.%, at least 80 wt.%, at least 90 wt.%, at least 95 wt.%, or at least 99 wt.%, as measured by HPLC.

[00328] Aspect 57. A solid state form of Compound I that is represented by the formula:

wherein the solid state form is amorphous.

[00329] Aspect 58. A pharmaceutical composition comprising a solid state form of any one of Aspects 1-57, and a pharmaceutically acceptable excipient.

[00330] Aspect 59. A solid dispersion comprising an amorphous solid state form of Compound I that is represented by the formula:

[00331] Aspect 60. A spray -dried solid dispersion comprising an amorphous solid state form of Compound I that is represented by the formula:

[00332] Aspect 61. A pharmaceutical composition comprising a solid dispersion comprising a compound that is 3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2-phenyl-5- (pyridin-2-ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one (Compound I) and a pharmaceutically acceptable excipient.

[00333] Aspect 62. The pharmaceutical composition according to Aspect 61, wherein the solid dispersion further comprises a polymer.

[00334] Aspect 63. The pharmaceutical composition according to Aspect 62, wherein the polymer is a water soluble polymer.

[00335] Aspect 64. The pharmaceutical composition according to any one of Aspects 62-63, wherein the polymer is a cellulosic polymer. [00336] Aspect 65. The pharmaceutical composition according to Aspect 61 or 62, wherein the solid dispersion comprises a polymer selected from cellulose ethers, cellulose esters, cellulose co-carboxy esters, cellulose phthalates, cellulose succinates, or mixtures thereof.

[00337] Aspect 66. The pharmaceutical composition according to Aspect 61 or 62, wherein the solid dispersion comprises a polymer selected from methylcellulose (MC); ethylcellulose (EC); hydroxy ethylcellulose (HEC); hydroxypropyl methyl cellulose (HPMC) such as HPMC 606 or HPMC E5; hydroxypropyl cellulose (HPC); carboxymethyl ethyl cellulose (CMEC); hydroxypropyl methyl cellulose acetosuccinate (HPMCAS) such as HPMCAS/SLS, HPMCAS AS-MF, HPMCAS-HF; hydroxypropyl methyl cellulose phthalate (HPMCP); cellulose acetate phthalate (CAP); cellulose acetate groups having at least a half of cellulose acetate in hydrolyzed form; polyviny lpyrrolidone such as PVP K-12, PVPVA, PVP K 29/32, or PVPVA 64; poly oxy ethylene-poly oxypropylene copolymers; polyvinylacetate (PVAc); poly(2-vinyl pyridine) (P2VP), TPGS, copovidone; cellulose acetate (CA); cellulose acetate butyrate (CAB); 5-carboxypentyl hydroxypropyl cellulose (CHC); polyacrylic acid (PAA); carboxymethylcellulose derivatives such as carboxymethyl cellulose (CMC) or carboxymethyl cellulose acetate butyrate (CMCAB); hydroxypropylmethylphthalate (HPMP); hydroxypropylmethylphthalate acetate succinate (HPMPAS); Eudragit EPO; Eudragit E-100; cellulose acetate adipate (CAAdP); cellulose acetate suberate (CASub); methylcellulose adipate (MCAd); cellulose acetate butyrate sebacate (CAB Seb); cellulose acetate butyrate suberate (CAB Sub); cellulose acetate sebacate (CASeb); cellulose acetate phthalate (CAPhth); cellulose succinate (CS); cellulose acetate butyrate suberate (CABSu); HPCPenl06-AA-H-Hydroxypropyl pent-4-enyl cellulose; HPC-SSL; HP-β-CD; or mixtures thereof.

[00338] Aspect 67. The pharmaceutical composition according to any one of Aspects 61-66, wherein the solid dispersion is a spray dried dispersion.

[00339] 68. The pharmaceutical composition of any one of Aspects 61-67, wherein Compound I is present in a substantially amorphous solid state form in the solid dispersion.

[00340] 69. A method of treating cancer in a subject, comprising administering to the subject an effective amount of the solid state form of any one of Aspects 1-60 or the pharmaceutical composition of any one of Aspects 61-69.

[00341] Aspect 70. The method of Aspect 69, wherein the cancer comprises a solid tumor. [00342] Aspect 71. The method of Aspect 69, wherein the cancer is selected from lung cancer, pancreatic cancer, cancer of the esophagus, lymphoma, or mesothelioma.

[00343] Aspect 72. The method of any one of Aspects 69-71, further comprising administering a therapeutically effective amount of an additional therapeutic agent.

[00344] Aspect 73. The method of Aspect 72, wherein the additional therapeutic agent is a taxane such as docetaxel, paclitaxel, or nab-paclitaxel.

[00345] Aspect 74. The method of Aspect 72, wherein the additional therapeutic agent is a platinum-based chemotherapeutic such as cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetra nitrate, phenanthriplatin, picoplatin, or satraplatin.

[00346] Aspect 75. The method of Aspect 72, wherein the additional therapeutic agent is a DNA synthesis inhibitor such as gemcitabine.

[00347] Aspect 76. The method of Aspect 72, wherein the additional therapeutic agent is nab-paclitaxel and gemcitabine.

[00348] Aspect 77. The method of Aspect 76, wherein the cancer is pancreatic cancer.

[00349] Aspect 78. The method of any one of Aspects 72-77, wherein the solid state form and the additional therapeutic agent are administered concurrently.

[00350] Aspect 79. The method of any one of Aspects 72-77, wherein the solid state form and the additional therapeutic agent are administered sequentially.

[00351] Aspect 80. Use of a solid state form according to any one of Aspects 1-60 or the pharmaceutical composition of any one of Aspects 61-66 for the manufacture of a medicament for treating cancer.

[00352] Aspect 81. The use of Aspect 80, wherein the cancer comprises a solid tumor.

[00353] Aspect 82. The use of Aspect 80, wherein the cancer is lung cancer, pancreatic cancer, cancer of the esophagus, lymphoma, or mesothelioma.

[00354] Aspect 83. The solid state form of Compound I according to any one of Aspects 1-60 or the pharmaceutical composition of any one of Aspects 61-66 for treating cancer, wherein the solid state form or the pharmaceutical composition is optionally used in combination with an additional therapeutic agent.

[00355] Aspect 84. The solid state form of Compound I or pharmaceutical composition according to Aspect 83, wherein the cancer comprises a solid tumor. [00356] Aspect 85. The solid state form of Compound I or pharmaceutical composition according to Aspect 83 or 84, wherein the cancer is selected from lung cancer, pancreatic cancer, cancer of the esophagus, lymphoma, or mesothelioma.

[00357] Aspect 86. The solid state form of Compound I or pharmaceutical composition according to any one of Aspects 83-85, wherein the additional therapeutic agent is a taxane such as docetaxel, paclitaxel, or nab-paclitaxel.

[00358] Aspect 87. The solid state form of Compound I or pharmaceutical composition according to any one of Aspects 83-85, wherein the additional therapeutic agent is a platinum-based chemotherapeutic such as cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetra nitrate, phenanthnplatin, picoplatin, or satraplatin.

[00359] Aspect 88. The solid state form of Compound I according to any one of Aspects 1-60 or the pharmaceutical composition of any one of Aspects 61-66, wherein the additional therapeutic agent is a DNA synthesis inhibitor such as gemcitabine.

[00360] Aspect 89. A method of treating disease in a subject wherein the disease is responsive to inhibition of methionine adenosyltransferase 2A (MAT2A) comprising administering to the subject an effective amount of a solid state form of Compound I according to any one of Aspects 1-60 or the pharmaceutical composition of any one of Aspects 61-66.

[00361] Aspect 90. A process for preparing a solid dispersion of Compound I comprising combining a solid state form of any one of Aspects 1-60 with a polymer and a solvent to form a mixture; and spray-drying the mixture to produce the solid dispersion; wherein the solid dispersion comprises Compound I in a substantially amorphous form.

[00362] Aspect 91. The process of Aspect 90, wherein the mixture is an emulsion, solution, or suspension.

[00363] Aspect 92. A product produced by the process of Aspect 90 or 91.

[00364] Aspect 93. A process for preparing the amorphous solid state form of Compound I of Aspect 57, comprising dissolving a crystalline form of Compound I of any one of Aspects 1-60 in a solvent to form a solution and producing the solid state form that is amorphous Compound I from the solution.

[00365] Aspect 94. The process according to Aspect 93, wherein the solvent is benzyl alcohol. [00366] Aspect 95. The process according to Aspect 93 or 94, comprising precipitating the amorphous form from the solution.

[00367] Aspect 96. The process according to Aspect 95, wherein the solution is heated to a temperature that is above 20 °C, such as about 50-70°C.

[00368] Aspect 97. The process according to Aspect 95 or 96 wherein the precipitation is performed at a solution temperature that is about room temperature or lower, such as a temperature of about -20-15°C.

[00369] The invention is illustrated by the following examples, which are not intended to be limiting.

[00370] Exemplifications

[00371] As depicted in the Examples below, crystalline and amorphous forms are prepared according to the following general procedures.

[00372] As described in greater detail in the following paragraphs, it has now been found that the crystalline anhydrous free form of Compound I has supenor properties relative to the solvated and other salt forms of the compound.

[00373] The solid state screening studies described herein included numerous experiments and explored various crystallization modes, solvents, and temperatures (5-40°C). These efforts non-solvated forms, hydrates, solvates, salts and co-crystals of Compound I. Of these solid state forms, the anhydrous Form D was found to be superior. Forms D and K-C of Compound I stood out as leading crystalline salt forms with sharp XRPD peaks, although Form D was found to be more stable than Form K-C in competitive ripening studies in several organic solvents. Good crystallinity of drug substance typically translates to better physical and chemical stability and is therefore a desirable characteristic of an active pharmaceutically ingredient (API). Moreover, the thermogravimetric analysis (TGA) data reflects negligible weight loss for Form D of Compound I, therefore indicating minimal residual solvents and an anhydrate polymorph, which is often preferred over solvated I hydrated forms for oral solid dosage form development. The differential scanning calorimetry data further indicates one sharp melting endotherm prior to decomposition, indicates a low likelihood of polymorphic changes and low possibility of phase transformations that are often undesirable from the perspective of physical stability of the API.

[00374] Thermodynamic stability studies using slurry competition experiments indicated that Form D of Compound I is the more thermodynamically stable form identified to date. [00375] The relatively clean DSC profile with the sharp melting endotherm for Form D of Compound I, coupled with excellent thermodynamic properties and low hygroscopicity, is an indication of reliable solid state properties of this particular solid state form from the perspective of physical stability and suitability of oral solid dosage form development. Moreover as anhydrous form there was no concerns with additional solvents during the formulation development of Form D.

[00376] Provided herein are various solid state forms of the compound referred to herein as Compound I which include particular solvated forms, salt forms, anhydrous forms and amorphous forms of Compound I.

Example 1 -Abbreviations, Solutions, Instruments, Synthesis of Compound I

[00377] Typical abbreviations used are outlined below.

Table 39. Abbreviations

[00378] Solutions

[00379] FaSSGF/SGF (Fast State Simulated Gastric Fluid)

[00380] Weigh 100 mg of sodium chloride into a 50-mL volumetric flask. Add appropriate volume of purified water and sonicate until all solids are completely dissolved. Add sufficient purified water closely to the target volume and adjust to pH 1.6. Weigh 3 mg of FaSSIF/FeSSIF/FaSSGF powder into the volumetric flask and sonicate until the powder is completely dissolved. Dilute to target volume with purified water and mix well.

[00381] FaSSIF (Fast State Simulated Intestinal Fluid)

[00382] Weigh 0. 170 g of monobasic sodium phosphate, 0.021 g of sodium hydroxide and 0.31 g of sodium chloride into a 50-mL volumetric flask. Add appropriate volume of purified water and sonicate until all solids are completely dissolved. Add sufficient purified water closely to the target volume and adjust to pH 6.5. Weigh 110 mg of FaSSIF/FeSSIF/FaSSGF powder into the volumetric flask and sonicate until the powder is completely dissolved. Dilute to target volume with purified water and mix well.

[00383] FeSSIF (F ed State Simulated Intestinal Fluid)

[00384] Weigh 0.41 mL of glacial acetic acid, 0.202 g of sodium hydroxide and 0.594 g of sodium chloride into a 50-mL volumetric flask. Add appropriate volume of purified water and sonicate until all solids are completely dissolved. Add sufficient purified water closely to the target volume and adjust to pH 5.0. Weigh 560 mg of FaSSIF/FeSSIF/FaSSGF powder into the volumetric flask and sonicate until the powder is completely dissolved. Dilute to target volume with purified water and mix well.

Example 2 - Base Compound I Materials

[00385] Two samples of Compound I, i.e., Form A and Form A2, were utilized as described herein. Both samples were prepared using the free base of Compound I as prepared in International Patent Publication No. WO-2018/045071.

[00386] Form A of Compound I, a partially de-solvated solid, was prepared from a MeOH/DCM crystallization of the free base of Compound I, followed by a MeOH/water wash. This sample was analysed using XRPD, DSC, and TGA. See, FIG. 20 for the XRPD pattern that shows that the solid is crystalline. TGA showed about 1.9% weight loss up to 140 °C. The DSC showed an endothermic event with onset at 183.6 °C followed by an exothermic event with onset at 195.2 °C, which is followed by melting at onset of 328.9 °C. [00387] Form A2 is a mixture of forms, including a dichloromethane solvate form. Form A2 was prepared from a mixture of DCM/t-BuOH/acetonitrile/water that crystallized during the concentration phase. While still a slurry, the material was filtered and washed with acetonitrile. This sample was analysed using XRPD, DSC, and TGA. DSC analysis showed a small endotherm with onset at about 135°C, a very small endotherm with onset at about 175°C immediately followed by a small exotherm, and a sharp melting/ decomposition endotherm with onset at 333.7°C (AHf = 96.5 J/g). TGA-IR analysis showed a weight loss of about 1.8% water and about 5.2% di chloromethane on heating up to 184°C. See, FIGs. XX.

Example 3 - Polymorph and Salt Screenings #1 of Compound I

[00388] The XRPD data were collected using a Rigaku MiniFlex 600. Samples were prepared on Si zero-return wafers. The XRPD parameters are listed in Table 40.

Table 40

[00389] TGA and DSC data were collected using a Mettler Toledo TGA/DSC3+.

Detailed parameters are listed in Table 41.

Table 41

[00390] An Agilent 1220 HPLC was utilized for HPLC analysis and detailed chromatographic conditions for solubility analysis are listed in Table 42.

Table 42

[00391] A. Polymorph Screening

[00392] Polymorph screening experiments were conducted with different solution crystallization and solid transition methods, as listed in Table 43, using Form A of Compound I as disclosed in Example 2.

Table 43. Summary of polymorph screening experiments of Compound I

[00393] XRPD were performed on Forms D, K, H, F, I, L, Q, R, S, T, U, 17-A, 17- B, 23-A, 23-B, 23-C, and A. See, the XRPD patterns in FIGs. 1-16 and 20. TGA/DSC data spectra were obtained for Forms D, A, F, H, I, K, L, Q, R, S, T, U, 17-A, 23-A, and 23-C. See, Table 44 and FIGs. 21, 22, and 24-39. DVS spectra were obtained for Forms D, 17-B, 23-A, and 23-C. See, FIGs. 23 and 40-42.

Table 44. Summary of solid-state characterization of Compound I

[00394] B. Salt Screening

[00395] Several salts of Compound I were prepared as follows:

• 25-30 mg of Compound I was weighed in a 2 mL vial;

• 1 equivalent of the respective counter-ion was added to the respective vial;

• 5 vol distilled water was added to the respective vial; • The vial was stirred at room temperature for about 1 hour;

• The vial was placed in a vacuum oven (50 °C) for over-night;

• 300 pL solvent was added into the vial;

• The vial solution was heated to 40 °C and retained at that temperature for 1 hour;

• The vial solution was cooled to room temperature and held at that temperature for 2 days, i. e. , over the weekend;

• The wet solids were collected;

• The XRPD of the wet solids was obtained;

• The wet solids were dried at 50 °C for a few hours;

• The XRPD of the dry solids was obtained;

• The dry solids were humidified at a high relative humidity for greater than 12 hours;

• The XRPD of the humidified solid was obtained.

[00396] See, Table 45 for a summary of the salt screening results.

Table 45

[00397] The XRPD of each sample was obtained. See, FIGs. 17A-17E, 18-A-18E, and 19A-19F. DSC were run on each sample and TGA on certain samples as detailed in Table 46. See, FIGs. 43-54.

Table 46. Summary of characterization of different salts

Example 4 - Polymorph Screenings #2

[00398] Additional experiments were conducted and resulted in two solid state forms of Compound I. Form B-K was prepared by temperature-cycled ripening (TC), rapid cooling (RC), or slow evaporation (EV) using Form A2 of Compound I. The temperature cycled ripening included cycling slurries of Compound I in a solvent at 5-40 °C for four days. Rapid cooling included heating slurries containing a solvent and Compound to 40°C followed by hot filtration, then storing the solutions at 5°C for three days. Slow evaporation included evaporating solutions containing Compound I in a solvent at room temperature for up to 21 days, followed by rapid evaporation of remaining solutions under reduced pressure. See, Table 47 for the solvents and crystallization techniques.

Table 47

[00399] The XRPD data were collected using a PANalytical X’Pert Pro diffractometer using Ni-filtered Cu Kα (45 kV/40 mA) radiation and X'celerator™ RTMS (Real Time Multi-Strip) detector. Configuration on the incidental beam side: 0.04 rad Soller slits, anti-scatter slit (0.25°), and 10 mm beam mask. Configuration on the diffracted beam side: fixed divergence slit (0.25°) and 0.04 rad Soller slit. Samples were mounted flat on zero-background Si wafers.

[00400] DSC was conducted with a TA Instruments Q100 or Q-2000 differential scanning calorimeter equipped with an autosampler and a refrigerated cooling system under 40 mL/min N₂ purge. DSC thermograms were obtained at 10°C/min or 15°C/min in crimped Al pans.

[00401] TGA thermograms were obtained with a TA Instruments Q50 or Q500 thermogravimetric analyzer under 40 mL/min N₂ purge at 10°C/min or 15°C/min in Al pans.

[00402] Form K-C was prepared by heating Compound I at 15°C/minute to 225°C. Form K-C was found to be a crystalline non-solvated form. See, the XRPD pattern in FIG. 55 which showed crystalline features. DSC analysis showed a single sharp melting endotherm with onset at 330.6°C. TGA analysis showed negligible (0.2%) weight loss prior to melting/ decomposition. See, FIG. 56.

Example 5 - Salt Screening #2

[00403] Additional screening experiments were conducted in an effort to isolate the salts of Compound I in Table 48 using various bases.

Table 48

[00404] The XRPD data were collected using a X-ray spectrometer, scan of 3.0/45.0/0.02/0.6(sec), Cu(30kV,15mA), I(max)=1784. See, the XRPD patterns in FIGs. 57, 60, 63, and 66 for Forms Li-W, Na-W, K-W, and Ca-W, respectively.

[00405] DSC was conducted using a Q200 V24.4 Build 116 spectrometer by TA instruments using a ramp method. See, the DSC thermograms in FIGs. 58, 61, and 64, respectively.

[00406] TGA thermograms were obtained using a Q500 V20. 13 Build 39 instrument by TA instruments and ramp of 20 °C per minute to 600 °C. See, the TGA thermograms in FIGs. 59, 62, and 65, for Forms Li-W, Na-W, and K-W, respectively.

[00407] A. Lithium Salt Form Li-W

[00408] The lithium salt was prepared as follows:

[00409] XRPD, DSC, and TGA spectroscopy were performed on this sample. See,e.g., FIGs. 57-59.

[00410] B. Sodium Salt Form Na-W

[00411] The sodium salt form Na-W was prepared as follows:

[00412] XRPD, DSC, and TGA spectroscopy were performed on this sample. See, e.g., FIGs. 60-62.

[00413] C. Potassium Salt Form K-W

[00414] The potassium salt Form K-W was prepared as follows:

[00415] XRPD, DSC, and TGA spectroscopy were performed on this sample. See, e.g., FIGs. 63-65.

[00416] D. Calcium Salt Form Ca-W

[00417] The calcium salt was prepared adding calcium hydroxide (1.05-1.15 equivalents) to a 0.5 mL of solution of Compound I in DCM/MeOH (3:2, 9.79 mg, 0.02 mmol), with continuous stirring at 40 °C overnight. Solutions were then filtered and the solid dried to provide Form Ca-W of Compound I. XRPD was performed on this sample. See, FIG. 66.

Example 6 - Thermodynamic Stabilit Studies

[00418] The thermodynamic stability relationship between typical experimental procedures are described below.

[00419] Four solvent systems were selected for competitive slurry at two different temperatures. The solvents were isopropanol, ethyl acetate, DCM:MeOH (3:2 vol), and water:DMSO (9: 1 vol). The temperatures were 23 °C and 50 °C for all samples with the exception of DCM:MeOH which was at 35 °C. All the solvents were initially saturated by slurring Form A at the temperatures noted in Table 49 for about 2 hours. The stir bars were then removed and the vial retained at the target temperature allowing the solid to settle. The saturated supernatant was then transferred into a new empty vial, which already had been heated to the target temperatures on hot plate. Each sample was the added (a tip of spatula; about 3-5 mg of each) to the saturated solution. The solid mixture was slurried using a stir bar and the first sample was taken after 2 days of slurry and then again after 4 days.

Table 49

[00420] Free base Form D was determined to be the thermodynamically more stable form among the forms identified to date.

Example 7 - Solubility Studies for Salt Screen #1

[00421] Sodium, potassium and calcium salt forms prepared as described herein were analyzed to evaluate their solubility. Various salts were slurried in water, fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF) at 37 °C for 2 days. Then the stir bars were removed and allowed the solid to settle at 37 °C. The relatively clear supernatant was withdrawn by syringe and filtered through a 0.4 μm syringe filter. The resulting clear solution was analyzed by HPLC without further dilution. The results are presented in Tables 50 and 51.

Table 50

Table 51

[00422] All salts converted completely or partially to Pattern D. The solubilities were not also significantly higher than the free form Pattern D.

Example 8 - Hygroscopicity Studies

[00423] All co-crystals and salts were exposed to 75% relative humidity at 40 °C for 1 week. The procedure included the following:

• adding about 20-30 mg of each sample to a 4 mL vial;

• covering the vial with one layer of a Kimwipe tissue, which was then taped to the external wall of the vial;

• the vial was then placed in a 20 mL vial which contained saturated sodium chloride slurry;

• the 20 mL vial was capped and placed on a 40 °C hot plate.

[00424] All samples remained unchanged with the exception of co-crystal 17B which lost some of its crystallinity.

Example 9 - Solubility Studies for Salt Screen #2

[00425] A slurry of potassium salt Form K-W of Compound I in water, FaSSIF, FeSSIF, and FaSSGF was stirred and filtered by syringe filter (VWR, PTFE, 0.45 μm). The solubility was analyzed by HPLC. The results of the aqueous solubility are presented in Table 52. The solubility in FaSSIF, FeSSIF, and FaSSGF are presented in Table 53.

Table 52. The aqueous solubility of Form K-W

Table 53. The solubility of Form K-W in FaSSIF, FeSSIR, and FaSSGF

Example 10 - Cooling Crystallizations

[00426] Cooling crystallization were conducted in solvent systems. See, Table 54. For slow cooling, the solution was cooled from 60 °C to 23 °C at a 5 °C per hour cooling rate. If no solid was obtained at room temperature then the solution was further cooled to 5 °C using a jacketed block connected to bath circulator. The slow cooling crystallization from benzyl alcohol resulted in amorphous sticky solid. Drying of this solid also showed no crystallinity.

Table 54

[00427] For fast cooling experiments, the API was dissolved in the solvent 60 °C and then the vial was placed in ice bath at once to rapidly cool the solution. See, Table 55. If the solid was not precipitated within about 1 hr, it was transferred to a -20 °C freezer.

Table 55

Example 11 - Amorphous Solid Dispersion of Compound I

[00428] A spray-dried dispersion of Compound I and a polymer as described herein is prepared. A solution of a crystalline solid state form of Compound I and the polymer in a volatile solvent is spray dried using, e.g., a Buchi B-290. After spray drying, the solid dispersion is dried overnight at an elevated temperature to remove residual solvent to provide the amorphous solid dispersion of Compound I.

Example 12 - Competitive Slurry of Various Forms

[00429] Four solvent systems were selected for competitive slurry at two different temperatures. The solvents were isopropanol, ethyl acetate, DCM:MeOH (3:2 vol), WaterDMSO (9: 1 vol) and the temperatures were 23 °C and 50 °C. However, the higher temperature for DCM:MeOH system was at 35 °C. All the solvents were initially saturated by slurring Pattern A at the target temperatures for about 2 hours then the stir bars were removed and kept the vial at the target temperature allowing the solid to settle. Then, the saturated supernatant was transferred into new empty vials which were already heated to the target temperatures on hot plate. Then a tip of spatula of samples of Forms A, B, C, D, E, F, G, H, I, J, K, M, L, M, P, Q, R, S, T, and U were added (3-5 mg of each) to these saturated solutions. The solid mixture was slurried using stir bar and the first sample was taken after 4 days of slurry.

[00430] After 4 days, the product of each sample was obtained and an XRPD pattern was obtained. See, Table 56.

I l l

Example 13 - Routes to Compound I

[00431] A. Route Al Overall Scheme

Scheme 1

[00432] As shown below, the step from INT-l/INT-2 to INT-3 is scalable and delivers better yield and purity over the processes in the art. Further, the use of NaOt-Bu in the final step, i.e., deprotection of methyl group, was an improvement over HC1 deprotection; the latter conditions providing genotoxic impurities that were difficult to remove.

[00433] Procedure Al : Condensation

[00434] To a reactor containing tributylamine (24.4 g, 132 mmol) at 150°C was charged 4-(cyclohex-l-en-l-yl)-3-phenyl-lH-pyrazol-5-amine (30.00 g, 125 mmol) and dimethyl 2-(4-methoxyphenyl)mal onate (38.8 g, 163 mmol). Once the solids dissolved and the reaction warmed back to 150°C, this temperature was maintained for 2.25 hours and then was cooled to 25°C over a 20 min period. N,N-Dimethylacetamide (180 mL) was charged to the reactor over a 20 min period and the solution was stirred at 25°C overnight. Water (45 mL) was added to the amber brown solution over a 3 hour period. The reaction was warmed to 30°C and filtered to remove fine black particulates. The filtrate was added back to the cleaned reactor and the temperature was adjusted to 25°C. Seed crystals of the product (150 mg) were added and the mixture was cooled to 20°C over a 30 min period and held for 2 hours. During this time, solid came out. More water (145 mL) was added over an 8 hour period and held at 20°C for another 8 hours. The suspension was filtered, washed with 1 : 1 DMA:water (60 mL), water (3x 60 mL) and MTBE (3x 120 mL) in succession and then dried in a 50°C vacuum oven overnight to collect 52. 17 g (69.5%) of a white solid.

[00435] Procedure Bl: Chlorination

[00436] To a reactor was charged INT-3 (46.95 g, 78 mmol) followed by phosphorus oxychloride (50.6 ml, 541 mmol) at 25°C. The mixture was stirred at 25°C for 30 min and then was heated to near reflux (105°C) for 20 hours. The temperature was cooled to 25°C. The reaction was concentrated by distillation at 55°C under vacuum (-120 Torr) to 71- 94 mL. Toluene (141 mL) was added and the reaction was concentrated to 95-141 mL reaction volume). More toluene (141 mL) was added and the reaction was concentrated to 95- 141 mL. The reaction was cooled to 0°C and methanol (50 mL) was added slowly while keeping the temperature ≤2.5°C. The reaction, a suspension, was stirred for 1 hour at 0°C, filtered and slurry-washed with methanol (2x 50 mL). The collected solid was air-dried under vacuum suction for 30 min and then moved to a 50°C vacuum oven overnight to recover a yellow solid that weighed 33.04 g, 93.6% yield, 97.0% purity).

[00437] Procedure Cl: Methoxylation

[00438] To a reactor was charged INT-4 (30.0 g, 66.6 mmol) and DCM (395 mL).

The mixture was stirred until a solution formed and then was cooled to -10°C for 10 min. A solution of NaOMe in MeOH (24.3%, 21.94 mL, 93 mmol) was added dropwise to the reaction while keeping the temperature below -5.0°C. The solution was stirred for 3 h at - 10°C. When complete, a mixture of acetic acid (1.91 m, 33.3 mmol) and DCM (15.01 mL) was added at -10°C and the reaction was warmed to 10°C. Water (75 mL) was added to the reaction and the mixture was stirred for 20 min. The layers were separated and the aqueous was removed. Repeat once. The organic layer was concentrated under vacuum to 120 mL. Seed (330 mg, 1 wt%) was added and the organic layer was concentrated further to 75 mL. The solvent was exchanged with MTBE (132 mL) and was concentrated to 60-90 mL under vacuum and was repeated once. More MTBE was added to bring the total volume to 200 mL. The mixture was stirred and warmed to 40°C for 1 hour and then was cooled over a 3 hour period to 20°C. The suspension was stirred for 1-12 h, filtered, washed with MTBE (50 mL) and dried in a 50°C vacuum oven overnight to obtain a light yellow solid weighing 28.38 g (95.5%).

[00439] Procedure DI: Pd-mediated amination to prepare Compound I

[00440] To a reactor was charged INT-5(1 wt), 2-aminopyridine (INT-6, 1.5 equiv), palladium(II) acetate (0.20 equiv), xantphos (0.20 equiv) and K₂CO₃ (2.0 equiv). The reactor was evacuated carefully and flushed with nitrogen (3x). 2-Methyltetrahydrofuran (10.7 vol) was added and the reaction mixture was warmed to 80°C within 20 min. After 2-3 h, the reaction was complete (int-5 <1%, mix of INT-7 and Compound I). The mixture was cooled to 20°C, NaOt-Bu (2.2 equiv) and water (2.17 equiv) was added and the reaction was rewarmed to 80°C and held for 1.5-3 h until complete (INT-7 <6%). The mixture was cooled, treated with aqueous citric acid (0.375 M, 17 vol) to pH 6-7, stirred at 20°C for 3 h and filtered. The wet cake was slurried and filtered in succession with 1:1 MeOH: water (8 vol), MeOH (6.4 vol) and 2-MeTHF (7 vol). DCM (50 vol) at 25-30°C was added and the suspension was warmed to 35°C to form a solution and then was concentrated to 15 vol. More DCM (34 vol) and MeOH (7 vol) was added and the suspension was warmed to 35°C to form a solution. Activated carbon (0.2 wts) was added. The slurry was stirred at 35°C for 3 h and then was filtered over Celite (0.22 wts) at 35°C. The filter cake was washed with DCM (9 vol) and the combined filtrates were concentrated to 5 vol at 15°C. The ratio of DCM:MeOH was assessed by GC and was adjusted with either DCM or MeOH to make the ratio 1:1. The suspension was cooled to 15°C, stirred for 5 h and isolated by filtration. This is the DCM solvate. The DCM solvate was re-suspended in EtOAc (12 vol) and was concentrated to 13 vol. More EtOAc (7 vol) was added. The temperature was adjusted to 50°C, stirred for 20 h and monitored by XRPD until the form matches the non-solvated form, and then was filtered and dried in a vacuum oven at 50°C to afford Compound I (89% yield, >99% purity).

[00441] B. Route A2

[00442] As shown below, the formation of INT-3 is higher yielding that the corresponding step in Route Al and replaces uses milder reagents. Further, the starting material for the last step, i.e., INT-9, is a more stable substrate for the Pd chemistry. This provides a higher yield and a much lower Pd load (2% vs. 15%). Thus, the Pd is easier to remove.

Scheme 2

[00443] Procedure A2: Condensation

[00444] To a vessel was added INT-1 (1.0 eq, 1.0 wt), INT-2 (1.5 eq, 1.5 wt), DMAc (5.6 wt) and triethylamine (2.0 eq, 0.86 wt) to produce a solution. This solution was flowed through a 170°C oven with a residence time of 60 min at a rate of 120 mL/min. Upon exiting the oven, the solution was diluted by flowing methanol into the outflow at a rate of 360 mL/min. The mixture was collected in anew' vessel and maintained 45°C until all the material from the first vessel was processed. The mixture was cooled to 30-35°C and then was seeded with 0.1% wt of INT-3 crystals. After stirring for 3 h, the suspension was cooled to 15-20°C and was held for 3 h. The suspension 'as concentrated under vacuum until the MeOH content was ca. 3% and then MTBE (7 wt) and tri ethylamine (0.5 wt) was added. The suspension was stirred at 15-20°C for 3 h, was cooled to 0-10°C and then was held for 4 h at 0-10°C. The suspension was filtered, slurried with MTBE (3.8 wt) for 2 h at 0-10°C, filtered and washed with MTBE (0.60 wt). The wet cake was dried under vacuum at 60-70°C for 24 h to give the product, INT-3, as a triethylamine salt (1.74 wt, 81% yield).

[00445] Procedure B2: Chlorination

[00446] Phosphorus oxychloride (2.7 wt, 9.1 eq) was added to a reactor and was cooled to 10-20°C. INT-3-tri ethylamine salt (1.0 wt) w as added and after stirring for 2 h, a solution formed. The solution was warmed to 100-110°C and was held for 20 h or until residual INT-3 was <0.3%. The mixture was cooled to 20C over 90 min, was concentrated to 2 vol and solvent-exchanged with toluene (2-3x 2.6 wt) until residual phosphorus oxychloride was <3%. The mixture was cooled to 0°C and was treated slowly with methanol (0.78 wt). After stirring at 0C for 1 h, the mixture was filtered and the wet cake was rinsed with methanol (1.77 wt). The wet cake was dried under vacuum for 20 h at 50-60°C to recover 0.79 wt (91%) of INT-4.

[00447] Procedure C2: Methoxylation/Hydrolysis

[00448] A solution of INT-4 (1.0 wt) and THF (9.2 wt) cooled to -10°C was treated dropwise with NaOMe (1.1 eq) and was held at this temperature for 20 h or until residual INT-4 was ≤5.0%. The intermediate, INT-5, was treated with aqueous NaOH (11.0 eq) at -10°C and then the mixture was warmed to 45°C. After stirring for 10 h at 45°C or until residual INT-5 was <1.0% relative to INT-9, additional water (2.1 wt) was added to the reactor at 20°C and was stirred for 1 h. After standing for 2 h, the aqueous layer was removed and 1 N HC1 (1.6 wt) was added over a 2.5 h period. Seed (0.05%) was added to the reactor, which was then cooled to 5°C over a 3 h period. Water (15 wt) was added dropwise over a 5 h period and the suspension was stirred at 5°C for 20 h. The suspension was filtered and washed with isopropyl acetate (2x 1.8 wt). The wet cake was transferred to a reactor under nitrogen, THF (22 wt) was added and the mixture was concentrated to 3-4 vol. More THF (31 wt) was added. The mixture was warmed to 45°C and was stirred for 3 h to give a solution. Half of the solution was polish-filtered into another reactor and was concentrated to 7-8 vol. Seed (0.41 wt) was added, the suspension was stirred at 18°C for 3 h and was concentrated to 2-3 vol. The remaining half of the solution from the first reactor was transferred to the second reactor and the suspension was concentrated to 6-8 vol. The suspension was w armed to 65- 70°C, held for 1 h and then was concentrated to 2-3 vol while keeping the temperature below 35°C. MTBE (4.3 wt) was added over 3 h and then the temperature was cooled to 15-20°C and was held for 8 h. The suspension was filtered, was washed with MTBE (2x 1.4 wt) and was dried under vacuum at 60-70°C for 25 h or until constant weight was achieved to give the product, INT-9, as a white solid (84%).

[00449] Procedure D2: Pd-mediated amination to prepare Compound I

[00450] To a reactor was charged o-xylene (6.8 wt) and the solvent was degassed with nitrogen. The remaining reactants INT-9 6 (1.0 eq), INT-6 (0.23 wt, 1.5 eq), palladium acetate (0.011 wt, 0.02 eq), BINAP (0.072 wt, 0.05 eq) and sodium tert-butoxide (0.67 wt, 3.0 eq) were charged and the mixture was degassed further. The mixture was heated to 120- 125 °C over a 2 h period and the mixture was maintained at this temperature for 2 h. The mixture was cooled to 25°C and 2-MeTHF (4.4 wt) was added. The mixture was stirred for 2 h at 25°C and then aqueous citric acid (0.38 M, 4.6 wt) was added at 25°C over an 8 h period until the pH = 7. The mixture was held at 25°C for 10 h and then was cooled to 5°C and held for 24 h. The suspension was filtered. 2-MeTHF (12.7 wt) was added, the suspension was slurried at 15°C (removes BINAP by-products) for 4 h and the mixture was filtered to give a wet cake. The wet cake was dissolved in a mixture of DCM (49 wt) and MeOH (8 wt) when warmed to 30-40°C. The solution was concentrated to 5 vol. The DCM/MeOH ratio was assessed and was adjusted to —1/1 DCM/MeOH. The temperature was increased to 40°C and held for 3 h, cooled to 15 -25 °C over 8 h, held for 4 h, and filtered. The wet cake was slurried in 1/1 DCM/MeOH (5.3 wt) for 3 h at 20°C, was cooled to 0-10°C over 2 h, was held for 3 h and was filtered. The wet cake was dried under vacuum at 50°C for 20 h (palladium <10 ppm). Another round of crystallization may be conducted, if necessary, to further reduce the palladium content. The product was suspended in EtOAc (12 vol), concentrated to 4 vol, more EtOAc (10 vol) was added and the suspension was slurried at 50°C for 18 h until the form matched the target polymorph form B. The suspension was cooled to 25°C, filtered and dried under vacuum at 55-60°C for 48 h to obtain a crystalline solid (0.79 wt, 70% yield).

[00451] C Route B

[00452] This route has several advantages over those in the art and Routes Al and A2 described above. As shown below, Route B is one step shorter, potentially higher yielding, easier chemistry, and less expensive than other routes in the art. Further, this route lacks palladium, thereby eliminating additional steps required to remove the palladium starting material, as well as impurities produced due to the palladium reagent. This route also provide Compound I in purities generally reaching about 100%.

Scheme 3

[00453] Procedure El: Piv-protection

[00454] To a reactor was added INT-10 (10.00 g, 62.8 mmol) and DCM (80 mL) to a reactor followed by potassium hydroxide (4.5 M, 80 ml, 358 mmol) and then pivalic anhydride (14.14 ml, 69.1 mmol). Once the reaction was complete by HPLC (3 to 15 h), the layers were separated and the aqueous layer was extracted with DCM (2x 30 mL). The combined organic layers were washed with water (2x 50 mL) and then with sat. NaCl (50 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford INT-11 (an off-white solid).

[00455] Procedure Fl: Cyclohexenylation

[00456] The crude solid INT-11 was taken up in 1,4-dioxane (90 ml). Cyclohexanone (18.94 ml, 183 mmol) was added followed by pTsOH hydrate (0.603 g, 3.14 mmol). The solution was stirred at 25°C until the reaction was complete. EtOAc (100 mL) and sat. NaHCO₃ (100 mL) and water (20 mL) were added and the mixture was stirred for 5 min. The layers were separated. The organic layer was separated, washed with sat. NaCl, dried (Na₂SO₄), filtered and concentrated to a thick off-white/light tan solid. The solid was recrystallized as follows: EtOH (130 L) was added, the reactor was warmed to 65°C, held for one hour and cooled to 20°C over a 90 min period. The reactor was cooled to 10°C and was held for 30 min. The white suspension was filtered and rinsed with cold ethanol (~35 mL) and then dried in a 50°C vacuum oven to give 14.23 g (70. 1% yield over two steps).

[00457] Procedure E2: Piv-protection

[00458] To a reactor was charged INT-10 (1.0 eq) and 2-MeTHF (20 vol) at 20°C and the mixture was stirred until a solution formed. The solution was cooled to -10°C. Both LiOt-Bu and Piv₂O were added portion- wise and held before the next addition: LiOt-Bu (0.60 eq) and Piv₂O (0.60 eq), 4-8 h; LiOt-Bu (0.35 eq) and Piv₂O (0.35 eq), 4-8 h; LiOt-Bu (0.10 eq) and Piv₂O (0.10 eq), 2-8 h and, if necessary, LiOt-Bu (0.05 eq) and Piv₂O (0.05 eq), 1-4 h. Once complete, water (5 vol) was added, stirred to mix and the reaction was warmed to 20°C. The organic layer was separated and washed once more with water (5 vol). The organic layer was concentrated (1-2 vol) and diluted with methylcyclohexane (2.0 vol) six times. After the last dilution, the suspension was cooled to 0°C over a 4 h period, held for 2 h, filtered and dried in a 50°C vacuum oven for 10-20 h to obtain an off-white solid (INT-11) in 80% yield.

[00459] Procedure F2: Cyclohexenylation

[00460] To a reactor was charged INT-11 (1.0 eq) and MeCN (7.9 vol). The mixture was stirred to form a solution, which was cooled to 15°C. pTsOH hydrate (0.04 eq.) was added in one portion followed by cyclohexanone (2.5 eq) over a 10 min period. The reaction was stirred at 15°C until complete (4-20 h, <1% INT-11), and then water (10.5 vol) was added over a 2 h period. The suspension was stirred for 2-5 h, filtered and washed with 4:3 MeCN:water (7 vol). The isolated crude solid was suspended in MeCN (12 vol) and warmed to 75°C to form a solution. The solution was cooled to 65°C, seeded, cooled to 25°C over >3 h and held for 2-5 h longer. Water (2.4 vol) was added over a 2 h period. The suspension was stirred at 25°C for 2-5 h, filtered and rinsed with 5: 1 MeCN:water. The wet cake was dried in a 50°C vacuum oven for 10-20 h to obtain INT-12 as a white crystalline solid (>99.5% purity) in 82% yield.

[00461] Procedure A3: Condensation

[00462] To a reactor with a Dean-Stark trap and a condenser above was added INT- 2 (60.0 g, 252 mmol), 2-aminopyridine (23.94 g, 254 mmol) and toluene (252 mL). The suspension was stirred at 20°C until a solution formed, and then was warmed to reflux (~110°C internal) during which time the colorless solution turned yellow. After 23 h, the reaction was cooled to 20°C and filtered. The collected yellow solid is the pyrimidinone (12.8 g) whereas the filtrate is a mixture of INT-2 and INT-15. The filtrate was re-warmed to reflux for 24 h and then was re-cooled to 20°C and held for 15 min before filtration to collect another 18.34 g of pyrimidinone. A third cycle of heating the filtrate to reflux and cooling gave 16.57 g and a fourth cycle gave 8.55 g. The total recovery was 54.20 g (80.2%).

[00463] Procedure Gl: Synthesis of INT-15

[00464] To a reactor was charged the pyrimidinone (40.6 g, 151 mmol) and methanol (240 ml). To this solution was added methanesulfonic acid (10.8 ml, 166 mmol). The reaction was heated to 66-68°C (reflux) and held for 22 h. By HPLC, the product distribution was 4.5% pyrimidinone, 87% INT-15 and 7% INT-2. The reaction was neutralized with aqueous NaHCO₃ and was extracted with MTBE (2x). The combined organic layers were extracted with 2 M HC1 (2x). The combined aqueous layers were washed once with MTBE and then neutralized with 2 M NaOH to pH 7 keeping the temperature below 20°C and then extracted with MTBE (2x). The combined organic layers were washed with brine, dried and filtered. Purity was 96.3% pure. The impurities are the pyrimidinone (2.4%) and INT-2 (1.1%).

[00465] Procedure H: Carboxylation

[00466] A solution of methyl 4-methoxyphenylacetate (3.41 g, 18.3 mmol, 97% purity) in THF (30 mL) cooled to -10°C was evacuated and flushed four times with nitrogen. Added sodium bis(trimethylsilyl)amide in THF (2.0 M, 10.3 mL, 1. 1 eq) at a rate of 0.8 mL/min. The nitrogen line was replaced with a CO₂-filled balloon for 5 min. The reaction was evacuated and flushed with nitrogen (3x), more NaHMDS was added (0.55 eq), and CO2 was re-introduced by balloon. After 5 min, the remaining INT-13, was <10%. Water (40 mL) was added slowly (note: exothermic) and the reaction was warmed to 18°C. MTBE (20 mL) was added, the mixture was stirred for 30 min, and the whole reaction was filtered. The biphasic filtrate was separated and the aqueous layer was acidified to pH 1-2 with concentrated sulfuric acid (2 mL). Methanol (15 mL) was added. After 40 min, INT-14 seeds (a few mg) were added. After 1 h, water (20 mL) was added over 1 h. After 1 h, INT-14 was isolated by filtration and was rinsed with water (15 mL). The collected solid was under vacuum at 40°C to recover 3.0 g (71%) INT-14 as a white solid.

[00467] Procedure G2: Synthesis of INT-15 by Amide Coupling

[00468] To a reactor was added CDI (0.95 eq) and DCM (3.4 vol) and the mixture was cooled to 0°C. A solution of INT-14 (1.0 eq) in DCM (5.5 vol) was added over at least 30 min to the CDI/DCM mixture. The mixture was held at 0°C for at least 2 h, and then 2- aminopyridine (0.95 eq) was added in one portion. The reaction was held at 0°C for at least 12 h and then concentrated to 2 vol. MTBE (5 vol) was added and the new solution was concentrated to 2 vol. This was repeated once. A third portion of MTBE (5 vol) was added and the solution was extracted with water (5 vol) at least four times to remove residual 2- aminopyridine and imidazole. The MTBE solution was azeotropically dried by concentrating to 2 vol and then re-diluting with MTBE (2 vol). The MTBE solution was passed through a silica gel plug, and concentrated (to 3 vol) and re-dissolved in ethanol (5 vol) three times. The ethanolic solution was warmed to 45°C, was cooled to 10°C, and then was charged with INT- 15 seeds. The suspension was stirred at 10°C for at least 1 h, and then heptane (12 vol) was charged over at least 2 h at 10°C. The suspension was cooled to 5°C and then held for at least 12 h. The product was isolated by fdtration and was rinsed with heptane (2x 1 vol). The solids were dried at 40°C under vacuum for at least 10 h to yield a crystalline solid (75%).

[00469] Procedure H: Ketenimine Amination/Deprotection/Cyclization

[00470] A solution of triphenylphosphine oxide (1.20 eq) in DCM (3.3 vol) at 0°C was treated with oxalyl chloride (1.15 eq). After 15 min, a solution of INT-15 (1.54 eq) in DCM (1.4 vol) was added and after 15 min, 4-methylmorpholine (4.62 eq) was added slowly (exothermic) while keeping the temperature below 5°C. A solution of INT-12 (1.0 eq) in EtOAc (13 vol) was added slowly at 0°C, and after 15 min the mixture was warmed to 35°C and held for 24-36 h until residual INT-12 was <5%. The reaction was re-cooled to 0°C and was treated with HC1 in dioxane (4.62 eq). The mixture was held at 0°C for 2 h, was warmed to 20°C and held for at least 8 h, and then was warmed to 40°C for at least 4 h. The reaction was cooled to 2°C, was treated with sodium hydroxide to pH 8 and then was warmed to 35°C and held for 2 h. The crude product, Compound I, was isolated by filtration and was washed with water (2x 5 vol) and then with EtOH (5 vol). The wet cake was slurried in a 4: 1 water: EtOH (7 vol) mixture at 25°C for 1.5 h, was filtered and was washed with EtOH (3.5 vol). The wet cake was dried under vacuum at 50°C for at least 10 h, was re-dissolved in 4: 1

DCM:MeOH (20 vol), polish-filtered, and was concentrated to 10 vol. EtOAc (10 vol) was added and the mixture was concentrated to 10 vol. More EtOAc (5 vol) was added and the mixture was re-concentrated to 10 vol (repeat 4x to exchange DCM and MeOH to EtOAc), which induces Compound I to precipitate. The resulting suspension was warmed to 50°C and was held for at least 18 h to adjust Compound I to the correct polymorph. Once verified by

XRPD, the suspension was cooled to 25°C, filtered, rinsed with EtOAc (2x 1.65 vol) and dried under vacuum at 50°C to recover Compound I (75% yield) as a crystalline solid.

[00471] D. Impurities

[00472] The impurity profiles for Routes A and B were analyses. See, Tables 57 and 58.

[00473] Procedure II: Phosphine oxidation

[00474] To a vial with a stir bar was added xantphos (62.7 mg, 0. 108 mmol), acetonitrile (1 ml), water (0.020 ml, 1.111 mmol) and DMF (0.1 mL). To this suspension was added Selectfluor™ (81 mg, 0.217 mmol) and within minutes a solution formed. The mixture was stirred at 22°C for 16 h. LCMS showed the mass of the only peak is completely 611/612. The solvent was evaporated to a white solid, was re-suspended in water and filtered to obtain xantphos-bis(oxide).

[00475] Procedure 12: Phosphine oxidation

[00476] To a vial was added 2,2'-bis(diphenylphosphanyl)-l,T-binaphthalene (1.000 g, 1.606 mmol), acetonitrile (16 ml) and water (0.319 ml, 17.71 mmol) and Selectfluor™ (1.138 g, 3.21 mmol). This suspension was stirred at 22°C for 3 h. LCMS showed the reaction was complete. The reaction was concentrated, re-suspended in water, sonicated to make a fine powder and filtered. The collected solid was dried in a 50°C vacuum oven overnight to give a fine white powder. Yield -95%.

[00477] Procedure to INT-16

[00478] Step 1 follows procedure G2 except INT-12 is added as the amine. The intermediate is activated to the ketenimine following procedure H and, when complete, the

Piv-deprotection phase in this procedure using HC1 in dioxane is followed which induces the cyclization to INT-16.

[00479] Procedure to INT-17

[00480] INT-17 is the main impurity we see in Compound I during the process but the final purification removes it completely. The first step follows procedure Bl. Step 2 follows D2 to provide INT-17.

[00481] Procedure to INT-21

[00482] Step 1 follows Al, step 2 follows Bl, step 3 follows Cl and step 4 follows DI.

[00483] Procedure to INT-22

[00484] INT-22 is an impurity in the Al and A2 routes.

[00485] Procedure J: Allylic Bromination

[00486] To a flask was charged INT-7 (2.5 g, 5 mmol, 1 eq.), NBS (845 mg, 4.75 mmol, 0.95 eq.) and AIBN (160 mg, 1 mmol, 0.2 eq.) in CCl₄ (40 mL) at 20~25°C. The resulting mixture was stirred for 2 h at 40~45°C. The reaction was monitored by LCMS. The unknown impurity at 1.86 min and the desired bromide at 2.36 min). The reaction mixture was concentrated in vacuum at 40~45°C to get the residue, which was purified by AI₂O₃ column chromatography (eluent: 1/1 DCM/PE) to afford the bromide (550 mg) as a pale yellow solid.

[00487] Procedure K: Elimination

[00488] To a flask was charged the bromide (300 mg, 0.51 mmol, 1 eq.) in DCM (10 mL). To the mixture was added DBU (310 mg, 0.51 mmol, 4.0 eq.) at 20~25°C. The resulting mixture was stirred for 5 h at reflux under nitrogen protection. Once reaction to the desired impurity was observed by HPLC, the reaction mixture was cooled to 20-25°C, diluted with water (10 mL) and separated. The aqueous phase was extracted with DCM (10 mL), washed with brine (10 mL) and concentrated to get 280 mg crude product as a yellow oil, which was purified by prep-HPLC to afford INT-22 (30 mg).

[00489] Procedure to INT-24

[00490] INT-24 is an impurity in the Al and A2 routes. Step 1 follows Al, step 2 follows Bl, step 3 follows Cl and step 4 follows DI. Example 14

[00491] Compound I (2.0 g), polymer (18.0 g) and solvent (9: 1 DCM:MeOH, 200 mL) are mixed at 20-40°C to prepare a solution. The dissolving solvent for Compound I can range from 3: 1 to 9:1 DCM:MeOH.

[00492] A 1: 1 MTBE:heptane mixture (2400 mL) is prepared. The mixture is distributed to three 1 L bottles (800 mL/bottle) and are chilled to 3°C. In a hood, a spray nozzle is mounted above to spray into a 1 L bottle that contains the above solvent mixture and a stir bar. The bottle sits on a stirrer and stirring is initiated to create a vortex. The spray nozzle is attached to a peristaltic pump via a flexible hose. Inert solvents tested that succeeded: heptane, 1: 1 MTBE:heptane, water, and 95:5 w/w water: surfactant (Kolliphor P 188).

[00493] The spraying operation: the peristaltic pump aspirates this solution and feeds it into the spray nozzle which directs the solvent into a fine stream. The stream is directed into the rapidly vortexing solution. Approximately 70 mL of the Compound I/polymer solution is sprayed into each bottle. Once all the solution mixture and a rinse has been directed into the solvent, the stirring is stopped.

[00494] The suspensions are filtered and the white product is dried in a 50°C vacuum oven with a nitrogen stream to reduce the residual solvent levels to below the desired specifications to recover 19.0 g (95.0% recovery).

[00495] Table 59 illustrates the initial loading and actual loading.

Table 59

Example 15

[00496] The compositions of Tables 60A and 60B were prepared by combining the Compound I with the excipients and solvents in the noted amounts. The compositions were then spray dried.

Table 60A

Table 60B

Example 16: Solid Dosage Form

[00497] The current batch formula for Compound I tablets is provided in Table 61. The solid dispersion intermediate of Compound I and hypromellose acetate succinate is manufactured using spray-dry ing. The 25 mg and 100 mg tablets are then manufactured from the solid dispersion intermediate and compendial excipients. The quantities of each component are based on a batch size of 20,000 tablets. The batch size may be modified to meet production needs. Adjustments in batch size will not affect the percent composition of the formulation.

Table 61. Batch Formula for Compound I Tablets (25:75 Compound LHPMCAS SDI)

[00498] Step 1 : Preparation of Compound I Solid Dispersion Intermediate (SDI)

[00499] Weighing, spray-drying, and secondary drying of intermediate:

[00500] Compound I and hypromellose acetate succinate (25/75% w/w) are weighed and dissolved in dichloromethane and methanol and spray-dried to produce amorphous Compound I solid dispersion intermediate (SDI). The SDI is further dried during a secondary drying step.

[00501 ] Step 2: Manufacture of Compound I Tablets. 25 mg and 100 mg

[00502] Weighing and screening intragranular ingredients

[00503] Compound I SDI and all other excipients are weighed and sieved for blending.

[00504] Intragranule Blending

[00505] Compound I SDI is mixed with microcrystalline cellulose, croscarmellose sodium, and sodium stearyl fumarate in a suitable blender.

[00506] Dry granulation/sizing

[00507] The intra-granule blend is roller compacted and the compacted material is screened to produce granules.

[00508] Weighing and screening extragranular ingredients

[00509] Extra-granular microcrystalline cellulose, croscarmellose sodium, and sodium stearyl fumarate are weighed and sieved for blending.

[00510] Extragranule Blending

[00511] The screened granules and extra-granular excipients are added to a suitable blender and blended.

[00512] Compression

[00513] The blend is compressed using a rotary tablet press.

[00514] Solid Dispersion

[00515] Higher drug loading is possible. The 50:50 Compound I:HPMCAS, 35:65 Compound I:HPMCAS SDI and 25:75 Compound I:HPMCAS SDI are particularly suitable ranges for formulation as:

- SDI (Solid Dispersion Intermediate) exhibits improved in vitro dissolution performance relative to bulk crystalline material (see below)

- The formulation demonstrated acceptable physical stability

- The formulations can be manufactured and scaled-up using standard spray dry ing techniques and equipment

[00516] In vitro dissolution performance of SDIs

[00517] Pre-weighed SDI powder is briefly suspended in media (e.g. by 10 sec vortex mixing with 4.0 mL media) and transferred to a pre-heated (37 °C) volume of 50 mL of 0.1N HC1 (aq.) (simulated gastric fluid or SGF, pH ~ 1.0, without pepsin or bile salts), in a USP Type 2 mini-vessel (100 mL total vessel volume) while stirring (paddles) at 100 rpm. After 30 minutes of gastric pH exposure, an equal volume of PBS buffered, 2x concentrated fasted-state simulated intestinal fluid (FaSSIF) is added to the SGF, resulting in a final pH of

6.5-6.8 in FaSSIF (100mM PBS containing 2.24 mg/mL SIF powder (original) (Biorelevant

Inc.) in a total volume of 100 mL. Aliquots (1.0 mL) of dissolution media are taken at selected time-points before and after the simulated gastric transfer, spun-down (13000 rpm) to pellet out undissolved solids, and the supernatant sampled and further diluted in an appropriate diluent to determine API total drug concentration (e.g. free and colloidal/polymer-bound drug in solution) utilizing a suitable HPLC method.

Table 62. HPLC Parameters for Non-Sink Dissolution Sample Analysis

[00518] The data collected are summarized in Table 63.

[00519] Assay and related substances of AG-270 SDI and stability samples were evaluated using an experimental HPLC method for which details are outlined in Table 64.

Table 64. HPLC Parameters

[00520] Solvents/range

[00521] Organic solubility of Compound I was determined by HPLC in varying DCM (dichloromethane):MeOH and other solvent ratios. See, Table 65. Compound I solubility decreased with increasing MeOH content in the spray solution. See, FIG. 67. Solubility was also evaluated with the addition of small amounts of acetone in the hopes of it acting as a co-solvent (HPMCAS polymer is significantly more soluble in acetone than in MeOH or DCM). However due to the low solubility of the API, the addition of acetone was not beneficial, while addition of water did increased solubility.

Table 65

[00522] While API solubility and spray solution viscosity are the main hurdles for increasing the spray solution concentration, by increasing the methanol content of the spray solution 5% (to 85: 15 DCM:MeOH) the % solids can be increased from 7.5 wt% to 8.5 wt% total solids.

[00523] Compound I: HPMCAS in a 90: 10 or 85: 15 DCM :MeOH spray solution were demonstrated to be chemically stable, and visually stable without precipitation up to 7 days with continuous stirring at ambient room temperature, or when held at controlled room temperature of 25°C without stirring.

[00524] While a number of embodiments have been described, the scope of this disclosure is to be defined by the appended claims, and not by the specific embodiments that have been represented by way of example. The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly know n to one with ordinary skill in the art.

Claims

WHAT IS CLAIMED IS:

1. A solid state form of Compound I or a salt thereof, wherein the Compound I is represented by the formula:

2. The solid state form of claim 1 wherein the solid state form is substantially crystalline.

3. The solid state form of claim 2 wherein the solid state form is substantially anhydrous.

4. The solid state form of any one of claims 1-3, wherein the solid state form is of Compound I as a free base.

5. The solid state form of claim 1, wherein the solid state form is of a salt of Compound I.

6. The solid state form of any one of claims 1-5, wherein the solid state form is at least 60 wt.% of a single crystalline form, at least 70 wt.% of a single crystalline form, at least 80 wt.% of a single crystalline form, at least 90 wt.% of a single crystalline form, at least 95 wt.% of a single crystalline form, or at least 99 wt.% of a single crystalline form.

7. The solid state form of any one of claims 1-5, wherein the solid state form has a chemical purity of at least 60 wt.%, at least 70 wt.%, at least 80 wt.%, at least 90 wt.%, at least 95wt%, or at least 99 wt.%, as measured by HPLC.

8. An anhydrous solid state form of Compound I that is represented by the formula:

9. The solid state form of claim 8 that is crystalline Form D that is characterized by two or more X-ray powder diffraction peaks at 26 angles (± 0.2°) chosen from 7.6°, 10.7°, 19.0° and 23.7°.

10. The solid state form of claim 9 characterized by an X-ray powder diffraction pattern substantially similar to FIG. 1.

11. The solid state form of claim 8 that is crystalline Form K-C that is characterized by two or more X-ray powder diffraction peaks at 20 angles (± 0.2°) chosen from 5.2°, 10.4°, 11.7°, and 26.3°.

12. The solid state form of claim 11 characterized by an X-ray powder diffraction pattern substantially similar to FIG. 55.

13. A solid state form of a basic salt of Compound I, wherein Compound I is represented by the formula:

137

14. The solid state form of claim 13, wherein the basic salt is a sodium salt, a potassium salt, a lithium salt, or a calcium salt.

15. The solid state form of claim 13 or 14, wherein the salt is crystalline or amorphous.

16. A solid state form of a hydrate of Compound I, wherein Compound I is represented by the formula:

17. The solid state form of any one of claims 1-16, wherein the solid state form is at least 60 wt.% a single crystalline form, at least 70 wt.% a single crystalline form, at least 80 wt.% a single crystalline form, at least 90 wt.% a single crystalline form, at least 95 wt.% a single crystalline form, or at least 99 wt.% a single crystalline form.

18. The solid state form of any one of claims 9-16, wherein solid state form has a chemical purity of at least 60 wt.%, at least 70 wt.%, at least 80 wt.%, at least 90 wt.%, at least 95 wt.%, or at least 99 wt.%, as measured by HPLC.

19. A solid state form of Compound I that is represented by the formula:

wherein the solid state form is amorphous.

20. A pharmaceutical composition comprising a solid state form of any one of claims 1-

19, and a pharmaceutically acceptable excipient.

21. A solid dispersion comprising an amorphous solid state form of Compound I that is represented by the formula:

22. A spray-dried solid dispersion comprising an amorphous solid state form of Compound I that is represented by the formula:

23. A pharmaceutical composition comprising a solid dispersion comprising a compound that is 3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-2- ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one (Compound I) and a pharmaceutically acceptable excipient.

24. The pharmaceutical composition of claim 23, wherein the solid dispersion further comprises a polymer.

25. The pharmaceutical composition of claim 24, wherein the polymer is a water soluble polymer.

26. The pharmaceutical composition of any one of claims 24-25, wherein the polymer is a cellulosic poly mer.

27. The pharmaceutical composition of claim 23 or 24, wherein the solid dispersion comprises a polymer selected from cellulose ethers, cellulose esters, cellulose ω- carboxy esters, cellulose phthalates, cellulose succinates, or mixtures thereof.

28. The pharmaceutical composition of claim 23 or 24, wherein the solid dispersion comprises a polymer selected from methylcellulose (MC); ethylcellulose (EC); hydroxyethylcellulose (HEC); hydroxypropyl methyl cellulose (HPMC) such as HPMC 606 or HPMC E5; hydroxypropyl cellulose (HPC); carboxymethyl ethyl cellulose (CMEC); hydroxypropyl methyl cellulose acetosuccinate (HPMCAS) such as HPMCAS/SLS, HPMCAS AS-MF, HPMCAS-HF, HPMCAS-H, HPMCAS-L, HPMCAS-M, HPMCAS 912 HP, HPMCAS 912, or HPMCAS HP-55; hydroxypropyl methyl cellulose phthalate (HPMCP); cellulose acetate phthalate (CAP); cellulose acetate groups having at least a half of cellulose acetate in hydrolyzed form; polyvinylpyrrolidone such as PVP K-12, PVPVA, PVP K 29/32, or PVPVA 64; polyoxy ethylene-polyoxypropylene copolymers; polyvinylacetate (PVAc); polypvinyl pyridine) (P2VP), TPGS, copovidone; cellulose acetate (CA); cellulose acetate butyrate (CAB); 5-carboxypentyl hydroxypropyl cellulose (CHC); polyacrylic acid (PAA); carboxymethylcellulose derivatives such as carboxymethyl cellulose (CMC) or carboxymethyl cellulose acetate butyrate (CMCAB); hydroxypropylmethylphthalate (HPMP); hydroxypropylmethylphthalate acetate succinate (HPMP AS); Eudragit EPO; Eudragit E-100; cellulose acetate adipate (CAAdP); cellulose acetate suberate (CASub); methylcellulose adipate (MCAd); cellulose acetate butyrate sebacate (CAB Seb); cellulose acetate butyrate suberate (CAB Sub); cellulose acetate sebacate (CASeb); cellulose acetate phthalate (CAPhth); cellulose succinate (CS); cellulose acetate butyrate suberate (CABSu); HPCPen106- AA-H-hydroxypropyl pent-4-enyl cellulose; HPC-SSL; HP-β-CD; or mixtures thereof.

29. The pharmaceutical composition of any one of claims 24-28, wherein the molar ratio of Compound I to the polymer is about 25:75 to about 50:50, or optionally about 25:75, or optionally about 35:65, or optionally about 50:50.

30. The pharmaceutical composition of any one of claims 23-29, wherein the solid dispersion comprises HPMCAS.

31. The pharmaceutical composition of any one of claims 23-30, wherein the solid dispersion comprises HPMCAS, microcrystalline cellulose, croscarmellose sodium, and sodium stearyl fumarate.

32. The pharmaceutical composition of any one of claims 23-31, wherein the solid dispersion is a spray dried dispersion or spray-precipitated dispersion, preferably a spray dried dispersion.

33. The pharmaceutical composition of any one of claims 23-32, wherein Compound I is present in a substantially amorphous solid state form in the solid dispersion.

34. A method of treating cancer in a subject, comprising administering to the subject an effective amount of the solid state form of any one of claims 1-19 or the pharmaceutical composition of any one of claims 23-33.

35. The method of claim 34, wherein the cancer comprises a solid tumor.

36. The method of claim 34, wherein the cancer is selected from lung cancer, pancreatic cancer, cancer of the esophagus, lymphoma, or mesothelioma.

37. The method of any one of claims 34-36, further comprising administering a therapeutically effective amount of an additional therapeutic agent.

38. The method of claim 37, wherein the additional therapeutic agent is a taxane such as docetaxel, paclitaxel, or nab-paclitaxel.

39. The method of claim 37, wherein the additional therapeutic agent is a platinum-based chemotherapeutic such as cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetra nitrate, phenanthriplatin, picoplatin, or satraplatin.

40. The method of claim 37, wherein the additional therapeutic agent is a DNA synthesis inhibitor such as gemcitabine.

41. The method of claim 37, wherein the additional therapeutic agent is nab-paclitaxel and gemcitabine.

42. The method of claim 41, wherein the cancer is pancreatic cancer.

43. The method of any one of claims 37-42, wherein the solid state form and the additional therapeutic agent are administered concurrently.

44. The method of any one of claims 37-42, wherein the solid state form and the additional therapeutic agent are administered sequentially.

45. Use of a solid state form of any one of claims 1-19 or the pharmaceutical composition of any one of claims 23-33 for the manufacture of a medicament for treating cancer.

46. The use of claim 45, wherein the cancer comprises a solid tumor.

47. The use of claim 45, wherein the cancer is lung cancer, pancreatic cancer, cancer of the esophagus, lymphoma, or mesothelioma.

48. The solid state form of Compound I of any one of claims 1-19 or the pharmaceutical composition of any one of claims 23-33 for treating cancer, wherein the solid state form or the pharmaceutical composition is optionally used in combination with an additional therapeutic agent.

49. The solid state form of Compound I or pharmaceutical composition of claim 48, wherein the cancer comprises a solid tumor.

50. The solid state form of Compound I or pharmaceutical composition of claim 48 or 49, wherein the cancer is selected from lung cancer, pancreatic cancer, cancer of the esophagus, lymphoma, or mesothelioma.

51. The solid state form of Compound I or pharmaceutical composition of any one of claims 48-50, wherein the additional therapeutic agent is a taxane such as docetaxel, paclitaxel, or nab-paclitaxel.

52. The solid state form of Compound I or pharmaceutical composition of any one of claims 48-51, wherein the additional therapeutic agent is a platinum-based chemotherapeutic such as cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetra nitrate, phenanthriplatin, picoplatin, or satraplatin.

53. The solid state form of Compound I of any one of claims 1-19 or the pharmaceutical composition of any one of claims 23-33, wherein the additional therapeutic agent is a DNA synthesis inhibitor such as gemcitabine.

54. A method of treating disease in a subject wherein the disease is responsive to inhibition of methionine adenosyltransferase 2A (MAT2A) comprising administering to the subject an effective amount of a solid state form of Compound I of any one of claims 1-19 or the pharmaceutical composition of any one of claims 23-33.

55. A process for preparing a solid dispersion of Compound I comprising combining a solid state form of any one of claims 1-19 with a polymer and a solvent to form a mixture; and spray-drying or spray-precipitating the mixture to produce the solid dispersion; wherein the solid dispersion comprises Compound I in a substantially amorphous form.

56. The process of claim 55, wherein the mixture is an emulsion, solution, or suspension.

57. A product produced by the process of claim 55 or 56.

58. A process for preparing the amorphous solid state form of Compound I of claim 19, comprising dissolving a crystalline form of Compound I of any one of claims 1-18 in a solvent to form a solution and producing the solid state form that is amorphous Compound I from the solution.

59. The process of claim 58, wherein the solvent is benzyl alcohol.

60. The process of claim 58 or 59, comprising precipitating the amorphous form from the solution.

61. The process of claim 60, wherein the solution is heated to a temperature that is above

20 °C, such as about 50-70°C.

62. The process of claim 60 or 61, wherein the precipitation is performed at a solution temperature that is about room temperature or lower, such as a temperature of about - 20-15°C.

63. A process for preparing Compound I of the following structure:

the process comprising:

• converting compound INT-15 to ketenimine compound INT-15K of the following structure:

• reacting compound INT-15K with compound INT-12 to form compound INT- 12A;

• deprotecting compound INT-12A to form compound INT-12B;

• cyclizing compound INT-12B to form Compound I.

64. The process of claim 63, wherein compound INT-15Kis prepared by reacting compound INT-15 with triphenylphosphine chloride or triphenylphosphine bromide, followed by a base.

65. The process of claim 64, comprising reacting triphenylphosphine oxide and oxalyl chloride to form the triphenylphosphine chloride.

66. The process of claim 65, wherein triphenylphosphine oxide and oxalyl chloride are combined before contacting with compound INT-15.

67. The process of any one of claims 64 to 66, wherein the temperature is a reduced temperature, such as about -10 to about 20°C, optionally about 10°C.

68. The process of any one of claims 64 to 67, wherein the base is an amine base such as N-methylmorpholine, triethyl amine, 2,6-lutidine, pyridine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, or l,4-diazabicyclo[2.2.2]octane.

69. The process of any one of claims 64 to 68, comprising an excess of the base, or optionally about more than 1 equivalents, or optionally at least about 1.5 equivalents, or optionally at least about 3 equivalents.

70. The process of any one of claims 63 to 69, wherein compound INT-12 is reacted with compound INT-15K at a reduced temperature, such as about -25 to about 20°C, optionally about 0°C.

71. The process of claim 70, wherein the temperature is raised to an elevated temperature, such as about 25 to about 45°C, optionally about 35°C.

72. The process of any one of claims 63 to 71, comprising a molar excess of compound INT-15K relative to compound INT-12.

73. The process of any one of claims 63 to 72, comprising at least 1.1 equivalents of compound INT-15 relative to 1 equivalent of compound INT-12, or optionally at least 1.2 equivalents of compound INT-15 relative to 1 equivalent of compound INT-12, or optionally at least 1.25 equivalents of compound INT-15 relative to 1 equivalent of compound INT-12, or optionally at least 1.3 equivalents of compound INT-15 relative to 1 equivalent of compound INT-12, or optionally at least 1.5 equivalents of compound INT-15 relative to 1 equivalent of compound INT-12

74. The process of any one of claims 63 to 73, wherein the deprotecting is performed using an acid or a base.

75. The method of claim 74, wherein the acid is a strong acid, such as HC1 or methanesulfonic acid, preferably HC1.

76. The method of claim 74, wherein the base is potassium tert-butoxide.

77. The process of any one of claims 63 to 76, wherein the deprotecting is performed at a reduced temperature, such as about -25 to about 20°C, optionally about 0°C.

78. The process of any one of claims 63 to 77, wherein the deprotecting is performed in an aqueous organic solvent, optionally an ether such as dioxane or cyclopentyl methyl ether, an alcohol such as isopropyl alcohol, or ethyl acetate, or preferably dioxane.

79. The process of any one of claims 63 to 78, wherein the cyclizing is performed at elevated temperatures, such as about 30 to about 50°C, optionally about 25 to about 45°C.

80. The process of any one of claims 63 to 79, further comprising coupling compound

INT-14 with 2-aminopyridine to form compound INT-15:

81. The process of claim 80, wherein the coupling is performed using a coupling agent such as l,l'-carbonyldiimidazole (CDI), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), 2,2-dichloro-5-(2-phenylethyl)-4- (tnmethylsilyl)-3-furanone (DPTF), 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methyl- morpholin-4-ium chloride (DMT-MM), (l-cyano-2-ethoxy-2- oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), or N,N’-diisopropylcarbodiimide (DIC), optionally CDI.

82. The process of claim 80 or 81, wherein the coupling is performed at a reduced temperature, such as about -25 to about 20°C, optionally about 0°C.

83. The process of any one of claims 80 to 82, wherein compound INT-14 is added to a solution comprising the coupling compound.

84. The process of any one of claims 80 to 83, further comprising carboxylating methyl 4- methoxyphenylacetate (INT-13) to form compound INT-14

85. The process of claim 84, wherein the carboxylation is performed using carbon dioxide, such as a carbon dioxide gas or solid carbon dioxide.

86. The process of claim 84 or 85, further comprising a base such as a strong non- nucleophilic base such as sodium hexamethyldisilazide, lithium hexamethyldisilazide, or potassium hexamethyldisilazide.

87. The process of any one of claims 84 to 86, that is performed at a reduced temperature, such as about -100 to about 0°C, or optionally about -90 to about -50°C, or optionally about -50 to about -70°C.

88. The process of any one of claims 84 to 87, further comprising one or more warming steps.

89. The process of claim 88, wherein at least one wanning step comprises warming to a temperature of about -35 to about -15°C, or optionally about -30 to about -20°, or optionally -25°C.

90. The process of claim 89, wherein a second wanning step comprises warming to about -15 to about 5°C, or optionally about -5°C.

91. The process of claim 90, wherein a third warming step comprises wanning to about room temperature.

92. The process of any one of claims 86 to 91, wherein an excess of the base is utilized, such as at least about 1 to about 4 equivalents, or optionally about 1.1 to about 3.5 equivalents, or optionally about 1.1 to about 3.3 equivalents, or optionally 1.5 equivalents.

93. The process of any one of claims 63 to 92, further comprising reacting compound

INT-25 with methanesulfonic acid to prepare compound INT-15

94. The process of claim 93, that is performed at an elevated temperature, such as about

50 to about 80°C, optionally about 60 to about 70°C, or optionally about 65 to about 70°C.

95. The process of any one of claims 63 to 94, further comprising reacting compound

INT-2 with 2-aminopyridine to provide compound INT-15, compound INT-25, or a combination thereof

96. The process of claim 95, that is performed in an organic solvent such as an organic solvent with a high boiling point, or optionally toluene.

97. The process of claim 95 or 96, that is performed at an elevated temperature, such as about 90 to about 120°C, optionally about 100 to about 110°C, or optionally about 110°C.

98. The process of any one of claims 63 to 97, further comprising reacting compound

INT-11 with cyclohexanone to provide compound INT-12

99. The process of claim 98, that is performed at a reduced temperature, such as about 0 to about 20°C, optionally about 15°C.

100. The process of claim 98 or 99, comprising an excess of cyclohexanone, such as at least about 1.5 equivalents, at least about 2 equivalents, or at least about 2.5 equivalents.

101. The process of any one of claims 98 to 100, that is performed in the presence of a strong organic acid, such as p-toluenesulfonic acid.

102. The process of claim 101, comprising a catalytic amount of the strong organic acid, such as about 0.01 to about 0.1 equivalents, optionally about 0.03 to about 0.07 equivalents, or optionally about 0.04 equivalents.

103. The process of any one of claims 98 to 102, further comprising protecting the pyrazole group of compound INT-10 to provide compound INT-11

104. The process of claim 103, wherein the pyrazole is protected with a pi valyl group.

105. The process of claim 103 or 104, wherein the protecting is performed using pivalic anhydride or pivalic chloride.

106. The process of any one of claims 103 to 105, wherein the protecting further comprises an alkali t-butoxide, such as lithium t-butoxide, sodium t-butoxide, or potassium t-butoxide, optionally lithium t-butoxide.

107. The process of claim 105 or 106, wherein portions of the pivalic anhydride or pivalic chloride, alkali t-butoxide, or a combination thereof are added to compound INT-10.

108. The process of claim 107, wherein the first portion comprises at least about 0.50 equivalents of the pivalic anhydride or pivalic chloride, alkali t-butoxide, or a combination thereof, optionally about 0.50 equivalents.

109. The process of claim 108, wherein the second portion comprises at least about 0.30 equivalents of the pivalic anhydride or pivalic chloride, alkali t-butoxide, or a combination thereof, optionally about 0.35 equivalents.

110. The process of claim 109, wherein the third portion comprises at least about 0.20 equivalents of the pivalic anhydride or pivalic chloride, alkali t-butoxide, or a combination thereof, optionally about 0. 1 equivalents.

111. The process of claim 110, wherein the fourth portion comprises at least about 0. 10 equivalents of the pivalic anhydride or pivalic chloride, alkali t-butoxide, or a combination thereof, optionally about 0.05 equivalents.

112. The process of any one of claims 103 to 111, wherein the protecting further comprises a base such as an alkali hydroxide, such as sodium hydroxide, lithium hydroxide, or potassium hydroxide, optionally potassium hydroxide, or an amine such as triethylamine.

113. The process of any one of the preceding claims, that lacks a palladium reagent.

114. Compound I prepared by a process of any one of the preceding claims.

115. The compound I of claim 114, wherein the purity is about 100%.

116. A spray -precipitated solid dispersion comprising an amorphous solid state form of Compound I that is represented by the formula: